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    • 专利摘要:
    oral pharmaceutical composition, testosterone undecanoate dosage form and method of treating testosterone deficiency or its symptoms a pharmaceutical testosterone undecanoate formulation is provided. methods of treating a testosterone deficiency or its symptoms with the inventive formulations are also provided.
    公开号:BR112012025961B1
    申请号:R112012025961-0
    申请日:2010-04-12
    公开日:2021-06-15
    发明作者:Robert E. Dudley；Panayiotis P. Constantinides
    申请人:Clarus Therapeutics, Inc；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    [001] The present invention generally relates to oral formulations of testosterone esters for the treatment of testosterone deficiency. More particularly, the present invention relates to pharmaceutical composition comprising testosterone undecanoate (TU) with improved and extended absorption and pharmacokinetics. BACKGROUND OF THE INVENTION
    [002] Testosterone (T) is a primary androgenic hormone produced in the interstitial cells of the testes and is responsible for normal growth, development and maintenance of male sex organs and secondary sex characteristics (eg, deepened voice, muscle development, facial hair, etc. .). Throughout adulthood, testosterone is required for the proper functioning of the testes and its accessory structures, prostate and seminal vesicles; for a feeling of well-being; and for maintenance of libido, erectile potency.
    Testosterone deficiency — insufficient secretion of T characterized by low serum concentrations of T — can give rise to medical conditions (eg, hypogonadism) in men. Symptoms associated with male hypogonadism include impotence and reduced sexual desire, fatigue and loss of energy, mood depression, regression of secondary sex characteristics, reduced muscle mass, and increased fat mass. Additionally, hypogonadism in men is a risk factor for osteoporosis, metabolic syndrome, type II diabetes, and cardiovascular disease.
    [004] Several testosterone replacement therapies are commercially available for the treatment of male hypogonadism. Pharmaceutical preparations include both testosterone and testosterone derivatives in the form of intramuscular injections, implants, oral T-alkylated tablets (eg, methyltestosterone), topical gels, or topical patches. All current T therapies, however, fail to adequately provide an easy and clinically effective method of releasing T. For example, intramuscular injections are painful and are associated with significant fluctuations in serum T levels between doses; T patches are usually associated with T levels in the lower normal range (ie, clinically ineffective) and usually cause substantial skin irritation; and T gels were associated with unsafe transfer of T from the user to women and children. In addition, the only “approved” oral T therapy, methyltestosterone, is associated with a significant occurrence of liver toxicity. Over time, therefore, current methods of treating testosterone deficiency suffer from poor adherence and thus unsatisfactory treatment of men with low T.
    [005] Testosterone and its esters are poorly bioavailable—due to extensive intestinal and hepatic first-pass metabolism—or not effective—due to an inability of the body to release testosterone from its testosterone prodrug. For example, testosterone and testosterone esters with side chains less than 10 carbons in length are primarily absorbed through the portal circulation resulting in substantial, if not complete, first-pass metabolism. Long carbon chain fatty acid esters (ie 14 or more carbons) can be absorbed by intestinal lymphatics, but the longer the fatty acid chain, the slower the rate and extent of ester hydrolysis by esterases to release testosterone thus resulting in weak (ie, clinically ineffective) pharmacological activity.
    [006] In addition to the selection of a testosterone ester, the formulation of testosterone esters presents unique challenges. The gastrointestinal environment is decidedly aqueous in nature, which requires drugs to be solubilized for absorption. However, testosterone and particularly its esters are extremely insoluble in water and aqueous media, and yet if the T or T-ester is initially solubilized in the formulation, the formulation must be able to maintain the drug in a soluble or dispersed form without precipitation or otherwise, coming out of solution in vivo (although said property can be tested in vitro, for example, by mixing the contents of a formulation in simulated intestinal fluid). Furthermore, an oral T formulation must effectively release T or T-ester according to a desired release profile. Thus, an effective formulation of T or T-ester must balance good solubility with optimal release and satisfaction of a target plasma or serum concentration profile.
    [007] For these reasons, among others, no oral formulations of testosterone or testosterone esters have been approved by the United States Food and Drug Administration (FDA) to date. In fact, the only FDA-approved oral testosterone product so far is methyltestosterone (in which a methyl group covalently attached to a testosterone "core" at the C-17 position to inhibit hepatic metabolism; further note that the methyltestosterone is not a testosterone prodrug) and it was approved several decades ago. Unfortunately, methyltestosterone use has been associated with a significant incidence of liver toxicity, and it is rarely prescribed to treat men with low testosterone.
    [008] As noted above, fatty acid esters of testosterone provide yet another potential mode of release of testosterone to the body (ie, as a “pro-drug”). Once absorbed, testosterone can be released from its ester through the action of non-specific tissue and plasma esterases. Furthermore, by increasing the relative hydrophobicity of the testosterone fraction and the lipophilicity of the resulting molecule as determined by its partition coefficient value in n-octanol-water (log P), such prodrugs can be absorbed, at least partially, through the intestinal lymphatics, thus reducing first-pass metabolism by the liver. In general, lipophilic compounds having a log P value of at least 5 and oil solubility of at least 50 mg/ml are mainly transported through the lymphatic system.
    [009] Despite their promises, testosterone prodrugs, including testosterone esters, have not been formulated in such a way as to achieve serious testosterone levels sustained at eugonadal levels (ie, mean serum T concentration being in the range of about about 300 to 1100 ng/dL). In fact, a pharmaceutical preparation of a testosterone prodrug, including testosterone esters, must still be approved by the FDA.
    [010] Thus, there remains a need for an oral formulation of a testosterone ester, which provides optimal serum testosterone levels that are clinically effective to treat male hypogonadism (ie, those with a serum T concentration of < 300 ng/ dL) over an extended period of time. SUMMARY OF THE INVENTION
    [011] In an embodiment of the present invention, an oral pharmaceutical composition is provided comprising testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a total lipophilic surfactant at the total hydrophilic surfactant ratio (w/w ratio ) being in the range of about 6:1 to 3.5:1, whose composition, on oral administration once or twice a day, provides an average serum concentration of testosterone at steady state being in the range of about 300 to about 1100 ng/dL. The pharmaceutical composition provides a Cmax which, when administered with a meal, does not exceed 2500 ng/dL, preferably does not exceed 1800 ng/dL, and most preferably does not exceed 1500 ng/dL.
    [012] According to a preferred embodiment, the at least one hydrophilic surfactant comprises Cremophor RH 40 (polyoxyethyleneglycerol trihydroxystearate); the at least one lipophilic surfactant comprises oleic acid. Pharmaceutical compositions of the invention may comprise 18 to 22 percent by weight of solubilized testosterone undecanoate, and may further be substantially free of monohydric alcohols such as ethanol.
    [013] In another embodiment of the invention, a dosage form of testosterone undecanoate is provided comprising testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant, which dosage form, in the oral administration of a or twice daily to a subject suffering from hypogonadism or its symptoms, provides a mean steady-state serum testosterone concentration being in the range of about 300 to about 1100 ng/dL, while avoiding an occurrence of a Cmax value. that exceeds 2500 ng/dL, more preferably avoids an occurrence of a Cmax value that exceeds 1800 ng/dL, and more preferably avoids an occurrence of a Cmax value that exceeds 1500 ng/dL.
    [014] In yet another embodiment of the present invention, a pharmaceutical composition is provided comprising testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant, which composition, in oral administration with a meal containing a content of fat ranging from as low as 20% by weight to as high as 50% by weight provides a mean serum testosterone concentration that is statistically insignificant to be observed in oral administration with a meal containing a fat content of about 30% by weight. Weight.
    [015] In yet another embodiment of the invention, a pharmaceutical composition is provided comprising testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a total lipophilic surfactant at the total hydrophilic surfactant ratio (w/w) being in the range of about 6:1 to 3.5:1, whose composition, on oral administration once or twice a day, provides a fast-phase serum testosterone half-life of about 5 hours and a half. serum testosterone terminal life of about 29 hours.
    [016] In yet another embodiment of the invention, a pharmaceutical composition is provided comprising testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a ratio of total lipophilic surfactant to total hydrophilic surfactant (w/w). ) being in the range of about 6:1 to 3.5:1, whose composition, on oral administration once or twice a day to a subject suffering from testosterone deficiency or its symptoms, provides an average serum testosterone concentration on day 30 of a daily treatment regimen, which is substantially the same as that observed on day 7. According to the invention, the mean serum testosterone concentration obtained on day 30 of a daily treatment regimen may still be substantially the same than that observed on day 60.
    [017] In another embodiment of the invention, a method of treating testosterone deficiency or its symptoms is provided comprising orally administering to a subject suffering from testosterone deficiency or its symptoms an effective amount of a pharmaceutical composition comprising testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a ratio of total lipophilic surfactant to total hydrophilic surfactant (w/w) being in the range of about 6:1 to 3.5:1 to generate an average serum concentration of steady-state testosterone being in the range of about 300 to about 1100 ng/dL. The composition can be administered once a day or twice a day, and can generate a Cmax value being in the range of about 900 to 1100 ng/dL.
    [018] According to the method, the composition can be administered with a meal comprising at least 20% by weight of fat. The method can yield substantially no diurnal testosterone pharmacokinetic changes, a mean serum Tmax value being in the range of about 3 to 7 hours after oral administration, and substantially no significant decline in steady-state serum testosterone response on repeated dosing.
    [019] In a preferred embodiment of the present invention, a pharmaceutical composition is provided comprising: (a) 15 to 25 percent by weight of a solubilized testosterone undecanoate; (b) 12 to 18 percent by weight of at least one surfactant hydrophilic; (c) 50 to 65 percent by weight of at least one lipophilic surfactant; (d) 10 to 15 percent by weight of a mixture of borage oil and mint oil, the composition of which may be free of generally monohydric alcohols specifically, ethanol and, upon oral administration to a subject in need thereof, generates a serum testosterone half-life (TT) being in the range of about 10 hours to about 18 hours. Cremophor RH40 is a preferred hydrophilic surfactant and a preferred lipophilic surfactant is oleic acid. Borage oil and peppermint oil are both considered lipophilic surfactants.
    [020] In a particularly preferred embodiment, the composition comprises: (a) 18 to 22 percent by weight of a solubilized detestosterone undecanoate; (b) 15 to 17 percent by weight of at least one hydrophilic surfactant; (c) 50 to 55 percent by weight of at least one lipophilic surfactant; and; (d) 10 to 15 percent by weight of a mixture of borage oil and mint oil.
    [021] The ratio of borage oil to mint oil can range from 8:1 to 3:1; preferably from 6:1 to 5:1; more preferably from 5:1 to 4:1. In addition to Cremophor RH40, Solutol HS-15, Tween 80 and TPGS are preferred hydrophilic surfactants; and, in addition to oleic acid, Glycerol monoleate, propylene glycol laurate and Capmul MCM are preferred lipophilic surfactants. Combinations of two or more preferred lipophilic and two or more hydrophilic surfactants are further contemplated.
    [022] In another embodiment of the present invention, a method of treating testosterone deficiency is provided, the method comprising orally administering to a hypogonadal subject an effective amount of a pharmaceutical composition comprising: (a) 15 to 25 percent by weight of an undecanoate solubilized detestosterone; (b) 12 to 18 percent by weight of one or more hydrophilic surfactants; (c) 50 to 65 percent by weight of one or more preferred lipophilic agents; (d) 10 to 15 percent by weight of an ethanol-free blend of borage oil and mint oil, which is administered once or twice a day orally. day generates a mean (or mean) steady-state serum testosterone concentration, Cave, being in the range of about 300 and about 1100 ng/dL in the subject. The composition can optionally be administered with a meal whose fat content ranges from about 15% by weight to about 25% by weight or more.
    [023] According to the method, any of the following pharmacokinetic parameters can be achieved in the subject:(a) Serum testosterone Cmax within 900 and 1100ng/dL in the subject;(b) substantially no pharmacokinetic variation of daytime testosterone;(c) serum Tmax 3 to 7 hours after administering the composition; and (d) substantially no decline in serum testosterone response is observed on repeated dosing.
    [024] In this regard, before explaining at least one embodiment of the invention in detail, it is further understood that the invention is not limited in this application to the construction details and component arrangements set out in the following description or illustrated in the drawings. The invention is capable of modalities beyond those described and of being practiced and conducted in various ways. Furthermore, it should be understood that the phraseology and terminology employed here, as well as the abstract, are for the purpose of description and should not be considered limiting.
    [025] As such, those skilled in the art will appreciate that the design on which this disclosure is based can readily be used as a basis for the design of other fractions, methods and systems to carry out the various purposes of the present invention. For example, some embodiments of the invention may combine TU with other active drugs, including other hormones, in an oral delivery system that, in part, prevents or alleviates symptoms associated with testosterone deficiency. It is important, therefore, that the claims are considered to include such equivalent constructions, which do not depart from the scope and spirit of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS
    [026] Figure 1 provides serum T levels over a 24-hour period of once or twice a day orally of a TU formulation of the invention.
    [027] Figure 2 shows a serum T response over time in hypogonadal men on administration of a formulation of the invention vs. a conventional oral TU formulation comprising TU in oleic acid (Restandol).
    [028] Figure 3 provides Tmax values of serum T levels in subjects containing consumed meals of varying fat content (as a percentage by weight) prior to oral administration of a TU formulation of the invention.
    [029] Figure 4 provides Cmax values of serum T levels in subjects having consumed meals of varying fat content (as a percentage by weight) prior to oral administration of a TU formulation of the invention.
    [030] Figure 5 provides area under the curve (AUC) values of serum T levels in subjects having consumed meals of varying fat content (as a percentage by weight) prior to oral administration of a TU formulation of the invention. DETAILED DESCRIPTION OF THE INVENTION
    [031] The present invention provides an oral pharmaceutical composition comprising TU, which when administered no more than twice a day to hypogonadal men, provides steady-state serum levels of testosterone (concentrations) in said men, who are within a desired range of “normal” or eugonadal (ie, about 300 to 1100 ng/dL) while avoiding high Cmax values that are considered by the United States Food and Drug Administration to be undesirable, if not unacceptable. For example, FDA approval guidelines state that less than 85% of treated subjects have a Cmax value of 1500 ng/dL or greater, and that none can have a Cmax value exceeding 2500 ng/dL. Less than 5% of treated subjects may have a Cmax value that is in the range of 1800 to 2500 ng/dL. In addition, the formulations of the invention are designed to be self-emulsifying drug delivery systems (SEDDS) so that a TU-containing emulsion (or dispersion) is formed in admixture with intestinal fluids in the gastrointestinal tract.
    [032] In one embodiment of the present invention, testosterone and/or esters at the C-17 position of the testosterone molecule, alone or in combination with other active ingredients, can be orally released using the inventive formulation. For example, the combination of testosterone undecanoate with an orally active Type I or Type II 5α-reductase inhibitor or the combination of testosterone undecanoate with a synthetic progestin may be preferred in some embodiments.
    [033] While many of the embodiments of the present invention will be described and exemplified with the acid ester of testosterone undecanoate (i.e., TU), other hydrophobic ester compounds, including T, can be adopted for oral release based on the teachings of the specification. Indeed, it should be readily apparent to those skilled in the art from the teachings herein that the inventive drug delivery systems and compositions thereof may be suitable for oral delivery of other testosterone esters, such as those of short chain fatty acids ( C2C6), medium chain (C7-C13) and long chain (C14-C24), preferably medium chain fatty acid esters of testosterone.
    [034] The formulations of the present invention comprise a T-ester dissolved in a mixture comprising one or more preferred lipophilic and one or more hydrophilic surfactants. A lipophilic surfactant as defined herein has a hydrophilic-lipophilic balance (HLB) value of less than 10, and preferably less than 5. A hydrophilic surfactant herein has an HLB value of more than 10. (HLB is an empirical expression for the ratio of hydrophilic and hydrophobic groups of an amphiphilic surface active molecule such as a surfactant. It is used to index surfactants and its values range from about 1 to about 45 and include both nonionic and ionic surfactants. , more soluble/dispersible in water is the surfactant.)
    [035] According to an aspect of the present invention, each of the components of the delivery system (ie lipophilic and hydrophilic surfactants) individually having solubilizing characteristics and contributes, in part, to solubilize the active ingredient. Those preferred lipophilics which substantially contribute to drug dissolution are defined herein as "primary" solvents. It should be appreciated, however, that solubility can be affected by solvent/formulation temperature. The formulations of the present invention comprising, for example, about 20% testosterone undecanoate, remain soluble at or above 30°C, including in the range of 30 to about 40°C.
    [036] A hydrophilic surfactant component may be required to achieve desirable dispersibility of the formulation in the GI tract and drug release. That is, a hydrophilic surfactant, in addition to serving as a secondary solvent, may be required to release the drug from within the lipid carrier matrix, or primary solvent. In this regard, a high HLB surfactant such as Cremophor RH40 can generally be satisfactory. High HLB surfactant levels (amounts) can be adjusted to provide optimal drug release without compromising active ingredient solubilization.
    [037] Preferred lipophilic surfactants suitable in drug delivery systems of the present invention include: Fatty acids (C6-C24, preferably C10-C24, more preferably C14-C24), e.g., octanoic acid, decanoic acid, undecanoic acid, lauric acid , myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid. Oleic acid is preferred. Fatty acid mono- and/or di-glycerides, such as Imwitor 988 (glyceryl mono-/di-caprylate), Imwitor 742 (glyceryl mono-/di-caprylate/caprate), Imwitor 308 (glyceryl mono- caprylate), Imwitor 191 (glyceryl mono-stearate), Softigen 701 (glyceryl mono-/di-ricinoleate), Capmul MCM (glyceryl mono-/di-caprylate/caprate), Capmul MCM(L) (liquid form of Capmul MCM) , Capmul GMO (glyceryl monooleate), Capmul GDL (glyceryl dilaurate), Maisine (glyceryl monolinoleate), Peceol (glyceryl monooleate), Myverol 18-92 (monoglycerides distilled from sunflower oil) and Myverol 18 -06 (monoglycerides distilled from hydrogenated soybean oil), Precirol ATO 5 (glyceryl palmitostearate) and Gelucire 39/01 (semi-synthetic glycerides, ie C12-18 mono-, di- and tri-glycerides). Preferred members of this class of preferred lipophilics are the partial glycerides of oleic, palmitic and stearic acids and mixtures thereof. Acetic, succinic, lactic, citric and/or tartaric esters of mono- and/or di-glycerides of fatty acids, per example, Myvacet 9-45 (distilled acetylated monoglycerides), Miglyol 829 (caprylic/capric diglyceryl succinate), Myverol SMG (mono/disuccinylated monoglycerides), Imwitor 370 (glyceryl stearate citrate), Imwitor 375 (glyceryl monostearate/citrate) and Crodatem T22 (diacetyl tartaric esters of monoglycerides). Propylene glycol mono- and/or di-esters of fatty acids, for example, Lauroglycol (propylene glycol monolaurate), Mirpyl (propylene glycol monomyristate), Captex 200 (propylene glycol dicaprylate/dicaprate) , Miglyol 840 (propylene glycol dicaprylate/dicaprate) and Neobee M-20 (propylene glycol dicaprylate/dicaprate). Polyglycerol fatty acid esters such as Plurol oleic (polyglyceryl oleate), Caprol ET (polyglyceryl mixed fatty acids) and Drewpol 10.10.10 (polyglyceryl oleate).Low ethoxylate castor oil (HLB<10) as Etocas 5 (5 moles of ethylene oxide reacted with 1 mole of castor oil) and Sandoxylate 5 (5 moles of ethylene oxide reacted with 1 mole of castor oil). Acid and ester ethoxylates formed by reaction of ethylene oxide with fatty acids or glycerol fatty acid esters (HLB<10) such as Crodet 04 (polyoxyethylene (4)) lauric acid), Cithrol 2MS (polyoxyethylene (2) stearic acid), Marlosol 183 (polyoxyethylene (3) stearic acid) and Marlowet G12DO (glyceryl 12 EO dioleate). Sorbitan fatty acid esters, eg Span 20 (sorbitan monolaurate) , Crill 1 (sorbitan monolaurate) and Crill 4 (sorbitan monooleate). Transesterification products of triglycerides from natural or hydrogenated vegetable oil and a polyalkylene polyol (HLB<10), eg Labrafil M1944CS (Apricot Seed Oil polyethoxylated), Labrafil M2125CS (oil and polyoxyethylated corn) and Gelucire 37/06 (polyoxyethylated hydrogenated coconut). Labrafil M1944CS is preferred. Alcohols ethoxylates (HLB<10), eg Volpo N3 (polyoxyethylated (3) oleyl ether), Brij 93 (polyoxyethylated (2) oleyl ether), Marlowet LA4 (polyoxyethylated (4) lauryl ether).Pluronics , for example, polyoxyethylene-polyoxypropylene (HLB<10) copolymers and block copolymers, for example, Synperonic PE L42 (HLB = 8) and Synperonic PE L61 (HLB = 3). Suitable preferred lipophilic blends such as those listed above , can be used if desired, and in some cases are considered to be advantageous.
    [038] Any pharmaceutically acceptable hydrophilic surfactant (ie, containing an HLB value greater than 10) can be used in the present invention. Some non-limiting examples include: Castor oil or castor oil hydrogenated ethoxylates (HLB>10), e.g. Cremophor EL (polyoxyethylene (35) castor oil), Cremophor RH40 (polyoxyethylene (40) hydrogenated castor oil), Etocas 40 (polyoxyethylene (40) castor oil), Nikkol HCO-60 (polyoxyethylene (60) hydrogenated castor oil), Solutol HS-15 (polyethylene glycol 660 hydroxystearate), Labrasol (caprilocaproyl macrogol-8 glycerides), α-tocopherol- polyethylene glycol-1000-succinate (TPGS) and ascorbyl-6 palmitate. Cremophor RH40 is preferred. Polyoxyethylene sorbitan fatty acid derivatives, for example, Tween 20 (polyoxyethylene (20) monolaurate), Tween 80 (polyoxyethylene (20) monooleate), Crillet 4 (polyoxyethylene (20) monooleate) and Montanox 40 (polyoxyethylene (20) monopalmitate). Tween 80 (Polysorbate 80) is preferred. Gelucires, preferably Gelucire 50/13 (PEG mono- and diesters of palmitic acid and stearic acid. (In reference to Gelucires, the first number (ie, 50) corresponds to the melting point of the material and the second (ie 13) to HLB number.)Fatty acid ethoxylates (HLB>10), eg Myrj 45 (polyoxyethylene (8) stearate), Tagat L(polyoxyethylene (30) monolaurate), Marlosol 1820 (polyoxyethylene (20) stearate) and Marlosol OL15 (polyoxyethylene (15) oleate) Myrj 45 is preferred.Alcohol ethoxylates (HLB>10), eg Brij 96 (polyoxyethylene (10) oleyl ether), Volpo 015 (polyoxyethylene (15) oleyl ether), Marlowet OA30 (polyoxyethylene (30) oleyl ether) and Marlowet LMA20 (polyoxyethylene (20) C12-C14 fatty ether). Polyoxyethylene-polyoxypropylene (HLB>10) block copolymers and copolymers, which are commercially available under the brand name Pluronics or Poloxamers such as Poloxamers 188 and 407 still known as Syperonic PE L44 (HLB = 16) and Syperonic F127 (HLB = 22), respectively. Anionic surfactants, eg sodium lauryl sulfate, sodium oleate and sodium dioctylsulfosuccinate. Alkylphenol surfactants (HLB>10), eg Triton N-101 (polyoxyethylene (9-10) nonylphenol) and Synperonic NP9 (polyoxyethylene (9) nonylphenol).
    [039] As mentioned, in one aspect of the present invention, each of the components of the delivery system (ie, lipophilic and hydrophilic surfactants) individually has solvent characteristics and contributes, in part, to solubilize the active ingredient. Thus, without wishing to be bound by or limited to theory, the present invention does not require additional solvents such as co-solvents, but these may optionally be included in the inventive systems and formulations.
    [040] Optional co-solvents suitable with the present invention are, for example, water, short chain mono, di and polyhydric alcohols such as ethanol, benzyl alcohol, glycerol, propylene glycol, propylene carbonate, polyethylene glycol with an average molecular weight of about 200 to about 10,000, diethylene glycol monoethyl ether (eg, Transcutol HP), and combinations thereof. Preferably, said co-solvents, especially ethanol or other monoethanols, are excluded together.
    [041] Additional oils that may be incorporated into embodiments of the present invention include complete glycerol triesters of medium chain (C7-C13) or long chain (C14-C22) fatty acids with low molecular weight (up to Ce) mono, di alcohols. or polyhydric. Some examples of oils for use in this invention thus include: vegetable oils (eg soybean oil, safflower seed oil, corn oil, olive oil, castor oil, cottonseed oil, arachis oil, oil of sunflower seed, coconut oil, palm oil, rapeseed oil, evening primrose oil, grape seed oil, wheat germ oil, sesame oil, avocado oil, almond oil, borage, mint, and apricot seed) and animal oils (eg fish liver oil, shark oil and mink skin oil).
    [042] In other embodiments of the present invention, methods and compositions to modulate (ie, sustain) the available serum testosterone rate through the incorporation of components that can biochemically modulate (1) TU uptake, (2) TU metabolism to T, and/or (3) metabolism of T to dihydrotestosterone (DHT). For example, the inclusion of long-chain fatty acid esters can increase TU absorption. In this way, more TU can prevent hydrolysis in the intestine and enter the bloodstream. In other words, the fatty acid ester competitively inhibits esterases that could otherwise metabolize TU. Examples of other esters or combinations thereof include botanical extracts or benign esters used as food additives (eg propylparaben, octylacetate and ethylacetate).
    [043] Other components that can modulate TU uptake include synthetic “natural” and synthetic inhibitors of 5α-reductase, which is an enzyme present in enterocytes and other tissues that catalyzes the conversion of T to DHT. Complete or partial inhibition of this conversion can either increase or sustain increased serum T levels after oral dosing with TU while concomitantly reducing serum DHT levels. Borage oil, which contains a significant amount of the 5α-reductase inhibitor, gamma-linolenic acid (GLA), is an example of a “natural” modulator of TU metabolism. In addition to within the borage oil, of course, GLA could be added directly as a separate component of a TU formulation of the invention. Many natural 5α-reductase inhibitors are known in the art (for example, epigallocatechin gallate, a catechin derived primarily from green tea, and saw palmetto extract from Serenoa repens berries), all of which may be suitable in the present invention. Non-limiting examples of synthetic 5α-reductase inhibitors for use in the present invention include compounds such as finasteride, dutasteride and the like.
    [044] In addition to 5α-reductase inhibitors, the present invention contemplates the use of T metabolism inhibitors through other mechanisms. One such point of inhibition may be the cytochrome P450 CYP3A4 isozyme, which is present in enterocytes and liver cells and thus is capable of metabolizing testosterone. Thus, selected embodiments of the invention include peppermint oil, which is known to contain components capable of inhibiting CYP3A4 activity.
    [045] Other optional ingredients that can be included in the compositions of the present invention are those that are conventionally used in oil-based drug delivery systems, for example, antioxidants such as tocopherol, tocopherol acetate, ascorbic acid, butylhydroxytoluene (BHT) , ascorbyl palmitate, butylhydroxyanisole and propyl gallate; pH stabilizers such as citric acid, tartaric acid, fumaric acid, acetic acid, glycine, arginine, lysine and potassium hydrogen phosphate; thickening/suspending agents such as hydrogenated vegetable oils, beeswax, colloidal silicon dioxide, mannitol, gums, celluloses, silicates, bentonite; flavoring agents such as cherry, lemon, and anise flavors; sweeteners such as aspartame, acesulfane K, sucralose, saccharin and cyclamates; etc.
    [046] The present inventors have learned that the relative ratios of one or more preferred lipophilic and one or more hydrophilic surfactants can be critical to achieving the desired pharmacokinetics of the present invention. More specifically, the inventors have discovered a ratio of total lipophilic surfactant to total hydrophilic surfactant, which is not able to solubilize a relatively large amount of T-ester (eg greater than 15%, 18%, 20%, 22%, or 25%) but one that is still capable of providing optimal T-ester release from within the formulation. Preferably, the ratio of total oil (eg, oleic acid + borage oil + mint oil, all of which are considered to be preferred lipophilic) to hydrophilic surfactant (w/w) is in the range of about 6:1 to 1:1 , 6:1 to 3.1, 6:1 to 3.5:1, or 6:1 to 4:1; and more preferably, from about 5:1 to 3:1, and more preferably, from about 4:1 to 3:1.
    [047] The following relative concentrations, by weight, are preferred (the percentages are based on the total weight of the formulation): Hydrophilic surfactant: 10 to 20%, more preferably 12 to 18%, and most preferably 15 to 17%. 50 to 70%, more preferably 50 to 65%, and more preferably 50 to 55%. Other oils: 5 to 15%, more preferably 7 to 15%, and most preferably 10 to 13%. Drugs: 10 to 30%, more preferably 15 to 25%, and more preferably 18 to 22%.
    [048] The formulations of the present invention have self-emulsifying properties, forming a final emulsion on dilution with aqueous medium or intestinal fluids in vivo. In other words, the formulations can have a high surfactant and lipid content designed for optimal dispersion of the mixture in an aqueous medium. Qualitative description of the self-emulsification property of the inventive formulations can be visually observed during its dissolution in vitro. On the other hand, quantitative measurements can be taken of the particle size of the emulsified droplets using laser light scattering and/or turbidity measurements in the dissolution medium by UV/VIS spectrophotometer. Any of these methodologies are available and known to one of skill in the art.
    [049] The pharmaceutical compositions according to the present invention are preferably liquid or semi-solid at ambient temperatures. Furthermore, these pharmaceutical compositions can be transformed into solid forms by adsorption onto solid carrier particles, silicon dioxide, calcium silicate or magnesium aluminum metasilicate to obtain free-flowing powders that can be filled into hard capsules or compressed into tablets. . See, for example, US 2003/0072798, the disclosure of which is incorporated in its entirety by reference. Therefore, the term “solubilized” here should be interpreted to describe an active ingredient (API) which is either dissolved in a liquid solution or which is evenly dispersed in a solid carrier. Even sachet dosage forms can be formed and used.
    [050] The present invention preferably comprises an API that is solubilized in the presence of lipid surfactant excipients (eg any combination of lipophilic and hydrophilic surfactants noted above). Thus, the melting point of the surfactants used is a factor that can determine whether the resulting composition will be a liquid or semi-solid at room temperature. Particularly preferred compositions of the present invention are oral liquid unit dosage forms, most preferably filled in hard or soft capsules, for example, gelatin or non-gelatin capsules such as those made of cellulose, carrageenan or pollulan. The technology for lipid encapsulation based pharmaceutical preparations is well known to a person skilled in the art. As the inventive delivery systems described here are not limited to any encapsulation method, specific encapsulation techniques need not be discussed yet.
    [051] Drug carrier systems and pharmaceutical preparations according to the present invention can be prepared by conventional techniques for lipid-based drug carrier systems. In a typical procedure for preparing preferred carrier systems of this invention, a lipophilic surfactant component is weighed into a suitable stainless steel vessel and a surfactant component is then weighed and added to the vessel along with any additional component. In a preferred method, the hydrophobic drug may first be added to a lipophilic surfactant component (eg, oleic acid) and completely dissolved before adding a hydrophilic surfactant component. In either case, mixing of the components can be carried out by use of a homogenizing mixer or other high and high temperature shear device particularly when melting points of surfactants are used to ensure that all components are in a homogeneous liquid state before or after the addition of the drug.
    [052] In a situation where a hydrophobic drug is weighed and added to a combined lipid mixture, mixing is continued, preferably at high temperature, until a homogeneous solution is prepared. The formulation can be de-aerated prior to encapsulation in soft or hard capsules. In some cases, the fill formulation can be kept at temperature using an appropriate lined vessel to aid processing. Also, in some cases, the homogeneous solution can be filtered (eg through a 5 micron filter) before filling into the capsules.
    [053] Returning to testosterone release, the pharmaceutical compositions of the present invention may be suitable for testosterone therapy. Testosterone is the main endogenous in man. Leydig cells in the testes produce approximately 7 mg of testosterone each day resulting in concentrations ranging from about 300 to about 1100 ng/dL. Women also synthesize testosterone in both the ovary and adrenal gland, but the amount is about one-tenth that seen in eugonadal men. The majority (>98%) of circulating testosterone is bound to sex hormone-binding globulin and albumin and is biologically active only when released in free form. The term "free" is thus defined as not being bound to or confined within, for example, biomolecules, cells and/or lipid matrices of the inventive formulations described herein. Generally, “free” drugs described here refer to a drug that is accessible to metabolize enzymes circulating in the serum.
    [054] Although the present invention should not be limited to the release of testosterone or any particular ester thereof, TU has been shown to offer unique physical and chemical characteristics that make its use preferred in some modalities. The present inventors have learned that the acid ester of testosterone undecanoate, in particular, can lead to better bioavailability than found with other equivalent esters (eg, testosterone enanthate (TE)).
    [055] What's more, the use of TU in the formulations of the present invention is associated with a substantially lower serum DHT to T ratio than has been reported for other forms of T replacement - including oral TU formulations (Table 1). Testosterone interacts with androgen receptors directly or after its conversion to DHT through the action of 5α-reductase. DHT is a more potent androgen than testosterone and its elevated levels are believed by some scientists to increase the risk of prostate cancer. Thus, the present invention provides yet another advantage not expected by other known testosterone delivery vehicles. Table 1: Comparison of Serum DHT and DHT:TO Ratios Observed in Response to T Replacement by Various Routes of Administration

    1 Atkinson, LE, Chang, YL and Synder, PJ. (1998) Long-term experience with testosterone replacement through scrotal skin. In: Testosterone: Action, Deficiency and Substitution (Nieschlag, E and Behre, HM, eds). Springer-Verlag, Berlin, pp. 365-3882 Swerdloff, RS, et a (2000). Long-term pharmacokinetics of transdermal testosterone gel in hipogonadal men. J. Clin. Endocrinol. Metab. 85: 4500-4510.3 Wang, C et al (2004). Long-term testosterone gel (AndroGel®) treatment maintains beneficial effects on sexual function and mood, lean and fat mass and bone mineral density in hypogonadal men. J. Clin. Endocrinol. Metab. 89:2085-2098.4 Houwing, NS et al (2003). Pharmacokinetic study in women of three different doses of a new formulation of oral testosterone undecanoate, Andriol Testocaps. Pharmcotherapy: 23: 1257-1265.5 Gooren, LJG (1994). A ten-year safety study of the oral testosterone androgen undecanoate. J.Androl. 15:212215.
    [056] Specific embodiments of the present invention will now be described in non-limiting examples. Table 2 provides details of the composition of various TU formulations in accordance with the teachings of the present invention. For calculation purposes, 1 mg of T is equivalent to 1.58 mg of T undecanoate.
    [057] The composition details of Table 2 (mg/capsule and percent by weight) are based on an approximate filling weight of 800 mg fill weight per hard gelatin capsule '00'. However, at testosterone ester amounts less than about 100 mg/capsule, formulations can be proportionately adjusted to lower total fill weights that would allow for the use of smaller hard gelatin capsules (eg size '0' or smaller size if necessary).
    [058] As such, it should be apparent to one skilled in the art that many, if not all, surfactants within a category (eg lipophilic, hydrophilic, etc.) can be exchanged with another surfactant from the same category. Thus, while Table 1 lists formulations comprising oleic acid, one skilled in the art would recognize that other preferred lipophilics (for example, those listed above) may be suitable as such. Similarly, while Table 1 lists formulations comprising Cremophor RH40 (HLB = 13), one skilled in the art should recognize that other hydrophilic surfactants (eg those listed above) may be appropriate. Borage oil, peppermint oil, BHT, and ascorbyl palmitate can be replaced with similar chemicals or eliminated.


    1 Milligram weights rounded to almost the whole number; 800 (±10%)2 ± 8 mg
    [059] Preferred TU formulations filled in size "00" capsules according to the present invention are:

    [060] In vivo and in vitro performance data of the formulations according to the invention will be described below. However, the scope of the invention should not be limited to the following examples nor the specific formulations studied in the examples.Example 1 - Single Day Study
    [061] Formulation B has been studied for its single-day pharmacokinetic profile on once or twice daily administration for hypogonadal men. The study was designed as an open-label, single-day dosing, sequential, crossover pharmacokinetic study. Twelve (12) hypogonadal men were enrolled after giving informed consent, and all 12 subjects completed the study. Each subject received a daily dose of formulation B as follows:1. 200 mg T (as TU) QD, ie 2 capsules/dose.2. 200 mg T (as TU) BID (100 mg/dose), ie 1 capsule/dose.3. 400 mg T (as TU) BID (200 mg/dose).
    [062] Doses were administered as capsules to subjects five minutes after a meal (breakfast for QD, and breakfast and dinner for BID). Table 3 provides the relevant PK parameters from the study:

    a Values shown for half-life and time to maximum concentration are averages and range,b Indicated doses are in T equivalents. Each TU capsule contained 158.3 mg TU, which corresponds to 100 mg T equivalent.
    [063] The mean serum T concentration over the 24-hour period after dosing (Cavg) indicated a positive increase in serum T levels for all regimens studied, with the best response obtained in Regimen 3 (Cavg 385 ng/dL) . The mean peak T concentration observed in response to the oral T preparations evaluated in the study never exceeded the upper limit of normal (ie, 1100 ng/dL). And while some individual subjects had Cmax T values above the normal limit, the vast majority of these peaks were in the range of 1200 to 1400 ng/dL. No subject in any treatment arm had a Cmax in excess of 1500 ng/dL.
    [064] Mean serum half-life (T1/2) was approximately 15 hours for Regimens 1 and 2; for Regimen 3, T1/2 was 8 hours. In each regimen, serum DHT concentrations increased in conjunction with serum T levels. Mean DHT:T (Ravg) ratios at all times were modestly above the normal ranges as determined by liquid chromatography and mass spectroscopy (LC /MS/MS) (ie, 0.03-0.1), but were clinically not significant.
    [065] TU dosing at 200 mg T equivalent, BID with food generated the most promising results with 75% of subjects achieving a serum T Cavg above 300 ng/dL (lower normal eugonadal limit). Similarly, 75% of subjects achieved a mean serum T within the normal range (ie, 0.03 to 0.1 ng/dL). Those subjects who did not achieve a Cavg of at least 300 ng/dL were all above 200 ng/dL, indicating that a modest increase in TU dose could be an effective oral T replacement therapy in these subjects.
    [066] Serum T and DHT concentrations increased together in most subjects regardless of T-ester dose with excellent dose linearity for TU dose was observed when data were corrected for baseline serum T. Although the DHT:T ratios were modestly elevated, any elevation was considered clinically insignificant. Less inter-subject variability was observed with the formulation than equivalent formulations of other T-esters (eg, TE). Furthermore, in the “BID” dosing regimens, there was no difference in mean peak serum T concentrations or in 12-hour AUCs between the morning and evening dose.
    [067] Regarding safety, although headache was reported as an adverse effect, in each treatment regimen, no adverse events were reported by more than one subject. No adverse events or deaths occurred during the study, and no subjects prematurely discontinued the study due to adverse events. Therefore, all adverse events were considered to be of mild intensity.Examples 2 - Seven-Day Study
    [068] Formulation B has been studied for its acute tolerability and steady-state serum pharmacokinetic profile in two doses given twice daily to hypogonadal men. The study was designed as an open-label, repeated-dose, crossover (food effect-evaluated in one arm) pharmacokinetic study.
    [069] Twenty-nine (29) hypogonadal men were enrolled after giving written informed consent, 24 of whom completed the study. Each subject who completed the study received a Formulation B regimen as follows:1. 7 daily doses of 600 mg T as TU BID (300mg/dose), ie 3 capsules/dose.2. 8 daily doses of 400 mg T as TU BID (200mg/dose).
    [070] Doses were given as capsules to subjects 30 minutes after starting meals (breakfast and dinner), except for Day 8 when the morning dose was given on an empty stomach.
    [071] Peak exposure (Cmax) to T and total exposure (AUC) to T were dose-proportional after correction for endogenous baseline T. The time to peak T concentrations (Tmax) occurred approximately 4 hours after dosing with each of the treatments. As such, serum concentrations of both TU and DHTU have increased and are within the dosing range with concentrations at the beginning and end of the dosing range less than 20% of the peak concentration for TU and less than 25% of the peak concentration for DHTU. Baseline T concentrations due to endogenous T production progressively for each treatment. The observation is consistent with a progressive and persistent suppression of gonadotropins by exogenous T, thus resulting in reduced production of endogenous T. At least partial suppression was maintained for a 14-day washout period.
    [072] Again, serum T pharmacokinetics showed no diurnal variation with serum T concentrations. The nightly dose (administered at approximately 8 PM) produced a similar concentration-time profile as the daytime dose (administered at approximately 8 AM) (Figure 1) . In view of similarity between concentrations after day and night doses (evaluated in Regimen 1), 12-hour PK data from Regime 2 (fed) were used to accurately predict a complete 24-hour PK profile in response to 200 mg T (as TU), BID dosage. The simulated results indicated that (a) 77% of subjects achieved a serum T Cavg in the eugonadal range over the 24-hour period based on AUC thus meeting the current FDA efficacy requirement of 75% for a T-replacement product; and (b) none of the subjects had a Cmax in excess of 1500 ng/dL, which exceeds current FDA criteria which is less than 85% of subjects with a Cmax greater than 1500 ng/dL for a T replacement product Therefore, still consistent with current FDA-required efficacy endpoints, no subject had a Cmax in excess of 2500 ng/dL and less than 5% of the subjects studied had a Cmax in the 1800-2500 ng/dL range. It is noteworthy that these results were achieved in the absence of any dose adjustment. Table 4 provides a comparison of a steady-state PK between Morning and Afternoon T with BID Dosing:


    [073] Administration of TU as a high-fat meal produces a similar serum T-concentration-time profile as administration with a standard meal. In contrast, administration of TU under fasted conditions resulted in a greater than 50% reduction in serum T exposure (Cmax and AUC). Table 5. In all cases, a strong correlation between the observed Cmax and the calculated Cavg was observed, suggesting that targeting a particular Cavg with the oral T-ester formulation may result in predictable peak T levels after dosing.

    [074] DHT concentrations tracked T concentrations, although DHT concentrations were only 11-34% of T concentrations. The conversion of T to DHT showed slight non-linearity, increasing at a rate less than the proportional concentration compared to T. The DHT/T ratio was lowest when T concentrations were highest, and the DHT/T ratio before the start of TU treatment was approximately 0.1, while during treatment, at steady-state, the ratio mean was 0.24 and ranged from approximately 0.1 to 0.35 depending on sampling time after oral TU was administered.
    [075] The mean estradiol concentration before the start of oral TU treatment was approximately 11 pg/ml, and ranged from 19 pg/ml to 33 pg/ml on Day 7 of the various treatments (pre-dose concentrations). Pre-dose steady-state estradiol concentrations were approximately 20 to 30 pg/mL. Example 3 - Four-Week Study
    [076] Formulation B was further studied to determine the time required to reach steady state when hypogonadal men are treated twice daily with twice daily dosing of 200 mg T (as TU) (ie 2 capsules/dose ). The study was designed as an open-label, repeat-dose pharmacokinetic study.
    [077] Fifteen (15) hypogonadal men were enrolled after giving written informed consent, and all completed the study. Each subject received twice-daily doses of 200 mg T as TU for 28 days.
    [078] For each subject, serial PK sampling from “Day 28” was scheduled for Day 32 of the study. Therefore, each dose-compliant subject received a total of 31 daily doses of 400 mg T as TU (ie, 200 mg T, BID), and a final morning dose of 200 mg T as TU. Doses were administered as capsules, with the instructed subjects taking doses 30 minutes after starting meals (breakfast and dinner). Table 6 provides the relevant PK data from the study:


    [079] 86.7% of the subjects reached T Cavg within the normal range, with no subjects containing Cmax concentrations greater than 1800 ng/dL, and with just 13.3% of subjects having Cmax concentrations greater than 1500 ng/dL. (Note: No dose adjustments were made during the course of the study to titrate subjects to be within the targeted efficacy and safety ranges.) The half-life of T in response to TU in the tested formulation was appreciably longer than that reported for T alone or for orally administered TU in prior art formulations. For example, in clinical studies of an oral formulation of TU consistent with the invention described herein, an elimination half-life (α phase) of about 5 hours was observed compared to a value estimated to be about half that (or ie, 2 to 3 hours) based on published serum T profiles after oral dosing of a prior art TU formulation. A long (i.e. terminal) elimination half-life of 29 hours was further observed with the inventive TU oral formulation. The production of endogenous T, however, by administration of exogenous T, with only limited suppression occurring for the first 3 days, and requiring 5-7 days of continued treatment for maximum suppression.
    [080] T and DHT concentrations reached steady state by Day 7 of treatment. T and DHT concentrations were higher on Day 3 than on Day 5, indicating that a period of time was required for exogenously administered T to suppress endogenous T production thus allowing steady state to be achieved in response to an oral TU. In fact, the addition of exogenous T suppressed endogenous T levels from pre-treatment of 276 ng/dL to 108 ng/dL after 28 days of treatment with supplemental T.
    [081] Significantly, however, once steady state was reached for serum T in response to twice daily oral TU, little to no decline in serum T response was observed over time (ie, none trend towards serum T level without continued TU assay). For example, the Cavg on Day 15 was substantially similar to the Cavg observed on Day 28 (Figure 2). In contrast, oral TU formulations in the technique have been reported to trend toward a lower mean T over time (Cantrill, J.A. Clinical Endocrinol (1984) 21: 97-107). In hypogonadal men treated with an oral TU formulation, known in the art, it was reported that the serum T response observed after 4 weeks of therapy was about 30% less than that seen on the initial day of therapy in hypogonadal men - the majority of which they had a form of a primary hypogonadism and thus lower serum T levels (eg, <100 ng/dL), so the reduction in T cannot be explained by isolated endogenous T suppression].
    [082] Serum DHT concentrations closely followed T concentrations, with DHT DHT/T values increasing 4- to 7-fold during treatment. The mean DHT/T ratio over a 12 hour dose range was 0.245, although values over a dose range ranged from a mean peak ratio of 0.380 to a mean trough ratio of 0.131. DHT concentrations returned to pretreatment levels within 36 hours of treatment discontinuing oral TU. However, T concentrations did not return to pretreatment levels as quickly, ostensibly because the suppression of endogenous T production/release is not as quickly reversed.
    [083] Estradiol (E2) concentrations showed a progressive monotonic rise to steady state, which was further reached by Day 7 of treatment. E2 concentrations still showed systematic variation over the dosing interval that accompanied changes in T. The mean values of Cmax, Cavg, and Cmin for E2 were 30.6 pg/mL, 22.0 pg/mL, and 15.5pg/ mL, respectively. E2 concentrations returned to pretreatment levels within 36 hours of discontinuation of oral TU treatment.
    [084] The mean concentrations of Cmax, Cavg, and Cmin in steady state (Day 28 morning dose) for T were 995 ng/dL, 516 ng/dL, and 199 ng/dL, respectively. Median Tmax to T occurred at 5.0 hours after dosing. Cmin averages 23.5% of Cmax, resulting in a fluctuation index of 156%. The elimination half-life of T could only be assessed in about half of the subjects, and its median value in those subjects was 18.4 hours (mean T1/2 was 29 hours).
    [085] Any effect of dietary fat on the pharmacokinetics of Formulation B in hypogonadal men was studied in an open-label, two-center, five-way crossover study. After a washout period of 4-10 days, a single dose of 300 mg T (475 mg TU, 3 capsules of Formulation B) was administered to sixteen hypogonadal men with a basal serum T level of 205.5+25.3 ng/dL (mean ± SE, range 23-334.1 ng/dL). Subjects were randomized to receive the drug in the fasting state or 30 minutes after consumption of meals containing ~800 calories with specific amounts of fat (% by weight): very little fat (6 to 10%); low fat (20%); “normal” fat diet (30%); or high in fat (50%). The “normal” diet was a priori established as the comparator (ie, reference diet) for statistical comparison purposes. Serum blood samples were collected for a total of 24 hours after drug administration to determine serum testosterone and dihydrotestosterone (DHT) levels by liquid chromatography-mass spectroscopy (LC/MS/MS).
    [086] The pharmacokinetic parameters (Table 7, Figures 3-5) observed for serum T in response to a single high-dose oral TU were shown to be similar for a low-fat diet and normal-fat diet - in fact both were bioequivalent ( that is, the 90% confidence interval was between 85 to 125%). Tsérica's PK parameters were further observed when normal and high-fat meals were compared. And although the high-fat meal generated a higher serum T-response (although not statistically significant), the mean least squares ratio was within 70 to 143% when compared to the normal fat meal - a clinically non-significant difference of <30 %.
    1CAvg is calculated as AUC /T (T = dose interval = 12 hours for BID dose)
    [087] The variability in PK response appeared to be greatest after the first dose, or first after some doses of oral TU and decreased as therapy continued. Consequently, any impact of dietary fat across the low-normal target range on serum T PK parameters is likely to be negligible during chronic dosing. This stance is consistent with the findings of PK from the 7-day treatment (Example 2) and from the 30-day treatment (Example 3), where repeated dose studies of oral TU where PK under different meal conditions still showed similar results for Cmax and Cavg distributions [both studies administered 200 mg T (as TU), BID].
    [088] Statistical comparisons of serum T-response observed after oral TU is taken without food or with a very low-fat, low-fat, or high-fat diet versus a normal-fat diet (ie, reference diet) revealed that there was no statistically significant difference at p<0.05 level between low-fat or high-fat diets versus the normal diet. Conversely, administration of oral TU as the SEDDS formulation while fasting or with a very low-fat breakfast generated significantly different (i.e., lower) serum T PK parameters from a normal diet. Thus, the fat content of meals received with the inventive formulations may differ substantially from "normal", without a clinically significant impact on the T levels obtained. Thus, a patient is allowed flexibility in meal-to-meal, and day-to-day eating habits that may not hitherto be possible with known oral TU formulations. Oral TU formulations known in the art to date have been unable to achieve any significant serum T level in the fed state. Example 5 - In vitro dissolution tests
    [089] The dissolution studies of formulations of the present invention were studied in vitro to assess their correlations with the PK profiles observed in vivo. In a first study, the dissolution of Formulation B was studied. Andriol Testocaps® (40 mg TU per softgel dissolved in a mixture of castor oil and propylene glycol laurate) was included for comparison. The study was conducted with essentially equivalent doses of TU, ie 1 Formulation B capsule (158.3 mg TU) and 4 Testocaps softgels (4x40 mg = 160 mg TU). Dissolution (ie, the release of TU from the respective formulations) was studied in Fed-State Simulated Intestinal Fluid (FeSSIF) medium, which simulates the intestinal fluid on stimulation by a meal. FeSSIF contains sodium hydroxide, glacial acetic acid, potassium chloride, lecithin, and sodium taurocholate. The final emulsion is adjusted to pH 5.0.
    [090] The data are presented in Tables 8 and 9 demonstrate that the inventive formulation released approximately 40% of TU within the first 30 minutes and about 60% of the total capsule after 4 hours. For Testocaps®, however, there is little or no drug released (1%) for all 4 hours. The main difference observed in TU dissolution from these two formulations can be attributed, at least in part, to the presence of hydrophilic surfactant, eg Cremophor RH40, in Formulation B. In contrast, Andriol Testocaps® (incorporating an oil (Oil) of Castor) and a lipophilic surfactant (Propylene Glycol Laureate) only.

    [091] In a second study, Formulation A was subjected to a similar test, but using a 5% Triton X100 potassium phosphate buffer (pH 6.8) as a dissolution medium. Results are given in Table 10 below. In this study, 98% of the TU of the inventive formulation was released within the first 15 minutes of dissolution and once again the presence of hydrophilic surfactant Cremophor RH40 certainly facilitated this rapid dissolution and release of TU.

    [092] In yet another embodiment of the present invention, the pharmaceutical compositions disclosed herein may further be appropriate to alleviate some of the side effects of certain strategies for male contraception. For example, progestin-based male contraception substantially suppresses luteinizing hormone (LH) and follicle stimulating hormone (FSH), and thus suppresses spermatogenesis, resulting in clinical azoospermia (defined as less than about 1 million sperm/mL of semen for 2 consecutive months). However, progestin administration still has the undesirable side effect of significantly lowering steady-state testosterone levels.
    [093] In such situations, for example, it may be preferable to provide progestin preparations concomitantly with or a testosterone derivative (eg, TU). More preferably, a pharmaceutical preparation according to the invention is provided, comprising progestin - in an amount sufficient to substantially suppress the production of LH and FSH - in combination with testosterone. In some modalities, the pharmaceutical preparation is for oral delivery once a day.
    [094] The formulations of the present invention can provide extended-release formulations that can release serum testosterone for several hours. In fact, the serum testosterone half-life according to the invention is between 3 and 7 hours, preferably greater than 4, 5, or 6 hours. The serum half-life of testosterone in men, in contrast, is considered to be in the range of 10 to 100 minutes.
    [095] Without wanting to bind or limit theory, it is believed that inventive formulations achieve these results, in one aspect, by increasing the absorption of a drug in them by the intestinal lymphatic system rather than through the portal circulation. In another aspect, again without being bound by or limiting theory, it is believed that using a testosterone ester, the time required for deesterification to occur contributes to a longer half-life of T.
    [096] The oral dosages of the present invention can be taken by a patient in need of testosterone therapy once every about twelve hours to maintain desirable serum testosterone levels. In a more preferred embodiment, oral dosages are taken by a patient in need of testosterone therapy once every about twenty-four hours. In general, "desirable" testosterone levels are those levels found in a human subject characterized as not deficient in testosterone.
    [097] Although the invention has been described in relation to specific embodiments thereof, it will be understood that it is capable of other modifications and this application is intended to cover any variations, uses or alterations of the invention below. In general, the principles of the invention and including those departures from the present disclosure, as they come within customary practice or known in the art to which the invention belongs, and how it may be applied to the essential characteristics set forth above and as hereinafter within the scope of the appended claims .
    权利要求:
    Claims (11)
    [0001]
    1. ORAL PHARMACEUTICAL COMPOSITION, characterized by comprising: a. 18-22 weight percent solubilized testosterone undecanoate; b. 50-55 percent by weight of at least one lipophilic surfactant; c. 15-17 percent by weight of at least one hydrophilic surfactant; d. 10-13 percent by weight of other oils; and is. a 5-α reductase inhibitor, wherein said lipophilic surfactant is oleic acid, said hydrophilic surfactant is polyoxyethylene (40) hydrogenated castor oil, and said 5-α reductase inhibitor is borage oil.
    [0002]
    2. COMPOSITION according to claim 1, characterized in that it comprises an inhibitor of isoenzyme P450 CYP3A4.
    [0003]
    3. COMPOSITION according to claim 1, characterized in that said hydrophilic surfactant is polyoxyethylene (40) hydrogenated castor oil.
    [0004]
    4. COMPOSITION according to claim 1, characterized in that at least one lipophilic surfactant comprises oleic acid.
    [0005]
    5. COMPOSITION according to claim 1, characterized in that the 5-α reductase inhibitor is borage seed oil.
    [0006]
    6. COMPOSITION according to claim 2, characterized in that said inhibitor of isoenzyme P450 CYP3A4 is peppermint oil.
    [0007]
    A COMPOSITION according to claim 1, characterized in that it comprises: (a) 19.8 percent by weight of detestosterone undecanoate; (b) 51.6 percent by weight of oleic acid; (c) 16.1 per percent by weight polyoxyethylene (40) hydrogenated castor oil; and (d) 0.03 percent butylhydroxytoluene (BHT).
    [0008]
    The COMPOSITION of claim 7, characterized in that said composition comprises 10 percent by weight of 5-α reductase inhibitor, and wherein the 5-α reductase inhibitor is borage seed oil.
    [0009]
    A COMPOSITION according to claim 7, characterized in that it comprises 2.5 percent by weight of isoenzyme inhibitor p450 CYP3A4 and wherein the isoenzyme inhibitor P450 CYP3A4 is peppermint oil.
    [0010]
    10. COMPOSITION according to claim 7, characterized in that the ratio of lipophilic surfactants to hydrophilic surfactants is 4:1.
    [0011]
    11. COMPOSITION according to any one of claims 1 or 7, characterized in that testosterone undecanoate is dissolved in a solution above 30°C.
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    同族专利:
    公开号 | 公开日
    CA2795908A1|2011-10-20|
    EP2803350B1|2017-09-20|
    BR112012025961A2|2018-05-15|
    JP2013523880A|2013-06-17|
    KR20130074770A|2013-07-04|
    WO2011129812A1|2011-10-20|
    HK1180593A1|2013-10-25|
    MX2012011952A|2013-02-07|
    MX352328B|2017-11-21|
    IL222315D0|2012-12-31|
    CN102883710A|2013-01-16|
    SG184540A1|2012-11-29|
    ZA201207517B|2013-06-26|
    JP5992397B2|2016-09-14|
    EP2558073A1|2013-02-20|
    CA2795908C|2015-10-13|
    EP2803350A1|2014-11-19|
    KR101460871B1|2014-11-11|
    AU2010351080A1|2012-11-01|
    IL222315A|2017-07-31|
    NZ602821A|2014-07-25|
    DK2558073T3|2014-12-08|
    AU2010351080B2|2014-08-28|
    EP2558073B1|2014-09-10|
    ES2525520T3|2014-12-26|
    CN102883710B|2014-09-10|
    RU2012142997A|2014-06-20|
    KR20140012215A|2014-01-29|
    KR101607034B1|2016-03-28|
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    法律状态:
    2018-06-12| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-06-19| B25G| Requested change of headquarter approved|Owner name: CLARUS THERAPEUTICS, INC. (US) |
    2019-01-29| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2019-12-17| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2019-12-24| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-05-19| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]|
    2020-10-27| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|
    2021-02-02| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|
    2021-05-11| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-06-15| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 12/04/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/US2010/030788|WO2011129812A1|2010-04-12|2010-04-12|Oral testosterone ester formulations and methods of treating testoterone deficiency comprising same|
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