intranasal testosterone bioadhesive gel formulations and their use to treat male hypogonadism

专利摘要:
INTRANASAL TESTOSTERONE BIOADHESIVE GEL FORMULATIONS AND USE OF THEM TO TREAT MALE INDIVIDUAL HYPOGONADISM. The present invention relates to leg testosterone bioadhesive gel formulations for intrasanal administration and testosterone replacement treatment methods for using leg testosterone bioadhesive gel formulations to provide prolonged intranasal delivery of testosterone to testosterone deficient males. to treat, for example, male subjects with hypogonadism.
公开号:BR112013029332A2
申请号:R112013029332-2
申请日:2012-05-15
公开日:2021-06-01
发明作者:Wayne Kreppner；Siobhan Fogarty；Werner Oberegger；Paul José Pierre Marie Maes
申请人:Trimel Biopharma Srl；
IPC主号:

专利说明:

INTRANASAL TESTOSTERONE BIOADHESIVE GEL FORMULATIONS AND USE OF THE SAME TO TREAT HYPOGONADISM OF INDIVIDUALS OF MALE
FIELD OF THE INVENTION The present invention relates to 4.0% and 4.5% intranasal testosterone bioadhesive gels for providing prolonged intranasal delivery of testosterone to a male subject and methods of intranasal treatment to safely provide sustained release of testosterone to treat sex subjects. male with hypogonadism. In particular, the present invention relates to improved testosterone replacement therapy (TRT) and prolonged intranasal testosterone gel formulations for treating male hypogonadism. The present invention also relates to a system for intranasally dispensing a precise dosage amount of such gels in smaller volumes at an ideal anatomical location within each male's nostril, such that an effective amount of testosterone is deposited within each nostril in optimal anatomical location for TRT, including to effectively treat testosterone deficiency in male subjects such as hypogonadism.
BACKGROUND OF THE INVENTION Androgens are a group of C19 steroids that cause masculinization of the genital tract and the development and maintenance of male secondary sexual characteristics. They also contribute to increasing muscle mass, bone mass, libido, and sexual performance in men. Testosterone is the main androgen secreted by Leydig cells in the testes, and its production increases during puberty. See, for example, Tietz: Textbook of Clinical Chemistry and Molecular Diagnostics, 4th edition, Editors: Burtis CA, Ashwood ER, and Bruns DE (2006.). Androgen deficiency is now recognized as a relatively common condition in aging males. See, for example, 2. Wang C, Swerdloff R.S.: —Androgen replacement therapy. Ann Med, 29:365-370 (1997); Matsumoto A.M.: Andropause: clinical implications of the decline in serum Testosterone level with aging in men. J Gerontol A Med Sci, 57: M76-M99 (2002); and Haren Mtet al.: Andropause: a quality-of-life issue in older evils. Med Clin North Am, 90: 1005-1023 (2006). Testosterone hormone therapy is indicated for replacement therapy and male individuals having conditions associated with a deficiency or absence of endogenous testosterone, as well as to treat male hypogonadism. It can cause sexual dysfunction, loss of muscle mass, increased fat, infertility, thinning of beard and body hair, and other conditions.
Hypogonadism is defined as a deficiency of testosterone. — Male hypogonadism may be congenital or may develop later in life due to, for example, injury, trauma, surgery, infection, illness, drugs, and/or aging. Generally, childhood-onset male hypogonadism has minimal consequences and usually remains undiagnosed until puberty is delayed. Symptoms or signs associated with —Childhood-onset male hypogonadism, if left untreated, include poor muscle and body hair development, including poor growth of facial, pubic, chest, and armpit hair, a high-pitched voice, growth excessive arms and legs relative to the trunk of the body, a small scrotum, abnormal phallic and testicular growth, and other growth problems, eg growth and maturation of the prostate and seminal vesicles. In adult-onset male hypogonadism, symptoms may include impaired sperm production, osteoporosis, wasting muscle, or changes in body musculature, fat distribution, fatigue and loss of energy, weakness, anemia, changes in mood, eg depression and anger, a decline in cognitive abilities including memory loss and inability to concentrate, sleep disturbances, gynecomastia, a reduction in both beard and body hair, impotence, erectile dysfunction a decrease in volume of ejaculation, infertility, a decrease in sexual desire (loss of libido), and a regression of other secondary sexual characteristics.
Male hypogonadism is termed either primary hypogonadism, which is due to a disturbance of the testes, or central or secondary hypogonadism that results from a disturbance in the hypothalamic-pituitary axis. In primary hypogonadism, there is a lack of testosterone production in the testes—because the testes do not respond to FSH and LH. As a result, elevations in both FSH and LH hormones are seen in primary male hypogonadism. The most common cause of primary male hypogonadism is Klinefelter's Syndrome. Other congenital causes of primary hypogonadism may include, for example, Congenital Bilateral Anorchia, Leydig Cell Hypoplasia (Leydig Cell Aplasia), undescended testes (cryptorchidism), Noonan syndrome, Myotonic Mytrophy (MD) and defects in synthesis testosterone enzyme. Causes of adult-onset primary hypogonadism can include aging, autoimmune diseases, surgery, chemotherapy, radiation, infection, illness, surgery, alcoholism, drug therapy, and drug use. In secondary or central hypogonadism, insufficient amounts of FSHeLlH are produced in the hypothalamus. Genital causes of secondary or central hypogonadism include, for example, Kallmann syndrome, Prader Willi syndrome (PWS), Dandy Walker syndrome (malformation), isolated luteinizing hormone (LH) deficiency, and idiopathic hypogonadotrophic hypogonadism (IHH). Causes of adult-onset secondary or central hypogonadism can include aging, disease, infections, tumors, bleeding, nutritional deficiencies, alcoholism, liver cirrhosis, obesity, weight loss, Cushing's syndrome, hypopituitarism, hyperprolactinemia, hemochromatosis, surgery, trauma, drug therapy, and drug use. In primary male hypogonadism, the levels observed for testosterone are below normal but are generally above normal for FSH and LH. In secondary or central male hypogonadism, the levels observed for testosterone, FSH and LH are below normal. Thus, diagnosis of primary or secondary male hypogonadism is typically confirmed by hormone levels and, by testing, blood testosterone levels in both primary and secondary hypogonadism are characterized as low and must be replaced. Treatment usually varies with etiology, but typically includes testosterone replacement therapy. In the United States, testosterone can be given as an intramuscular injection, a transdermal patch, or a transdermal gel. In other countries, oral testosterone preparations may be available. In view of the fact that millions of men in the United States, as well as around the world, suffer from hypogonadism, there is a real and immediate need for an effective and convenient medical treatment that can treat this disorder so that the quality of life of these people can be improved. A therapeutic goal of such therapy to address this immediate need may be to restore testosterone levels in men to Young Adult levels in hopes of alleviating symptoms commonly associated with hypogonadism due to possibly testosterone deficiency.
SUMMARY OF THE INVENTION The present invention overcomes the limitations and disadvantages associated with current testosterone replacement therapy (TRT) and, in particular, current testosterone therapy for the treatment of hypogonadism in male subjects through the discovery of novel leg testosterone gels and methods of use for TRT and to treat hypogonadism. In particular, the present invention overcomes the limitations and disadvantages of currently available options for administering testosterone by discovering new and improved dosage potency testosterone gel formulations specifically designed for intrasanal administration to deliver therapeutically effective amounts of testosterone to treat individuals. males who suffer from and/or have been diagnosed with testosterone deficiency, including hypogonadism.
The term "a therapeutically effective amount" means an amount of testosterone sufficient to induce a therapeutic or prophylactic effect for use in testosterone replacement or supplemental therapy to treat male testosterone deficiency, i.e., hypogonadism in males.
Thus, in general, the present invention provides new and improved testosterone gel formulations of substantially less irritating dosage potency, formulated with testosterone in amounts of between about 4% and 8.0% by weight, and preferably between about 4.0 % and about 4.5% by weight, and more preferably about 4.0%, about 4.5% and 8.0% by weight, for nasal administration to deliver a therapeutically equivalent amount of an effective amount of testosterone to effectively treat male subjects. who are diagnosed with testosterone deficiency, including hypogonadism.
In accordance with the present invention, the diffusion rates of testosterone in the intranasal gels of the present invention across a Franz cell membrane, as contemplated by the present invention, are between about 28 and 100 slope/mgT%, and preferably about of 30 and 95 slope/mgT%. For those intranasal gels formulated with between about 4.0% and 4.5% testosterone, preferred testosterone diffusion rates are between about 28 and 35 slope/mgT%.
The present invention is also directed to novel methods for the leg administration of nasal testosterone gels. In general, the new methods involve depositing intranasal testosterone gels topically into the nasal cavity of each nostril to deliver a therapeutically effective amount of testosterone in smaller volumes over the lifetime of the dose to provide effective constant brain and/or blood levels. of testosterone to use TRT, especially to effectively treat males needing testosterone to treat hypogonadism.
More specifically, the present invention is directed to bioavailable intranasal testosterone gel formulations suitable for leg administration for use in TRT and to treat hypogonadal subjects. In accordance with the present invention, and by way of example. The present invention contemplates: * Treatment with unit dose devices pre-filled with 125 ul 4.0% testosterone gel to deliver approximately 5.0 mg of testosterone per nostril (intranasal) given, for example, three times a day (total dose 30mg/day); * — Treatment with unit dose devices pre-filled with approximately 150uL 4.5% gel to deliver approximately 6.75 mg of testosterone per nostril (intranasal) given eg twice daily (total dose 27.0 mg/day); and/or * — Treatment with unit dose devices pre-filled with about 125 ul 4.5% gel to deliver about 5,625 mg of testosterone per nostril (intranasal) given, for example, three times a day (total dose 33.75 mg /day). Generally speaking, the intranasal testosterone gel formulations of the present invention are formulated with about 4% and 4.5% testosterone by weight, and testosterone is well absorbed when such gel formulations are administered legibly to hypogonadal subjects. More specifically, testosterone is rapidly absorbed after leg administration with a peak concentration reached within 36 minutes to 1 hour 6 minutes (mean Tmax) after intranasal administration and maximum serum concentration is reached after about 1-2 hours post nasal administration. Peak Testosterone concentration over a 24-hour interval is observed during the first administration (0-10 hours) in approximately 57% to 71% of hypogonadal men while approximately 29% to 43% of subjects have their peak testosterone concentration. within 24h during subsequent administrations.
Formulations containing 4% testosterone and 4.5% by weight provide admirable properties. Importantly, the solubility of testosterone in pure castor oil is 3.6% maximum, dropping to around 3.36% with 4% Labrafil. The addition of fumed silica (Aerosil, CabOsil) can increase the — solubility of testosterone in castor oil by up to 4.5% even with 4% Labrafil. This is counterintuitive to a person skilled in the art. However, without wishing to be bound by any particular theory, it is believed that this increase in solubility in the presence of silica is due, at least in part, to the fact that SiO absorbs about 10% of the testosterone. In accordance with the novel methods of the present invention, intranasal testosterone gels are topically deposited on the outer outer walls (opposite the nasal septum) within the nasal cavity of each nostril, preferably about mid to about the upper section of the outer outer wall (opposite nasal septum) just below the outer outer wall cartilage section within the nasal cavity of each nostril. Once the gel deposition is complete within each nostril of the nose, the external nose is then gently and carefully squeezed and/or rubbed by the subject so that the deposited gel remains in contact with the mucous membranes within the nasal cavity to sustained release of testosterone over the lifetime of the dose. Typical deposited leg application of testosterone gel dosage amounts are between about 50 to about 150 microliters per nostril, and preferably about 125 to about 150 microliters per nostril.
In carrying out the methods of the present invention, approximately between about 50 microliters and about 150 microliters of an intranasal testosterone gel of the present invention is applied to each nostril of a subject once or twice daily or three times a day, for example, for one, two, three, four or more consecutive weeks, or for two, three, four, five or six consecutive days or more, or intermittently such as alternate days or once, twice or three times a week, or on demand once or twice during the same day as TRT or to treat male testosterone deficiency, including male hypogonadism.
Additionally, the present invention contemplates testosterone gel formulations for nasal administration that are pharmaceutically equivalent, therapeutically — equivalent, — bioequivalent — and/or interchangeable, —regardless of the method selected to demonstrate equivalents or bioequivalence, such as pharmacokinetic methodologies, microdialysis, methods in vitro and in vivo and/or clinical endpoints described herein. Thus, the present invention contemplates testosterone gel formulations for nasal administration which are bioequivalent, - pharmaceutically - equivalent and/or therapeutically equivalent, especially testosterone gel formulations for nasal administration which are 0.15% testosterone by weight of the gel formulation, 0.45% testosterone by weight of the gel formulation and 0.6% by weight testosterone of the gel formulation, when used in accordance with the therapy of the present invention to treat anorgasmia and/or HSDD by intranasal administration. Thus, the present invention contemplates: (a) pharmaceutically equivalent testosterone gel formulations for nasal administration which contain the same amount of testosterone in the same dosage form; (b) bioequivalent testosterone gel formulations for nasal administration which are chemically equivalent and which, when administered to the same individuals at the same dosing regimens, result in comparable bioavailabilities; (c) therapeutically equivalent testosterone gel formulations for nasal administration which, when administered to the same subjects at the same dosage regimens, provide essentially the same efficacy and/or toxicity; and (d) interchangeable testosterone gel formulations for nasal administration of the present invention which are pharmaceutically equivalent, bioequivalent and therapeutically equivalent.
While the intranasal testosterone gels of the present invention are preferred pharmaceutical preparations when practicing the novel methods of the present invention, it should be understood that the novel topical intranasal gel formulations and methods of the present invention also contemplate the administration of any suitable active ingredient, such as alone or in combination with testosterone or other active ingredients such as neurosteroids or sex hormones (eg androgens and progestins such as testosterone, estradiol, estrogen, oestrone, progesterone, etc.), — neurotransmitters, (eg acetylcholinay epinephrine, norepinephrine, dopamine, serotonin, melatonin, histamine, glutamate, gamma-aminobutyric acid, aspartate, glycine, adenosine, ATP, GTP, oxytocin, vasopressin, endorphin, nitric oxide, pregnenolone, etc.), prostaglandin, benzodiazepines such as diazepam. , lorazepam, etc., and PDEF inhibitors like sildenafil, i tadalafil, vardena fil, etc., in any suitable pharmaceutical preparation, such as a liquid, cream, ointment, balm or gel. Examples of additional topical formulations for practice in accordance with the novel methods of the present invention include the leg topical formulations disclosed, for example, in Patent Nos. US 5,578,588, 5,756,071 and 5,756,071 and Patent Publication Nos. US 2005/0100564, 2007/0149454 and 2009/0227550, all of which are incorporated herein by reference in their entirety.
The present invention is also directed to packaged drugs comprising the new and improved testosterone gel formulations for nasal administration of the invention. For example, the present invention contemplates pre-filled single or multiple dose applicator systems for leg administration to strategically and uniquely deposit nasal testosterone gels in preferred locations within the nasal cavity to practice the new methods and teachings of the present. invention. Generally speaking, the applicator systems of the present invention are, for example, airless dip tube fluid dispensing systems, pumps, pre-filled single-dose syringes, or any other system suitable for practicing the methods of the present invention. Applicator systems or pumps include, for example, a chamber, pre-filled with a single dose or multiple doses of an intranasal testosterone gel of the present invention, which is closed by an actuating mouthpiece or cap. The actuator nozzle may comprise an exit channel and tip, wherein the actuator nozzle is molded to match an interior surface of a user's nostril for (a) consistent delivery of uniform dose amounts of an intranasal testosterone gel of the present invention during leg application within the nasal cavity, and (b) deposition at the indicated location within each nostril of a patient as contemplated by the new methods and teachings of the present invention. Examples of pre-filled multiple dose applicator systems include, for example, (a) the COMOD system available from Ursatec, Verpackung-GmbH, Schillerstr. 4, 66606 St. Wendel, Germany, (b) the Albion or Digital airless applicators available from Airlessystems, RD 149 27380 Charleval, France or 250 North Route 303 Congers, NY 10950, (c) the nasal applicators from Neopac, The Tube, Hoffmann Neopac AG, Burgdorfstrasse 22, Postfach, 3672 Oberdiessbach, Switzerland, or (d) the syringes described in the examples hereinafter.
A nasal multiple dose dispensing device in accordance with embodiments of the present invention, such as the airless applicator systems - Albion or Digital available from Airlessystems, comprises a fluid container and a dispensing pump for delivering multiple doses of a gel or another topical formulation. In one embodiment of the present invention, the nasal multi-dose dispensing device is adapted for an airless fluid dispensing system. In another embodiment of the present invention, the nasal multi-dose dispensing device is adapted for a dip tube fluid dispensing system.
An example of an airless system that is contemplated by the present invention is one that will deliver a liquid, including gel, without the need for a gas pump or pressurized air to be in contact with the liquid (or gel). In general, an airless system of the present invention comprises a flexible bag containing the liquid, a solid cylindrical container, a movable piston, an aspiration pump, a metering valve and a delivery nozzle, as depicted, for example, in the Figs. 1-4. See also Figs. 7A, 7B, 8A, 8B, 9A, 9B, 10A, 10B and 11.
In accordance with the present invention, the multi-dose dispenser 100 of Fig 1 is provided with a fluid container 120, a dispensing pump 140 and a cap 102.
The fluid container 120 comprises a container body 122, a base 124 and a neck 126. The dispensing pump 140 is secured to the neck by a bush 128. The upper end of the container body 122 is closed by the dispensing pump 140. The bush 128 tightly presses a neck gasket 150 against the upper end of container body 122. Container body 122 forms a vacuum and houses the fluid to be dispensed.
The dispensing pump 140 is closed by its actuator nozzle 130, which retains the rod 144 in the head of the rod. Actuator nozzle 130 comprises an output channel 132 and tip 134.
Actuator nozzle 130 is molded to match the inside surface of a user's nostril. Actuator nozzle 130 is movable between an open-down position and a closed-up position. The user removes the cap 102 and inserts the actuator nozzle 130 into the user's nostril. When the user presses the actuator nozzle 130 down to the open position, fluid in the metering chamber 180 is withdrawn by the dispensing pump 140 and exits at the tip 134 through the outlet channel 132 of the actuator nozzle 130.
Fig. 2 shows a cross-sectional view of the dispensing pump 140.
The dispensing pump has a body 142 provided with a bottom inlet having an inlet valve 160 with a ball 162 as its valve member. The ball 162 is held in place by a frame 164 and a return spring 170.
At its lower end, the rod 144 carries a spring cap 172. A piston 174 is located above the spring cap 172. The rod 144 passes through an axial hole in the base of the piston 176.
The side walls of the piston 174 seal against the dispensing pump body 142 by means of tabs. Bushing 128 securely presses a stem gasket 152 against stem collar 146, distributor pump body 142 and top of piston 174.
A precompression spring 178 is placed between the piston base 176 and the stem collar 146. The precompression spring 178 biases the actuator nozzle 130 through the stem 144 into the closed position.
The return spring 170, which returns the piston 174 back up, is compressed between two opposing seats on the frame 164 and the spring cap.
172.
Dispensing pump 140 has a metering chamber 180 formed between frame 164 and piston 174. When the user presses the actuator nozzle down to the open position, fluid in the metering chamber is withdrawn by the metering pump 140 and dispensed from the dispenser tip of the actuator nozzle 130.
When the user releases the actuating nozzle 130 upwards to the closed position, a fluid in the container body 122 is drawn into the dosing chamber 180 by the dispensing pump 140. Thus, a dose of fluid is ready for the next actuation of the nozzle actuator by the user.
In another embodiment of the present invention, the dispenser 200 of Fig 3 is provided with a fluid container 220, a dispensing pump 240 and a cap 202.
Fluid container 220 comprises a container body 222, a base 224 and a neck 226. The dispensing pump 240 is secured to the neck by a bushing 228. The upper end of the container body 222 is closed by the dispensing pump 240. The bushing 228 firmly presses a neck gasket 250 against the upper end of container body 222. Container body 222 houses the fluid to be dispensed.
The dispensing pump 240 is closed by its actuator nozzle 230, which retains the rod 244 in the head of the rod. Actuator nozzle 230 comprises an output channel 232 and tip 234. Actuator nozzle 230 is molded to match the inner surface of a user's nostril. Actuator nozzle 230 is movable between an open-down position and a closed-up position. The user removes the cap 202 and inserts the actuator nozzle 230 into the user's nostril. When the user presses the actuator nozzle 230 down to the open position, —fluid in the metering chamber 280 is drawn out by the dispensing pump 240 and exits at the tip 234 through the output channel 232 of the actuator nozzle 230.
Fig. 4 shows a cross-sectional view of the dispensing pump 240.
The dispensing pump has a body 242 provided with a bottom inlet having an inlet valve 260 with a ball 262 as its valve member. Ball 262 is held in place by a frame 264 and a return spring 270. Optionally, a dip tube 290 can extend downward from inlet valve 260 and is immersed in the liquid contained in the container body.
At its lower end, the rod 244 carries a spring cap 272. A piston 274 is located above the spring cap 272. The rod 244 passes through an axial hole in the base of the piston 276.
The side walls of the piston 274 seal against the dispensing pump body 242 by means of tabs. Bushing 228 securely presses a stem gasket 252 against stem collar 246, distributor pump body 242 and top of piston 274.
A precompression spring 278 is placed between the piston base 276 and the stem collar 246. The precompression spring 278 biases the actuator nozzle 230 through the stem 244 into the closed position.
The return spring 270, which returns the piston 274 back up, is compressed between two opposing seats on the frame 264 and the spring cap.
272. Dispensing pump 240 has a metering chamber 280 formed between frame 264 and piston 274. When the user presses the actuator nozzle down to the open position, air enters metering chamber 280, which forces fluid into the dosing chamber to be removed by the dispensing pump 240 and dispensed from the tip of the actuator nozzle 230.
When the user releases the actuator nozzle 230 upwards to the closed position, the air contained in the dosing chamber 280 forces the fluid in the container body 222 to be withdrawn into the dosing chamber 280. Thus, a dose of fluid is ready. for the next actuation of the actuator nozzle by the user.
The amount of fluid drawn by the dispensing pump into the metering chamber is a fixed volume. Dispenser pumps can be a variety of sizes to accommodate a range of delivery volumes. For example, a dispensing pump can have a delivery volume of 140 ul.
The dispensers of the present invention may dispense topical intranasal gel or other topical intranasal formulations, preferably percutaneously, which contain alternative or additional active ingredients,
such as neurosteroids or sex hormones (eg, androgens and progestins, such as testosterone, estradiol, estrogen, oestrone, progesterone, etc.), neurotransmitters, (eg, acetylcholine, epinephrine, norepinephrine, dopamine, serotonin, melatonin, histamine, glutamate , gamma-aminobutyric acid, aspartate, glycine, adenosine, ATP, GTP, oxytocin, vasopressin, endorphin, nitric oxide, pregnenolone, etc.), prostaglandin, benzodiazepines such as diazepam, midazolam, lorazepam, etc., and PDEF inhibitors such as PDEF inhibitors sildenafil, tadalafil, vardenafil, etc., in the form of a liquid, cream, ointment, balm or gel. Dispensers can be suitable for cosmetic, dermatological or pharmaceutical applications. Examples of topical intranasal formulations for topical leg application which may be dispensed in accordance with the present invention include the leg testosterone gels of the present invention or other topical intranasal gels in which testosterone is replenished or combined with another active ingredient in amounts effective, such as those active ingredients discussed herein above. Additionally, other testosterone formulations suitable and contemplated for dispensing from the dispensers and/or in accordance with the methods of the present invention include those formulations disclosed in, for example, Patent Nos. US 5,578,588, 5,756,071 and 5,756,071 and Patent Publication Nos. US 2005/0100564, 2007/0149454 and 2009/0227550, all of which are incorporated herein by reference in their entirety.
It should be understood by those of skill in the art that the amount of testosterone in a low dosage strength intranasal testosterone gel of the present invention that will be therapeutically effective in a specific situation will depend on such things as the dosage regimen, the site of application, the particular gel formulation, dose longevity and the condition being treated. As such, it is generally not practical to identify specific administration amounts here; However, it is believed that those skilled in the art will be able to determine appropriate therapeutically effective amounts based on the guidance provided herein, information available in the art pertaining to testosterone replacement therapy, and routine testing.
It should further be understood that the above summary of the present invention is not intended to describe every disclosed embodiment or every implementation of the present invention. The description further exemplifies — illustrative embodiments. At various places throughout the specification, guidance is provided through examples, examples which can be used in various combinations. In each case, the examples serve only as representative groups and should not be interpreted as exclusive examples.
BRIEF DESCRIPTION OF THE DRAWINGS The foregoing and other objects, advantages and features of the present invention, and the manner in which they are fulfilled, will become more readily apparent upon consideration of the following detailed description of the invention taken in conjunction with the accompanying figures and examples, which illustrate embodiments, in which: Fig. 1 is a side view of a first embodiment of the invention; Fig. 2 is a cross-sectional side view of the dispensing pump of the first embodiment of the invention; Fig. 3 is a side view of a second embodiment of the invention; Fig. 4 is a side cross-sectional view of the dispensing pump of the second embodiment of the invention; Fig. 5 is a side view of a second embodiment of the invention with respect to an airless bottle assembly of the invention; Fig. 6 is a side view of a second embodiment of the invention with respect to digital actuator and rounded cap; Fig. 7A depicts the right nostril of subject %£1 after a single dose syringe administration; Fig. 7B depicts the left nostril of subject £1 after a multiple dose dispenser administration; Fig. 8A depicts the right nostril of subject 2 after a single dose syringe administration; Fig. 8B depicts the left nostril of subject 2 after a multiple dose dispenser administration; Fig. 9A depicts the right nostril of subject %£3 after a single dose syringe administration; Fig. 9B depicts the left nostril of subject %3 after a multiple dose dispenser administration; Figs. 10A and 10B illustrate use of a multi-dose dispenser in accordance with the present invention; Fig. 11 illustrates a multi-dose dispenser in accordance with the present invention; Fig. 12 depicts Position schemes of a Franz Cell apparatus for comparing tests according to Example 5;
Fig. 13 is a graph showing the change in serum testosterone levels over time for a 4.5% bioadhesive testosterone gel administered into each nostril of a hypogonadal male twice daily in accordance with the present invention when compared to normal testosterone pharmacokinetics in healthy young adult males, as reported in Diver MJ. et al: Diurnal rhythms of total, free and bioavailable Testosterone and of SHBG in middle-aged men compared with those in young men. Clinical Endocrinology, 58: 710-717 (2003); Fig. 14 depicts a comparison between TBS 1 to 8% (Part |); Fig. 15 depicts a comparison between TBS 1 to 8% (Part |); Fig. 16 depicts a comparison between 6 hour and 24 hour run (RD11101 and RD11102) Fig. 17 depicts a comparison between TBS 1 to 4% (Part |); Fig. 18 depicts a comparison between 1 to 4% TBS (Part |1); Fig. 19 depicts a comparison between 1 to 4% TBS (Part III); Fig. 20 depicts comparative slower diffusion; Fig. 21 depicts a comparison between 6-hour and 24-hour run (RD11063 and RD11085); and Fig. 22 depicts a comparison between 400mg and 1 gram of gel (RD11063).
DETAILED DESCRIPTION By way of illustration and providing a more complete appreciation of the present invention and many of the current advantages thereof, the following detailed description and examples are given with respect to novel low dosage potency intranasal testosterone gels, devices and methods of application of the present invention. As used in the description of the invention and the appended claims, the singular forms "a" or "an" or "w/o" are used interchangeably and are intended to include the plural forms as well and fall within each meaning, the unless the context clearly indicates otherwise. Also as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the listed items, as well as the lack of combinations when interpreted in the alternative ("or"). As used herein, "at least one" is intended to mean "one or more" of the elements listed. Singular word forms are intended to include the plural forms of words and are used interchangeably where appropriate and fall within each meaning unless expressly stated otherwise.
Except where otherwise noted, capitalized and non-capitalized forms of all terms are inserted each sense.
Unless otherwise indicated, it is to be understood that all numbers expressing amounts, ratios, and numerical properties of ingredients, reaction conditions, and so on as used in the specification and claims are contemplated to be capable of being modified in all cases by the term "about".
All parts, percentages, reasons, etc. here are by weight unless otherwise noted.
As used herein, "bioequivalence" or "bioequivalent" refers to nasally administered testosterone gel formulations or pharmaceuticals which are pharmaceutically equivalent and their bioavailabilities (rate and extent of absorption) after administration of the same molar dose or amount are similar to such a degree that their therapeutic effects, such as safety and efficacy, are essentially the same. In other words, bioequivalence or bioequivalent means the absence of a significant difference in the rate and extent to which testosterone becomes available from such formulations at the site of action of testosterone when administered at the same molar dose under similar conditions, e.g. rate at which testosterone can leave such a formulation and the rate at which testosterone can be absorbed and/or become available at the site of action to affect TRT, including hypogonadism. In other words, there is a high degree of similarity between the bioavailabilities of two testosterone gel formulation pharmaceuticals for nasal administration (same galenic) from the same molar dose, which are unlikely to produce clinically relevant differences in therapeutic effects , or adverse reactions, or both. The terms "bioequivalence" as well as "pharmaceutical equivalence" and "therapeutic equivalence" are also used herein as defined and/or used by (a) the FDA, (b) the Code of Federal Regulations ("CFR"), Title 21 , (c) Health Canada, (d) European Medicines Agency (EMEA), and/or (e) the Japanese Ministry of Health and Welfare Thus, it is to be understood that the present invention contemplates testosterone gel formulations for nasal or nasal administration. pharmaceuticals which may be bioequivalent to other testosterone gel formulations for nasal administration or pharmaceuticals from 16
: present invention. By way of example, a first testosterone gel formulation for nasal administration or pharmaceutical product is bioequivalent to a second testosterone gel formulation for nasal administration or pharmaceutical product, according to the present invention, when measuring at least one pharmacokinetic parameter (s), such as a Cmas Tmax, AUC, etc., of the first testosterone gel formulation for nasal administration or pharmaceutical product varies by no more than about +25% when compared to measuring the same pharmacokinetic parameter for the second testosterone gel formulation for nasal administration or pharmaceutical product of the present invention.
As used herein, "bioavailability" or "bioavailable" generally means the rate and extent of absorption of testosterone into the systemic circulation and, more specifically, the rate or measurements designed to reflect the rate and extent to which testosterone becomes available in the site of action or is absorbed from a pharmaceutical product and becomes available at the site of action. In other words, and by way of example, the extent and rate of absorption of testosterone from a less potent gel formulation for nasal administration of the present invention as reflected by a time-concentration curve of testosterone in the systemic circulation.
As used herein, the terms "pharmaceutical equivalent" or "pharmaceutically equivalent" refer to testosterone gel formulations for nasal administration or pharmaceuticals of the present invention that contain the same amount of testosterone, in the same dosage forms, but not necessarily containing the same inactive ingredients, for the same route of administration and corresponding to the same or comparable compendium or other applicable standards of identity, strength, quality and purity, including potency and, where applicable, uniformity and/or stability of content . Thus, it is to be understood that the present invention contemplates gel formulations of testosterone for nasal administration or pharmaceuticals which may be pharmaceutically equivalent to other gel formulations of testosterone for nasal administration or pharmaceuticals used in accordance with the present invention.
As used herein, "therapeutically equivalent" or "therapeutically equivalent" means those testosterone gel formulations for nasal administration or pharmaceuticals which (a) will produce the same clinical effect and safety profile when using testosterone pharmaceuticals for TRT and to treat testosterone deficiency, including hypogonadism, in male subjects in accordance with the present invention and (b) are pharmaceutical equivalents, for example, they contain testosterone in the same dosage form, they have the same route of administration; and they have the same testosterone potency. In other words, therapeutic equivalence means a chemical equivalent of a lower dosage potency testosterone formulation of the present invention (ie, containing the same amount of testosterone in the same dosage form when administered to the same individuals on the same dosing regimen) will provide essentially the same efficacy. ia and toxicity.
As used herein, "testosterone gel formulation for nasal administration" means a formulation comprising testosterone in combination with a solvent, a wetting agent, and a viscosity-increasing agent.
As used herein, "plasma testosterone level" means the plasma testosterone level of a subject. The plasma testosterone level is determined by methods known in the art.
"Diagnosis" or "prognosis," as used herein, refers to the use of information (eg, biological or chemical information from biological samples, signs and symptoms, physical examination results, psychological examination results, etc.) or use of information to anticipate the most likely outcomes, timelines, and/or responses to a particular treatment for a particular disease, disorder, or condition, based on comparisons with a plurality of individuals who share symptoms, signs, family histories, or other data relevant to consideration of a patient's health status, or confirmation of a subject's distress, eg, testosterone deficiency, including hypogonadism.
A "subject" under some modalities is an individual whose signs and symptoms, physical examination results and/or psychological examination results are to be determined and recorded in conjunction with the individual's condition (ie, disease or disorder state) and/or response to a drug or treatment candidate.
"Subject" as used herein is preferably, but not necessarily limited to, a human subject. The subject is a male or female individual, and is preferably female, and may be of any race or ethnicity, including, but not limited to, White, African-American,
African, Asian, Hispanic, Indian, etc. Subject as used herein may also include an animal, particularly a mammal such as a canine, feline, cattle, goat, equine, sheep, porcine, rodent (e.g., a rat and mouse), a lagomorph, a primate (including non-primate humans), etc., which can be treated according to the methods of the present invention or screened for veterinary medicine or pharmaceutical development purposes. A subject in accordance with some embodiments of the present invention includes a patient, human or otherwise, in need of therapeutic treatment of testosterone deficiency, including hypogonadism.
"Treatment," as used herein, includes any drug, pharmaceutical, method, procedure, lifestyle change, or other adjustments introduced in an attempt to effect a change in a particular aspect of a subject's health (ie, directed to a particular disease, disorder, or condition).
"Drug" or "drug substance," as used herein, refers to an active ingredient, such as a chemical entity or a biological entity, or combinations of chemical entities and/or biological entities, suitable to be administered to a subject. to treat testosterone deficiency, including hypogonadism. According to the present invention, the drug or drug substance is testosterone or a pharmaceutically acceptable salt or ester thereof.
The term "pharmaceutical" as used herein is synonymous with the terms "medicine", "medicament", "therapeutic intervention", or "pharmaceuticals". Most preferably, a pharmaceutical product is approved by a government agency for use in accordance with the methods of the present invention. A pharmaceutical product according to the present invention is an intranasal gel formulated with the drug substance, i.e. testosterone.
"Disease", "disorder" and "condition" are commonly recognized in the art and designate the presence of signs and/or symptoms in an individual or patient that are generally recognized as abnormal and/or undesirable. Diseases or conditions can be diagnosed and categorized based on pathological changes. The disease or condition can be selected from the types of diseases listed in standard texts, such as Harrison's Principles of Internal Medicine, 1997, or Robbins Pathologic Basis of Disease, 1998.
As used herein, "diagnosing" or "identifying a patient or subject having testosterone deficiency, such as hypogonadism, refers to a process of determining whether an individual suffers from a testosterone deficiency, such as hypogonadism. As used herein, " "control subject" means a subject who has not been diagnosed with testosterone deficiency or hypogonadism and/or does not exhibit — any detectable symptoms associated with these diseases. A "control subject" also means a subject who is not at risk of developing testosterone deficiency or hypogonadism as defined herein. The testosterone gel formulations of the invention are viscous, thixotropic oil-based formulations containing a testosterone solution intended for intranasal application. The non-irritating formulation is designed to adhere to the inner nose. Additionally, it acts as a controlling matrix, thus allowing sustained drug delivery through the nasal mucosa. Other pharmacologically inactive ingredients in the intranasal testosterone gel are castor oil USP, oleoyl macrogolglycerides EP and colloidal silicon dioxide NF. None of these excipients are of human or animal origin. All excipients are well known and included on the FDA's “Inactive Ingredient” list for Approved Pharmaceuticals. The steroid hormone testosterone is the active ingredient in the testosterone gel formulations of the invention. The manufacture of the drug substance poses no potential risk to humans; the synthetic pathway is well characterized. Table 1: Nomenclature Testosterone NomelNNh À cu Fegtasterama Compendium name Testosterone Í Chemical name 17b-hydroxyandrost-4-en-3-one i Other common names Androst-4-en-3-one, 17-hydroxy-, (1768) - : Trans-testosterone j : : — At-androsten-176-01-3-0na | e) CAS registration number | 58-22-0 i proquina code 8139 : j Structural Formula
CH PA AND EF [>
CI o Molecular Formula C19H280.2
Relative Molecular Mass
288.4 The physicochemical properties of testosterone are listed in Table 2.
Table 2: General Properties of Testosterone White or slightly cream colored crystals or crystalline powder. It is odorless and stable in air.
Solubility Practically insoluble in water (0.024 g / L), freely soluble in dehydrated alcohol, chloroform and methylene chloride, soluble in dioxane and vegetable oils, slightly soluble in ether.
Testosterone, for inventive testosterone gel formulations, appears as white or slightly creamy white crystals or crystalline powder.
It is freely soluble in methanol and ethanol, soluble in acetone and isopropanol and insoluble in n-heptane. It can also be considered as insoluble in water (S2oc=2.41 x 10 g/L + 0.04 x 10 g/L); its n-OctanolWater partition coefficient (log Pow determined by HPLC) is 2.84. The solubility of testosterone in oils was determined to be 0.8% in isopropylmyristate,
0.5% in peanut oil, 0.6% in soybean oil, 0.5% in corn oil, 0.7% in cottonseed oil and up to 4% in castor oil.
As testosterone is completely dissolved within the formulations of the present invention, physical characteristics of the drug substance do not influence the performance of the pharmaceutical, gel formulations of the testosterone of the invention. The manufacturability of the inventive testosterone gel formulations, however, is influenced by the testosterone particle size.
When using a particle size of 50% < 25 microns, 90% < 50 microns the solubility of the drug substance in the matrix is especially favorable.
According to the present invention, the testosterone drug may be, for example, crystalline, amorphous, micronised, non-micronised, powdered, small-particle or large-particle form when formulating testosterone gels.
The intranasals of the present invention.
An exemplary range of testosterone particle sizes include from about 0.5 microns to about 200 microns.
Preferably, the particle size of testosterone is in a range of from about 5 microns to about 100 microns, and a testosterone is in crystalline or amorphous form and non-micronized or micronized.
Preferably, a testosterone is in micronized crystalline or amorphous form.
The molecular structure of testosterone does not contain functional groups that can be protonated or deprotonated in the physiological pH range.
Therefore, testosterone should be considered as a neutral molecule with no pKa value in the range of 1-14. As it is neutral, testosterone is compatible with excipients.
The testosterone gel formulations of the invention are viscous, thixotropic, oil-based formulations containing a testosterone solution intended for intranasal application.
The non-irritating formulation is designed to adhere to the inner nose.
Additionally, it acts as a controlling matrix, thus allowing sustained drug delivery through the nasal mucosa.
Other pharmacologically inactive ingredients in the intranasal testosterone gel are castor oil USP, oleoyl macrogolglycerides EP and colloidal silicon dioxide NF.
None of these excipients are of human or animal origin.
All excipients are well known and included on the FDA's “Inactive Ingredient” list for Approved Pharmaceuticals.
According to the "Handbook of Pharmaceutical Additives" oleoyl polyoxylglycerides are used as a hydrophilic oil for topical, injectable and nasal use.
In FDA-approved medicinal products it is used as a co-emulsifier in emulsions/lotions/topical creams and in emulsions/vaginal creams.
In France this excipient is approved for nasal preparations such as "Rhino-Sulforgan" (Laboratoire Jolly-Jatel, France; containing 10% oleoyl polyoxyglycerides) and "Huile Gomenolee 2% ("Laboratoire Gomenol, France; — containing 10% oleoyl polyoxyglycerides) . Thus, as for castor oil it can be deduced that oleoyl polyoxyglycerides is suitable for a route of application in which safety and tolerance are of paramount importance (eg injectable and nasal or vaginal preparations).
Ú Oleoyl macrogolglycerides are also referred to as Labrafil M 1944 CS, apricot seed oil PEG-6 esters, Peglycol-5-oleate, blend of glycerides and polyethylene esters.
Castor oil, which is used as a solvent for the testosterone gel formulations of the invention, is a fixed oil.
Such oils have the advantage of being non-volatile or scattering (in contrast to essential oils or liquid paraffin), but they have the disadvantage of being hydrophobic.
The nasal mucosa contains 95-97% water.
Without the oleoyl macrogolglycerides, castor oil containing the active ingredient forms a non-interactive layer on the mucous membrane.
In order to obtain proper contact between the castor oil layer and the mucous membrane, the hydrophilic oil of oleoyl macrogolglycerides is added to the formulation to form an emulsion between the castor oil and the mucosal fluid.
Oleoyl macrogolglycerides are used in semi-solids in concentrations ranging from about 3 to 20%, depending on the application.
The amount of oleoyl macrogolglycerides in the testosterone gel formulations of the invention is high enough to allow better contact of the carrier oil with the mucous membrane and low enough to have minimal impact on the amount of testosterone that can be incorporated into the carrier oil.
A favorable concentration of oleoyl microgolglycerides in the testosterone gel formulations of the invention is found to be 4% of the formulation.
According to the "Handbook of Pharmaceutical Additives" colloidal silicon dioxide is used as an oil adsorbent, heat stabilizer and gelling agent.
In FDA-approved medicinal products it is used with dental gels, sublingual tablets, endocervical gels, suppositories, emulsions/creams/tablets/vaginal tampons and inhalation capsules.
In addition, it is used as an excipient in "Testoderm with adhesives" (Alza Corporation, approved 1996) a transdermal testosterone patch.
Thus, it can be deduced that colloidal silicon dioxide is suitable for a route of application where safety and tolerance are of the highest importance (eg inhalation, endocervical, vaginal or rectal preparations).
For clinical trial sources, intranasal testosterone gel is supplied in single-dose syringes consisting of a syringe body made of polypropylene, a molded polyethylene plunger, and a syringe cap made of high-density polyethylene. Syringes are wrapped in aluminum foil as secondary packaging. The pre-filled single-dose syringes used according to the study in the Examples are filled as follows: (a) 4% intranasal testosterone bioadhesive gel — 148 microliters and 5.92 mgs of testosterone; (b) 4.5% intranasal testosterone bioadhesive gel — 148 microliters and 6.66 mg of testosterone; and (c) 4.5% intranasal testosterone bioadhesive gel — 148 microliters and 7785 mg of testosterone.
The oil in the inventive testosterone gel formulations is thickened with colloidal silicon dioxide, which acts as a gel-forming agent. This compound is commonly used to harden oil gels.
The intended dosage form for the testosterone gel formulations of the invention is a semi-solid, not a liquid. The formulation is thickened with colloidal silicon dioxide. It is believed that colloidal silicon dioxide contributes to the gel's thixotropic properties, simplifying drug delivery to the nostril.
Colloidal silicon dioxide is generally an inert material which is well tolerated as an excipient in mucosal applications such as suppositories. Colloidal silicon dioxide is typically used in these preparations in concentrations ranging from about 0.5 to 10%. The concentration of colloidal silicon dioxide in the inventive testosterone gel formulations is high enough to achieve gel formation but at a level that has an impact - minimal incorporation of testosterone into the carrier oil.
Preferably, the intranasal testosterone gels of the present invention generally have a viscosity in the range of between about 3,000 cps and about 27,000 cps. It should, however, be understood by those skilled in the art that, while the aforementioned viscosity range is believed to be a preferred viscosity range, any suitable viscosities or viscosity ranges that do not defeat the objectives of the present invention are contemplated.
A detailed batch description of a testosterone gel formulation of the invention is shown in Table 3. Table 3: Composition of a testosterone gel formulation of the invention macrogolglycerides Testosterone gel formulations of the invention are stored at room temperature (2025°C or 68 to 77ºF). Temperature deviations from 15 to 30°C or 59 to 86°*F are allowed for the testosterone gel formulations of the invention.
Stability data support a shelf life of 12 months.
Single-dose syringes are chosen for the primary packaging of clinical supplies for the clinical trial described below to allow for ease of dosing, the ability to generate multiple doses by varying the fill volume and consistency of delivered dose.
The syringe consists of a syringe barrel, a plunger and a syringe cap.
The syringe barrels are molded from polypropylene, the plunger is molded from polyethylene and the cap is HDPE.
These syringes are designed and manufactured to deliver sterile and non-sterile solutions, liquids and gels at low volumes.
For additional protection of the environment (ie, exposure to dust, light, moisture and oxygen), the syringes are packaged in a laminated aluminum pouch wrapper.
The syringes and caps are designed for use in a clinical setting and meet the requirements of the EU Medical Devices Directive 93/42/EEC of June 14, 1993 and as attached.
As this container closure is only intended for use in this portion of the clinical program, further studies will not be performed on the syringe and syringe components.
For an additional protective element, two syringes are contained in a secondary packaging consisting of an aluminum foil pouch.
Two syringes are packed in the aluminum foil pouch and each pouch is sealed.
The bag consists of a flexible 3-ply sheet laminate of a) 12 micron polyester, b) 12 micron aluminum and c) a 75 micron polyethylene.
It is manufactured by Fioeter Flexibles GmbH, and supplied under the name "CLIMAPAC 1112-12-75".
The invention provides intranasal bioadhesive testosterone gel formulations to be administered intranasally, wherein the dosage of the formulation is from about 4.0% or 4.5% testosterone by weight of said gel. The methods and treatments of the present invention are suitable for TRT in men and are especially suitable for treating testosterone deficient male subjects, such as those who are diagnosed with hypogonadism. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will prevail. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting.
EXAMPLES Having now generally described the invention, the same will be more readily understood by reference to the following Examples which are provided by way of illustration, and are not intended to be limiting of the present invention, unless specified. The following examples are offered for illustrative purposes only and are not intended to limit the scope of what the inventors regard as their invention. EXAMPLE 1 Description and Composition of Testosterone Gel Formulations of the Invention Compositions of three different concentrations of the pharmaceutical to be administered in the present clinical trial are provided in the tables below. Description of Dosage Form The testosterone gel formulations of the invention are viscous, thixotropic oil-based formulations containing solubilized testosterone intended for intranasal application. The pharmaceutical product is formulated with the compendium inactive ingredients: castor oil, oleoyl polyoxylglycerides and colloidal silicon dioxide. Two different doses of the inventive testosterone gel formulations are administered intranasally: 0.4% w/w and 0.45% w/w. An excess is added to each syringe to account for the gel that is retained in the syringe after dosing. This overage remains consistent at 23 µl regardless of the volume of gel in the syringe. 4.0% and 4.5% Testosterone Intranasal Compositions Table 1: Components, Quantity, Quality and Function Standards - 0.4% Testosterone Gel Formulation of the Invention | Component Quantity | Quantity Quantity Function Default of | (% w/w) per Syringe delivered Quality (mg) per Serving (mg) Testosterone 4.0% 5.92 5.0 Active ingredient
USP Castor | l Oleoil 4.0% 5.92 5.0 Ph. Eur. Agent | macrogol- wetting agent | glycerides oil Silicon dioxide) 4.0% 5.92 5.0 Colloidal agent USP/NF viscosity increase Table 6 Components, Quantity, Quality and Function Standards - — Testosterone gel formulation of the invention at 0.6% B Component Quantity | Quantity Quantity Function Standard (% w/w) per Syringe delivered Quality | (mg) per Dose I (mg) | Testosterone 0.6% 0.74 Active ingredient USP
| Oleoil 4.0% 4.92 4.0 Ph. Agent | Eur/N humectant polyoxylglycerides (F. hydrophilic oil) | Silicon dioxide | 4.0% 4.92 4.0 Agent of | colloidal NF increase of | viscosity [rm om | in | in | Table 2: Components, Quantity, Quality and Function Standards, — — TBS-:5.6mg/125uI syringe (4.5% gel) — Component | Quantity | Quantity Quantity Function Standard (% w/w) per Syringe delivered Quality (mg) per Serving (mg) | Testosterone 4.5% 5.63 Ingredient | asset USP | —87.5% oil 129.5 109.37 | Solvent USP Castor Oleoil 4.0% 5.92 5.0 Agent Ph.
Eur. macrogol- wetting glycerides (hydrophilic oil) Silicon dioxide) 4.0% 5.92 5.0 Colloidal agent USP/NF viscosity increase Table 3: Components, Quantity, Quality and Function Standards,
TBS-1: 6.75 mg/150 ul syringe (4.5% gel) UÚUÚúÚÚÂÚÚÚÀNÀ O |Component Quantity | Quantity Quantity Function Default of | (% w/w) per Syringe delivered Quality | | (mg) per | | Dose (mg) |
Testosterone 4.5% 7.79 6.75 Active Ingredient USP 87.5% Oil 151.37 131.25. | Solvent USP me Ro Rs mes E | Oleoil 4.0% 6.92 Agent Ph.
Eur. macrogol- wetting agent | Glycerides (Oil Silicon Dioxide) 4.0% 6.92 6.0 Colloidal Agent USP/NF Increased | viscosity ] Container Testosterone gel formulations of the invention are supplied in single-dose polypropylene syringes.
Two syringes of each dosage are packaged in a protective aluminum foil pouch.
EXAMPLE 2 Intranasal Testosterone Gel Formulations The testosterone gel formulations of the invention are testosterone formulations in an intranasal gel proposed to evaluate the pharmacokinetics of two different doses of the testosterone gel formulations of the invention to the testosterone gel formulations of the invention in hypogonadal men.
The active ingredient, testosterone, is supplied by Bayer Schering.
Challenges for nasal delivery include: U requirements for particles larger than pulmonary delivery (ie, only particles > 10 µm are heavy enough to avoid entering the respiratory tract); .º concentrations must be higher due to the smaller volumes that can be administered; Rapid clearance of the therapeutic agent from the deposition site results in less time available for absorption; 20 . potential for local tissue irritation; and U limited formulation manipulation possibilities to alter drug delivery profiles.
Testosterone is indicated for TRT in males who are deficient in testosterone for any number of reasons, including hypogonadism. Options currently available for administering testosterone are oral, buccal, injectable, implantable and transdermal (patches and gels) An intranasal testosterone gel (3.2%) is developed for the treatment of hypogonadism in men and has been administered to hypogonadal men in several clinical trials, see for example, Mattern, C. et al., 2008 The Aging Male 11(4):171-178 (Dec 2008, which is incorporated herein by reference in its entirety. In a phase II study NCOTOO975650, the which was performed in the US in men with testosterone deficiency and which was complementary to the Romanian study reported in Mattern et al., Supra, the 3.2% intranasal gels as reported in Mattern et al, Supra, failed to reach plasma levels of Testosterone required by the FDA to support TRT efficacy in men with testosterone deficiency. The intranasal testosterone gel formulations of the present invention are developed at concentrations of about 4.0% testosterone and 4.5%.
EXAMPLE 3 Excess Testosterone Gel Formulations of the Invention No excess is added to the formulation. An excess is added to each syringe to account for the gel that is retained in the syringe after dosing. This overage remains consistent at 23 µl regardless of gel volume in the syringe. Theoretical fill and dispense amounts for testosterone gel formulations of the invention are provided below.
Syringe Dosage Volume of Theoretical Volume dispensed Theoretical filling (1) (pl) Gel formulation of 148 125 Testosterone of the invention a
4.0% 148 125 Testosterone gel formulation of the invention a
4.5%
173 150 Testosterone gel formulation of the invention a
4.5% EXAMPLE 4 Physicochemical and Biological Properties Testosterone Gel Formulations of the Invention The testosterone bioadhesive gel formulations of the invention have a viscosity in the range of 3,000 to 10,000 mPa x sec Viscosity is important because it facilitates gel maintenance in the nasal cavity in contact with the nasal mucosa. When the viscosity is less than approximately 3,000 mPa x sec (ie, 3,000 centipoise), the gel tends to be pulled by gravity away from the nasal cavity. EXAMPLE 5 Batch Formula Testosterone Gel Formulations of the Invention Three different concentrations of testosterone gel formulations of the invention, 0.15%, 0.45% and 0.6%, are manufactured for the proposed clinical trial. Batch formulas for these batches are shown in Table 5 below. Table 5: 200 KG Batch Formulas for 4.0% and 4.5% Testosterone Bioadhesive Gel Formulations of the Invention in 8 kg Batch Size. | Testosterone USP ag ag | Oleoyl polyoxyglycerides, Ph. Eur./NF ocean) ms EXAMPLE 6 Manufacturing Process and Process Controls [Testosterone gel formulations of the invention Material is manufactured according to the following process.
Manufacturing Process Flow Diagram Composite Activity Control 12 Cemiaadeens | Weighing |] [ Tesdetentionos 1st Demo destica each — A road Í Castor Oil (portion 1) Pres i Premix - Lorna te asarmemernd ana taermteansermeree—e— 1 Í Testosterone (micronized) a Í Ricin (portion 1) i Oil Castor Oil (portion 2) mc me Premix in Castor Oil * Í (portion 2) reset, Pe Í Polyoxyglyceride Oleoyl from] Polyoxyglyceride Oleoyl Blend Tontntataninineananantantant and ataa sean aneneeanaannas i with Mixture | Í Sorting Check undissolved aggregates | i Mix lil prTTmmmmemmmmm DT Silica Sodium Grout Ns Í Visual check - Appearance — É Po LDiOND colloidal silicon = mp prstyrade Colloidal silicon dioxide rertesereveeeseversen snes careeeenrennrsccnnenccan Í with Il triada Mixture Í Cooling Test | (in online donor screening) i Ingredient Blend—Volume Gel The premix is prepared by mixing, with a propellant mixer, the entire amount of testosterone with 1 portion of castor oil for 10 minutes.
Mixture | is prepared by adding the premix to the remaining castor oil and mixing for 60 minutes.
The product temperature is kept below 50°C throughout the mixing process.
Oleoyl polyxoylglycerides are preheated to 40 - 50°C and blended for 10 minutes before being added to Blend |. This is identified as
Mix II. It is mixed for 45 minutes while keeping the product temperature below 50°C. Mix 1l is then sieved through a sieve to remove any undissolved testosterone aggregates.
Mix 11l is prepared by mixing colloidal silicon dioxide to Mix 11l and mixing for 15 minutes while maintaining the product temperature below 50°C. A visual check is conducted after this step to ensure the gel is clear.
On completion of mixing the gel is stirred and cooled to a product temperature below 30°C. The product is then discharged into stainless steel drums and the bulk gel sample is taken for analytical testing.
Filling and Packaging - Clinical Supplies After the final gel mixture is released by the quality control laboratory, the filling and packaging process is carried out by filling a predetermined volume into the syringe followed by application of the syringe cap. Two syringes are packed in an aluminum pouch.
Syringes are filled using a pipette with the gel withdrawn from a holding tank. The pipette tip is discarded after the syringe is filled and the syringe cap is applied. Each syringe is individually labeled.
After applying the label, two syringes are packaged in a pre-formed aluminum foil pouch and the pouch is sealed. Each bag is labeled.
EXAMPLE 7 The pharmaceutical product, TBS-1, is an oil-based, viscous, thixotropic formulation containing solubilized testosterone intended for intranasal application for the treatment of hypogonadism in men.
The pharmaceutical product is formulated with the following compendium inactive ingredients: castor oil, oleoyl macrogolglycerides, and colloidal silicon dioxide.
To allow different doses to be administered in the phase II program, a syringe is used as the single dose container for clinical supplies.
Syringes intended for use in the clinical program are needleless and a twist-off cap is applied to the end of the syringe. The syringe consists of a syringe barrel and plunger. The syringe barrel is formed from polypropylene.
The plunger is made of polyethylene.
The syringe cap is made of High Density Polyethylene (HDPE). New dose formulation of TBS-1 is manufactured for clinical study TBS-1- 2010-01 (submitted to Agency 07/28/2010; serial number 0019). The amount of testosterone in these formulations is 4.0% and 4.5% along with an adjustment of the amount of castor oil.
The precise formulation is listed in Tables 1, 2 and 3. TBS-1 is concentrated so that the same dose is administered intranasally in a smaller volume.
Three different concentrations of TBS-1 Gel will be administered in this clinical trial: 5.0mg/125ul syringe (4.0% gel), 5.6mg/125yul syringe (4.5% gel) and 6.75mg/150ul syringe (gel to 4.5%). An excess is added to each syringe to account for the gel that is retained in the syringe after dosing.
This surplus remains consistent regardless of the volume of gel in the syringe.
Composition The compositions of the three different concentrations of the pharmaceutical product to be administered in this clinical trial are provided in Tables 1,2 and3. Table 1: Components, Quantity, Quality and Function Standards, TBS-1: 5.0m/125uI syringe (4.0%) gel) - . | Quantity component | Quantity | Quantity Default Function of | (% w/w) by Syringe | delivered Quality | (mg) Per Serving (mg) Testosterone 4.0% 5.92 5.0 Active ingredient 88.0% Oil 130.24 110 Solvent USP ore pm | es | mo je E Oleoil 4.0% 5.92 Agent Ph.
Eur. macrogol- wetting glycerides (oil | hydrophilic) |
|Silicon dioxide) 4.0% 5.92 5.0 Colloidal agent! USP/NF viscosity increase Table 2: Components, Quantity, Quality and Function Standards, —TBS-1: 5.6mg/125ul syringe! (4.5% gel) o o " Component Quantity | Quantity | Quantity Standard Function of (% w/w) per Syringe | delivered Quality (mg) per Serving (mg) Testosterone 4.5% 5.63 Active ingredient
USP 87.5% Oil 129.5 109.37 | Solvent USP Castor Oleoil 4.0% 5.92 Ph. Eur. Agent macrogol- wetting glycerides (hydrophilic oil) Silicon dioxide) 4.0% 5.92 5.0 USP/NF colloidal agent viscosity increase Table 3: Components, Quantity, Quality and Function Standards, TBS-1: 6.75 mg/150 ul syringe (4.5% gel) and Component Quantity | Quantity | Quantity Default Function of | | (% w/w) by Syringe | delivered Quality (mg) per Serving (mg) |
| Testosterone 4.5% 7.79 6.75 Active ingredient |
USP 87.5% Oil 151.37 131.25 Solvent USP Castor | Oleoil 4.0% 6.92 Ph. Eur. Agent | | macrogol- wetting agent glycerides (hydrophilic oil) Silicon dioxide/ 4.0% 6.92 6.0 Agent | colloidal USP/NF increase | viscosity | TBS-1 Gel Container is filled in polypropylene single-dose syringes. Two syringes of each dosage are packaged in a protective aluminum foil pouch. Control of Pharmaceuticals [TBS-1, Gel] Specification [TBS-1, Gel] TBS-1 gel in bulk is tested to the following specifications for batch release. : Table 1: Specification for TBS-1 gel in bulk = : | Test Parameter Method/Reference Acceptance Criteria Formulation color Reference solution | Color 250 color APHA | Viscosity Viscometer 3,000 — 10,000 mPa x sec | USP Rotational <911> | Density Density 0.97 — 1.01 gem | Relative USP <699>
| Identification HPLC USP <621> Retention time | | UV USP <197U> matches sample from | reference | Impurities HPLC USP <621> Impurity C - Epitestosterone <0.5% | Impurity | - A-6-testosterone < 0.2% Each individual impurity unknown —0.1% Total impurities < 1.0% Finished TBS-1 Gel product packaged in single-dose syringes is tested to the following batch release specifications.
Table 2: Specification for TBS-1 Gel Packaged in Single-Dose Syringes = — : — - o Test Parameter Method/Reference | Acceptance Criteria Identification HPLC USP <621> | Retention time corresponds to UV USP <197U> reference sample UV spectrum corresponds to reference sample Impurities HPLC USP <621> | Impurity C — Epitestosterone < 0.5% Impurity | - A-B-testosterone < 0.2% Each unknown individual impurity < 0.1% Total impurities £ , —1.0% | USP HPLC Assay <621> |95-105% |
| Microbial limits —| USP <61> and <62> | TAMC <10ºcfug | | TYMC < 10 cfu/g P. aeruginosa 0/g | S. aureus 0/g USP <905> Complies with USP <905> TAMC — total aerobic microbial count TYMC — combined total yeast/fungus count Batch Analyzes [TBS-1, Gel] A preliminary batch (Batch No. 100304) , four pilot scale lots (Lot NoED187, ED188, ED 189 and ED 014), two non-GMP pilot lots (NA 090811-1 and NAO90723-1) and three commercial scale lots (Lot 9256, 0823 and 0743) of TBS - 1 were produced. Data from the new batches, 0823 and 0743 are described in Tables 4 and5. Table 3: Batch Description of TBS-1 — — Batch Size 200 kg 200 kg Manufacture Date June 2010 June 2010 Manufacture Location Haupt Pharma Haupt Pharma Batch No. Testosterone 89100760 89100760 (Bayer/ Schering) (Bayer/ Schering) Quantity of filling 148 Og 173 Og per container Lot 0743, testosterone gel at 4.5% by mass, is filled at two different dosage strengths, 5.6.mg (Lot 0943) and 6.75mg (Lot 0744), by varying the weight of the gel in the finishing syringe. Lot 0823, Testosterone Gel a
4.0% by mass is filled as a potency of a dose, 5.0mg (Lot 0942).
Table 4: Batch Analysis - Batch of TBS-1 0743 and 0823 | — Paramethod | Entry Criteria Lot No. 0743 | Lot No. 0823 Clear Gel Appearance Slightly Complies Complies with yellowish formulation 3,000 — 10,000 mPas/30s 5.217 5.086 | oem the ese gem | es | | Identification Retention time Complies 5.0 min | Complies 5.0 min matches Complies | Complies with reference sample UV spectrum corresponds to | reference sample | | Impurities Impurity C Epitestosterone 0.3 0.3 < 0.5% < 0.05 <0.05 Impurity | A-6-testosterone <0.05 <0.05 | | <0.2% 0.5 0.5 | | Single impurity = <01 | Total impurities < 1.0
95.0 — 105.0% 100% 100% | Microbial limits| TAMC < 10 cfu/g Complies Complies | | TYMC < 10 cfu/g Complies Complies P. aeruginosa Complies Complies detected/g Complies | S. aureus not detected/g Complies | AT TAMC — total aerobic microbial count
TYMC — Combined Total Yeast/Fungus Count Table 5: Batch Analysis - Batch TBS-100744, 09426 09438 Batch No. 0743 0823 0743 in bulk Appearance Slightly Gel Complies Complies Complies Yellowish Identification Retention Time Complies Complies 5.0 Complies 4.9 min Complies to 4.9 min min Fulfills reference sample | Complies Complies UV spectrum corresponds to | reference sample | | Impurities Impurity C < 0.5% 0.3% 0.3% 0.3% Impurity | <0.2% <0.05% <0.05% <0.05% Each unknown individual impurity <0.1% | 0.05% 0.05% 0.05% Total impurities <1.0% 0.3% 0.3% 0.3% | |
— | TAMC limits < 10 cfu/g Complies Complies Complies | microbes TYMC < 10 cfu/g Complies Complies Complies | P. aeruginosa 0/g Complies Complies Complies | S. aureus — 0/g Complies Complies Complies
W | | Variation Complies Complies Complies Complies EE Fri Stability [TBS-1, Gel] Summary of Stability and Conclusions [TBS-1, Gel] This section has been amended to include additional data on ongoing stability studies for initial batches of stability and for stability data on the pharmaceutical product in the syringes used for the Phase II clinical study. Only updated sections and new information have been included for review. All TBS-1 gel stability studies were performed by ACC GmbH Analytical Clinical Concepts, Schôntalweg 9-11, 63849 Leidersbach/Aschaffenburg, Germany. Stability studies corresponding to ICH requirements are ongoing. — Table 1: Stability Studies performed on TBS-1 Support Product Type End of Study Conditions Pharmaceutical Storage System | studies closing the Lots No. o stability | Available Container ICH Container | ED 187C 25°C/680% RH | 12 months Study | single dose of | ED 188 40°C/75% RH |6 months completed | white LDPE; | ED 189 | sterile air in
ICH pillow — [El 014 25°C/60% RH | 36 months | Pressure study; one more | 42 months completed packaging analysis of the secondary | bag of | 1CH aluminum (without | ED 187B 9 hours 200 Exposure | Study | photostability | nitrogen) Wh/m (300-full complete | 400 nm) 22 hours 1.2 Mill. Lxh. (400- | 800 nm) | Thermal cycle ED 188 12 hr -20ºC 4 weeks | Cycle study for completed 12 hr + 40°C | ICH Syringe with Pilot Scale 25ºC/680% RH | 6 months Study | (non GMP) 40°C/75% RH cap complete | 4.0 mg syringe
5.5mg | 7.0 mg ICH Drum of 9256 Temperature 6 months In | Environment steel progress | stainless steel | | under nitrogen
“JicH Syringe with Grease 9256 25ºC/60% RH |6months In | 9445 cap — 4.0 mg |40°C/75% RH progress | syringe 9246 — 5.5 mg | 9247 — 7.0mg | ICH Drum 0743 25ºC/60% RH | Home In | 0823 steel 40ºC/75% RH progress | stainless steel | under | nitrogen | ICH Syringe with 0943 25ºC/60% RH | Home In | 40°C/75% RH syringe progress In general, stability data provided in this section is completed to withstand a 'used for' 24 month period for TBS-1 stored under controlled room temperature conditions [ie, 25°C (77°F) ; deviations 15-30°C (59-86°F)]. The data also show that Special storage conditions for the pharmaceutical product are not required.
The packaging configuration is adequate to protect the pharmaceutical from light and the pharmaceutical does not physically degrade or change after exposure to temperature cycling wear.
Clinical supplies are applied for a one-year retest period when stored at controlled room temperature conditions [ie, 25°C (77°F); deviations 15-30°C (59-86°F)], to reflect the duration of the assay and available data.
As additional data is available the re-test period will be extended as appropriate.
Stability data [TBS-1, Gel]
In this section, updated stability data tables for a commercial size volume lot 9256, 0743, and 0823 and finished product lots 9445, 9446, 9447, 0943 are provided.
A 6-month real-time stability program is in progress on the commercial size volume (Batch 9256 A real-time 36-month and a 6-month accelerated stability program is in progress on three different doses of Batch 9256 packaged in syringes of 1 ml: Batch 9445 4.0 mg (3.2% gel), Batch 9446 5.5 mg (3.2% gel), Batch 9447 7.0 mg (3.2% gel) A 6 month real-time stability program is underway on the Batch at commercial scale volume 0743 (4.5% gel) and 0823 (4.0%) gel. A 36 month real-time and a 6 month accelerated stability program is underway in Lot 0943 (Bulk Lot 0743 filled in syringes) of 1 ml.) Table 2: Stability Schedule for Commercial Scale Bulk TBS-1 Gel and Finished Product Filled in 1 ml Syringes | Storage Conditions (°C, 6 RH) | Product Test Intervals | Completed (Intervals of | Circulation test) Ambient Temperature 9256 +2ºC,60+5% Om, 6m (12m, 24m, 36m) | 25 +2 ºC,60+5% 9446 Om, 6m (9m, 18m, | 30m,36m) 25+ 2ºC, 60 +5% 9447 Om, 6m (12m, 24m, 36m) | 25+ 2ºC,60+5% 0943 Om, (3m, 9m, 18m, | | | 30m, 36m) | i 40 +2ºC,75+5% 0943 Om, (3m, 6m) | Ambient Temperature 0743 Om, (3m, 6m) | Room Temperature 0823 Om, (3m, 6m) | Table 3: Stability data Batch of TBS-1 9256 (3.2% Gel by mass) manufactured in July 2009 Stored at Room Temperature Parameter of | Acceptance Criteria 07/2009 10/2009 01/2010 Appearance Gel slightly Complies Complies Complies | yellowish Color Color 250 200 200 200 | formulation
At Viscosity 3,000 — 10,000 mPa 5504 5325 5198 x sec FIPO 78.62 77.39 76.40 |
1.98 2.00 2.16 FIPO acidity (mg KOH/g) | FIPO index (meq 02/kg) 3.56 3.16 2.63 | | peroxides | Identification a. Retention time Complies Complies Complies | corresponds to RS Comply Comply Comply | | B. UV spectrum corresponds to RS | Impurities Imp C <0.5% 0.166 % 0.148 % 0.189% | Impl1£0.1% <0.05% 0.05% <0.05% | Each imp. individual 0.064 % 0.05 % 0.075% unknown < 01% l Fe À
Tax Total < 1.0 % 0.230 % 0.198 % 0.264% Imp. D 50.2%
95.0 - 105 % 99.4% 98.3 % 100.4% | TAMC limits < 10 cfu/g <10cfulg |<10cfuig |<10cfu/g | TYMC microbials < 10cfu/g <10cfug |<10cfuég |<10cfu/g | S.aureus 0/g No No Not detected/g detected/g | detected/g P. aeruginosa 0/g No No Not detected/g | detected/g | detected/g Table 4: Stability data 4.0 mg Batch of TBS-1 9445 (3.2% gel) 1ml syringe (25 + 2°C, 60 + %RH, horizontal) — — . Parameter of | Moment O Acceptance Criteria | 6 months 12 months test - = j aee OOo] formulation Dissolution > 80% within 120 87.8 % min within 120 minutes Impurities Imp C <0.5% 0.127 % Po Each imp. individual <0.05º% unknown < 0.1 % TAMC limits < 102cfu/g <10 cfu/g po microbial — | TYMC < 10 cfu/g <10 cfu/g [A] S. aureus 0/g No | detected/g | P. aeruginosa 0/g No | detected/g | Table 5: Stability Data 4.0 mg Lot of TBS-1 9445 (3.2% gel) Syringe of Im! , (40 +2ºC,75+5 % RH, horizontal) UU — Moment Criteria Parameter O | 3 months 6 months trial Acceptance Appearance Gel slightly Complies Complies yellowish | = “[I love the wording | Dissolution > 80% within 120] 87.8 % 87.3 % within min within 120 | 120 minutes | minutes | Impurities Imp C <0.5% 0.127% Jo128% |] | Impl<0.1% <0.05% f<oos%& | | Each imp. individual | < 0.05 % Rel RT 0.38: unknown < 0.1%) 0.177% | Rel RT 2.93: 0.066% Imp.
Total €1.0% — | 0.127% 0.371% Lo | TAMC limits < 10th cfwg —[<100fwg [<100mQ [| | microbes TYMC <10cfuig —|<10cfuwg |<10cfug | S. aureus 0/g No Not detected/g | detected/g P. aeruginosa 0/g Not Not detected/g | detected/g |
| Table 6: Stability data 5.5 mg Batch of TBS-1 9446 (3.2% gel) 1ml syringe (25 +2°C, — o [ Test Parameter | Acceptance Criteria | Moment O 3 months 6 | | months | Appearance Gel slightly Complies Complies | | yellowish | Dissolution >= 80% within 120 86.8 % 83.6 % | min within within "120 120 | minutes minutes | impurities Imp C <0.5% 0.125 % 0.126% | | Imp1<0.1% <0.05 % <oos%& | | Each individual imp — | <0.05 % <0.05 % unknown < 0.1 % Imp.
Total < 1.0% 0.125% 0.126% [| 1 | Microbial limits —) TAMC < 10 cfu/g <10 cfu/g <10 cfu/g | | TYMC < 10 cfu/g <10ctg —I<10cnmg | | S. aureus 0/g No Not detected/g detected/g P. aeruginosa 0/g No No | detected/g detected/g Table 7: Stability data 5.5 mg Batch of TBS-1 9446 (3.2% gel) 1ml syringe (40 + 2°C, 75 + 5% RH, horizontal UU Test Parameter Acceptance Criteria | Memento o months — months
| O. ommuection = > [am qe | Dissolution >= 80% within 120 86.8 % within | 86.8 % within min 120 of 120 minutes Impurities IMpC<s 0.5% 0.125 % 0.127% [A Imp1<0.1% <0.05% <0.05% [ Each imp. individual <0.05% Rel RT 0.38: | unknown < 0.1 % 0.102% | Rel RT 3.01: | 0.070
Í B | Tax Total £1.0 % 0.125% 0.299% | Na mo > [onto jees | | Microbial limits —| TAMC < 10º cfu/g <10ctwg —<10cm | | TYMC < 10 cfu/g <10cfug —|<10cfug | S. aureus 0/g No No | detected/g | detected/g | P.aeruginosa 0/g No Not detected/g detected/g | Table 8: Stability data 7.0 mg Batch of TBS-1 9447 (3.2% gel) 1ml syringe (25 + 2°C, 60 + 5% RH, horizontal) Ú Acceptance Criteria Parameter Moment O 6 months | 12 months | | Yen Test = = [a | formulation | Dissolution >> 80% within 120 83.5 % within min 120 minutes
| Impurities Imp C <0.5% 0.132 % [| Each imp. individual <0.05 % unknown < 0.1 % Imp.
Total 1.0 % 0.132% [FT TAMC Limits < 10 cfu/g < 10 cfu/g Po . microbial TYMC < 10 cfu/g <10 cfu/g PA Table 9: Stability data 7.0 mg Lot of TBS-1 9447 (3.2% gel) 1ml syringe (40 + 2°C, 75 + 5% RH, horizontal) o | Acceptance Criteria Parameter Moment O 3 months | 6 months Test eme = mom Dissolution 80% within 120 min | 83.5 % in | 85.4% | 120 minutes | inside | 120 | minutes | Impurities Imp C < 0.5 % 0.132 % 01326 |) Imp1<0.1% <0.05 % <oos%
| " Each individual imp. — | <0.05% Rel RT | unknown < 0.1 % 0.37: |
0.074% Rel RT | 3.13: | 0.069 | | Tax Total < 1.0 % 0.132% o275% | TAMC Limits < 10 cfu/g <10 cfu/g <10cmg| - | TYMC microbials < 10 cfu/g <10 cfu/g <10 cfu/g [ "Al S. aureus 0/g No Not detected/g detected/ | ) | P. aeruginosa 0/g No Not | detected/g detected/ ) | g Lp a da] ppa cough — Table 10: Stability data 5.6 mg TBS-1 Lot 0943 (4.5% gel) 1ml syringe (25 + 2°C, 60 + 5% RH, horizontal) : — Criteria Parameter Acceptance Moment O 3 | Test months Appearance Gel slightly Complies yellowish sometimes omulation - > [eme | Each individual imp.<0.05 % | | unknown < |
0.1%
Table 11: Stability data 5.6 mg TBS-1 Lot 0943 (4.5% gel) Iml syringe (40 + 2°C, 75 + 5% RH, horizontal) o : - Acceptance Criteria Parameter O Moment 3 6 months | Test months | | Gel Appearance Slightly Complies | yellowish | Tomueção port and the ”- eme | Imp 1<0.1% <0.05 % | Each imp. individual <0.05 % | | unknown < 0.1%
0.3 | Tax Total< 1.0 % |
96.0 — 105% 100% Na TAME Limits < 10 Gta | we always mierobia — | TvMestosfg complies with S. aureus 0/g always Table 12: Stability data TBS-1 Lot 0743 (45% Gel) in Volume Stored at Room Temperature o Acceptance Criteria Parameter Moment O 3 months 6 months | | Test |
Appearance Gel Slightly Complies yellowish By formulation| Being ” [eme | | Each imp. individual <0.05% unknown < 0.1% Table 14: Stability data TBS-1 Lot 0823 (Gel at 4.5%) in Volume Stored at Room Temperature minus Fonieço Test months Appearance Gel slightly Complies yellowish Pora tementán color 29 [eme | | Each imp. individual < 0.05% unknown | <0.1% [555 faso Tn qe [these Tam [ T | — EXAMPLE 8 This is a Phase 2 study designed to investigate the intranasal absorption of 4% of the drug three times daily and 4.5% of the drug administered twice daily and three times daily, and to compare the absorption of the previous study in — same subjects who responded to a 3.2% testosterone gel. In the previous study, Nasobol-01-2009, a 3.2% Testosterone gel is used to deliver Ú 4.0 mg, 5.5 mg and 7.0 mg of testosterone intranasally using gel volumes of 125 ul, 172 ul and 219 yL, respectively . In this study, 5.0 mg, 5.65 mg, and 6.75 mg of testosterone is administered in gel volumes of 125 μl, 125 μl, and 150 μl, respectively. This study allowed us to investigate the delivery of similar amounts of Testosterone in much smaller volumes.
In this open-label study, subjects are equally randomized into three treatment arms. Treatments are administered for a week, in a side project. At the end of one week, the three treatments are compared by conducting a 24-hour pharmacokinetic investigation of the systemic absorption of drug testosterone and its two physiological metabolites Dihydrotestosterone and estradiol.
8. Study Objectives
8.1 Primary Objective The primary objective of this study is to determine the bioavailability through PK analysis of a 4% TBS-1 Gel (applied three times a day) and a 4.5% TBS-1 Gel (applied twice a day and three times a day) times a day) in hypogonadal men.
8.2 Secondary endpoint The secondary endpoint of the study is to establish the safety profile for TBS-1.
9. Investigation plan
9.1 General Study Design and Plan Description This is an open, randomized, balanced, three-treatment (4.0% three times daily 4.5% twice daily and 4.5% three times daily) parallel design pharmacokinetic study of TBS -1 given intranasally. Serum concentrations of total Testosterone, Dihydrotestosterone and Estradiol are measured using validated LC/MS methods.
Hypogonadal subjects are required to visit the Clinic on three (3) occasions, of which one (1) visit (Visit 3) required an overnight stay for the previously described 24-hour pharmacokinetic profile.
The following pharmacokinetic parameters are determined for all subjects: U AUCo-t, Cava, Cmin, Cmax, tmax, PTF and PTS means, and standard error of means are calculated for the 24-hour interval.
10 . The percentage of subjects with a Caw, for Testosterone, Dihydrotestosterone and Estradiol, below, within and above the Reference Range for * the respective analyte is calculated.
Erythrocytosis, anemia, and infections are monitored by measurement of CBC at the screening visit and at the closing visit.
It is expected to include approximately 30 subjects. Twenty-two (22) subjects completed the study. Study participation is 2-3 weeks.
9.2 Discussion of Study Design Testosterone therapy for hypogonadal men should correct clinical abnormalities of testosterone deficiency, including disturbances of sexual function. Testosterone decreases body fat and increases lean muscle mass and bone density with minimal adverse effects.
There are several testosterone replacement products available that can be administered intramuscularly, orally as a buccal tablet to the gums, or topically as a plaster or gel. Current replacement therapies have certain drawbacks. Testosterone injections show large fluctuations in serum testosterone levels often above the reference range (5). Testosterone patches have a high rate of skin irritation (6,7). Testosterone gels, although popular in North America, are not always convenient and carry a risk of skin-to-skin transfer to family members (8,9). Oral Testosterone Undecanoate needs to be administered with a high-fat meal and levels are often low (10-12).
Intranasal administration of a novel testosterone formulation (TBS-1) has been shown to be effectively absorbed and shows excellent potential as a therapeutic product in the treatment of male hypogonadism (13). The nasal mucosa offers an alternative route of administration that is not subject to the first-pass s1 effect, has a high permeability and ease of administration with rapid absorption into the systemic circulation producing high plasma levels similar to those observed after intravenous administration.
The advantages of nasal testosterone gel, when compared to other formulations, are as follows: Convenient form of application allowing discreet use, the much smaller amount of active ingredient needed by the subject, and knowing that this type of administration is less likely to contaminate other family members (wife and children).
Several studies have indicated the usefulness of administering testosterone using nasal gels. The previous study conducted in 2009 serves to demonstrate the effectiveness of TBS-1 in treating hypogonadal men who — require Testosterone Replacement Therapy. Efficacy is determined by creating an optimal pharmacokinetic profile for serum testosterone levels following a twice daily multiple dose dosing profile for TBS-1 using three different testosterone potencies (8.0 mg, 11.0 mg and 14.0 mg) and comparing it to that of the active control, Androdermº. The secondary objective of this study is to establish a safety profile for TBS-1. This should be achieved by monitoring serious adverse and adverse events over the course of the entire study, and by comparing various safety parameters further to those obtained at baseline. These safety parameters consisted of vital signs, complete blood counts, a chemistry profile, an endocrine profile, and urinalysis. Additionally, changes to the nasal mucosa and prostate are then compared to baseline.
An important advantage of the power of the dose-finding design of this study is that it minimizes subject selection bias and the different reception groups often observed in sequential study designs.
The three clinical sites are monitored by Schiff & Company to ensure subject safety and clinical study performance in accordance with ICH E6 and FDA guidelines.
A central laboratory is used for the analysis of hematology and biochemistry parameters in order to obtain consistent and unbiased laboratory results. A second central laboratory is used for PK analysis.
The following are the specific activities in the study design during the subject's visits:
PROCEDURE Period | Day 1 | Day7 | Day8 of In/Ex vamo " “and Informed Consent” x Medical history ed Physical Examination * & Vital signs xxxx Demographic data of the xx Subject PROCEDURE xx ENT Examination Po Hematology! ENNH me Serum PSA xd Test for x Hepatitis B, C, & HIV Drug Screening by x Urineº Ethanol Test Px temagament — [x 1 | [| eme [1 |] orem [x |) serum months moans 1 xxxx Adverse * Physical examination at Screening and Day 8 only.' Informed consent will be given signed before the In/Ex Period of Screening Visit 1: Inclusion and Exclusion Period If subject had a previous normal prostate exam on Nasobol-01-2009, this will not be necessary. Chemical profile: Na/K, Glucose, Urea, Creatinine, Total Bilirubin, Albumin, Calcium, Phosphate, Uric Acid, AST, ALT, ALP, GGT and CK * Complete and differential blood count.
S Urine dipstick (non-microscopic). $ Cocaine, Cannabinoids, Opiates, Benzodiazepines. 7 Alcohol in urine by dipstick. Serum Testosterone, Dihydrotestosterone & Estradiol will be measured by a reference laboratory using a validated LC-MS/MS method for Te DHT and a validated LC-MS/MS or immunoassay method for Estradiol.
Screening Visit 1 and Subjects, after having voluntarily signed the Informed Consent Form, are investigated by the Clinical Investigator or his/her designated medicine/nursing professional who took the medical and physical history, the recordings of demographic data, and performed a routine physical examination.
Body weight and height are measured and BM! calculated.
Vital signs (sitting for 5 minutes) are measured (Blood pressure, heart rate, respiratory rate and body temperature). * If the subject had a normal digital rectal exam of the prostate in the recent Nasobol-01-2009 trial, it is not repeated.
* The clinical investigator assessed the subject's study eligibility based on the inclusion/exclusion criteria, and eligible subjects who are currently on Testosterone Replacement Therapy required to undergo a washout period; four (4) weeks for depot products administered intramuscularly (eg, Testosterone enanthate 200 mg/ml), and two (2) weeks for products administered orally or topically (plaster, gel, or buccal). At the end of the elimination period, subjects must return to have their serum Testosterone measured.
* Untreated subjects do not require a elimination period.
* “Blood for Serum Testosterone is collected under fasting conditions, at 0900 h + 30 minutes. Serum Testosterone level should be > 150 ng/dL, and < 300 ng/dL.
* “Blood is collected for Clinical Laboratory investigations after an overnight fast (8-10 hours fasting) and included the following: o Complete blood count (Hemoglobin, Hematocrit, MCV, MCHC, RBC, WBC & Differential) o Clinical chemical profile (Na/K, Glucose, Urea, Creatinine, Total Bilirubin, Albumin, Calcium, Phosphate, Uric acid, AST, ALT, ALP, GGT and CK) o Serum PSA o Test for HBV, HCV and HIV (Antigen of Hepatitis B surface, Hepatitis C antibody, Anti-HIV antibodies) o Whole blood sample for Hemoglobin Atc o Urine for dipstick urinalysis o Urine for drug screening (Cocaine, Cannabis, Opiates and Benzodiazepines). Subjects testing positive are not enrolled unless the positive test is due to interference from a medication prescribed by a physician.
o Urine for alcohol testing! * The nasal endoscopy ENT examination is performed by an otolaryngologist.
* Subjects meeting all inclusion and exclusion criteria are enrolled in the studies and randomized into one of three treatment groups (A, B, or C).
Visit 2 (day 1) * Subjects arrived at the Clinic fasting (6 - 8 hours fast) at 2000 hours or earlier.
* Instructions are given to individuals on the proper technique for intranasal dosing of TBS-1.
and Blood is collected at 2045 hours for baseline serum Testosterone, Dihydrotestosterone, and Estradiol concentrations.
* Vital signs (sitting for 5 minutes) are measured (Blood Pressure, Heart Rate, Respiratory Rate, and Body Temperature) to establish a baseline. *Subjects are given a one-week supply of grants: 18 Ú grants for Treatment A, 12 grants for Treatment B, and 18 grants for Treatment C. Grants required for dosing during the PK profile remained with the Clinical Investigator. Each pouch contained two syringes pre-filled with TBS-1 Gel for Treatment A, B, or C.
e Subjects administered their first dose of TBS-1 at 2100 hours according to their treatment group.
* Vital signs are measured at 2200 hours and subjects are sent home with their supply of bags for their treatment group.
Telephone Verification (Day 4) On Day 4, all subjects are called to verify compliance with study drug administration, compliance with abstaining from alcohol for 48 hours, and to document any adverse events that may have occurred. Subjects are reminded to bring all syringes for counting at Visit 3.
Visit 3 (day 7) * Subjects arrived at the Clinic fasting (6 - 8 hours fast) at 2000 hours or earlier.
and Blood is collected at 2045 hours for baseline serum concentrations of Testosterone, Dihydrotestosterone, and Estradiol.
e Subject underwent a 24-hour pharmacokinetic profile immediately after the 2100-hour dosing. Vital signs are recorded every hour for 2 hours after dosing.
* Security parameters are recorded.
* Subjects fasted for two hours after dose and then received dinner. After dinner, subjects fasted again overnight and continued to fast until 0900 hours on Day 8. Lunch and dinner on Day 8 occurred at regular times and are not subject to fasting conditions. Pharmacokinetic blood collections «* Drug administration should occur within + 5 minutes of the indicated time (2100 h and 0700 h for dosing twice a day and 2100 h, 0700 h and 1300 h for dosing three times a day).
e Blood collections must be done within +5 minutes from the indicated times when blood collection intervals are <30 minutes and within +15 minutes when blood collections are >30 minutes.
Ú * Treatment A: Blood samples for serum Testosterone, Dihydrotestosterone, and Estradiol measurements: Blood draws for dosing three times a day are taken at the following times after drug administration for 2100 hours; 0.33, 0.66, 1.0, 1.5, 2.0, 3.0, 6.0, 9.0, 9.75, 10.33,
10.66, 11.0, 11.5, 12.0, 13.0, 14.0, 15.75, 16.33, 16.66, 17.0, 17.5, 18.0,
20.0, 22.0 and 24.0 hours, (total blood collections; 25 + baseline).
* Treatment B: Blood samples for measurement of serum Testosterone, Dihydrotestosterone, and Estradiol: Blood collections for twice daily dosing are taken at the following time after drug administration for 2100 hours; 0.33, 0.66, 1.0, 1.5, 2.0, 3.0, 6.0, 9.0, 9.75, 10.33,
10.66, 11.0, 11.5, 12.0, 13.0, 16.0, 19.0, 22.0, and 24.0 hours, (total blood collections; 19 + baseline).
* Treatment C: Blood samples for measurement of serum Testosterone, Dihydrotestosterone, and Estradiol: Blood collections for dosing three times a day are taken at the following times after drug administration for 2100 hours; 0.33, 0.66, 1.0, 1.5, 2.0, 3.0, 6.0, 9.0, 9.75, 10.33,
10.66, 11.0, 11.5, 12.0, 13.0, 14.0, 15.75, 16.33, 16.66, 17.0, 17.5, 18.0,
20.0, 22.0 and 24.0 hours, (total blood collections; 25 + baseline).
+ The last blood draw in the PK profile included enough blood to measure the required clinical analysis laboratory safety parameters at closure.
Visit 3 (day 8), Closing visit Subjects underwent the following assessments: * A routine physical examination including vital signs (Blood Pressure, Heart Rate, Respiratory Rate, and Body Temperature).
* Nasal ENT exam. * Blood sample is taken for a complete blood count (Hemoglobin, Hematocrit, RBC, WBC and differential, MCV, MCHC). * Blood Sample for Chemical Profile (Na/K, Glucose, Urea, Creatinine, Calcium, Phosphate, Uric Acid, Total Bilirubin, Albumin, AST, ALT, ALP, GGT, and cK). * Blood sample for PSA. * Urine sample for urinalysis with dipstick.
9.3 Selection of Study Population Subjects are included in the study according to the following inclusion/exclusion criteria: Ú 9.3.1 Inclusion criteria
1. Male subjects reacting to high-dose intranasal testosterone in the Nasobol-01-2009 trial.
2. Written informed consent.
3. Males between 18 and 80 years of age.
4. Men with primary or secondary hypogonadism and morning (0900 h + 30 min) serum testosterone levels >150 ng/dl and <300 ng/dL in fasting blood.
5. BMl between 18.5 -35 kg/m².
6. All clinical laboratory assessments at the Screening Visit are from blood collected or urine collected after an overnight fast (10 hours), and are within +15% of the Analytical Laboratory reference range Clinics, except Serum Testosterone.
7. Normal otorhinolaryngological nasal endoscopic exam. See Appendix
16.1.1 for Exclusion criteria pertaining to endoscopic examination.
8. Previously, normal prostate examination (no palpable prostate mass) from Nasobol-01-2009 trial.
9. A serum PSA < 4.0 ng/mL.
9.3.2 Exclusion Criteria
1. Significant intercurrent illnesses of any kind, in particular liver, kidney, or heart disease, any form of diabetes mellitus or psychiatric illness.
2. Mobility limitations, defined as having difficulty walking two blocks on a flat surface or climbing 10 steps
3. Hematocrit > 54% at screening.
4. Cancer history, excluding skin cancer.
5. History of nasal surgery, specifically turbinoplasty, septoplasty, rhinoplasty, nose job, or sinus surgery.
6. Subject with anterior nasal fractures.
7. Subject with active allergies such as rhinitis, rhinorrhea and nasal congestion.
8. Subject with inflammatory mucosal disorders, specifically pemphigus, and Sjogren's syndrome.
9. Subject with sinus disease, specifically acute sinusitis, chronic sinusitis, or allergic fungal sinusitis.
10. History of nasal disturbances (eg, polyposis, recurrent epistaxis (> 1 nose bleed per month), decongestant abuse — nasal), or sleep apnea.
11. Subject using any form of intranasal medication administration, specifically nasal corticosteroids and oxymetazoline containing nasal sprays (eg Dristan 12-Hour Nasal Spray).
12. History of serious adverse drug reaction or leucopenia.
13. History of abnormal tendencies to bleeding or thrombophlebitis unrelated to venipuncture or intravenous puncture.
14. Test positive for hepatitis B, hepatitis C, or HIV.
15. Asthma history and ongoing asthma treatment.
16. History of sleep problems.
17. Smokers (> 10 cigarettes a day).
18. Regular drinkers of more than four (4) units of alcohol daily (1 unit = 300 mL of beer, 1 glass of wine, 1 scoop of —distilled) or those who may have difficulty abstaining from alcohol during the 48 hours prior to the 24-hour blood sample visit.
19. History of, or current evidence of, abuse of alcohol or any drug substance, lawful or illicit; or positive urine drug and alcohol screening for drug and alcohol abuse.
20. Current treatment with androgens (eg Dehydroepiandrostenedione, Androstenedione) or anabolic steroids (eg Testosterone, Dihydrotestosterone).
21. Treatment with Estrogens, GnRH antagonists, or Growth Hormone within the previous 12 months.
22.Treatment with drugs which interfere with testosterone metabolism, such as Anastrozole, Clomiphene, Dutasteride, Finasteride, Flutamide, Ketoconazole, Spironolactone and Testolactone.
23.Androgen treatment within the last four weeks (intramuscular, topical, oral, etc.).
24. Subject with poor compliance record or unlikely to maintain attendance.
25. Participation in any other research study while conducting this study or 30 days prior to the start of this study, with the exception of Nasobol-01-2009.
26. Blood donation (usually 550 mL) at any time. — during this study, and within the 12 week period prior to the start of this study.
9.3.3 Withdrawal of Subjects from Therapy or Assessment Subjects are informed that they are free to withdraw from the study at any time without having to give reasons for their withdrawal, and without consequences for their future medical care. They are asked to inform the investigator immediately of their decision. The subject's participation in the study may be interrupted for any of the following reasons: * Subject's own will. * “Significant non-compliance with study protocol and procedures. * “Intercurrent illness that interferes with the progress of the study. * Intolerable adverse event, including clinically significant abnormal laboratory findings, which, in the opinion of the Clinical Investigator, may interfere with the subject's safety. * Clinical Investigator's decision that withdrawal from the study is in the best interest of the subject. The clinical investigator had the right to terminate a study prematurely for safety reasons, after having informed and consulted the Sponsor. Sponsor had the right to terminate the study earlier if the clinical observations collected during the study suggested that it might not be justifiable to continue or for other reasons as described in the contract between Sponsor and the clinical sites (eg, administrative, regulatory, etc. .). However, this is not necessary. There are no premature terminations or dropouts from the study.
9.4 Treatments
9.4.1 Administered Treatments Subjects are centrally randomized to the following treatment groups in order to balance numbers evenly within groups across the three centers: * Treatment A (n=10): TBS-1 syringes pre-filled with 125 uL gel a
4.0% to deliver 5.0 mg of testosterone per nostril (intranasal) given three times daily at 2100, 0700, and 1300 hours. (total dose 30 mg/day) * Treatment B (n=10): Pre-filled TBS-1 syringes with 150 uL gel a
4.5% to deliver 6.75 mg of testosterone per nostril (intranasal) given twice daily at 2100 and 0700 hours. (total dose 27.0 mg/day) . * Treatment C (n=10): TBS-1 syringes pre-filled with 125 ul gel a
4.5% to deliver 5,625 mg of testosterone per nostril (intranasal) given three times daily at 2100, 0700, and 1300 hours. (total dose 33.75 mg/day)
9.4.2 Identity of Research Products Drug Name: TBS-1 (Syringes are pre-loaded to contain 5.0 mg,
5,625 mg, and 6.75 mg testosterone/syringe). Pharmaceutical form: Gel for nasal administration. Contents: Active ingredient: Testosterone. Excipients: Silicon Dioxide, Castor Oil, Labrafilº. Method of administration: Nasally, as a single dose to each nostril. Manufacturer: Haupt Pharma Amareg. Lot numbers: 0744, 0942, and 0943 Storage conditions: between 20 - 25°C. Packaging TBS-1 study drug is delivered to the clinical trial site as a ready-to-use syringe in an aluminum foil pouch (two syringes per pouch). Examples of Syringe and Bag Labels are described in Appendix 4 of the protocol.
9.4.3 Subject Assignment Method For Treatment Subjects who match the Entry Criteria are randomly assigned on a 1:1:1 basis to one of the three treatment groups. In screening, each subject is assigned a subject number per location in sequential order. Subject numbers consisted of 5 digits. The first two digits reflect the location number assigned to the investigator, followed by a 3-digit subject number. For example, 01-001 indicates location (01) and the first subject (001).
The subject number was used to identify the subject throughout the study and was entered in all documents. The same subject number was not assigned to more than one subject.
9.4.4 Study Dose Selection In a previous study, Nasobol-01-2009, a 3.2% testosterone gel is used to deliver 4.0 mg, 5.5 mg and 7.0 mg of testosterone intranasally using 125 ul gel volumes , 172 ul and 219 ul, respectively. In this study, 5.0 mg, 5.65 mg, and 6.75 mg of testosterone are administered in gel volumes of 125 μl, 125 μl, and 150 μl, respectively. This study . allows investigation of the delivery of similar amounts of Testosterone in: — much smaller volumes,
9.4.5 Selection and Dose Time for Each Subject This was based on the results of the previous study.
9.4.6 Blindness (lack of knowledge) There is no blindness, as this is an open study. the rationale for no blindness is that analytical endpoints, which are quantitative rather than qualitative, are measured, and are not subject to any bias to be introduced by the subjects or the Investigators.
9.4.7 Prior and Concurrent Therapy The following medications are prohibited during the course of the study: Subject using any form of intranasal medication administration, specifically nasal corticosteroids and oxymetazoline containing nasal sprays (eg, Dristan 12 Hour Nasal Spray).
Current treatment with androgens (eg Dehydroepiandrostenedione, Androstenedione) or anabolic steroids (eg Testosterone, Dihydrotestosterone). Treatment with Estrogens, GnRH antagonists, or Growth Hormone within the previous 12 months.
Treatment with drugs which interfere with testosterone metabolism, such as; Anastrozole, Clomiphene, Dutasteride, Finasteride, Flutamide, Ketoconazole, Spironolactone and Testolactone.
Androgen treatment within the last four weeks (intramuscular, —topical, buccal, etc.).
9.4.8 Compliance with treatment
All drugs are distributed according to protocol. It is the Investigator's primary responsibility to ensure that an accurate record of drug problems and returns is maintained. At the end of the study, the original packaging used is returned to the sponsor for destruction. Drug counts are verified by monitors during the course of the study and prior to destruction of remaining study drugs.
During Visit 2, subjects are given a week's supply of scholarships; 18 bags for Treatment A, 12 bags for Treatment B, and 18 bags for Treatment C. Each bag contained two syringes pre-filled with TBS-1 gel for Treatment A, B, or C. Subjects are instructed on how to administer the gel and also receive a diary to indicate the times of administration in your home.
: 9.5 Efficacy and safety variables 9.5.1 Measures of Efficacy and Safety Evaluated The primary efficacy endpoint is the AUC obtained within 24 hours of TBS-1 administration. From the AUC the 24-hour CavK is calculated.
. Area under the concentration curve (AUC) for both twice daily and three times daily dosing is determined for the time range 0 to 24 hours using the trapezoidal rule.
20 . The mean concentration over the dosing interval (Cavg) is calculated from the AUC using the following formula: Cavg = AUCo.1/T, with T = dosing interval time.
. Peak-Valley Fluctuation (PTF) and Peak-Valley Fluctuation (PTS) is calculated as follows: o PTF = (Cmax Cmin ) Cava Oo PTS = (Cmax Cmin ) Cmin . Cmin, Cmax And tmax It is made from the actual measured values. Values are determined in relation to the time of administration of Testosterone in treated subjects.
30 . The percentage of subjects with 24-hour Cawg values for serum Testosterone, DHT, and Estradiol above, within, and below the respective reference range are calculated.
.º Exploratory analyses. Additional PK Parameters can be performed as needed.
Security Data Analysis
Erythrocytosis, anemia, and infections are monitored by measuring complete blood counts at screening, and at the closing visit. An ENT physician examined subjects and identified any clinically significant changes to the nasal mucosa and then compared to baseline.
Clinical chemistry testing and urinalysis at Screening Visit 1 and at closure are assessed for hypo or hyperglycemia, renal function, liver function (hepatocellular or obstructive liver disease), skeletal/cardiac muscle damage, and changes in calcium homeostasis.
Serum PSA is measured as a precautionary measure to measure possible changes to the prostate, although changes to the prostate and serum PSA are not expected within a short period of treatment. - Measurement of serum Testosterone, Dihydrotestosterone and Estradiol at Screening Visit 1 and Visit 3 allowed any deviations beyond the upper limit of the reference range for the two physiological testosterone products, DHT, and Estradiol to be observed.
Safety analysis is performed on all subjects who received TBS-1. Occurrence of adverse events are presented by treatment group, by severity, and by study drugs. All adverse events are described and evaluated for causality and severity. Adverse events are classified using MedDRÁA. However, they are very few and all but two are not drug related.
Subject Subject Safety Monitoring and Emergency Procedures: Emergency Medication, Equipment and Subject Stretcher are available at the Study Center. During the "at home" phase, subjects have an emergency call number so they can contact the Clinical Investigator.
. Adverse events are defined as any untoward medical occurrence in a subject or subject clinical trials having administered a medicinal product and which may or may not have a causal relationship to this treatment. An adverse event, therefore, can be any unfavorable and unintended sign, laboratory result, symptom or illness temporarily associated with the use of an investigational medicinal product, whether considered related to it or not. Any pre-existing condition during the clinical trial which is made worse during the clinical trial should be considered an adverse event.
. An adverse reaction is defined as any harmful and involuntary response to an experimental drug related to any given dose. All adverse reactions judged by both the Clinical Investigator and Sponsor to be reasonably causally related to a medicinal product qualify as adverse reactions. This is intended to convey, in general, that there is evidence or an argument to suggest a causal relationship.
U An unexpected adverse reaction is defined as an adverse reaction, the nature, or severity of which is not consistent with the applicable product information.
10 . A serious adverse event or serious adverse reaction is defined as any untoward medical occurrence or effect which, at any dose, results in — death, is life threatening, requires hospitalization or extension of: — the Subject's existing hospitalization; results in persistent or significant disability or disability or is a congenital anomaly or birth defect.
15 . The observation period extends from the time the subject started study medication until the end of Visit 3 for hypogonadal subjects. AEs that are continuous at the end of the study period are followed until the investigator believes the AEs have achieved a stable clinical outcome.
20 . The percentage of subjects with a serum DHT and Estradiol greater than the upper limit of the reference range for the respective analyte.
U Closing day 8 findings are compared to screening results, and clinically significant changes identified in the following: o Vital Signs and Adverse Events: Blood Pressure, Body Temperature, Respiratory Rate, Heart Rate.
otorhinolaryngological exam.
o Complete blood count to assess changes in blood count — white blood cells, hemoglobin.
o Clinical chemical profile; Na/K, Glucose, Urea, Creatinine, Calcium, Phosphate, Uric Acid, Total Bilirubin, Albumin, AST, ALT, ALP, GGT, CK, and PSA.
.º Classifications: o A serious adverse event (SAE) or serious adverse reaction: Defined as any unfavorable medical occurrence or effect that, at any dose,
results in death, is life threatening, requires hospitalization or prolonged hospitalization in the Subject, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, an important medical condition, i.e., the AE compromised the subject, or requires intervention to avoid one of the consequences listed above.
o AE not serious: Qualguer AE not meeting the SAE Criteria.
o Intensity: An adverse event/reaction is classified as Mild, Moderate, or Severe.
f Causality: An adverse event may be considered an adverse reaction to an investigational medicinal product when a "reasonable causal relationship" exists between the event and the investigational product. The following degrees: —of causal relationship should be considered: 'Le Definitive: plausible temporal relationship with drug administration and withdrawal, and reappearing after drug resumption. = Probable: plausible temporal relationship with drug administration. "m Possible: plausible temporal relationship to drug administration but may reasonably be associated with other factors. L Unlikely: no plausible temporal relationship to drug administration. = Unknown: not enough evidence to establish a correlation with drug intake. = Unrelated: cannot be correlated with drug administration.
. Procedure to be followed in the event of adverse events: All adverse events detected by the Clinical Investigator are recorded in the special section of the Case Report Form. Any event that is considered serious, regardless of causal relationship, must be reported to the CRO and — Sponsor within 24 hours. There are no serious adverse events.
9.5.2 Appropriateness of Measurements All measurements used in this study are standard indications of efficacy, PK and safety and are generally recognized as reliable, accurate and relevant.
9.5.3. Primary Efficacy Variable(s) Serum Testosterone Pharmacokinetic Profiles for Subjects Dosed in Treatments A, B, and C who have:
Lt A 24-hour Cavg value > 300 ng/dL and < 1050 ng/dL.
2. The percentage of subjects in each treatment group with a 24-hour Cavg less than, within, and above the serum testosterone reference range of 300 ng/dl — 1050 ng/dL.
9.6 Data Quality Assurance CRF entries are verified by monitors against source documents. All database entries included CRF and Subject Diary Card data, PK results, and laboratory values. All data is 100% audited after being entered into the database for this report.
9.7 Statistical Methods Planned in the Protocol and Sample Size Determination: 9.7.1 Statistical and Analytical Plans. The PK analysis plan is described above. The analysis plan for Vital Signs and Lab Results are baseline results compared to final visit results after PK analysis. Other data including demographic data is descriptive. No statistical analysis is performed because group sizes are not selected on the basis of statistical significance.
9.7.2 Sample Size Determination Based on the results obtained by conducting several pharmacokinetic studies in groups of 10 Subjects per cohort, these are sufficient for an acceptable description of the pharmacokinetic parameters in this population. As this is a relatively modest Phase I PK study intended to investigate two higher concentrations of TBS-1 Gel, a true sample size calculation is not performed.
9.8 Changes to Study Conduct or Planned Analysis The protocol is amended on July 27, 2010. The requested change is at the time of blood draws. The number of blood draws remained the same. This change is necessary to allow full capture of the testosterone absorption peak after the third dose of TID which occurred at 1300 hours on day8 or 1600 hours after the initial 2100 hour drug administration on the previous day (Day 7).
10. SUBJECTS OF THE STUDY
10.1 Subject Disposition The study is conducted at three centers located in Miami, FL — Shreveport, LA and Tucson, AZ.
The three treatment groups are evenly divided among the three sites. Eight Subjects received Treatment A, seven Subjects received Treatments B and C, respectively. A total of 22 subjects are in the study. Additionally, five subjects who participated in the previous clinical trial failed screening and therefore were not randomized into the trial.
Table 10.1. Disposition of subjects by location and Treatment ID of| Treatment A: Treatment B: Treatment C: Local Total Pre-TBS-1 Syringe | TBS-1 Syringe | TBS-1 syringe filled with 125 micro- | pre-filled with | pre-filled with liters of drug 150 micro-liters | 125. micro-liters - drug drug ar a e [oa a RR 2 ER HA Hr
10.2 Protocol Deviations There are no significant pharmacokinetic deviations.
11. PHARMACOKINETICS AND STATISTICS
11.1 Analyzed datasets The PK population is defined as subjects who receive Treatment A, B or C, and who completed the study without major protocol violation or for whom the PK profile can be adequately characterized. The PK population is used for the analysis of PK data.
Based on the above criteria, Twenty-two (22) subjects are included in the PK population. Subject numbers by location and by treatment are shown below.
Table 11.1.1: Disposition of subjects in the PK population: 1 9 2 7 3 6
Number of Subjects A: TBS-1 125 ul of 4.0% Gel (three times a day) 8 B: TBS-1 150 ul of 4.5% Gel (twice 7 times a day) 7 C: TBS-1 125 ul of 4.5 % gel (three times a day)
11.2 Demographic Characteristics and Other Baselines Demographic data and characteristics are presented by dose group for all data for all Subjects treated in Table 11.2. * No significant differences were observed between the three groups for any of the characteristics. Table 11.2: Summary of Demographic Characteristics - all Subjects Treatment A: | Treatment B: | Treatment C: TBS syringe-| 1 pre-filled syringe syringe with| TBS-1 pre- TBS-1 pre- 125 ul Gela | filled with filled with
4.0% 150 ul Gel al 125 ul Gel a
4.5% 4.5% All Subjects no on or no & > » Black or African American race 1 1 TR TITE
Hispanic or Latino 4 3 3 10 Non-Hispanic and Non-Latin 4 4 4 12
52.38 53.86 51.57 52.59 The populations treated for Group A have a mean age of 52.38, for Group B 53.86, and for Group C 51.57. Standard deviations are 12.55, 11.04, and
9.90, respectively. Ethnic and racial distribution are essentially the same in each Group.
11.3 Measuring Compliance with Treatments Compliance with drug use during the in-home portion of the study is determined by an analysis of diaries and returned used bags and syringes. Although the method is not absolute, it is sufficient to establish reasonable compliance. A guy couldn't find his diary.
11.4 Pharmacokinetics and Statistical Results
114.1 Methods Blood concentrations are received from ABL and transferred electronically from Trimel Biopharma SRL to the PharmaNet statistical unit. Serum Testosterone and Dihydrotestosterone concentrations are given in ng/ml. However, serum concentrations are converted to ng/dL for PK calculation to match literature reference range units. During the trial, clinic 1 performs PK sampling one day after what is specified in the protocol that starts on Day 8 instead of Day 7. This change is not planned. Consequently, actual times are calculated with respect to drug administration of 2100 hours on Day 8 for clinical site subjects 1 and drug administration of 9:00 pm on Day 7 for clinical site subjects 2 and 3. For Subject No. 02- 003, dosing time is not recorded on Day 7. Consequently, programmed sampling times are used instead of actual sampling times for PK Calculations.
The 16.33 h and 16.67 h samples for subject 01-001 are collected at the same time due to technical reason.
The programmed sampling time is used for sampling 16.33 h while the actual sampling time is used for sampling 16.67 h.
Excluding the above exceptions, time deviations during sampling are handled as follows: for all sampling times, the difference between scheduled and actual sampling time is considered acceptable if it .- — is less than 1 minute.
When the difference exceeds this time limit, actual sampling times (rounded to three decimal digits) are used to calculate pharmacokinetic parameters, except for pre-dosing samples, which are always reported as zero (0.000), regardless of time deviations.
Scheduled sampling times are presented in concentration tables and graphs in the statistical report.
PK calculations are performed using WinNonlin "V version 5.2 (or newer), validated in accordance with industry expectations and regulatory requirements.
Descriptive statistical calculations are also performed using Microsoftº Office Excel 2003. Microsoft Office Excel 2003 and Microsoft Office Word 2003 are used for tabulating report data. Descriptive statistics (N, mean, standard deviation (SD), coefficient of variation (CV), median, minimum value (Min.), and maximum value (Min. )) of the serum concentrations versus time as well as all pharmacokinetic parameters are provided for each treatment at each dose level using the evaluable population.
All figures are presented using both linear (a) and semi-log (b) scales. To calculate the PK parameters of the last three drug administrations (Treatments A and C: O hour at 10 hours, 10 hours and 16 hours and 16 hours and 24 hours; Treatment B: O hours at 10 hours and 10 hours and 24 hours ), serum concentration values for Testosterone, Dihydrotestosterone, and Estradiol at time points 10 hours (pre-dosing for second drug administration) and 16 hours (pre-dosing for third drug administration under Treatments A and C) are obtained by assigning the serum concentration value observed at the time points 9.75 hours and 15.75 hours, respectively.
The following pharmacokinetic parameters are determined for all subjects by Testosterone, Dihydrotestosterone and Estradiol: For Treatments A and C (three times daily): AUCo-1, AUCo-10, AUC10-16, AUC16-24, Cmax, Cmax 0-10, Cmax 10-16, Cmax 16-24, Cmin, Cmin 0-10, Cmin 10-16, Cmin 16-24, Cava, Cavgo10, Cava 10-16, Cavg 16-24, Imax, max 0- 10, tmax 10-16 max 16-24, Imax 10-24, PTF, PTS. For Treatment B (twice daily): AUCo-1, AUCo-10, AUC10-24, Cmax, Cmax 0-10: Cmax 10-24, Cmin, Cmin 0-10, Cmin 10-24, Cava, Cava 0 -10, Cava 10-24; max, max 0-10; max 10-24, PTF, PTS. Additionally, the percentage of subjects with Ca'K Values for Serum Testosterone, Dihydrotestosterone, and Estradiol above, within, and below their respective reference range is calculated for each treatment. In addition, time mean percent of serum Testosterone, Dihydrotestosterone, and Estradiol values above (%TimeUp), within (%TimeInside), and below (%TimeUnder) the corresponding reference range are provided for each treatment. The calculation of all these pharmacokinetic parameters is explained below.
11.4.1.1 Maximum and Minimum Observed Concentrations and Time of Observed Peak Concentrations Cmax, the maximum observed concentrations and Tmax, The time to reach peak concentrations, as well as Cnmin, the minimum observed concentrations are determined for each subject and for each treatment as follows: dosage. This parameter is calculated for Treatments A, B and C. Cmax 0-10: Maximum observed concentration from time zero to 10 mm Ed eTementA Deo Maximum observed concentration from time 10 hours Maximum observed concentration from time point 16 hours to 24 hours. This parameter is calculated for Treatment B only. dosage. This parameter is calculated for Treatments A, B and C.
Cmin 0-10: Minimum concentration observed from time zero to 10 hours. This parameter is calculated for Treatments A, B and C.
Crmin 10-16: Minimum observed concentration from 10 hours to 16 hours. This parameter is calculated for Treatments A and C.
Cmin 16-24 Minimum observed concentration from 16 hours to 24 hours. This parameter is calculated for Treatments A and C.
Cmin 10-24: Minimum observed concentration from 10 hours to 24 hours. This parameter is calculated for Treatment B only.
tmaxi Time of Cmax observed over the dosing interval. This parameter is calculated for Treatments A,BeC.
tmaxo-10 Time of Cmax observed from time zero to 10 hours. This parameter is calculated for Treatments A, B and 'C.
tmax 10-16: Time of Cmax observed from time 10 hours to 16 hours. This parameter is calculated for Treatments A and C.
tmax 16-24: Crax time observed from 16 hours to 24 hours. This parameter is calculated for Treatments A and C.
t j Time of Cmax observed from time 10 hours to 24 max 10-24- to hours. This parameter is calculated for Treatment B only.
11.4.1.2 Areas Under the concentration-time curve The calculation of AUCs is performed using the linear trapezoidal method. AUCo"7 is computed from time of dosing (0) to time of dosing Q (O = 24 h). However, in case the 24-h sample is collected with a time offset, the AUC is estimated on the basis of at the concentration estimated at 24 hours using the regression line calculated from the elimination phase, not the concentration from the actual observation time.
In the case where the last concentration value (Y) is missing or does not correspond to a predicted sampling time (ie 10 hours and 16 hours), AUCx is extrapolated using the corresponding subject elimination phase, if calculable.
The following AUCs are calculated: AUCor: Area under the concentration-time curve for a dose range. This parameter is calculated for Treatments A, B and C. AUCo-10: Area under the concentration-time curve from the moment o BecC.
AUC10-16: Area under the concentration-time curve from 10 hours to 16 hours. This parameter is calculated for AeC Treatments.
AUC16-24: Area under the concentration-time curve from 16 hours to 24 hours. This parameter is calculated for AeC Treatments.
AUC10-24: Area under the concentration-time curve from 10 hours to 24 hours. This parameter is calculated for Treatment B only.
Cavg are calculated as follows: Cava! Mean concentration over the dosing interval, calculated as AUCO.17 (T=24 hours). This parameter is calculated for Treatments A, BeC. calculated as AUCO-10/10. This parameter is calculated for Treatments A, B and C.
Cavg 10-16: Mean concentration from time 10 hours to 16 hours, calculated as AUC10-16/6. This parameter is calculated for Treatments A and C. calculated as AUC15-24/8. This parameter is calculated for Treatments A and C.
Cavg 10-24: Mean concentration from time point 10 hours to 24 hours, calculated as AUC10-24/14. This parameter is calculated for Treatment B only.
11.4.1.3 Mean Drug Concentrations Cavg are calculated as follows: Mean concentration over the dosing interval, calculated as AUCO0.17 (T=24 hours). This parameter is calculated for Treatments A, B and C.
Cavg 0-10º Average concentration from time zero to 10 hours, calculated as AUCO0-10/10. This parameter is calculated for Treatments A, B and CC.
Cavg 10-16: Mean concentration from time 10 hours to 16 hours, calculated as AUC10-16/6. This parameter is calculated for Treatments A and C. Cavg 16-24: Mean concentration from time point 16 to 24 hours, calculated as AUC165-24/8. This parameter is calculated for Treatments A and C. Cavg 10-24: Mean concentration from time point 10 hours to 24 hours, calculated as AUC10-24/14. This parameter is calculated for Treatment B only.
11.4.1.4 Peak-Valley Fluctuation and Peak-Valley Fluctuation Peak-Valley Fluctuation (PTF) and Peak-Valley Fluctuation are calculated as follows: parameter is calculated for Treatments A, B and C. parameter is calculated for Treatments A, B and C.
11.4.1.5 Percent Time Above, Within and Below Reference Range and — Percentage of Subjects With CavQ Above, Within and Below Reference Range The percentage times during which observations fall above (%TimeUp), within (%TimeInside) , and below (%TimeBelow) the computed reference ranges for each subject and treatment for serum Testosterone, Dihydrotestosterone, and Estradiol. The percentage of subjects with Ca' values for serum Testosterone, Dihydrotestosterone and Estradiol above, within, and below their respective reference range is calculated for each treatment. The reference ranges 300ng/dl to 1050 ng/dl for Testosterone, 25.5 ng/dl to 97.8 ng/dl for Dihydrotestosterone and 3 pg/ml to 81 pg/ml for Estradiol. PTS: Oscillation between peak and valley, calculated as (Cmax-Cmin)/Cmin. This parameter is calculated for Treatments A, B and C.
11.4.1.6 Statistical Analysis Only descriptive statistics (N, mean, SD, CV, median, Min., and Max.) are calculated on the serum concentrations and the PK parameters for each treatment. No inferential statistical analysis is performed.
11.4.2 Pharmacokinetic Analysis and Statistical Issues
11.4.2.2 Missing data handling Samples that are not analyzed due to insufficient volume (refer to the bioanalytical report) are recorded as INV (insufficient volume for analysis) in the concentration tables.
These samples are defined as missing for pharmacokinetic and statistical analyses. As PK parameters can be estimated using the remaining data points, Subjects with missing data are kept in the PK analysis.
11.4.2.3 Pharmacokinetic Analysis The following pharmacokinetic parameters are determined for all subjects for Testosterone, Dihydrotestosterone and Estradiol: . For Treatments A and C (three times daily): AUCo-1, AUCo-10, AUC10-16, ! AUC16-24, Cmax, Cmax 0-10, Cmax 10-16, Cmax 16-24, Cmin, Cmin 0-10: Cmin 10-16, Cmin 16-24, Cavg, Cava 0-10: Cavg 10-16, Cavg 16-24, tmax, max 0-10, max 10-16; max 16-24, Imax 10-24, PTF, PTS. For Treatment B (twice daily): AUCo.1, AUCO-10, AUC10-24, Cmax, Cmax 0-10, Cmax 10-24, Cmin, Cmin 0-10, Cmin 10-24, Cava, Cavg 0 -10, Cava 10-24, Imax: imax o-10; max 10-24, PTF, PTS.
Additionally, the percentage of subjects with CawW Values for Serum Testosterone, Dihydrotestosterone, and Estradiol above, within, and below their respective reference range is calculated for each treatment. Thus, the Mean Percent Time of serum Testosterone, Dihydrotestosterone, and Estradiol values above (%TimeUp), within (%TimeInside), and below (%TimeUnder) the corresponding reference range are provided for each treatment. The calculation of all these pharmacokinetic parameters is explained below.
With the exception of Text Tables (numbered 11.4.2.3-1 a
11.4.2.3-3) and Text Figures (numbered 11.4.2.3-1 to 11.4.2.3-3), all tables and figures referenced in this section are displayed in sections 14.2.1 and
14.2.2, respectively. To summarize, TBS-1 treatments are identified —in the statistical report text by their treatment code: A (125 ul of 4% gel given three times daily for a total dose of 30 mg/day), B (150 ul from gel to
4.5% is given twice daily for a total dose of 27.0 mg/day) and C (125 ul of 4.5% gel given three times daily for a total dose of 33.75 mg/day).
Blood samples for pharmacokinetic analysis are collected before and after 2100 hour drug administration on Day 7 at 0.333, 0.667, 1.00,
1.50, 2.00, 3.00, 6.00, 9.00, 9.75, 10.33, 10.66, 11.0, 11.5, 12.0, 13.0, 14.0, 15.75,
16.33, 16.66, 17.0, 17.5, 18.0, 20.0, 22.0, and 24.0 hours for Treatments A and C. Blood samples for pharmacokinetic analysis are collected before and after drug administration from 2100 hours on Day 7 at 0.333, 0.667, 1.00 , 1.50, 2.00,
3.00, 6.00, 9.00, 9.75, 10.33, 10.66, 11.0, 11.5, 12.0, 13.0, 16.0, 19.0, 22.0, and 24.0 — hours for Treatment B. The actual sampling times used for PK calculation are displayed in Tables 14.2.1.22, 14.2.1.23 and 14.2.1.24 for Treatments A, B and C, respectively.
TESTOSTERONE Serum testosterone concentrations measured for each subject at each sampling time are shown in Tables 14.2.1.1, 14.2.1.2 and 14.2.1.3 according to treatment. The plots of individual serum levels over the sampling period are shown using both the linear (a) and semi-log (b) scales in Figures 14.2.2.1 to 14.2.2.22. Lines for the lower limit (300 ng/dL) and upper limit (1050 ng/dL) of the reference range for serum testosterone concentrations are also presented for informational purposes. Thus, a line for the mean drug concentration (Cav9) over the dosing interval (T=24 hours) is also shown in the individual profiles. Plots of mean serum levels over the sampling period are also shown using both the linear (a) and semi-log (b) scales in Figures 14.22.23, 14.22.24 and 14.22.25 for Treatments A, B and C, respectively. Error bars on these mean profiles correspond to one standard deviation. The lines for the lower and upper limit of the reference ranges are also shown in the averages figures. The mean portion on the linear scale for each treatment is also shown below in Text Figure 11.4.2.3.1. Figure 11.4.2.3-1: Mean Serum Testosterone Concentration (ng/dL) - Time Profile for each treatment o TO TBS-1(1254L of 4% gel) (A) soo O TBS-1(150uLdegela4d5%)( B) x —- TBS-1(1254L defrosts45%)(C) í E AN 3 600 ia eo g | Dk & “| Í Re ê 400 DS S and o SN . S 300 —2+ Á o 200 00 20 4o 6.0 8o 10.0 120 140 160 18.0 200 220 24.0 Time (h) Pharmacokinetic parameters calculated for each subject according to treatment are shown in Tables 14.2.1.4, 14.2.1.5 and 14.2.1.6 for Treatments A, B and C, respectively. They are summarized in Text Table 11.4.2.3-1. Table 11.42.3-1: Summary of Testosterone Pharmacokinetic Parameters for Each Treatment Treatment A (N=8) | Treatment B (N=7) | Treatment Cº (N =7) Parameter | Unit [table Tso [ova mess] so | ov% | mea | only young
1210.5) 4451.6| 1581. 1374.0 AUCo-10 h*ng/dL 4178.68 28.97 35.52 |4355.19 31.55 1 4 og 7 in o ss sá nal | 20 [ros art 260 forum o o nalar | neo Do ss 35. EXE
0.27 Tmax-10 h 1.01 0.678 /67.21| 0.695 9 40.18 0.422 [46.62
1062.5 AUC10-16 | h*ng/dL 2635.05 6 40.32 2301.51 |658.44/28.61 in it 23.6 o in [ses 238 noiar the Ao [e] 29 pngidl e of DS 41 e dede 9 63) se o e e re naldr ENNNEIT 43.88 ee | if the e sas Table 11.4.2.3-1: Summary of Testosterone Pharmacokinetic Parameters for Each Treatment Treatment A' (N=8) | Treatment B (N = 7) | Treatment Cº (N = 7) Parameter | SD Unit |CV% SD lCV% SD |CV%
0.67
1083.5 AUC16-24 h*ng/dL| 3016.52 8 35.92 2766.97 [838.13/30.29 nad 8.18 ENNNBEIA 59.20 day 32.08 re ras [6 26.26 nad 29th and de] ss [the 20.2
Maximum 0.404 [248] [=] Joss 0104
3300.6 35324 12650.5| h*ng/dl| 9920.07 Pieces 9781.39 pda 9505.03 tra nom | more ess om THESE nm | as [me less] 22 Jena ese) 25 ora los no | so wing fosz | 408 [147 oem 7»
114.3 108.8 1431 Tmax 4.61 627 | ( | 499 [543 | | 450 [64 ; % % Time Apbai 3447 — | 30.93/89.72 25.9 30.14 | 29.25 97.05 x :
36.40 2 171.22 % % ITempoDent run 65.16 —|30.46/46.75 68.21 |28.77 42.17 231
59.47 Oo 138.84 % : 282.8 157.3 TimeAci % 0.38 1.06 | 166.6) 1.65 | 260 |, ma 4.13 |688 | 7 Pit Below" % 1 (12.50%) 1 1 IN (% of ' OA (14.29%) (14.29%) Subjects)]
Cavg Within 6 6 IN (% of % | 7(87.50%) (85.71%) (85.71%) Subjects)] Ca, Above" o, o, Frights) % O (0%) O (0%) º o ) * Reference range = 300-1050 ng/dL. 1=TBS-1.125 ul 4.0% gel given three times daily (total dose 30 mg/day) 2=TBS-1.150 ul 4.5% gel given twice daily (total dose 27.0 mg/day) 3 = TBS -1, 125 ul 4.5% gel given three times daily (total dose 33.75 mg/day) The percentage times during which observations fall above (%TimeUp), within (%TimeInside), and below (%TimeDown) the reference range are computed for each subject and are presented in Tables
14.2.1.4, 14.2.1.5 and 14.2.1.6 for Treatments A, B and C, respectively. These results are also summarized in Text Table 11.4.2.3.1.
The percentage of subjects with CawK Values for Serum Testosterone above, within, and below the reference range is calculated for each treatment and is shown in Table 14.2.1.7. These results are also summarized in Text Table 11.4.2.3.1.
DI-HYDROTESTOSTERONE Serum concentrations of Dihydrotestosterone are measured for each subject at each sampling time and appear in Tables 14.2.1.8, 14.2.1.9 and 14.2.1.10 according to treatment. The plots of individual serum levels over the sampling period are shown using both the linear (a) and semi-log (b) scales in Figures 14.2.2.26 to 14.2.2.47. Lines for the lower limit (25.5 ng/dL) and upper limit (97.8 ng/dL) of the reference range for serum concentrations of Dihydrotestosterone are also presented for information purposes. Thus, a line for the mean drug concentration (Cava) over the dosing interval (T=24 hours) is also presented in the individual profiles.
The plots of mean serum levels over the sampling period are also presented using both the linear (a) and semi-log (b) scales in Figures 14.2.2.48, 14.22.49 and 14.22.50 for Treatments A, B and C,
respectively.
Error bars on these mean profiles correspond to one standard deviation.
The lines for the lower and upper limit of the reference ranges are also shown in the averages figures.
The average portion on the linear scale for each treatment is also “presented below in Text Figure 11.4.2.3-2. Figure 11.4.2.3-2: Mean serum Dihydrotestosterone concentration (ng/dL) - Time profile for each treatment so -&- TBS-1(125yL defrost4dO0%)(A) ss A and TBS-1(150uL defrost4d5 %) (8) s fose — TBS-1(125pL defrosts4d5%)(C) And so | LADA » E: 'N/ VS ”” 30 e O Pão 20 4th o 8th 10.0 120 14.0 160 180 20.0 220 240 . Time (h) For SAP, AUC, it is calculated based on the estimated concentration (Y) using the regression line calculated from the elimination phase data when the last concentration (Y) does not match a predicted sampling time.
For Subject No. 01002 and 02-007, the elimination phase is not well characterized due to fluctuation in serum Dihydrotestosterone concentration for the 10 to 16 hour and 0 to 10 hour intervals, respectively.
Therefore, AUC10-16 and Cavg 10-16 (derived from aucio-1s) could not be calculated for Subject No. 01-002 for Treatment A (N = 7 for these parameters). Thus, AUCo-10 AND Cavg 010 (derived from AUCo-10) could not be calculated for Subject No. 02-007 for Treatment A (N = 7 for these parameters). Pharmacokinetic parameters calculated for each subject according to treatment are shown in Tables 14.2.1.11, 14.21.12 and 14.2.1.13 for Treatments A, B and C, respectively.
They are summarized in Text Table 11.4.2.3-2. Table 11.4.2.3-2: Summary of Dihydrotestosterone Pharmacokinetic parameters for each treatment rat A' (N = 8) Treatment Bº Treatment C | Table [so| cv | average [so]Joveaalsolev| net nes | ma [and [96 | 008 [17 50 ssa [iss h es PSB | 7 AUC 10-16 3 10 94 2 52/04 echo se aa 5] o e ese | mois ng) 266 jo | ss |. 1. |. agi esizn|
PST ETEININKASPSNNBIDA | Trees | n | one ra deso | |. naphosios eso hay o sele] | | meira ja sa6 lanfao | --| ass and ee | the els 1] | Cau ng o aes rela . | - | | months ns in fotlas - |. -| [atous ma [aa fe ae the guy)
CENSRTEIANINSNNENHO nel | 265 [16] 42 | |. (266 ojos | Pier [nar | 336 [14 42 | |. |. 344/o2/26] [months | no | ne fas] ozz |. |. | msjosa | om rec | sea [ie | 56 | oro [ 2a [56 009 [16 mm] an ret [5 3e [only mo [36fes] ee ogia
| Table 11.4.2.3-2: Summary of Dihydrotestosterone Pharmacokinetic Parameters for Each Treatment Treatment A' (N=8) * |Treatment B /Treatment C (N=7) (N=7) Parameter Unit | table — |spjcvMedalso|cv half so cv
6.0/135 142 4.8 109) 1126 5.1/121 Tmax h 4.43 1 |.63 4 |.53 8 |.44 o AE | - 0 o — o234 080 03/36 ossjor 19 as TE Tas oslao [120061] 150 los 22] * Reference range =
25.5-97.8 ng/dL. 1=TBS-1, 125 uL, 4.0% gel given three times daily (total dose 30 mg/day) 2=TBS-1,150 uL, 4.5% gel given twice daily d total 27.0 mg/day. 35. 1107 30.114 36. 262 (total dose 27.0 mg/day) % 32.64 26.22 13.87 3 = TBS-1, 125 ul, from 13.62 06 |.63 41/41 4.5% gel given three times daily (total dose
33.75 mg/day) a = For these parameters, N = 7 for Treatment A. % TimeUnder"
35.52. 30,140. 36.|42. %TimeInside' % 67.36 13/15 73.78] 96 [74 86.13) 41 | o7
[om [5 [om Eee] 3 1 1 (Down Down* % (37.50 (14.2 (14.2 [IN (% of Subjects))] o %) º %) %) ICavg Within* 5 6 6 [N (% of Subjects)] % (62.50 (85.7 (85.7%)) 1 1 % o%4 Cavg Above* O o O [IN (% of Subjects)]” (0%) (0%) (0%) The percentage times during which observations fall above (%TimeUp), within (%TimeInside), and below (%TimeDown) the reference range are computed for each subject and are presented in the Tables
14.21.11, 14.21.12 and 14.21.13 for Treatments A, B and C, respectively. These results are also summarized in Text Table 11.4.2.3.2.
The percentage of subjects with Cawy Values for Serum Dihydrotestosterone above, within, and below the reference range is calculated for each treatment and is shown in Table 14.2.1.14. These results are also summarized in Text Table 11.4.2.3.2.
Estradiol Serum concentrations of Estradiol are measured for each subject at each sampling time appear in Tables 14.21.15, 14.21.16 and
14.2.1.17 according to treatment. The plots of individual serum levels over the sampling period are shown using both the linear (a) and semi-log (b) scales in Figures 14.2.2.51 to 14.2.2.72. Lines for the lower limit (3 pg/ml) and upper limit (81 pg/ml) of the reference range for serum concentrations of Estradiol are also presented for informational purposes. Thus, a line for the mean drug concentration (Cavg) over the dosing interval (T=24 hours) is also shown in the individual profiles.
The plots of mean serum levels over the sampling period are also presented using both the linear (a) and semi-log (b) scales in Figures 14.2.2.73, 14.22.74 and 14.22.75 for Treatments A, B and C , respectively. Error bars on these mean profiles correspond to one standard deviation. The lines for the lower and upper limit of the reference ranges are also shown in the averages figures.
The mean portion on the linear scale for each treatment is also shown below in Text Figure 11.4.2-3-3.
Figure 11.4.2.3-3: Mean Serum Estradiol Concentration (pg/mL) - Time Profile for each treatment 34 a " TO TO" TeS1(125 4 of 4% gel) (A) AS —O- TBS-1( 1504Ldefrost45%)(B) 301 7 À —k- — TBS-1(125yL of 4.5% gel) (C) z 26 | * Â 3 24 / RA to 3 J Ô eso RS SA, R ô 2» No. 8 so “o 20 40 60 80 100 120 14.0 16.0 180 20.0 220 24.0 Time (h) As for SAP (section 8.3), AUC ,., is calculated based on the estimated concentration (Y) using the regression line calculated from the elimination phase data when the last concentration (Y) does not match a predicted sampling time. However, for some Subjects the elimination phase is not well characterized due to fluctuations in serum Estradiol concentration as follows: * Subject No.: 02-007 for the 0 to 10 hour and 0 to 24 hour Treatment time intervals A. The following PK Parameters could not be calculated for this subject: AUCo-10, Cavg 0-10. AUCo-t, Cavg € PTF for Treatment A (N = 7 for these parameters).
and Subject Nos: 01-002 and 01-007 for the time interval 10 to 16 hours for Treatment A. The AUC10-16 and Cavg 10-16 could not be calculated for these subjects for Treatment A (N = 6 for these parameters).
and Subject No. 02-004 and 02-007 for the time range 16 to 24 hours for Treatment A. The AUC16-24 & Cavg 16.24 could not be calculated for this subject for Treatment A (N = 6 for these parameters).
* Subject to Us. 02-003 and 02-005 for the time interval of 0 to 10 hours for Treatment C. The AUCO io and Cavg 010 could not be calculated for these subjects for Treatment C (N = 5 for these parameters).
Pharmacokinetic parameters calculated for each subject according to treatment are shown in Tables 14.2.1.18, 14.2.1.19 and 14.2.1.20 for Treatments A, B and C, respectively. They are summarized in Text Table 11.4.2.3-3.
Table 11.4.2.3-3: Summary of Estradiol Pharmacokinetic Parameters —for each treatment Treatment A' (N= | Treat: Bº (N= Treatment & &N" is Parameter Unit £ mel 1. 234.9 40.8 26.5 AUCo-10" h*pg /ml 6 95.96 4 242.02 j64.26 5 267.78 175.37) 28.15
36.3 25.2 77 Cmax 0-10 Pg/mL 36.8 [134 3 35.8 9 35.5 5 21.80
36.3 32.6 8.0 ú" ” in >
40.8 26.5 7.5 Sos oro" i palm" 2 4 o
109. 40.8 3.3 Tmax0-10 h 2.62 |2.87 1.49 j0.608 2.68 126.14 67 5 8
144.7 35.6
37.2 8.8 o = By» [ese was E ss | O"
| . 8.6 Cava 10-16 palm | 247 phaco/859 | 2 of 72 Tm > [no je she | | ma bo and | | 27.5 | Aero Team | ass po des) | |
26.7 om | see | |
27.9 Cmin 10-24 pg/ml 15.9 j4.46 5
27.5 SA [| dede | 1
14.0 Tmax 10-24 h 124 |1.74 o ; 153.0 28.0 AUC16-24 h*pg/m 2 42.87 2 177.97 48.79) 27.41
38.2 7.9 Cmax 16-24 Pg/ml 27.2 |104 3 26.9 9 29.74
33.1 5.6 Cnmin 16-24 pg/ml 17.4 |5.75 1 17.0 5 33.28; 28.0 61 Cavg 16-24 pages/mL 191 |5.36 2 22.2 o 27.41
10.0 1.9 Tmax 16-24 h 18.8 1.88 1 18.5 2 10.36 bp 530.2 j196.8/37.1 137.9) 25.6 188.1 AUCor h*pg/ml 537.16 31.26 7 112 9/9 8
35.9 24.0 8.4 gold palm" 2
33.3 28.0 5.6 Cmin pg/mL 16.1 |5.36 1 15.7 |4.40 3 17.0 6 33.28
37.1 25.6 7.8 | Cave” Pomr ">
172. 116. 5.2 Tmax h 413 |7.13 4.51 |5.25 4.88 107.94 74 25 7
36.0 30.2 0.2
35.4 35.8 0.3 % % TimeDown* % % TimeInside * 100.0 or 100.00 100.00 % % Timeup”*
Cavg Below b.* IN (%O0 (0%) O (0%) 0 (0%) Subjects)] Table 11.4.2.3-3: Summary of Estradiol Pharmacokinetic Parameters for Each Treatment ' Treatment B (N = 3 Treatment A (N=8) 7 Treatment C* (N=7) Parameter |Unit | mada [so love] mens [60 fova| mas 159) am Cavg Inside p 7 7 [IN (% of 7 io % (100.00 (100.00 Subjects)] (100.00%) Y%) %) Cavg Above b,* No, INCde | o, (0%) O (0%) O (0%) Subjects)] * Reference range = 3-81 pg/mL. 1=TBS-1, 125 ul 4.0% gel given three times daily (total dose 30 mg/day) 2=TBS-1.150 ul 4.5% gel given twice daily (total dose 27.0 mg/day) 3 = TBS-1, 125 µl. of 4.5% gel given three times daily (total dose 33.75 mg/day) b = For these parameters, N = 7 for Treatment A. c= For these parameters, N = 6 for Treatment A. d = For these parameters, N = 5 for Treatment C.
The percentage times during which observations fall above (%TimeUp), within (%TimeInside), and below (%TimeUnder) the reference range are computed for each subject and are presented in the Tables
14.2.1.18, 14.2.1.19 and 14.2.1.20 for Treatments A, B and C, respectively. These results are also summarized in Text Table 11.4.2.3.3.
The percentage of subjects with Cavg Values for Serum Estradiol above, within, and below the reference range is calculated for each treatment and is shown in Table 14.2.1.21. These results are also summarized in Text Table 11.4.2.3.3.
11.4.2.4 Pharmacodynamic Analysis No pharmacodynamic analysis is planned or performed during this study.
11.4.7 Pharmacokinetic and Statistical Conclusions In this Phase I study, subjects are randomized into three treatment arms (4.0% TBS-1 given three times daily and 4.5% TBS-1 given twice and three times daily). Treatments are administered for one week intranasally, in a parallel project. At the end of one week, the three treatments are compared by conducting a 24-hour pharmacokinetic investigation of the systemic absorption of drug testosterone, and its two physiological metabolites Dihydrotestosterone and Estradiol.
TESTOSTERONE The pharmacokinetic profile of TBS-1 after single and repeated dosing is examined in 2 previous studies (TST-PKP-01-MAT/04 and TST-DF-02-MAT/05). These studies demonstrate that testosterone is well absorbed after intranasal administration. The maximum serum concentration is reached after 1-2 hours post administration. In the current study, Testosterone Formulations (4.0% TBS-1 is administered three times daily and 4.5% TBS-1 is administered two and three times daily) are rapidly absorbed with a peak concentration reached within 36 minutes to 1 hour 6 minutes (Mean Tmax) after intranasal administration. Peak Testosterone concentration over the 24-hour interval is observed during the first administration (0-10 hours) in approximately 57% to 71% of hypogonadal men while approximately 29% to 43% of subjects had their peak testosterone concentration in 24h during subsequent administrations.
When TBS-1 administrations are compared separately for the three times daily treatments, although the mean AUC is similar between formulations, a higher AUC is observed after the first administration compared to the two subsequent administrations (AUCo.10: 4178.68 and 4355.19 h *ng/dL > AUC10-16: 2635.05 and 2301.51 h*ng/dL < AUC16-24: 3016.52 and 2766.97 h*ng/dL for Treatments A and C, respectively). A higher AUC is observed for the second administration when compared to the first administration for Treatment B (AUCo.10: 4451.64 h*ng/dl - AUC10.24<: 5264.19 h*ng/dL). The difference in AUC between administrations for both the three times daily and twice daily formulations may be due to the different time periods elapsed between each administration.
AUCo-, averaged over the 24-hour dosing interval, is comparable across all treatments (AUCo1: 9920.07, 9781.39, and 9505.03 h*ng/dL for Treatments A, B, and C, respectively). Although the mean Crmax is similar between Treatments A and C, a trend towards a decrease in Cmax with subsequent administrations is observed (Cmax o-10: 786 and 857 ng/dL > Cmax 10-16: 698 and 675 ng/dL > Cmax 16-24: 556 and 595 ng/dL for Treatments A and C, respectively). Comparable mean Testosterone Cmax is observed for both Treatment B administrations (Cmax 0-10: 894 ng/dL - Cmax 102: 846 ng/dL). The difference in Cma between administrations for the three times daily formulations may be due to the different time periods that elapse between each administration.
The average Cmax calculated over the 24-hour dosing interval is slightly higher for Treatment B (150uL of 4.5% gel (twice daily)) (Cmax: 1050 ng/dL) compared to Treatments A and C (Cmax : 830 and 883 ng/dL, respectively). The upper limit of the physiological reference range (1050 ng/dL) is exceeded by 1 of 8 Subjects for Treatment A and 3 of 7 Subjects for Treatments B and C.
A trend towards a slight decrease in Ca'wW is observed when administrations are compared separately by treatments three times daily and twice daily (Cavg 010: 418 and 436 ng/dlL > Cavg 10-16: 439 and 384 ng/dL > Cavg 16-24: 377 and 346 ng/dL for Treatments A and C, respectively and Cayg 0-10: 445 ng/dL > Cavg 10-24: 376 ng/dL for Treatment B). The difference in Cay between administrations may be due to the different time periods that elapse between each administration.
The mean Cavg calculated over the 24-hour dosing interval is comparable for all treatments (Cavg: 413, 408, 396 ng/dL for Treatments A, B, and C, respectively). These results suggest a decrease in exposure (AUC, Cavg and Cmax) between each dose for the three times daily administration (Treatments A and C), but not for the twice daily administration (Treatment B). This exposure in exposure for the three times daily administrations can be partially explained by the negative feedback in the endogenous production of Testosterone from the HPG axis. In other words, due to the shorter time intervals between each administration for the three times a day groups, the HPG system's recovery from negative feedback would be less than for the twice daily group. Regardless of formulation, approximately 86%-88% of subjects had a mean drug concentration (Cavwg) within the physiological reference range (300 to 1050 ng/dL), 13%-14% of subjects had a Cavg below the physiologic range. reference and none of the Subjects had a Cayg above the reference range. The period of time during a day (24 hours) by which serum Testosterone concentrations are below, within and above the physiological reference range is covered respectively 30 to 35%, 59% to 68% and 0% of the 24 hour period for all formulations. This means that testosterone levels are within the normal range for about 14 to 16 hours a day. DIHYDROTESTOSTERONE Peak concentration of Dihydrotestosterone is reached within 1 hour 24 minutes and 2 hours 23 minutes (mean Tmax) after TBS-1 administrations.
When TBS-1 administrations are compared separately for the three times daily treatments, although the mean AUC is similar between formulations, a trend towards a decrease in AUC with subsequent administrations is observed (AUCp-10: 345.77 and 411.10 h*ng/ dL > AUC10-16: 186.33 and 222.62 h*ng/dL > AUC 16-24: 269.16 and 275.21 h*ng/dL for Treatments A and C, respectively). Comparable AUC is observed for both Treatment B administrations (AUCo9-10: 402.77 h*ng/dl - AUC10-21<: 543.29 h*ng/dL). The difference in AUC between administrations for the three times daily formulations may be due to the different time periods elapsed between each administration. The mean AUCo-7, calculated over the 24-hour dosing interval, is comparable between all treatments (AUCp-7: 818.95, 946.89 and
909.68 h*ng/dL for Treatments A, B and C, respectively).
Although the mean Cmax is similar between the three times daily formulations, a trend towards a decrease in Cmax with subsequent administrations is observed (Cmax 0-10: 51.4 and 59.0 ng/dL > Cmax 10-16: 44.2 and 48.9 ng/dL > Cmax 16-24:
41.3 and 426 ng/dl for Treatments A and C, respectively). Comparable mean Cma of Testosterone is observed for both Treatment B administrations (Cmax-10: 56.8 ng/dL - Cmax 10-24: 54.6 ng/dL). The difference in Cmax between administrations for the three times daily formulations may be due to the different time periods elapsed between each administration. The mean Cmax is calculated over the 24-hour dosing interval is comparable for all treatments (Cmax: 52.2, 61.0 and 60.3 ng/dL for Treatments A, B and C, respectively). The upper limit of the physiological reference range (97.8 ng/dL) is not exceeded by any subjects for any treatment. The calculated Cavg per administration are comparable between treatments and administrations (Cavg o-10: 34.6 and 41.1 ng/dL > Cavg 10-16: 31.1 and 37.1 ng/dL > Cavg 1624: 33.6 and 34.4 ng/dL for Treatments A and C , respectively and Cayg 0-10º
40.3 ng/dl>Cavg 10-24: 38.8 ng/dl for Treatment B). The mean Cavg calculated over the 24-hour dosing interval is comparable for all treatments (Caw: 34.1, 39.5, 37.9 ng/dl for Treatments A, B, and C, respectively).
Approximately 63% of subjects had their Cayvg included in the physiological reference range for DHT (25.5 to 97.8 ng/dL) after administration of Treatment A, with this number rising to about 86% when Treatments B and C are administered. No subjects had their Cavwg above the normal range while 38% and 14% of the subjects had their Cavg below the normal range for Treatment A and both Treatments B and C, respectively.
The period of time during a day (24 hours) by which serum DHT concentrations are below, within and above the physiological reference range is covered respectively 32.64%, 67.36% and 0% for Treatment A, 26.22%,
73.78% and 0% for Treatment B and 13.87%, 86.13% and 0% for Treatment C. This means that DHT levels are within the normal range for about 16, 18, and 21 hours a day for Treatments A, B, and C, respectively.
Estradiol Peak Estradiol concentration is reached within 1 hour 12 minutes and 2 hours 41 minutes (Mean Tmax) after TBS-1 administrations.
When TBS-1 administrations are compared separately for the three times daily treatments, although the mean AUC is similar between formulations, a trend towards a decrease in AUC with subsequent administrations is observed (AUCo10: 234.96 and 267.78 h*pg/ml > AUC10-16: 144.76 and 144.30 h*pg/ml < AUC16-24: 153.02 and 177.97 h*pg/ml for Treatments A and C,
respectively). Comparable AUC is observed for both Treatment B administrations (AUCo1o: 242.02 h*pguml - AUC10-2<: 295.12 h*pg/ml). The difference in AUC between administrations for the three times daily formulations may be due to the different time periods elapsed between each administration. AUCo., averaged over the 24-hour dosing interval, is comparable across all treatments (AUCo-7: 530.27, 537.16, and 601.91 h*pg/mL for Treatments A, B, and C, respectively). Although the mean Cmax is similar between the three times daily formulations, a trend towards a decrease in Cha with subsequent administrations is observed (Cmax10: 36.8 and 35.5 pg/ml > Cmax 10-16: 28.9 and 31.5 pg/ml > Cmax 16-24:
27.2 and 26.9 pgml for Treatments A and C, respectively). Comparable mean Testosterone Cmax is observed for both Treatment B administrations (Cmax0-10: 35.8 pg/mL - Cmax 10-24: 30.6 pg/mL). The difference in Crmax between administrations for the three times daily formulations may be due to the different time periods elapsed between each administration. The mean Cmax calculated over the 24-hour dosing interval is comparable for all treatments (cmax 37.9, 36.2 and 36.4 pg/mL for Treatments A, B and C, respectively). The upper limit of the physiological reference range (81 pg/ml) is not exceeded by any subjects for any treatment. and Cavg calculated by administration are comparable between treatments and administrations (Cavg o-10: 23.5 and 26.8 pg/ml > Cavg 10-16: 24.1 and 24.0 pgml > Cav 16-24: 19.1 and 22.2 pg/ml for Treatments A and C , respectively and Cayg o-10: 24.2 pg/ml. > Cavg 10-24: 21.1 pg/ml for Treatment B). The mean Cavg calculated over the 24-hour dosing interval is comparable for all treatments (Cavg: 22.1, 22.4, 25.1 pg/mL for Treatments A, B and C, respectively). All subjects had their CawK included in the physiological reference range for E, (3 to 81 pg/mL) after administration of all treatments. All subjects have E concentrations within the normal range over the 24-hour period. None of the Subjects have E> levels below or above the normal range at any time of day.
12. Security Assessment
12.1 Extent of exposure Subjects use the drug for 7 days in two locations and 8 days in another.
12.2 Adverse Events
12.2.1 Brief Summary of Adverse Events There are eight adverse events that occurred in six subjects. Six of the events occurred during Treatment A and two during Treatment B. Subjects 01-002 and 01-007 both experienced vertigo and both are indicated as possibly related to the study drug. Subject 01-002 had moderate severity that resolved after 5 days. Seven of the 8 adverse events are mild.
Six of the8 events are unrelated to the study drug.
Individual 02-004 is classified as having anemia by the investigator. Hemoglobin is at the lowest normal level and is considered drug related. Table 12.2.2 summarizes the events.
o C ç e E RN sl ss ee ã = E o co = = = o ie ES o SS ST TS — > = oo - - - oo S = = = Ty x SS oO o oO oO oO o Oo E = — T = = = = 6 oooooooo Es Es Es sy and ES se OD co x mo a Ps DD bx Vu o 3 SF 2 ST NY Ss 7 vo oooooooo sm Ss x 7 g ST Y ST TEE oooooooos so sa s Ss ss N a N o cN o oN and uu uu - lEgjl=8| 8 8 8 8 3 : S 2 22/23 ,2 2 É 08 22 oê o =| Ss = the Sm So | 2S|/2S 25 285/25 28/28 Es />2/ 329/2282 / 29 /22/2 o) 20) 20 é [6 4 4 4 5 4 Sd LO OO wu E) Wu wW E) WU x ox ox — — [A — x — yy ERAS: 8 go seeee &) W= Wu uu uu uu uu uu un Uu Cs o — — = — — — — s| & Ss oo = 4 = É 38 S ú 8 Ss 3 and l SS 8 S 8) & =) a '&$ S$ssg|) 24 E = f= s Ss = = o O FE = = uv = =/, o E PS o 8 & = É E ie Ss IF = s SEO o E DvD & C Õ ol” mo: ao É > > <q S & 8/6 $$ |) SS = o E o ui wW| if the s are | 8 8 O o [e 3 Ss a = o o o o o o o o bs Oo mm mm Pe Oo o >=
PO FC N o o rm = o o o = o O) = Oo o oO o o o o o O o o o o 2) ST Ss SF Q RT S Ss ST E a = = = NaN o o o o o o O —- [2] o o o f= o o o o o
NS sl a = sl Ss Ss Ç- & < < < «< < < =
And FO
12.24 Listing of adverse events by Subjects
Table 12.2.2 list of adverse events by subject.
12.3 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events There are no deaths, other serious adverse events, or other significant adverse events during the course of this study.
12.4.2 Assessment of Each Laboratory Parameter There are no clinically significant changes in laboratory values throughout the study as determined by the principal investigators. All subjects had some abnormal values at the initial visit and/or at the third visit. There are no consistent changes across visits.
Subject 01-007 had a uric acid level of 539 U/L with 289 as the upper limit of normal from the third visit. There are elevated glucose values in about half of the subjects compared to a normal first visit value. This occurred over all three dosages and is only slightly elevated. There is no clinical relevance.
12.5 Vital Signs, Physical Findings, and Other Safety-Related Observations There are no significant or significant changes in vital signs after administration of the test drug.
12.6 Safety Conclusions The TBS-1 Gel demonstrates in this and other studies that it is safe to use. There are no serious adverse events or any consequential events during this PK study or during the seven-day self-administration. Tables
14.3.2.1 to 143.2.8 show all laboratory values for visit 1 and visit 3.
13. Discussion and General Conclusions The primary objective of this study is to determine the bioavailability of a 4.0% TBS-1 Gel (applied three times a day) and a 4.5% TBS-1 Gel (applied twice a day and three times per day) in hypogonadal men.
In a previous study, Nasobol-01-2009, a 3.2% testosterone gel is used to deliver 4.0mg, 5.5mg and 7.0mg of testosterone intranasally using gel volumes of 125ul, 172ul and 219ul respectively . In this study, 5.0 mg, 5.65 mg, and 6.75 mg of testosterone are administered in gel volumes of 125 μl, 125 μl, and 150 μl, respectively. This study allowed us to investigate the delivery of similar amounts of Testosterone in — much smaller volumes.
The secondary objective of this study is to establish a safety profile for TBS-1. In this Phase II study, subjects are randomized into three treatment arms (4.0% TBS-1 given three times daily and 4.5% TBS-1 given twice and three times daily). Treatments are administered for one week intranasally, in a parallel project. At the end of one week, the three treatments are compared by conducting a 24-hour pharmacokinetic investigation of the systemic absorption of drug testosterone, and its two physiological metabolites Dihydrotestosterone and Estradiol. There are eight adverse events described by six subjects. Six of the events occurred during Treatment A and two occurred during Treatment B. Subjects 01-002 and 01-007 both experienced vertigo and both are indicated as possibly related to the study drug. The remainder are unrelated to the study drug. There are no vital signs or laboratory changes that are significant or significant. Erythrocytosis, anemia, or infections are not seen measuring complete blood counts at screening and closure. Clinical chemistry and urinalysis showed no changes in closure in hypo or hyperglycemia, renal function, liver function, skeletal/cardiac muscle damage, or changes in calcium homeostasis. There are no clinically significant changes to the nasal mucosa. The PK population is defined as subjects who received treatment A, B or C, and who completed the study without major protocol violations or for whom the PK profile can be adequately characterized. The PK population is used for the analysis of PK data. Based on these Criteria, Twenty-two (22) subjects are included in the PK population.
TESTOSTERONE The pharmacokinetic profile of TBS-1 after single and repeated dosing is examined in 2 previous studies (TST-PKP-O01—MAT/04 and TST-DF-02-MAT/05). These studies demonstrate that testosterone is well absorbed after intranasal administration. The maximum serum concentration is reached after 1-2 hours post administration. In the current study, Testosterone Formulations (4.0% TBS-1 given three times daily and 4.5% TBS-1 given twice and three times daily) are rapidly absorbed with a peak concentration reached within 36 minutes at 1 hour 6 minutes (mean Tmax) after intranasal administration. The maximum concentration of Testosterone over the 24-hour interval is observed during the first administration (0-10 hours)
in approximately 57% to 71% of hypogonadal men while approximately 29% to 43% of subjects had their maximum 24-hour testosterone concentration during subsequent administrations.
When TBS-1 administrations are compared separately for the three times daily treatments, although the mean AUC is similar between formulations, a higher AUC is observed after the first administration compared to the two subsequent administrations (AUCp-10: 4178.68 and 4355.19 h* ng/dL > AUC10-16: 2635.05 and 2301.51 h*ng/dl < AUC16-24: 3016.52 and 2766.97 h*ng/dL for Treatments A and C, respectively). A higher AUC is observed for the second administration when compared to the first administration for Treatment B (AUCp.10: 4451.64 h*ng/dl - AUC10-24: 5264.19 h*ng/dL). The difference in AUC between administrations for both the three times daily and twice daily formulations may be due to the different time periods elapsed between each administration.
The mean AUCo.7 calculated over the 24-hour dosing interval is comparable across all treatments (AUCo9-7: 9920.07, 9781.39 and 9505.03 h*ng/dl for Treatments A, B and C, respectively). When TBS-1 administrations are compared separately for the three times daily treatments. Although the mean Cma is similar between formulations, a trend towards a decrease in Cma with subsequent administrations is observed (Cmax 0-10: 786 and 857 ng/ dlL > Cmax 10-16: 6898 and 675 ng/dl > Cmax 16-24: 556 and 595 ng/dL for Treatments A and C, respectively). Comparable mean Testosterone Cmax is observed for both Treatment B administrations (Cmax 0-10: 894 ng/dlL - Cmax 10-24: 846 ng/dL). The difference in Cma between administrations for the three times daily formulations may be due to the different time periods elapsed between each administration.
The average Cmax calculated over the 24-hour dosing interval is slightly higher for Treatment B (150 µl of 4.5% gel (twice daily)) (Cmax: 1050 ng/dL) compared to Treatments A and C ( Cmax: 830 and 883 ng/dLl, respectively). The upper limit of the physiological reference range (1050 ng/dL) is exceeded by 1 of 8 Subjects for Treatment A and 3 of 7 Subjects for Treatments B and C.
A trend towards a slight decrease in Ca is observed when administrations are compared separately by treatments three times daily and twice daily (Cavg 010: 418 and 436 ng/dL > Cavg 10-16: 439 and 384 ng/dL > Cavg 16 -24: 377 and 346 ng/dL for Treatments A and C, respectively, and Cayg 0-10:
445 ng/dL > Cavg 10-24: 376 ng/dL for Treatment B). The difference in Caw between administrations may be due to different time periods elapsed between each administration.
The mean Ca calculated over the 24-hour dosing interval is comparable for all treatments (Cavg: 413, 408, 396 ng/dLl for Treatments A, B, and C, respectively). These results suggest a decrease in exposure (AUC, Cavg and Cma) between each dose for the three times daily administration (Treatments A and C), but not for the twice daily administration (Treatment B). This exposure in exposure for the three times daily administrations can be partially explained by the negative feedback in the endogenous production of Testosterone from the HPG axis.
In other words, due to the shorter time intervals between each administration for the three times a day groups, the HPG system's recovery from negative feedback would be less than for the twice daily group.
Regardless of formulation, approximately 86%-88% of subjects had a mean drug concentration (Ca) within the physiological reference range (300 to 1050 ng/dL), 13%-14% of subjects had a Cavg below the physiologic range. reference and none of the Subjects had a Cayg above the reference range.
The period of time during a day (24 hours) by which serum Testosterone concentrations are below, within and above the physiological reference range covered respectively 30 to 35%, 59% to 68% and 0% of the 24 hour period for all the formulations.
This means that testosterone levels are within the normal range for about 14 to 16 hours a day.
DIHYDROTESTOSTERONE Peak concentration of Dihydrotestosterone is reached within 1 hour 24 minutes and 2 hours 23 minutes (mean Tmax) after TBS-1 administrations. When TBS-1 administrations are compared separately for the three times daily treatments, although the mean AUC is similar between formulations, a trend towards a decrease in AUC with subsequent administrations is observed (AUCp5-10: 345.77 and 411.10 h*ng /dL > AUC10-16: 186.33 and 222.62 h*ng/dL > AUC16-24: 269.16 and 275.21 h*ng/dL for Treatments A and C, respectively). Comparable AUC is observed for both Treatment B administrations (AUCo-10: 402.77 h*ng/dl - AUC10-24: 543.29 h*ngldL). The difference in AUC between administrations for the three times daily formulations may be due to the different time periods elapsed between each administration.
The mean AUC.7 calculated over the 24-hour dosing interval is comparable across all treatments (AUCp.7: 818.95, 946.89 and 909.68 h*ng/dL for Treatments A, B, and C, respectively). Although the mean Cmax is similar between the three times daily formulations, a trend towards a decrease in Crma with subsequent administrations is observed (Cmax-10: 51.4 and 59.0 ng/dL > Cmax 10-16: 44.2 and 48.9 ng/dl > Cmax 16-24:
41.3 and 426 ngldl for Treatments A and C, respectively). Comparable mean Testosterone Chma is observed for both Treatment B administrations (Cmax 0-10: 56.8 ng/dL - Cmax 10-24: 54.6 ng/dL). The difference in Cmax between administrations for the three times daily formulations may be due to the different time periods elapsed between each administration. The mean Cmax calculated over the 24-hour dosing interval is comparable for all treatments (Cmax: 52.2, 61.0 and 60.3 ng/dL for Treatments A, B and C, respectively). The upper limit of the physiological reference range (97.8 ng/dL) is not exceeded by any subjects for any treatment.
The calculated Cavg per administration are comparable between treatments and administrations (Cavg 0-10: 34.6 and 41.1 ng/dl > Cavg 10-16: 31.1 and 37.1 ng/dL > Cavg 1624: 33.6 and 34.4 ng/dL for Treatments A and C , respectively and Cavg 0-10: 40.3 ng/dL > Cavg 10-24: 38.8 ng/dL for Treatment B). The mean Cavg calculated over the 24-hour dosing interval is comparable for all treatments (Car 34.1,39.5, 37.9 ng/dL for Treatments A, B, and C, respectively).
Approximately 63% of subjects had their Caw within the physiological reference range for DHT (25.5 to 97.8 ng/dLl) after administration of Treatment A, with this number rising to about 86% when Treatments B and C are administered. No subjects had their Cavyg above the normal range while 38% and 14% of the subjects had their Cavg below the normal range for Treatment A and both Treatments B and C, respectively.
The period of time during a day (24 hours) by which serum DHT concentrations are below, within and above the physiological reference range covered 32.64%, 67.36% and 0% for Treatment A, 26.22%, 73.78% and 0% respectively for Treatment B and 13.87%, 86.13% and 0% for Treatment C. This means that DHT levels are within the normal range for about 16, 18 and 21 hours a day for Treatments A, B and C, respectively.
Estradiol Peak Estradiol concentration is reached within 1 hour 12 —minutose2 hours41 minutes (mean Tmax) after TBS-1 administrations.
When TBS-1 administrations are compared separately for the three times daily treatments, although the mean AUC is similar between formulations, a trend towards a decrease in AUC with subsequent administrations is observed (AUCp-10: 234.96 and 267.78 h*pg/ mL > AUC10-16: 144.76 and 144.30 h*pg/uml < AUC16-24: 153.02 and 177.97 h*pg/ml for Treatments A and C, respectively). Comparable AUC is observed for both Treatment B administrations (AUCo.-10: 242.02 h*pg/ml. - AUC10.-2<: 295.12 h*pg/ml). The difference in AUC between administrations for the three times daily formulations may be due to the different time periods elapsed between each administration. The mean AUC".7 calculated over the 24-hour dosing interval is comparable between all treatments (AUCo-7: 530.27, 537.16, and 601.91 h*pg/mL for Treatments A, B, and C, respectively).
Although the mean Crax is similar between the three times daily formulations, a trend towards a decrease in Crma with subsequent administrations is observed (Cmax-10: 36.8 and 35.5 pg/ml > Cmax 10-16: 28.9 and 31.5 pg/ ml. > Cmax 16-24:
27.2 and 26.9 pgml for Treatments A and C, respectively). Comparable mean Cma of Testosterone is observed for both Treatment B administrations (Cmax 0-10: 35.8 pg/mL - Cmax 10-24: 30.6 pg/mL). The difference in Cmax | between administrations for the three times daily formulations may be due to the different time periods elapsed between each administration. The mean Cmax calculated over the 24-hour dosing interval is comparable for all treatments (Cmax: 37.9, 36.2 and 36.4 pg/mL for Treatments A, B and C, respectively). The upper limit of the physiological reference range (81 pg/ml) is not exceeded by any subjects for any treatment.
The calculated Cavg per administration are comparable between treatments and administrations (Cavg 0-10: 23.5 and 26.8 pg/ml > Cavg 10-16: 24.1 and 24.0 pg/ml > Cavg 16-24: 19.1 and 22.2 pg/ml for Treatments A and C, respectively and Cayg 0-10: 24.2 pg/ml > Cavg 10-24: 21.1 pg/ml for Treatment B). The mean Cavg calculated over the 24-hour dosing interval is comparable for all treatments (Ca: 22.1, 224, 251 pgml for Treatments A, B and C, respectively).
All subjects had their Caw included in the physiological reference range for E; (3 to 81 pg/ml) after administration of all treatments. all subjects had E concentrations within the normal range over the 24-hour period. None of the Subjects had Ez levels below or above the normal range at any time during the day.
CONCLUSIONS The TBS-1 formulations (4.0% TBS-1 Gel (applied three times a day) and 4.5% TBS-1 Gel (applied twice a day and three times a day)) are rapidly absorbed with a peak of Average Testosterone Observed Within 1 Hour Overall, Testosterone exposure (AUCo-7 & CmaJ at steady state is comparable across all treatments. Regardless of formulation, approximately 86%-88% of subjects had a drug concentration of Testosterone mean (Cavg) within the physiological reference range (300 to 1050 ng/dL) Testosterone levels are within the normal range for about 14 to 16 hours per day TBS-1 is safe for intrasanal administration at the indicated dosages and frequency There are no adverse events, changes in vital signs or changes—in laboratory results significant when compared to baseline. Based on these results, no clear evidence is found to indicate better performance of one of the formulations. TBS1A Report for 4% and 8% Gel Bulk Purpose: To follow IMP-Clinical Batch Manufacturing. The main points concern process flow and bulk appearance in stability. * —Improved process flow * — Bulk Gel Viscosity * —Stability (recrystallization) * — Evaluation of alternating grades and material sources * — In Vivo results, formulation changes to impact onset of release * —Test assays using Cell Franz, test selection List of raw materials identified for use in tests:
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5630 Rossa phase ame and the fame fe | fre esse fama fo [re were fame fm giga oeioo Super retneso |âmesta Jemãs | Proquina Non-Micronized Testosterone Equipment used: In addition to the Silverson high shear mixer, used only during the manufacture of the TBS1A IMP Clinical Lots, a propellant-type mixing unit is also included for testing in various pre-mix operations. The only application for the high shear action is for dispersing the active substances in co-solvents.
For more uniform mixing and temperature control, a jacketed pan with cleaning blades is recommended to remove material from the inside wall of the pan (especially critical for uniform bulk temperature during heating as well as cooling cycles). IMP Bath Manufacturing General Information Note During Batch Manufacturing Clinical IMP included high viscosity during premix preparation of the DMI/Transcutol co-solvent blend consisting of PVP K17/S640, Klucel HF and micronized Testosterone.
Mixture resulting in a sticky mass when added to Castor Oil using high shear mixer equipment.
With the same high-shear mixer equipment for the addition of Cab-O-Sil (hereinafter referred to as SiO>») it was not possible to obtain a vortex to incorporate the material and additional manual mixing was required during the addition stage, hence the recommendation for propeller-type mixing unit.
Although the material was sticky during that addition stage, on further mixing the viscosity of the final bulk Gel dropped to approximately 1,500 - 2,000 cps.
Mixing time and speed had to be controlled so as not to exceed the target gel temperature (no cooling system). Test design: Initial tests (Placebo) focused on changing the order of addition to identify impact on viscosity.
Previous process included the addition of SiO, in the final stage (see comments above), changed to SiO dispersion, to Castor Oil before addition of the alternating active mixture.
The resulting viscosity of the Castor Oil/SiO mixture, using various percentages, increased with the addition of a small percentage of Arlasolve (DMI). Next step was to duplicate these results using the active mixture (Co-solvents/PVP/HPC/active substance) and add that mixture to the Castor Oil and SiO> premix. This however, resulted in a low viscosity solution, indicating an impact of the active mixture on the formation of a viscous gel.
Since the co-solvent mixture without additional materials resulted in an increase in viscosity, the solvent amounts were divided into two parts, adding part of the solvent mixture only to the oil mixture and the remaining solvent mixture used to disperse the PVPs. , HPC and active.
The active mix with the reduced co-solvent turned out more viscous, in addition to having similar low viscosity when added to the castor oil premix.
Additional tests included the preparation of active in only DMI (in PVP) and obtained good viscosity.
HPC was prepared separately in Transcutol P,
creating stringing problems when added to the mix (similar to IMP observations). Addition of SIiO; at a level of 0.1 - 0.3% solved the problem.
The above process for dissolving active in the co-solvents is sufficient and does not need PVP to increase the solubility for the 4% formulation, however, not enough co-solvents in the formulation to achieve the solubility to 8% potency. Trials at 8% included a successful alternative approach to preparing the active dispersion containing PVP by adding SiO7s to that mixture.
As demonstrated in the evaluation tests evaluating the impact of SiO, added to DMI as well as Transcutol P resulted in good viscosity forming with DMI, however, not with Transcutol.
Active dispersion, therefore, is prepared by dissolving the PVP in DMI only, followed by addition of the active substance at 55C (50-60C) and portion of SiO, available. - Important to note that this process was only developed during test work at 8%, so it can be reduced to a potency of 4% if PVP indicates additional functionality (Franz's Cell Test). Comments regarding the addition of purified water (noted in Table xxx) indicate an increase in viscosity with tests containing HPC, no increase in viscosity in tests using only PVP.
These tests were only included for information to study water absorption and impact on viscosity after application to the nasal cavity.
Critical step during establishment of HPC is to provide at least 24 hours of solvation to obtain a clear solution.
As outlined in the test objectives, formulation ratios were implemented using also alternative grades and sources of materials and are identified in the formulation table.
To identify the impact of process change (such as viscosity-increasing reaction by adding the co-solvents), trials were performed to study impact whether related to DMI or Transcutol P.
Trials were started to disperse SiO2z (at the same rate as used for the Castor Oil blend) and DMI only, as well as in Transcutol P only.
Mixing with DMI resulted in a viscous mix, whereas Transcutol P mix was very fluid.
Similar Trials were initiated to utilize the co-solvents individually to study the Polymers' solubility as well as the active substance for potential reduction in Transcutol P.
No noticeable difference in solubility using the mixture or individual solvents at 4% potency.
However, if PVP and HPC are only prepared in DMI, separation of the two materials was observed when stored overnight (not apparent when mixed in the co-solvent mixture). To eliminate the tackiness of the dispersion when adding the active ingredient/polymer mixture, the HPC was removed from the formulation and using PVP only (individual grades K17-K29/32-K90, no mixtures). This resulted in various viscosity grades related to the grade used. Material also included the use of Labrafil M 1944 CS and is outlined in the batch description and selected for testing in the Franz Cell.
Comments: The various assays are described below for 4% as well as 8% potency. Assay lots of both potencies were selected for testing in . Franz's cell. Selected batches are identified.
All assays will be monitored for physical evidence of recrystallization and change in Appearance (separation), tested for change in viscosity. Test viscosity values will be documented and updated.
Pending Franz Cell result evaluation, formulation and process optimization can be implemented. This is critical to identify as the test design does not include impact on viscosity with respect to all process parameters (needs to include analytical testing and stability data).
Observations during viscosity testing using the Model DV-Il+ —Brookfield viscometer, with Spindle 6, at 50 mm for 30 seconds, actually showed an increase in viscosity values over the test time in samples prepared with HPC grade high viscosity. This can be attributed to the stickiness of the gel causing agglomeration to the rod and Spindle disc creating drag (not a true viscosity value of the reported results). The Bulk Gel from various assays is not thixotropic. Also tested in some tests, viscosity at 37°C.
Several assays were tested using the new Haupt method with Spindle 4 a6rpm. The various attached tables show the test numbers for Gels, Pre-Mixes and Active Placebos.
Discussion and Considerations for Follow-Up Trials with Both Potencies Although “viscosity improvement” was not the primary target for initiating trials, it was certainly an effort designed to study the cause of low viscosity considering the high percentage of SiO present in the formulation. A cross-check for alternative SiO source comparison did not indicate major differences, nor various Co-solvent ratios, limited fit as a certain percentage needed to dissolve Testosterone. Changes in PVP grades indicate an impact on viscosity when used in the active dispersion, however not when added to the rest of the mix. Changes in grades of HPC (alternative used thin material source) showed impact on — —Gelfinal, however, higher molecular weight of HPC, tackiness impact and stringing in final Gel. Viscosity testing after several weeks showed a - separation in the Viscose Settling Gel at the bottom of the container.
With SiO indication, retaining Testosterone, adding more to increase viscosity was not an option, the goal was to reduce the % used. Especially for the 4% power TBS1IA. which indicated a much higher percentage of retained T compared to 8% TBS1A. The aim was at least to obtain the same ratio of SiO,> to T from the 8% power to the 4% power (thus aimed at reducing to 3%). With trials complete and showing impact on process-related viscosity and formulation changes, a reduction in SiO; to the definitely possible for the 4% potency they could also include the use of PVP in the formulation when taking advantage of the process change at the 8% potency. Above is based on viscosity only; however, impact of formulation changes to slow the initial absorption rate in vivo can only be assessed from the data obtained in the assays used for the analytical test using the Franz Cell. These results will be reviewed and evaluated with possible recommendations for additional testing or for duplicating previous or DOE-based trials.
The attached tables for viscosity show the date of manufacture and latest test results (to aid test selection in the Franz Cell). In the Comment column, original data will be referenced or referenced in the description of the test process.
Further evaluation of alternative source material is recommended as a primary formulation and process for each potency has been established for direct comparison. TBS1A formulation/composition - 4% Table 1A (See formulations in Examples above and including Example 10) SiO2 % Substance Number | Transcut Grade Oil| HPC C=Cabosil , . the Labrafil %DMI%. . active assay % castor PVP% olP% | In that% | A=Aerosil 200 RD11037 K17 =3 ' 52 000000 5630 = | 25 0000000 | C=4 2 RD11038 4 K17 =3 57 000000 5630 = | 20 0000000 | C=4 2 RD11039 K17=3 29 29 5630 = | 20 10 0000000 |C=3 2 RD11040 4 25 10 57 0000000 | 000000 6+4 00000000 | C = 4 o RD11041 4 K17=3|25 10 53 0000000 | 5630 = 6+4 0000000 |C=3 2 RD11042 4 25 10 29 29 000000 6+4 000000 |C=3 00 (split) RD11050 4 24
66.7 000000 K17=3)20+4 | 0000000 | N-H=0.3/A=2
1% RD11050A |4 24" additional to 11050 667 000000 |Ki7T=3|20+4 | 0000000 N-H=03|2 RD11051 |a 24
66.7 000000 |K30=3/20+4 | 0000000! N-M=0.3/A=2
66.7 Joooooo |K3o=3 0000000 | NM = 0.3/ 1 % RD11051A |, 24 additional 20+4 to 11051 i inal RD11053 4 22 617 lonoooo |K17=3/18*86 16 NH=0.3/A=3 4+2 RD11054 4 23 614 Joooooo IK3o=3 /16+7 |5 A=3 41 RD11055 —|4 23 620 ooo |Kso=3|16+7 |5 0000000 |C=3 4+1 RD110568 4 28
62.0 /000000 |Kg0=3/20+8 00000 |0000000 |c=3 Rp11059 of 75.0 Joooooo |K30= |1, > 0000000 |C=2.5
2.5 10+4 RD11060 4 18
71.5 000000 K30= j|9+9 1 00000000 | C=3.5
2.0 RD11061 4
71.0 2 Ki7=2 2 0000000 | C=3 RD11062 SO 22 6 4 62.35 | 0000000 | K30=1. |6+16 2+4 N-H= A=3 - o 0.15 RD11063 4 KI7=1. | 48
FR K30=1. 0000000
70.5 0000000 5 6+12 o NH=0.2] A=4 Lo dd dd RD11064 Transfer Adici Increase Formula of onar o n to include RD1106 0.3% jviscosida HPC 2 of H20 RD11065 Transfer Adici Increase Formula of onar n to include RD1106 0.3% qiscosidad HPC 3 de e H20 RD11066 Transfer Adici None NONE going to increase HPC RD1104 0.3% in 1 viscosidad H20 de
RD11070 Transfer Adici None NO increase onar increase HPC RD1103 0.38% |na 7 viscoside H20 from RD11071 Transfer Addici None NO increase onar increase HPC RD1104 0.3% |na 2 viscoside H20 from RD11072 | Transfer Add None NONE go of onar increase HPC ' RD1104 0.3% | no of viscoside H20 of RD11073 16 4 70.5 | 000000 [9% | 10+6 ix, A=3 000 (3) NM=0.5 (0.25) RD11074 Transfer Add Transfer Add 0.3% RD1107 0.3% RD110 H20 RD11075 16 See HPC (base) 6+10 pre- 4 68.0 000000 ms 0000000 | mixtures | A=3 RD11076 Addition Base RD11075 RD11067
RD11077 Addition Base RD11075 RD11068 RD11078 Addition Base RD11075 RD11069 RD11079 Transfer Adici Form of onar to include RD1107 0.3% HPC 6 of H20 RD11080 Transfer Adici Form of onar to include RD1107 0.3% HPC 7 of H20 RD11081 Transfer Adici Form onar a includes RD1107 0.3% HPC 8 of H20 RD11082 10 See See 0000 See RD1107 | RD110
81.0 000000 000 RD110| 3(3 73 00000000 73(3 (0.25) RD11085 |4 16 N-L =0.2 0000 10+6 N-M =0.3
70.7 000000 A=2.8 000
RD11086 4 16 N-L =0.2 Add 707 cogo00 0000 10+6 N-M =0.3 A=28
0.3% of '000 H20 Batch % RD11037 IMP Batch Process Duplication (4%) without HPC. K1i7 and S630 dissolved in DMI/Transcutol mixture followed by addition of active substance. Clear solution. Pre-heated castor oil added to the above active mixture. Clear solution observed. Followed with the addition of low-shear Cabosil. Viscosity at the time of manufacture 500 cps, followed by testing after 48 hours resulted in 620 cps. - Lower viscosity primarily due to absent HPC (note that 4% IMP had approximately 1,500 cps) - 10 Lot % RD11038 Change in order of addition using same formulation with a reduction of DMI/Transcutol and adjusted with castor oil. Cabosil was mixed with castor oil to give a clear viscous solution. The active mixture was prepared as per RD11037. Castor Oil/Cabosil Blend Viscosity changed to 1180 cps (expected high viscosity based on addition of Co-Solvents during Placebo Assays). Potential impact of PVP and active substance of the solvent mixture. Batch % RD11039 Duplicate performance based on Placebo mix also containing Labrafil in castor oil plus Cabosil (for IP). Same low viscosity reaction when adding active mixture. Batch % RD11040 Duplicate Placebo Process by adding to the Castor Oil/Cabosil Blend a portion of the co-solvent DMI/Transcutol P blend. Viscosity of oil mixture increased. Prepared the active blend with the remaining co-solvents without the PVP and added to the oil blend. Final Gel Viscosity in bulk was 10,400 cps. Potential for F/C . Batch % RD11041 Process was repeated as for RD11040 including PVP K17 and S630 with active mixture and viscosity was reduced to 500 cps (increased to
1,500 cps after 3 weeks). Clear indication of impact of PVP on viscosity reduction using K17 and S630. Lot t% RD11042 Repeat test with Castor Oil/Labrafil addition as for RD11037, and reduced Cabosil, with active co-solvent mixture but no PVP.
Viscosity of 1,750 cps The following tests are designed to identify shift impact at higher grades of PVP as well as an alternate source of HPC (2 grades). Premixes were made as outlined in Table 3 by concentrating on the blends without Labrafil using Native Castor Oil and Aerosil 200. Lot tt RD11050 Castor Oil and Aerosil 200 dispersion (pre-blend |) was prepared and viscosity increased by adding part of the DMI (4%). The preparation of active-mixture uses the premix of RD11047A (PVP K17-3%) in DMI only, added 0.3% HPC Nisso H followed by addition of active substance.
Active mix has been added to premix | Lot f! RD11050A Same basic formulation as RD11050 with addition change to an additional 1% portion Aerosil 200 Batch % RD11051 Castor Oil and Aerosil 200 Dispersion (Pre-Mix 1) was prepared and viscosity increased by adding part of the DMI (4% ). The preparation of the active mixture uses the premix of RD11047B (PVP K30-3%) in DMI only, added 0.3% HPC Nisso M followed by addition of active substance.
Active mix has been added to the premix | Lot t& RD11051A Same basic formulation as RD11051 with addition change to an additional 1% portion Aerosil 200 Lot t RD11053 Castor Oil and Aerosil 200 dispersion (pre-mix 1) was prepared and viscosity increased by adding part of the DMI and Transcutol P.
The preparation of the active mixture uses the premix of RD11048A (PVP K17-3%), added with 0.3% HPC Nisso H followed by addition of active substance.
Active mix has been added to premix | Lot tt RD11054
Dispersion (pre-mix 1) of Castor Oil and Aerosil 200 was prepared and viscosity increased by adding part of the DMI and Transcutol P.
The preparation of the active mixture uses the premix of RD11048B (PVP K30-3%), added with 0.3% HPC Nisso H followed by addition of active substance.
Active mix has been added to premix | Batch % RD11055 Dispersion (Premix 1) of Castor Oil and Aerosil 200 was prepared and viscosity increased by adding part of the DMI and Transcutol P.
The preparation of the active mix uses the premix of RD11048C (PVP K90-3%). No HPC added.
Active mix has been added to premix | Batch ft RD11056 Dispersion (Pre-Mix 1) of Castor Oil and Aerosil 200 was prepared and viscosity increased by adding part of the DMI.
The preparation of the active mix - uses the premix of RD11047C (PVP K90-3%). No HPC added.
Active mix has been added to premix | Batch % RD11059 Prepared Blend of Castor Oil and Cabosil (2.5%). Active substance was dissolved in DMI and Transcutol P.
Resulted in a milky appearance.
Adding that mixture to the Castor Oil premix, the mixture did not clear.
PVP solution (K30) with DMI was prepared, added to the mixture, no change in Appearance however reduced viscosity.
Note, no change in rating adding 0.1% HPC blend to Appearance, slight increase in viscosity.
Test not reported under test lot number.
Batch f RD11060 Castor Oil was prepared by adding 3.5% Cabosil, followed by addition of a mixture of DMI/Transcutol P for thickening.
The active dispersion was prepared in a PVP (K30) with DMI as a co-solvent. (No HPC) Batch % RD11061 Castor Oil was prepared by adding 3% Cabosil, followed by addition of Labrafil (2%) for thickening.
The active dispersion was prepared in a DMI blend containing PVP K17 (2%). Mixture resulted in low viscosity, however it should be considered for F/C testing.
Batch % RD11062 Native castor oil blended with Aerosil 200 (3%) and added to a DMI/Transcutol P (6+2) blend for thickening.
A PVP mix of
K17 and K30 was dissolved in DMI/Transcutol P and followed by HPC H and solvate for 4 days.
Mixture was reheated prior to addition of active substance.
Castor oil premix was heated before adding the active dispersion.
Recommended for F/C Lot ft RD11063 Native Castor Oil blended with Aerosil 200 (4%) and added DMI! (6%) resulting in a high viscose blend.
A PVP mixture of K17 and 129/32 was dissolved in DMI, added to HPC Nisso H (0.2). In overnight definition, perceived separation, re-mixing was necessary.
Substance — active has been added to High Viscosity Castor Oil Premix.
To be accompanied with composition modification - Potential for F/C or to use RD11065 Lot t RD11064 - Addition of 0.3% to the portion of Lot RD11062 Lot % RD11065 Addition of 0.3% to the portion of Lot RD11063 Lot f RD11066 Addition of 0.3% to the portion Lot portion RD11041 Lot % RD11070 0.3% addition to Lot portion RD11037 Lot tt RD11071 0.3% addition to Lot portion RD11042 Lot t RD11072 0.3% addition to Lot portion RD11040 Lot % RD11073 Castor Oil Premix / Aerosil 200 prepared.
Dissolve in DMI (6%) without PVP, Testosterone and add to the Castor Oil premix.
A viscosity of 6,300 cps is obtained.
In a mixture of Transcutol P and DMI disperse the HPC M (only used 0.25% prep) and add to the main mixture. —Proposed for F/C Lot t RD11074 Addition of 0.3% to the Lot portion RD11072 Lot t RD11075 Prepared a masterbatch to complete 3x500 g trials consisting of Castor Oil (68%) Aerosil 200 (3%) DMI (6%) . To this mixture was added PVP K29-32 (1%) in DMI (10) and active substance.
dough divided into
3 parts to be completed by 3 trials containing different mixtures and grades of Nisso HPC in Transcutol (lots ref RD11067/68/69) Lot t RD11076 Mass used from RD11075 and added HPC mixture —RD11067 (Transcutol P with Nisso H ( 0.15%) Batch % RD11077 Mass used from RD11075 and HPC blend added RD11068 (Transcutol P with Nisso H (0.2%)) Batch %& RD11078 Mass used from RD11075 and HPC blend added RD11069 (Transcutol P with Nisso H (0.1) and M (0.1)) Lot %& RD11079 Addition of 0.3% to the Lot portion RD11076 - Lot tRD11080 Add 0.3% to the Lot portion RD11077 Lot HXRD11081 Add 0.3% to the Lot portion RD11078 Lot XRD11082 Tentative run to prepare a batch without the use of SiO, failed Batch tRD11085 Castor Oil Premix prepared by adding 2.5% Aerosil 200 followed with a blend of DMI (10) and Testosterone.
Obtained Viscosity of 3,100 cps.
Followed by the addition of HPC Nisso L (0.2%) and Nisso M (0.3%) mixed in DMI and Transcutol plus 0.3% Aerosil 200 to reduce stickiness.
Material was added without any stringing to the master mix and had a viscosity of 4,800 cps on the day of manufacture and 4,900 cps 3 weeks later.
Proposed for F/C Lot tRD11086 Addition of 0.3% to Lot portion RD11085 Table 2 TBS1A 4% potency Viscosity values using Spindle 6, 20 rom, F/C Repeat test Ref Franz Cell: Number of | Assay Test date and batch values Comments
RD11037 Jul 15/11 Oct 04/11 Clear solution, previous results at 940 cps July 620 cps and follow-up test 9/15/11 was 900 cps RD11038 Jul 15/11 Oct 04/11 Clear solution, original test 1,180 cps, 1,800 cps | follow-up 09/15/11 1,660 cps RD11039 Jul 20/11 Oct 04/11 Clear solution, previous results at 1,380 cps | Jul 980cps and follow-up test 9/15/11 was 1,300 cps RD11040 Jul 20/11 Oct 04/11 Gel Claro, previous results at 11,040 cps | Jul 10,400 cps and test: follow up 9/15/11 was 10,140 RD11041 Jul 21/11 Oct 04/11 Clear solution, previous results at '1,420 cps | July 500 cps and follow-up test 9/15/11 was 1,500 cps RD11042 Jul 21/11 Oct 04/11 Clear solution, test 9/15/11 was 1,720 1,430 cps | cps RD11050 Aug.09/11 Original sticky mix from review, 09/15/11 results 2,460 Do not use Test Lot for F/C Oct 04/11 Test Lean mix, HPC decanted to bottom not valid as a slurry RD11050A | Aug.09/11 Original sticky mix from review, results 09/15/11 3,000 cps (increase during test from 2,400) Do not use Test Lot for F/C Oct 04/11 Test Lean mix, HPC decanted to bottom ; like a mud not valid RD11051 Aug.09/11 Oct 04/11 Sure, results 09/15/11 1,940 cps 2,100 cps* | Note: viscosity values increase during 30 sec test
RD11051A | Aug.09/11 Oct 04/11 Sure, results 09/15/11 2,560 cps 2,540 cps* | Note: Viscosity values increase during 30 sec test RD11053 Aug.10/11 Oct 04/11 Clear but sticky with air bubbles 4,500 cps | , results 09/15/11 4,060 cps Note: Viscosity values increase during 30 sec test RD11054 Aug.10/11 09/15/11 HPC globules test, 15,000 cps Do not use Test Lot Oct 04/11 for F /C , Note: viscosity values 14,000 cps° increase during 30 sec test HPC growth on Spindle RD11055 Aug.10/11 09/15/11, EBEEEE Do not use Test Lot for F/C Note: error message indicates limit Oct 04/11 tester above 20,000 in this EEEEEE definition RD11056 Aug.10/11 09/15/11, EEEEEE Do not use Test Lot for F/C Oct 04/11 Note: error message indicates EEEEEE limit | tester above 20,000 in this definition RD11059 Aug.22/11 Oct 04/11 Test Do not use Test Lot for F/C not valid HPC Separation ( ) HPC growth on Spindle RD11060 Aug.23/11 Oct 05/11 3,540 cp: Uniform texture RD11061 Aug.23/11 Oct 05/11 960 cps Uniform texture
RD11062 Aug.24/11 Oct 05/11 Original viscosity 2,400 cps 3,200 cps) RD11063 Aug.24/11 Oct 05/11 Original viscosity 1,600 cps 3,460 cps RD11064 Aug.31/11 Oct 05/11 Original viscosity 5,800 cps Light, 6,440 cps | thick, RD11065 Aug.31/11 Added .3% H20 to RD11063 Oct 05/11 09/31/11 resulted in 9,100 cps 12,500 cps | Air bubbles or RD110 Aug.31/11 Oct 05/11 Added .3% H20 to RD11041 2,600 cps 11/31/11 in solid 1,500 cps Light. thick RD11070 Aug.31/11 Added .3% H20 to RD110370 Oct 05/11 tt 720 Li 2 1,540 cps resulted in clear liquid cps RD11071 Aug.31/11 Added .3% H20 to RD11042 Oct 05/11 9 /31/11 resulted in 1,760 cps Liquid and 1,820 cps clear RD11072 Aug.31/11 Added .3% H20 to RD11040 resulted in 7,920 cps Oct 05/11 Clear and thick, no change in viscosity 7,920 cps RD11073 Sep.07/ 11 Oct 05/11 Started On Site with Viscosity of 5,500 cps 9,980 cps RD11074 Sep.07/11 Added .3% H20 to RD11073 Oct 05/11 increases viscosity to 7,200 cps. 10,100 cps RD11076 Sep.06/11 Oct 05/11 Clear, however, perceived separation in 1,700 cps | mass RD11077 Sep.06/11 Oct 05/11 1,600 cps Light
RD11078 Sep.06/11 Oct 05/11 2,700 cps | Clear and fluid RD11079 Sep.06/11 Oct 05/11 Added 0.3% H20 to RD11076 3,500 cps | Clear, RD11080 fluid Sep.06/11 Oct 05/11 Added 0.3% H20 to RD11077 3,900 cps | Of course, fluid RD11081 Sep.06/11 Oct 05/11 | Added 0.3% H20 to RD11078 2,600 cps | Clear, RD11085 fluid Sep.14/11 Oct 05/11 | Original test 4,800 cps Thick and 4,900 cps | Clear RD11086 Sep.20/11 Addition of 0.3% H20 to RD11085 = : Oct 05/11 5,200 cps original 5,180 cps Thick and Clear Gel TBS1A 8% Formulation/composition Table 3 Substance. ; SiO2 %, the active HPC. Number . . Oil of . Transcutol Grade| C=Cabosil . | micronizes, Labrafil % DM! % In this, d ricin test % PVP % P% % A=Aerosil at "1200%
The RD11087 27 N-L +7 =
55.9 0000000 | 0000000 0.2 A=2.6 N-M RD11088 Same plus same | 0000000 | 0000000 | same | same (0.3% from to H20)
RD11089 Ki7=3 = N-M 165 — |ooooooo | 639=2125 —|10 os [65 RD11089 Same Same Same |0000000 | same | same | same (0.3% of à H20) RD11090 N-H= Ki7= 0.3
39.0 0000000 5.0 32 12 N-M=/C=3.5
0.2 RD11100 Added CcC=2% same | 0000000 |same | same | same for a total of 5.5 RD11101 N-L = Ki7 = 0.4
46.1 0000000 5.0 25 10 N-M=|/C=51
0.4 RD11102 N-L =| C=5.1 plus
0.4 | Addition of Ki7 N-M = | 1% for 461 0000000 5.0 - 25 10 0.4 | total of 6.1
TT RD11103 | NL = [C=51 plus
0.4 addition of 461 —looooooo FP los 10 N-M = 0.3% water
5.0 04 RD11104 Ki7= N-L = "EL and E Es RD11105 same | same same | same | same same | A=5.0 the addition of
0.5% Process Outline for Active Tests: Lot % RD11087 : Test was started without PVP to identify impact on T solubility. The active dispersion in % DMI used did not provide a clear solution and was not clearer when added to the oil blend castor/SiO2. Even the co-solvents present in the HPC Blend did not provide a Clear Gel in bulk. To the HPV 0.1% SiO mixture was added to reduce stringing and stickiness. Viscosity at 4,400 This assay however, will be selected for the Franz Cell Test to identify diffusion rate eliminating PVP. Lot % RD11088
0.3% water was added to a portion of Lot RD11087 to identify impact on viscosity. As observed in the 4% tests, increase in viscosity is not evident in the mass mixed with SiO> in the HPC. This test is not considered for F/C. Lot % RD11089 This assay used the same quantitative formulation as the 8% Clinical IMP, however using an alternative source of HPC (original source of HPC Klucel HF). It also had minor process changes, dissolved PVP in DMI only and added active substance. HPC was prepared in Transcutol and added to the main mass separately. A clear solution was obtained when adding the active co-solvent mixture to the Castor Oil and non-significant stringing with the addition of HPC after addition of SiO,.
Gel Viscosity on the Day of Manufacture was 1,800 cps, when retested after 24 hours, 3,700 and after 48 hours up to 4,300. The retest on October 3rd (see table) recorded 4,500 cps. This assay was selected for F/C Test Lot XRD11089A
0.3% water was added to a portion of Lot RD11089 to identify impact on viscosity. Viscosity change over time similar to the test above, day of manufacture 2,700 cps, when retested after 24 hours, 3,920 and after 48 hours to 4,600. The retest on October 3 (see table) recorded 5,040 cps. Selected for water impact study Lot % RD11090 Used high percentage of DMI and Transcutol to be split to various premixes, similar with SiO, to have added HPC. After the pre-mixture of oil-dericin and SiO>z, however, due to the lower ratio between the 2 excipients, the mixture became quite thick and became even thicker when adding part of the DMI. Completed the test, finished in low viscosity, day of manufacture 900 cps, test Oct 03 -1,260 cps. Lower level of SiO was considered to study impact, however considering processing issue (see RD11100) Not suitable for F/C testing Lot t RD11100 Using a portion of above assay RD11090, added additional 2% SiOz (for total of 5.5%) to study the impact on viscosity. Increased to 1,900 cps on Fabrication Day and re-test October 3 (see table) resulted in a value of 3,060 Lot %& RD11101 To potentially reduce the impact of PVP needed to dissolve the active substance during addition to the mixture of Castor oil/SiO,, 2% SiO was added to the DMI-PVP-Testosterone mixture, obtaining a viscous mixture. After adding that mixture to the Castor Oil dispersion containing 1% SiO,, a viscous mixture was maintained at the temperature of 50% (which would thicken on cooling). Further increase in viscosity with the addition of the —HPC mix and final amount of SiO 2 .
Viscosity after Gel cooling to 21°C was 3,800 cps. (note that re-testing over time will be necessary, lot manufactured in Oct 03) This test selected for F/C Lot tfRD11102 Aiming at a viscosity of 5,000 cps for the TBS1A project, the RD11101 above has been so far the best candidate to assess the impact of additional SiO addition, hence a portion of that Additional Lot 1% SiO was added. The rationale for 6% was to obtain the same ratio of active substance to SiO,z as the target level of 3% SiO, for the 4% potency.
Viscosity increases to 8,000 cps, this Batch was selected for F/C study to identify impact of viscosity on diffusion rate compared to RD11101 of same composition with exception of 1% addition in SiO,z, may need to consider in Assay obtained.
: Batch XRD11103 Addition of water to impact viscosity, not considered for follow-up testing (see Viscosity Table for results, increase to RD11101 from 3,800 to 4,500 cps) Batch fRD11104 Included this test to evaluate addition of Labrafil. Labrafil was added to Castor Oil mixed with 1% SiIO>. As noted earlier, addition of Labrafil to SiO-containing castor oil increases viscosity. Every other mixture prepared and added as per test RD11101, with addition of 2% SiO, to complete mixing. This mixture contains a higher percentage of air bubbles, common in formulations containing Labrafil. Viscosity — obtains 3,300 cps, will be monitored and tested at various times.
Selected for F/C Test.
Batch XRD11105 Added to RD11104 an additional 0.5% SiO (% adjusted to avoid high increase observed in RD11102) Increase from 3,300 to 4,100 cps Not selected for F/C Test Note: Placebo tests are collected to identify impact on viscosity using the 2 different sources for Castor Oil and SiO>. These trials will also answer potential questions related to TBS1 and TBS2.
TABLE 4 TBS1A 8% power
: Viscosity values using Spindle t6, 20 rpm, Franz Cell = F/C Manufacturing Date Test Number Test Date and Batch Values Comments RD11087 Sep 20/11 Oct 03/11 No PVP, unclear solution, 4,400 cps 2.6% SiO, Selected for Franz Cell 4,040 cps RD11087 | RD11089 Sep 25/11 Oct 03/11 Based on original IMP, | 4,500 cps HPC source change and small process step changes Selected for Franz Cell RD11089A Sep 25/11 Oct 03/11 As RD11089 plus 5,040 cps 0.3% H20 Selected for Franz Cell 11/3 Potential for F/C 1,260 cps RD11091 Sep 11/26 Oct Added 0.3% H20 to RD11090 75 in | so Je RD11100 Sep 11/26 Oct Added RD11090 to 11/3 to reach 5% SiO content, 3,060 cps RD11101 Oct 11/3 Oct 5% SiO, 11/04 Selected for Franz Cell 3,800 cps
' RD11102 Oct 04/11 Oct 6% SiO, 04/11 Selected for Cell of Franz 8,000 cps RD11103 Oct 04/11 Oct 0.3% with 5% SiO, 04/11 4,500 cps RD11104 Oct 04/11 Oct Includes 4% of Labrafil, same 05/11 comp for polymers that 3,300 cps RD11101 (air bubbles) Selected or Cell of Franz RD11105 Oct 05/11 Oct Added 0.5% SiO, | 11/5 in addition to RD11104 4,100 cps Premix RD Assays (used for addition in active assays) Table 5 É Assay / Evaluation Composition Results/ Used in comment testing Assay RD * EVOO1A observation (pg | Dissolving HPC DMI— 100g Low grade of No 41) In that grade M Transcutol P 50 | viscosity transferred g Stored to | for use for Nisso HPC M - 2.5g | hydration tests RD 72 hrs Adequate viscosity for additional additions
EVOO1B (pg | Dissolving HPC DMI— 100g Grade 41) In that Grade H Transcutol P 50 | viscosity high g Nisso HPC H-2.5g | Stored for | No hydration transferred 72hrs to use for too much viscosity | High RD tests EVOO2A (pg | Disperse Cabosil in DMI - 1259g Obtained dispersion No 41) DMI (purpose of Cabosil 10 g clear viscous transferred to study impact on Ratio for use for 'Gel viscosity related to final RD tests) Castor oil/ Cabosil EVOO2B (pg | Disperse Cabosil in Transcutol P 250 g Did not obtain No 41) Transcutol P Cabosil 20g none transferred (purpose of study Related reason increase for use for impact on with oil viscosity. RD tests viscosity in Castor Gel/Cabosil Solution milky end) in Appearance
| RD11047 A | Addition of PVP K17 DMI- —100g Suitable for Used in DMI only.
PVPK17 159 additional mixture in assay Ratio represents with HPC He RD for i 3% PVP with active substance. addition of base in the formula of | Note: Used grade HPC-H and Final Bulk Gel | of viscosity of | high HPC substance with | active (see Grade of RD1150 and viscosity of RD1150A) Low PVP RD11047B | Addition of PVP K29/32 | DM|I-100g Suitable for Used in DM! only.
PVP K29/3215g additional mixture in assay Ratio represents with HPC M and RD to 3% PVP with active substance. addition of base in the formula of | Note: Used grade HPC-M and Final Bulk Gel | of viscosity of | minor HPC substance with active (see Grade of RD1151and viscosity of RD1151A) High PVP RD11047C | Addition of PVP K90 DMI- 100 g Not suitable Used in DMI only.
PVP K90 159 to add in Ratio assay represents any grade of RD without 3% PVP with HPC, however HPC based on formula of | suitable for addition to final mass gel | add portion | RD11056 active,
| RD11048 A | Addition of PVP K17 DMI- 80g Suitable for Used in DMI and Transcutol Transcutol P20 g additional mixture in assay PVP K17 159g with HPC He RD for Ratio represents active substance. addition of 3% PVP with Note: used HPC-H grade and base on formula of | viscosity of — | Gel substance in final mass | High HPC with | active (see Grade of RD11053 PVP lower viscosity RD11048B | Addition of PVP K29/32 | DMI-80 g Suitable for Used in DMI and Transcutol P. | Transcutol P20 q additional mixture in test PVP K29/3215 g with HPC M and RD for Ratio represents active substance. Addition of 3% PVP with Note: used grade HPC-M and based on formula of | viscosity of — | Gel substance in final mass | Lower HPC with active (see Grade of RD11054 Viscosity of high PVP RD11048C | Addition of PVP K90 DMI- 100 g Not suitable Used in DMI and Transcutol PVP K90 159 to add in assay P Ratio represents any degree of RD without 3% PVP with HPC, however, HPC based on formula of | suitable for addition Final mass gel | add portion | active RD11055.
RD11067 HPC Prep in TP=40g N-H Used in Transcutol P only |=0.759g RD11076
RD11068 HPC Prep in TP=40g NH Used in Transcutol P only |=1.09g RD11077 RD11069 HPC Prep in TP=40g NH Used in Transcutol P only |=0.5gN- RD11078 M=0.59g RD11075 Oil Solution Prep base used castor / RD11076/RD11077/ Aerosil200/ RD11078 DMI/ - Details in Table 2 | PVP K30 Testosterone Placebo Assays TBS1 Table 6 Assay Lot o . Results/ Evaluation Composition o É comments Evaluate change in Labrafil M 1944 CS Viscosity 10,460 cps viscosity using 500g RD11032 Labrafil versus 40g Cab-O-Sil Castor Oil Cr O Evaluate change in Castor Oil 500 g viscosity by adding Cab-O-Sil - --40 g RD11033 Cabosil first in Oil Note: Viscosity ratio 14 460 cps of Cr O castor used in IMP Impact when adding DMI and — | RD11032 -270g RD11034 Transcutol mixed RD11032) DMI - 1259 Reduced viscosity Transcutol P50 g to 8,740
Impact when adding DMI and Impact when adding RD11035 Transcuto! to the mixture RD11033| DMI and Transcutorvà — | Reduced Viscosity Blend RD11032 to 3,600 RD11036A Castor Oil Blend and — | Castor oil 125 g High viscosity outside Labrafil, Cabosil Labrafil..........1259 addition of range followed by DMI/Transcutol —|Cabosil......... 20 g P DMI.. 1259 Transcutol P 50g RD11036B Castor Oil Blend and — | Dericin oil O 125 Labrafil followed by g DMI/Transcutol P, add | Labrafil........... 1259 ' Cabosil last Cabosil.........20g Viscosity 7,680 cps : DMI... 1259 Transcutol P 50g RD11043 Castor Oil and CabOsil, Castor Oil O 285 followed by mixture of g DMI/Transcutol P and HPC Cabosil 209g H DMI... 100 g Transcutol P 50g HPC H 2.59 RD11043 Castor oil and CabOsil, Castor oil 0 285 g followed by mixture of Cabosil 209 DMI/Transcutol P and HPC DMI...100g M and PVP K1i7 Transcutol P 50g HPCM ...........2.59g PVP K15 .......159 RD11057P TBS-2 Placebo for Analytical Laboratory Method
RD11058P Mixture of Castor Oil and From A to D represents RD11058P = 2740 cps | A-B-C-D-E-F Cabosil followed by addition of | % Labrafil 2-4% Part A 2% = 11,400 Labrafil with change in Part B 3% = 14,000 viscosity Part C 3.5% = 14,440 E —Impact Part D 4% = 14,900 acid addition Part E with acid = oleic 1.520 F addition impact Part F - 10% DMI a to DMI to RD11058- part A A = 13,500 cps (increase from 11,400) RD11083P Assay Purpose for HPC Blend Prep| Base viscosity decrease stringing and DMI/TranscutolP prior to addition of adhesiveness of Solvate Blend plus Nisso Blend of HPC was HPC when adding to HPC L and M solvates | 5,300 cps, after base oil blend for 48 hours followed by addition of Castor/Aerosil Blend and DM! by addition of SiO, HPC (no stringing) RD11084P Used portion of RD1108P to add 0.3% H20 to assess impact on viscosity EXAMPLE 10 Franz Cell Studies—Diffusion Testosterone Rates Generally, dip the membrane for 30 minutes in the diffusion solution.
After placing the membrane on the Franz Cell, place the ring and donor chamber on the membrane and squeeze. Add approx. one gram of gel (TBS 1A 4% or 8%). Check the diffusion solution level in Franz Cells. Must be on the mark. Put "parafilm" on the sampling port to avoid. Withdraw 0.3ml of Sample at 60, 120, 180, 240, 300 and 360 minutes using a syringe. Add diffusion solution to reach the Franz Cells mark. Each Sample must be collected on insertion. A typical Franz Cell used in accordance with this Example 9 and the invention is depicted in Fig. 12. Materials include: Diffusion Solution: Ethanol/Water 50:50 Membrane: Millipore 0.451.1m. Temperature: 37º +0.5ºC. Agitation speed: 600 rpm. Medium volume: 20ml. Surface area: 1.7671 cm Number of Franz Cells: 6.
: Sampling time (minutes): 60, 120, 180, 240, 300 and 360.
- Aliquot volume: 0.3ml.
- Insertion: 0.4ml.
The TBS1A formulations are as follows and as reported in the Examples above and here. The results of the diffusion rate of testosterone across the Franz cell membrane, normalized for each of the gel concentrations being tested, measured as slope/mgT%, are reported below in the Franz Cell table.
4% TBS1A Assay Formulations Used in Franz Cell Assay Batch Batch Size 500 g RD11063 Lo o o mean | Micronized Testosterone 4.0 12% DMI to Disperse PVP and Active Substance Castor Oil (V — O) 70.8 4% SiO in Oil Steps: Castor plus 6% PVP K17 1.5 A: Add all of SiO, to Castor Oil
: PVP K30 1.5 Followed by portion of DMI PVP K90 B: to DMI add PVP, follow Co PVP 5630 with HPC and hold for 24 hrs C: add active substance Transcutol PD: — add mixture 1 A) HPC Nisso M 0.0 Range of Temp NMT 60C HPC Nisso H 0.2 Homogenize SiO> active mixture (Cabosil —Aerosil 4.0 Viscosity 3,650 cps 200) 5/10/11) Assay Lot Is Lot Size 500 g RD11085 Lo do = ratsceuederranm Micronized Testosterone 4.0 10% DMI used for dissolve active substance Castor oil (V — O) 70.7 2.5% SiO,> mixed with Castor oil PVP K17 A: active substance/DMI mixture
PVP K30 to Castor Oil/SiO mixture, PVP K90 B: add SiO7z to HPC after 24 h
16.0 6% DMI used for C: add Mix HPC HPC dispersion to Transcutol P mass Used for main HPC dispersion and solvation for 24 hrs HPC Nisso L 0.2 0.3% SiO, mixed with Mix 1 HPC HPC Nisso M 0.3 Range Temp NMT 60C SiO, (Cabosil —Aerosil 2.8 Viscosity 4,900 cps 200) (10/05/11) Lot Ass Ass Batch Size 500 g RD11038 Raw Materials/Grade Process Castor Oil (V — O) 57.0 All Cabosil to Castor Oil | A: Add to Castor Oil /Si02 PVP Ki7 3.0 Mix Active Blend PVP PVP Ks0 | ao A Co PVP 5630 Lao
20.0 All DMI and Transcutol P to disperse PVP
HPC Nisso M Homogenize active mixture HPC Nisso H [o Ó SiO,2 (Cabosil —Aerosil 4.0 Viscosity 1,800 200) cps Assay Batch Is 7 h batch 500 RD11039 batch size g Castor oil (V —O) 29.0 Blend Oil of castor+Labrafil+Cabosil Co PVP 5630 2.0 PVP to DMI+Tr-P followed by active substance Bm DR PO Labrafil year o SiO,z (Cabosil —Aerosil 3.0 iscosity 1.380 200) Test Lot RD11040 Lot size 500 g
' Mix in 12% DM! and 6% NEN Tr-P memo EE 13% DMI+4% TrP Ber a Pero a Pee AEE [cones — BE E | A [tame [ia A [HPeNSsoH | a TT — = SiO, (Cabosil —Aerosil 4.0 Viscosity 11,040 ag mm eee o Batch size 500 g LE IEEE enem | Micronized testosterone 4.0 Active substance dissolves in nes E nam | Oeoderama vo) 200 fOeodemanemesos | [ve jo É 5"“IerIddHCG:FA Bee RR a Pero TE [69 Pu sao a Bm Po DO Trance [ro OO Ter Pa O
[TI EEE rrensor [HPeNSsoR [a amen nm ES 200) 1,430 cps Assay role Is Batch size 500 g RD11051 o TE en esa se Frara| |Myronized testosterone | to faonmomePVenTTAAÁE | [Oloderien (Vo) | 667 [OeodememasSiosta| HPC adding
PR O eamenaso, Leve ro gg O IJZZJZ“““0i [cups to A Mer A mere RR FIA [HPerso Di OO A HeeNssen aa A
SiO, (Cabosil —Aerosil 2.0 Viscosity 2,100 ag tm Jr eeeste|
Assay Lot Is RD11055 Batch Size 500 g Lo do emceuaderarm Micronized Testosterone 4.0 DMI 16% +Transc 4% + pvp + om O ae
—[BemaTmNTo eo JómodemamersaAE [o [Pei oa] "A rXZ—<ao€ ever Rg Pere TE OO | co PvP mon Br Ea TA [Mansenir o UNCLE Hen [a A [Here Ns BO OA [HPe Ns OO E | 200) Test Test Batch t RD11078 Batch size 500 g Lo E stages they act] Testosteronamiananzada | xo DMI 67.8% A eeerion | PVP K30 1.0 DMI 10% + pvp + substance Base prep RD11075 Am E aeee Seen Pe [E pit saso | ae A Bm Ro DIO ensamop — [ so [TamcPramesnhão — | repemRDITOSS | Henson met eme
HPC Nisso H 0.1 Castor oil in =TrE E mm ES
200) 2,700 cps Stamp oie Is Lot Size 500 g RD11054
Lo dd enesuesrem Testosteronamiramada [to fo [Oesderien (vo) was ómodememensa mam [| Eve Rg O ÕAZXZZZ
PVP K30 3.0 16% DMI+Trans a o A [ve go gg TT | co PvP sega a a ag IT" Mransenarp so DT HPeNSo a o eme A sesero ese
200 cps
Test Batch Is ' RD11061 Batch Size 500 g Lo = cc we [Myronized Testosterone | go [The Oeoderama (vo) [710 [OEoderemersioareem |
PVP Ki7 DM! 16% + Transc 2% + PVP+ active substance Bm o masa o aa O SiO, (Cabosil —Aerosil 3.0 Viscosity 200) 960 cps om $ 8 8 8 8 À = 8 8 8 8 e 2: es Ê 3 z 8 & &8 & &88s 882 3 883888 E nn o no Aa A un qqq mon xe [e o So So S SS Sd SO o do o PP O ºP º d oos 2 s 8 8 2 8 8 8 Es 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8838 32 js SS && SS &S& 5 SS 85 SS SS 8 Ss SS SS FR oo = on = zonaoxo TE | 3 3 8 8 5 3 8 3 SR 3 8 R 3 E SEE 4 ú Ss of od SS 4 od of E RR = do $ 3 4 E | & Rg s r E& 6 RR $S eo à il SS 3 3 RR 6 SS R 2 s la e E 8 8 EX. 8 8 3 SS 3232833 33 ãêsas EQ E 8 S à à 3 3 Es 3 8 8 E | Ê EE Sé S ã& 8 8 84 8 8 8 8 8 | 8 8 $ $ & e Bono 8 8 0 8 8 Bo pon o le 8 no Ss 8 8 à a le s 2 Ss Ss g qm & So 43 3 ô % 2 4 8 2 E ls &s S - 4 gd é SS 4 $ right is gd SG is 3 It is 3 ds 8 2 38 <s $$ 4 $ sil SS $ 4 oz 3 & 8 8% 3 28388 E [E 8 8 8 ms e CO Os E za ow SE ma nm oq | o E ge nm om os sã e dg 8 3 $$ 3 SS 85 3d 3d sds: 3 S 8 & 3 83 ã SS gy a se RE 3d 8 ES s es + o Moo ã 4 4 q jm mm 8 om om 8 IF m ” 2 o 3 oo oe o E o ocooolo oooooo 2 o FP º = zm os Sw ee 0 oa IF o gos eao + no a E oo nn E8oE fo o 8 4 8 oo hollow ooo ol oooo coco Eox oooo Ss o eo oool oo ooo Es ooooo 88333 Tl oooo Bos É 3 8 3 é at 3 8 E- Lo oooe ce o 3d ES lo ooo ooo É 3 333 za $E [oo & w 8 8 8 o. 8 Ss SS 8 8 o vu «1
Ê = W 8 8 8 OR 2 4 ss Ss ex fo co RX 8 4 RX 4 RW 4 4/8 E 4 4 à à RX If | o o e oe o o o o v | At the 3 o o g * and Z8 it MW mm NON SS lh o o 'o o o o 3 ã the third | o o o o o o o o o o o o o o o o o o o o ss E o o o o o o o ooocoool o o o o m o m o m
N Ss ES o ZE oo mm ” mm m” m” oo no o ” ” ooo ” or 2 8.2 qn o 5) o A NOR o Sos : 2 oa H a " dh a NR >: : : E zo 3 3 $ 8838: 3 2 3 3 - o8s | 5 ss € € € 4 $ $ 3 |5 & $ 3 2 | O 8 o Bo es RO e mam aoo de e e eeev 8 Ss É oqo ES É É É É $ o 8 = FT SA E mm | o sw OD SO A e 3 8 1st 8 sã sã s 8 $ 8 8 8 3 ER 2 3% EB sas o 3 38 58 53 2 $ & = 2 3 | 8 3 to 3 8 3/5 8 83 88 38 3 $ 8 3 Ss = 3 4 3 38 38 Si | 2 "2 "2 Pr 8 g 9 ê 2 B 8 GE Bs: Z2 " = = = E q - y 8 8 8 S$ 8 & & & 8 8
SON P OP Soo 8 8 8 88 3 8 & 8 8 are of the 4 Ss of the Os 2 8 8 3 Ss Ss ss e & $$ 3 8 ” 8 & 3 3 8 RE SH A q R E ER
E RE OS 3 E 3 8 RR 8 8 8 nm e gg a is 8 2 8 E & SS gg E 8 4 go a sm ee oe coco = mono 8 eoooooo give 4 e oe oHFã - e oe o 3 os o nm ox 2 8 o
RR E RR E o no oo ce ooo mo ooo and ºtúno mnoe sn tooo 8 o 8 o 3 RR SS 8 vom oe e Bog gp 2 o 8 2 8 8 8 8 8 3 3 383 a 8 8 8 2 2 2 two
The In Vitro TBS-1A Gel Release Rate Validation concerning the Release Rate Study Summary for 4.0% TBS-1A Gel and 4.5% TBS-1A Gel are presented in Exhibits A and B presented in attachment. These summaries summarize the release rate experiment data for exemplary TBS-1A gels. There are four Nasobol Gels (0.15%, 0.6%, 4.0% and
4.5%) for method validation. The purpose of the Day 1 and Day 2 test is to determine the intraday/interday slope specificity and precision (release rate), Day 3 and Day 4 are to assess slope sensitivity to Sample potency variation. See Exhibit A (4.0%) and Exhibit B (4.5%) attached hereto, both of which are incorporated herein by reference in their entirety. Reference List
1. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 4th edition, 2006. Editors; Burtis CA, Ashwood ER, and Bruns DE.
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3. Matsumoto AM. Andropause: clinical implications of the decline in serum Testosterone leveis with aging in men. J Gerontol A Med Sci 2002; 57: M76-M99. 4, Haren MT, Kim MJ, Tariq SH, Wittert GA, Morley JE. Andropause: a quality-of-life issue in older males. Med Clin North Am 2006; 90: 1005-1023. D. Nieschlag E. Testosterone treatment comes of age: new options for hypogonadal men. Clin Endocrinol (Oxf) 2006: 65: 275-281.
6. Tenover JL. The androgen-deficient aging male: current treatment options. Rev Urol 2003; 5 (Suppl): S22-S28.
7. Jockenhovel F. Testosterone Therapy — what, when and to whom Aging Male 2004; 7: 319-324.
8. Kunz GH, Klein KO, Clemons RD, Gottschalk ME, Jones KL. Virilization of young children after topical androgen use by their parents. Pediatrics 2004;114:282-284.
9. Brachet C, Vermeulen J, Heinrichs C. Children's virilization and the use of a Testosterone gel by their fathers. Eur J Pediatr 2005; 164: 646-647.
10. Bagchus WM, Hust R, Maris F, Schnabel PG, Houwing NS. Important effect of food on the bioavailability of oral Testosterone undecanoate. —Pharmacotherapy 2003; 23:319-325.
11. Haren M, Chapman IM, Haren MT, MacKintosh S, Coates P, Morley JE. Oral Testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low normal gonadal status. J Gerontol A Biol Sci Med Sci 2003; 58: 618-625.
12. Haren M, Chapman |, Coates P, Morley JE, Wittert G. Effect of 12 month oral Testosterone on Testosterone deficiency symptoms in symptomatic elderly males with low-normal gonadal status. Age Age 2005; 34: 123-130.
Mattern C, Hoffmann C, Morley JE, Badiu C. The Aging Male 2008; 11: 171-178.

权利要求:
Claims (28)
[1]
1. Testosterone gel formulation for nasal administration, referred to testosterone gel formulation characterized by the fact that it comprises: a. about 4.0% testosterone by weight of said gel formulation b. a pharmaceutically acceptable vehicle.
[2]
2. Testosterone gel formulation for nasal administration, referred to testosterone gel formulation characterized by the fact that it comprises: a. about 4.5% testosterone by weight of said gel formulation b. a pharmaceutically acceptable vehicle.
[3]
3. Testosterone gel formulation for nasal administration, referred to: Testosterone gel formulation characterized by the fact that it comprises: Cc. about 8.0% testosterone by weight of said gel formulation d. a pharmaceutically acceptable vehicle.
[4]
4. Testosterone gel formulation according to claim 1 - 3, characterized in that the gel formulation comprises a solvent, a wetting agent, and a viscosity-increasing agent.
[5]
5. Testosterone gel formulation according to claim 4, characterized in that the solvent is castor oil.
[6]
6. Testosterone gel formulation according to claim 4, characterized in that said wetting agent is an oleoyl polyoxyglyceride.
[7]
7. Testosterone gel formulation according to claim 4, characterized in that said viscosity-increasing agent is colloidal silicon dioxide.
[8]
8. Testosterone gel formulation according to claim 1 - 3, characterized in that said gel formulation comprises castor oil, oleoyl polyoxyglycerides and colloidal silicon dioxide.
[9]
9. Testosterone gel formulation according to any one of claims 1-8, characterized in that said gel formulation is a bioequivalent formulation.
[10]
10. Testosterone gel formulation according to any one of claims 1-8, characterized in that said gel formulation is a pharmaceutically equivalent formulation.
[11]
11. Testosterone gel formulation according to any one of claims 1-8, characterized in that said gel formulation is a therapeutically equivalent formulation.
[12]
12. A packaged drug characterized in that it comprises: (a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 4.0% testosterone by weight ; and (b) associated instructions for using said testosterone gel formulation for testosterone replacement therapy, or for treating hypogonadism or testosterone deficiency.
[13]
13. Packaged drug product characterized in that it comprises: (a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 4.5% testosterone by weight ; and (b) associated instructions for using said testosterone gel formulation for testosterone replacement therapy, or for treating hypogonadism or testosterone deficiency.
[14]
14. Packaged drug product characterized in that it comprises: (a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 8.0% testosterone by weight ; and (b) associated instructions for using said testosterone gel formulation for testosterone replacement therapy, or for treating hypogonadism or testosterone deficiency.
[15]
15. The packaged drug according to claim 12 - 14, characterized in that said testosterone is present as a pharmaceutical composition comprising a therapeutically effective amount of testosterone or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier .
[16]
16. Packaged drug, according to claim 12-14, characterized in that it additionally comprises a step of identifying a subject in need of said drug.
[17]
17. A method for treating hypogonadism in a male subject, the method characterized in that it comprises administering — intranasally to a male subject such a gel formulation according to any one of claims 1-16 to deliver a therapeutically amount of testosterone to effectively treat hypogonadism.
[18]
18. Method of treatment of testosterone deficiency in a male subject, the method characterized in that it comprises — administering intranasally to a male subject said gel formulation, according to any one of claims 1-16, to deliver a therapeutically effective amount of testosterone to effectively treat testosterone deficiency.
[19]
19. A method of providing testosterone replacement therapy in a male subject, the method characterized in that it comprises intranasally administering to a male subject said gel formulation according to any one of claims 1-16 to deliver a therapeutically effective amount of testosterone to effectively provide testosterone replacement therapy.
[20]
20. Method of preparing a testosterone gel formulation for nasal administration, said testosterone gel formulation comprising about 4.0% testosterone by weight of said gel formulation; and a pharmaceutically acceptable carrier, the method characterized in that it comprises: a. combining micronized testosterone in contact with a solvent to form a first mixture; B. combining oleoyl polyoxyglycerides with the first mixture to form a second mixture; and combining colloidal silicon dioxide with the second mixture to provide a testosterone gel formulation for nasal administration.
[21]
21. Method of preparing a testosterone gel formulation for nasal administration, said testosterone gel formulation comprising about 4.5% testosterone by weight of said gel formulation; and a pharmaceutically acceptable carrier, the method characterized in that — comprises: a. combining micronized testosterone in contact with a solvent to form a first mixture; B. combining oleoyl polyoxyglycerides with the first mixture to form a second mixture; and Cc. combine colloidal silicon dioxide with the second mixture to provide a testosterone gel formulation for nasal administration.
[22]
22. Method of preparing a testosterone gel formulation for nasal administration, said testosterone gel formulation comprising about 8.0% testosterone by weight of said gel formulation; and a pharmaceutically acceptable carrier, the method characterized in that it comprises: a. combining micronized testosterone in contact with a solvent to form a first mixture; B. combining oleoyl polyoxyglycerides with the first mixture to form a second mixture; and Cc. combine colloidal silicon dioxide with the second mixture to provide a testosterone gel formulation for nasal administration.
[23]
23. Gel formulation according to claims 1 - 22, characterized by the fact that the testosterone gel formulation has a testosterone diffusion rate of between about 28 to about 100 slope/mgT%.
[24]
24. Gel formulation according to claims 1 - 22, characterized by the fact that the testosterone gel formulation has a testosterone diffusion rate of between about 30 to about 95 slope/mgT%.
[25]
25. Gel formulation according to claims | — 22, characterized by the fact that the testosterone gel formulation has a testosterone diffusion rate of between about 28 to about 35 slope/mngT%.
[26]
26. Testosterone gel formulation for nasal administration, said testosterone gel formulation characterized by the fact that it comprises: a. testosterone; and b. a pharmaceutically acceptable carrier, wherein the testosterone gel formulation has a testosterone diffusion rate of between about 28 to about 100 slope/mgT%.
[27]
27. Testosterone gel formulation for nasal administration, said testosterone gel formulation characterized by the fact that it comprises: a. testosterone; and b. a pharmaceutically acceptable carrier, wherein the testosterone gel formulation has a testosterone diffusion rate of between about 30 to about 95 slope/mgT%.
[28]
28. Testosterone gel formulation for nasal administration, said testosterone gel formulation characterized by the fact that it comprises: a. testosterone; and b. a pharmaceutically acceptable carrier, wherein the testosterone gel formulation has a testosterone diffusion rate of between about 28 to about 35 slope/mgT%.

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法律状态:
2021-07-13| B11A| Dismissal acc. art.33 of ipl - examination not requested within 36 months of filing|

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2021-07-13| B25A| Requested transfer of rights approved|Owner name: ACERUS PHARMACEUTICALS SRL (BB) |

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2021-09-28| B04C| Request for examination: application reinstated [chapter 4.3 patent gazette]|

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2021-10-05| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2021-10-19| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2022-02-15| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201161486324P| true| 2011-05-15|2011-05-15|

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US61/486,324|2011-05-15|

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US201161486634P| true| 2011-05-16|2011-05-16|

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US61/486,634|2011-05-16|

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PCT/IB2012/001112|WO2012156820A1|2011-05-15|2012-05-15|Intranasal testosterone bio-adhesive gel formulations and use thereof for treating male hypogonadism|

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