oral pharmaceutical composition in the form of a capsule or tablet comprising 17-hydroxyprogesterone

专利摘要:
oral pharmaceutical composition, pharmaceutically acceptable oral dosage form and use thereof in one embodiment, the present invention provides bioavailable oral dosage forms containing 17-hydroxyprogesterone esters, as well as related methods. oral dosage forms can be formulated to support pregnancy and can include a therapeutically effective amount of a 17-hydroxyprogesterone ester and a pharmaceutically acceptable carrier. in another embodiment, a pharmaceutically acceptable oral dosage form to support pregnancy or non-pregnancy is provided. the pharmaceutically acceptable oral dosage can include a therapeutically effective amount of a 17-hydroxyprogesterone ester and a pharmaceutically acceptable carrier. the oral dosage form, when measured using a usp type-ii dissolution apparatus in 900 ml of deionized water with 0.5% (w / v) sodium lauryl sulfate at 50 rpm at 37 ° c, releases at least 20 % by weight plus 17-hydroxyprogesterone ester after 60 minutes or alternatively releases at least 20% by weight more after 60 minutes than an equivalent oral dosage form without the carrier.
公开号:BR112014001942B1
申请号:R112014001942
申请日:2012-07-27
公开日:2020-04-22
发明作者:Chickmath Basawaraj；Giliyar Chandrashekar；Nachiappan Chidambaram；V Patel Mahesh；Kumar Nachaegari Satish；Venka Teshwaran Srinivansan
申请人:Lipocine Inc；
IPC主号:

专利说明:

(54) Title: ORAL PHARMACEUTICAL COMPOSITION IN THE FORM OF A CAPSULE OR A TABLET UNDERSTANDING 17-HYDROXYPROGESTERONE CAPROATE AND USE OF THE REFERRED COMPOSITION FOR TREATING A PREGNANT PREGNANT FEMALE SUBJECT TO RISK OF 31.3 PREMATURE (51) INT. 57; A61K 31/56; A61K 9/48; A61K 9/20; A61K 47/30.
(30) Unionist Priority: 07/28/2011 US 13 / 193,571.
(73) Holder (s): LIPOCINE INC.
(72) Inventor (s): CHANDRASHEKAR GILIYAR; SRINIVANSAN VENKA TESHWARAN; BASAWARAJ CHICKMATH; SATISH KUMAR NACHAEGARI; CHIDAMBARAM NACHIAPPAN; MAHESH V. PATEL.
(86) PCT Application: PCT US2012048708 of 7/27/2012 (87) PCT Publication: WO 2013/016697 of 1/31/2013 (85) Date of Beginning of the National Phase: 27/01/2014 (57) Summary: ORAL PHARMACEUTICAL COMPOSITION, PHARMACEUTICALLY ACCEPTABLE ORAL DOSAGE FORM AND USE OF THE SAME In one embodiment, the present invention provides bioavailable oral dosage forms containing 17-hydroxyprogesterone esters, as well as related methods. Oral dosage forms can be formulated to support pregnancy and can include a therapeutically effective amount of a 17-hydroxyprogesterone ester and a pharmaceutically acceptable carrier. In another embodiment, a pharmaceutically acceptable oral dosage form to support pregnancy or non-pregnancy is provided. The pharmaceutically acceptable oral dosage can include a therapeutically effective amount of a 17-hydroxyprogesterone ester and a pharmaceutically acceptable carrier. The oral dosage form, when measured using a USP Type-ll dissolution apparatus in 900 mL of deionized water with 0.5% (w / v) sodium lauryl sulfate at 50 RPM at 37 ° C, releases at least 20 % by weight plus 17-hydroxyprogesterone ester after 60 minutes or alternatively releases at least 20% by weight more after 60 minutes than an equivalently dosed oral dosage form without the carrier.
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ORAL PHARMACEUTICAL COMPOSITION IN THE FORM OF A CAPSULE OR A TABLET UNDERSTANDING 17 HYDROXYPROGESTERONE CAPROATE AND USE OF THE REFERRED COMPOSITION TO TREAT A PREGNANT PREGNANT FEMALE SUBJECT AT RISK OF PREMATURE BIRTH
FIELD OF THE INVENTION
The present invention relates to compositions containing 17h hydroxyprogesterone ester, its oral dosage forms and associated methods. In this sense, this invention involves the fields of chemistry, pharmaceutical sciences, medicine and other health sciences.
BACKGROUND OF THE INVENTION
17-alpha hydroxyprogesterone (referred to alternatively below as 17hhydroxyprogesterone or 17HP) is an endogenous C-21 steroid hormone, produced during the synthesis of glucocorticoids and sex steroids. Like progesterone, 17HP is a natural progestogen. This has been isolated from both the adrenal glands and the corpus luteum. 17HP esters are reported to have progestogenic effects and therefore can be used for indications related to support for pregnancy, as well as support for non-pregnancy in pre- and post-menopausal women. It is reported that 17HP, without esterification, has no progestational activity. However, synthetic 17HP esters, such as 17-hydroxyprogesterone acetate or 17-alphahydroxyprogesterone caproate (also referred to below as 17 hydroxyprogesterone caproate or 17 HPC) have been shown to exhibit marked progestational activity when administered intramuscularly in experiments with animals. 17-hydroxyprogesterone caproate is a commonly used progestin available for intramuscular injection to prevent Premature Birth (alternatively referred to below as PTB). This synthetic caproate ester is supposed to be inactive when administered through the mouth, but functions as a long-acting progestin when administered intramuscularly. The metabolism of 17HP and the metabolism of 17-hydroxyprogesterone caproate in the human female are not yet fully established. Human and animal data indicate that intramuscularly administered 17-hydroxyprogesterone caproate has a more potent progestational effect on the endometrium and is more durable than progesterone (alternatively referred to below as P). This may be due to a more avid binding of 17-hydroxyprogesterone caproate to progesterone receptors (referred to alternatively below as PR) and placental glucocorticoid receptors (referred to alternatively below as GR) that could prevent an increase in the release hormone. placental corticotropin, which
Petition 870190127031, of 12/02/2019, p. 15/21
2/69 is associated with the onset of labor. The 17-hydroxyprogesterone caproate is supposed to be effective in providing luteal support in patients undergoing IVF Embryo Transfer Cycles.
PTB is clinically defined as delivery at 20 to 36 weeks of gestation. According to the 2009 Center for Disease Control Reporting, PTB occurs in about 12.3% of births in the United States alone, which translates to about half a million PTBs annually. Spontaneous PTB accounts for approximately 70-80% of PTB. Of all pregnancies in the United States, one in eight live births has been born prematurely, representing an increase of> 18% since 1990. Late preterm birth between 35-36 weeks of gestation contributes to more than half of all PTBs. PTB is the main cause of neonatal morbidity and mortality. The risk of mortality is three times greater in 35-36 weeks and morbidities, such as respiratory distress that requires oxygen, temperature instability, hypoglycemia, jaundice, attention deficit disorders, cerebral palsy, developmental delay, etc. are quite common, the time and costs related to PTB in intensive care are the main economic, social and health issue with an average cost of a quantity of PTB delivery up to 10x that of normal delivery.
The main risk factors involved in PTB are as follows: History of previous spontaneous PTB (past history of obstetrics), cervical length (<2.5 cm in mid-pregnancy), presence of fetal fibronectin in vaginal secretions; multiple pregnancy, low maternal body mass index (BMI), maternal race; maternal age (<17 and> 35 years) and smoking. The previous history of at least one PTB is a good indicator of the potential for future occurrence with 17-50% of recurrence potential and 28-70% of recurrence potential with two previous PTBs. The benefits of prolonged pregnancy for term delivery with therapeutic intervention include improved child survival due to gestational age and reduced neonatal hospital stay.
Intramuscular injection of 17-hydroxyprogesterone caproate is available to reduce the risk of PTB in women with single-stage pregnancies and a history of simple spontaneous PTB. The injection marketed as Makena® (250mg of 17-hydroxyprogesterone caproate in 1 mL) determines regular visits to the doctor's office, since the typical treatment cycle consists of 16-20 weeks of repeated injection each week. This therapy regime could result in an increase in the patient's distress and / or anxiety, in addition to
3/69 to increase the risk of repeated travel for the patient and the fetus. The interference of injection therapy with personal and family activities and disruptions in professional life are also a major disadvantage.
In addition, adverse events with the injection of 17h hydroxyprogesterone caproate (eg Makena®) once a week (every 7 days), reactions at the injection site (~ 45%), such as hives, itching, swelling, formation nodule and pain at the injection site were reported to be significant.
Hydroxyprogesterone esters, such as acetate, caproate, undecanoate are more lipophilic than hydroxyprogesterone. The active substance (17h hydroxyprogesterone caproate) in Makena® is known to be extremely insoluble in water (<20ng / mL) and very lipophilic with a ClogP of about 5.7. In addition, 17-hydroxyprogesterone caproate has the potential to be metabolized in the presence of fetal and adult hepatocytes and is a substrate for cytochrome inactivation, such as CYP3A4, which is excessively expressed in pregnant women (~ 40% positive regulation ). Due to its extremely low solubility in water and its potential to be susceptible to first-pass liver inactivation, the oral distribution of 17HP long-chain esters remained a challenge. It is reported that there is no oral activity with 17 hydroxyprogesterone caproate, a 17 HP ester, (Saxton DJ et.al. Reproductive Biology and Endocrinology 2004, 2:80 ', Greene MF, NJEM 348: 2453-2455) . This could probably be due to none or very poor bioavailability of 17 HPC. Although highly desired, the development of an active oral composition of a long-chain hydroxylprogesterone ester remains to this day a significant unmet need. In addition, the development of dosage forms that allow the administration of a smaller number of dosage units per dose and / or at a reduced frequency per day, is more often desirable.
SUMMARY OF THE INVENTION
Now surprisingly it has been found that 17HP esters can be effectively distributed orally in mammals. The oral pharmaceutical compositions and dosage forms of the present inventions can provide an effective bioavailability of a 17HP ester. In addition, the compositions and / or dosage forms disclosed in this document provide an enhancement of the effective release for 17 HP esters. It was also surprisingly found that a 17HP ester can be formulated in oral compositions and in their oral dosage forms with a higher w / w load
4/69 percentage of the ester. For example, it has been found that when one or more solubilizing agents, such as, for example, benzyl alcohol, benzyl benzoate etc., a significant amount (i.e. greater than 12% w / w) of the 17HP ester can be solubilized in the composition or dosage form. The increased drug load in the compositions and dosage forms of the current inventions can provide avid advantages, including, but not limited to, the reduced size or volume of the dosage unit (i.e., tablet, capsule, syrup, elixir, drink, etc.). ), the reduced number of dosage units to be taken by a single administration, better patient compliance, etc., as patients can usually take a smaller number of dosage units per day in order to obtain a sufficient dose to provide the desired effectiveness. In a different aspect, it was also surprisingly found that an effective bioavailability of the 17HP ester can be provided by the compositions of the current inventions which, when dispersed in an aqueous medium, provide clear or colloidal dispersions to nebulous or unclear, having the drug total or partially solubilized in the dispersions.
It has also been found that the compositions of the present invention allow the production of solid dosage forms, such as tablets, capsules, granules, spheres, particulate materials etc., which can solve the disadvantages of having the 17HP ester in the form of a liquid solution in the dosing unit. This eliminates a number of undesirable drawbacks, such as the specialized manufacturing process and / or equipment, poor chemical and / or physical stability of the typical ester for liquid solutions, due to the nature of the ester or solvents used and so on.
All oral dosage forms of the present inventions which have the drug in the form of a solution, suspension, particulate materials, etc., can be produced by conventional processing and manufacturing methods known in the art.
The present invention provides compositions and oral dosage forms containing 17HP esters, as well as related methods. Oral compositions and dosage forms can be formulated to include a therapeutically effective amount of a 17HP ester and a pharmaceutically acceptable carrier, in one embodiment, a pharmaceutically acceptable oral dosage form for supporting pregnancy and supporting non-pregnancy is provided. The pharmaceutically acceptable oral dosage can include a therapeutically effective amount of a 17HP ester and a pharmaceutically acceptable carrier. The shape
5/69 oral dosage, when measured using a USP Type-ll dissolution apparatus in 900 mL of deionized water with 0.5% (w / v) sodium lauryl sulfate at 50 RPM at 37 ° C, can release at least minus 20% by weight of the 17HP ester dose after 60 minutes.
In yet another embodiment, a pharmaceutically acceptable oral dosage form to support pregnancy or non-pregnancy is provided. The pharmaceutically acceptable oral dosage can include a therapeutically effective amount of a 17HP ester and a pharmaceutically acceptable carrier. The oral dosage form, when measured using a USP Type-ll dissolution apparatus in 900 ml of deionized water with 0.5% (w / v) sodium lauryl sulfate at 50 RPM at 37 ° C, can release at least 20% by weight plus 17HP ester after 60 minutes than an equivalent oral dosage form without the carrier.
In some respects, the oral dosage forms of the present invention can be used to treat pregnant female subjects who are at risk of premature birth. Such treatment methods may include the step of administering the oral pharmaceutical composition to the female subject orally. In some respects, the dosage amount is an amount sufficient to provide a desired therapeutic effect. In another embodiment, oral dosage forms can be administered to subjects in need. Administration of the oral dosage form can treat at least one selected condition of premature labor, premature birth, infertility and miscarriage. Conditions and relative treatment can be based on your measurements of primary and secondary outcomes associated with 17HP ester administration.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph of the in vitro release profile of an oral dosage form containing 17-hydroxyprogesterone caproate, in accordance with a particular embodiment of the present invention, compared to a non-carrier dose of 17-hydroxyprogesterone caproate.
FIG. 2 is a graph of the in vitro release profiles of oral 17-hydroxyprogesterone containing dosage forms, in accordance with a particular embodiment of the present invention.
FIG. 3 is a graph of in vitro release profiles of oral dosage forms containing 17-hydroxyprogesterone, in accordance with a particular embodiment of the present invention.
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Reference will be made to the exemplary modalities illustrated, and a specific language will be used in this document to describe them, it will be understood, however, that no limitation of the scope of the invention is intended by this.
DETAILED DESCRIPTION OF THE EXEMPLARY MODE (S)
Before oral dosage forms and delivery methods present and the use of 17-hydroxyprogesterone esters are disclosed and described, it should be understood that this invention is not limited to the particular process steps and materials disclosed in this document, but is extended to their equivalents, as would be recognized by those skilled in the art. It should also be understood that the terminology used in this document is used for the purpose of describing particular modalities only and is not intended to be limiting.
It should be noted that, the forms in the singular one an, and the (a) include referents in the plural, unless the context clearly expresses the opposite. Thus, for example, reference to an excipient includes reference to one or more of those excipients, and reference to the carrier includes reference to one or more of those carriers.
Definitions
As used herein, drugs, active agents, bioactive agents, pharmaceutically active agents, therapeutically active agents and pharmaceuticals, can be used interchangeably to refer to an agent or substance that has measurably selected or specified physiological activity when administered to a patient. subject in a significant or effective amount, it should be understood that the term drug is expressly encompassed by this definition, just as many drugs and pro-drugs are known to have specific physiological activities. These terms of the art are well known in pharmaceutical and medicinal techniques. In addition, when these terms are used, or when a particular active agent is specifically identified by name or category, it is understood that the quote is intended to include the active agent per se, as well as the pharmaceutically acceptable salts, esters or compounds significantly related to it, including, without limitation, prodrugs, active metabolites, isomers and the like.
As used in this document, the term recurrent is used to refer to a repetition or recurrence of at least one incidence such as miscarriage, premature birth or premature labor or
7/69 multifetal pregnancy or any medical situation in reference with or without the same partner, with or without previous live birth.
As used herein, the term treatment, when used in conjunction with the administration of a 17-hydroxyprogesterone ester, refers to the administration of the 17-hydroxyprogesterone ester to subjects who are asymptomatic or symptomatic. In other words, treatment may refer to the act of reducing or eliminating a condition (that is, the symptoms manifested), or it may refer to prophylactic treatment, (that is, administration to a subject who does not manifest the symptoms, in order to prevent its occurrence). This prophylactic treatment can also be referred to as condition prevention, preventive action, preventive measure, etc.
As used in this document, the term ester represents compounds produced by the reaction between acids and alcohols with the elimination of water. As described in this document, the term ester can also represent the class of organic compounds corresponding to inorganic salts formed from an organic acid and an alcohol. In one aspect, the 17-hydroxyprogesterone ester may be the caproate ester, but it may also represent the esters of longer-chain fatty acids, such as undecanoic and higher acid, which are normally absorbed lymphatically and prevent hepatic metabolism first pass for better efficiency or safety.
As used herein, the terms formulation and composition are used interchangeably and refer to a mixture of two or more compounds, elements or molecules. In some respects, the terms formulation and composition can be used to refer to a mixture of one or more active agents with a carrier or other excipients. In addition, the term dosage form can include one or more formulations or compositions provided in a format for administration to a subject. When any of the above terms is modified by the oral term, those terms refer to the compositions, formulations or dosage forms formulated and intended for oral administration to subjects.
The terms pharmaceutically acceptable carrier or carrier are used interchangeably and refer to a pharmaceutically acceptable substance that allows for a pharmaceutical composition and / or a dosage form of a 17-hydroxyprogesterone ester. In addition, in some respects, the carrier is an element or ingredient that can be varied to alter the
8/69 rate and / or degree of release of the active agent, for example, a 17-hydroxyprogesterone ester, composition and / or dosage form. In one aspect of the invention, a pharmaceutically acceptable carrier is a compound, or a mixture of compounds, that determines, controls or contributes, at least in part, to the release of a 17-hydroxyprogesterone ester from an oral pharmaceutical composition and / or dosage form, when tested using a USP Type II device in about 900 mL of simulated intestinal fluid (according to USP, SIF, without enzyme) having 0.5% w / w sodium lauryl sulfate at about 37 ° C and 50 rpm.
In another embodiment, the composition or dosage form provides a release of the 17-hydroxyprogesterone ester, such that when tested using a USP Type II device in about 900 mL of simulated intestinal fluid, having 0.5% w / w lauryl sodium sulfate at about 37 ° C and 50 rpm, at least 20% plus the 17-hydroxyprogesterone ester is released after the first 60 minutes, compared to an equivalent dose of an ester of the 17-hydroxyprogesterone oral dosage form without the pharmaceutically acceptable carrier. In another particular embodiment, the composition or dosage form releases at least 40% more of the 17-hydroxyprogesterone ester after the first 60 minutes, compared to an equivalent dose of an ester of the 17-hydroxyprogesterone oral dosage form without the pharmaceutically acceptable carrier.
It should be noted that the release of the 17-hydroxyprogesterone ester from the composition or dosage form can be tested in a suitable solubilizing medium or in an aqueous non-solubilizing medium at about 37 ° C, in a USP Type II apparatus at 50 rpm. For example, the aqueous medium can be water, simulated gastric fluid (SGF) with or without enzyme, simulated intestinal fluid (SIF) with or without enzyme, a hydro-alcoholic solution, a surfactant solution and the like. The aqueous medium can be used for the purpose of determining the rate and / or degree of release of the 17-hydroxyprogesterone ester from compositions or dosage forms. The aqueous medium can be a non-solubilizing aqueous medium (for example, having little or no surfactant in the medium) for the entire amount of the ester present in the composition or in the dosage form. In one embodiment, the aqueous, non-solubilizing medium can solubilize about 90% or less of the amount of ester present in the composition or in the dosage form. In another embodiment, the non-solubilizing aqueous medium can solubilize about 80% or less, about 70% or less, about 60% or less, about
9/69 of 50% or less, about 30% or less, or about 20% or less of the total amount of the ester present in the composition or in the dosage form.
On the other hand, in another embodiment, the aqueous medium is capable of substantially solubilizing the entire 17-hydroxyprogesterone ester present in the composition or dosage form. In one embodiment, the aqueous medium can solubilize at least about 90% of the amount of the 17-hydroxyprogesterone ester present in the composition or dosage form. In a particular embodiment, the aqueous medium can solubilize about 1.5 times or more, about 3 times or more, 5 times or more the amount of the 17-hydroxyprogesterone ester present in the composition or dosage form.
As used herein, subject refers to a mammal that can benefit from administering a composition of the drug or method of this invention. Examples of subjects include humans and may also include other animals, such as horses, pigs, cattle, dogs, cats, rabbits and aquatic mammals. In a specific aspect, a subject is a human. In another aspect, the subject is a female. In yet another aspect, the oral dosage form of the current invention is for a female who needs support during pregnancy.
The term oral administration represents any method of administration, in which the active agent can be administered by swallowing, chewing, or sucking or drinking an oral dosage form. Such solid or liquid oral dosage forms are traditionally intended to substantially release and / or distribute the active agent in the gastrointestinal tract beyond the mouth and / or the oral cavity. Examples of solid dosage forms include conventional tablets, multilayer tablets, capsules, lozenges, etc., which do not substantially release the drug in the mouth or oral cavity.
As used herein, the terms release and release rate are used interchangeably to refer to the discharge or release of a substance, including, without limitation, a drug, from the dosage form in a surrounding environment, as an aqueous medium both in both in vitro and in vivo.
As used herein, the term lipophilic, when used in combination with solid and liquid lipophilic additives (referred to alternatively below as LA), refers to additives that adore oil and generally have little or no solubility in water. Lipophilic surfactants (alternatively referred to below as LS) refer to lipophilic additives that have
10/69 HLB values of 10 or less, preferably between 2 to 10. On the other hand, the term hydrophilic, when used in combination with solid and liquid hydrophilic additives (referred to alternatively below as HA), refers to additives that adore water, and generally have medium or good water solubility. Hydrophilic surfactants (alternatively referred to below as HS) are hydrophilic additives that have significant active surface properties and have HLB values of more than 10.
As used herein, the term lipid or lipid substance, when used in connection with various compounds, refers to fatty acid (unless otherwise specified, having a chain length greater than Ce) or esters of fatty acids or glycerides of fatty acid esters, their mixtures and derivatives, although it does not include their salts.
In some aspects of the present invention, the drug release can be a controlled release. As used in this document, the term controlled release represents the release of the drug from the dosage form, according to a predetermined profile. In some aspects, the selected controlled release may be intermediate, delayed, extended, sustained, pulsatile, gastric, enteric or colon. In another aspect, the combinations of the release profiles mentioned above can be used in order to obtain specific distribution results, such as an immediate release followed by a delayed and / or sustained release of the active agent.
As used in this document, a composition or dosage form provides immediate release when more than about 90% of the drug is released after the first 30 minutes, in a USP simulated gastric fluid (SGF) with or without an enzyme.
As used in this document, the term pregnancy support, when used to describe the functionality of the oral compositions or dosage forms of the present invention, can refer to the provision of exogenous progestational support from inception to birth, including, but not limited to premature birth, premature labor and miscarriage. Pregnancy support can provide improved pregnancy quality for the pregnant woman, the fetus, or both. Furthermore, pregnancy support can also include increased fertility for a woman trying to conceive.
As used herein, the term non-pregnancy support, when used to describe the functionality of the oral compositions or dosage forms of the present invention, can refer to conditions that require
11/69 exogenous supplementation of a progestin agent for a non-pregnant subject, such as a non-pregnant woman, including, but not limited to, delaying or preventing the occurrence of unwanted pregnancies, preventing or treating conditions due to progesterone deficiencies, such as amenorrhea, fibroid tissues, contraception, suppression of postpartum lactation, treatment of dysfunctional uterine bleeding, endometriosis, endometrial hyperplasia, cervical hyperplasia, hormone replacement therapy, treatment of hypoventilation, prevention and treatment of osteoporosis, breast maintenance, hypothyroidism, migraines , temporomandibular joint syndrome, catamenial epilepsy, renal and / or endometrial carcinomas. In one embodiment, the term non-pregnancy support, when used to describe the functionality of the oral compositions or dosage forms of the present invention, may refer to conditions that require exogenous supplementation of the progestin agent of the invention to a male human, for example , to effect contraception, to go against estrogenic activity, etc. It is noted that the present compositions and dosage forms of the 17-hydroxyprogesterone ester can be administered alone or in combination with another therapy. In another embodiment, the current compositions of the invention and the 17-hydroxyprogesterone ester dosage forms can be used to supplement, increase, mitigate, treat, cure or prevent, or provide prophylaxis to a subject in need.
As used herein, an effective amount or a therapeutically effective amount of a drug refers to a non-toxic, but sufficient amount of the drug to obtain therapeutic results in treating a condition for which the drug is known to be effective. It is understood that several biological factors can affect a substance's ability to perform its intended task. Therefore, an effective amount or a therapeutically effective amount may be dependent, in some cases, on these biological factors. In addition, while the achievement of therapeutic effects can be measured by a physician or other qualified medical personnel, using assessments known in the art, it is recognized that individual variation and response to treatments can make achieving therapeutic effects a bit of a decision. subjective. Determining an effective amount is well within the skill of a person skilled in the art of pharmaceutical science and medicine. See, for example, Meiner and Tonascia, Clinical Trials: Design, Conduct, and Analysis, Monographs in Epidemiology and Biostatistics, Vol. 8 (1986), incorporated in this document for reference.
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As used in this document, the term about is used to provide flexibility for a numeric range parameter, provided that a given value may be slightly above or slightly below the parameter. As used in this document, a plurality of items, structural elements, composition elements and / or materials can be presented in a common list for convenience. However, these lists must be interpreted as if each member of the list was individually identified as a separate and exclusive member. Thus, no individual member of that list should be interpreted as a de facto equivalent to any other member of the same list, based on its presentation in a common group without any indication to the contrary.
Concentrations, quantities, levels and other numerical data can be expressed or presented in this document in an interval format. It should be understood that such a range format is used purely for convenience and conciseness and, therefore, it should be interpreted flexibly to include not only numeric values reported explicitly, such as range limits, but also to include all numeric values individual or subintervals encompassed within that range, as if each numeric and subinterval value were explicitly reported. As an illustration, a numerical range of about 1 to about 5 should be interpreted to include not only the values explicitly reported from about 1 to about 5, but also include individual values and subintervals within the indicated range. Thus, included in this numeric range are the individual values, such as 2, 3 and 4 and the subintervals, such as 1-3, 2-4 and 3-5, etc., as well as 1, 2, 3, 4 and 5, individually. This same principle applies to ranges that report only a numerical value, such as a minimum or a maximum. In addition, such an interpretation should apply regardless of the breadth of the interval or the characteristics being described.
Invention
Reference will now be made in detail to the preferred embodiments of the invention. Since the invention will be described in conjunction with the preferred embodiments, it will be understood that it is not intended to limit the invention to those preferred embodiments. Rather, it is intended to cover alternatives, variants, modifications and equivalents that can be included within the spirit and scope of the invention, as defined by the appended claims.
During pregnancy, it has been shown that serum progestogens, including
13/69 levels of progesterone and 17-hydroxyprogesterone are decreased in pregnant women in cases of intrauterine death, premature labor, threatened premature labor, premature rupture of membranes, amnionitis and placental detachment. As discussed above, 17-hydroxyprogesterone esters have been found to have the potential for use in pregnancy to treat and / or prevent the following conditions or occurrences: miscarriage in women who have had previous miscarriage, history of recurrent miscarriage, stillbirth previous, previous premature delivery (<37 weeks), previous premature rupture (<37 weeks) of membranes or PROM, hypertension or toxemia related to previous pregnancy, detachment of the previous placenta, threatened preterm labor or cerclage, multiple pregnancy, primary infertility or secondary, congenital uterine abnormality or any other condition where the levels of endogenous progestogen (eg progesterone) are lower than in normal pregnancy.
Primary and secondary outcome measures can be used to determine the need and / or effectiveness of the ester of 17-hydroxyprogesterone supplementation therapy for pregnancy-related support to a particular subject and its direct or indirect effect on neonates. Typical primary and secondary outcome measures for preterm birth and preterm labor include, without limitation,
Primary Outcome Measures (Maternal):
1. Perinatal mortality
2. Premature birth (less than 32 weeks of gestation)
3. Premature birth (less than 34 weeks of gestation)
4. Premature birth (less than 37 weeks of gestation)
5. Main neuronal development deficiency in childhood care
Secondary Outcome Measures (Maternal):
1. Premature labor threatened
2. Spontaneous rupture of membranes in pre-labor
3. Adverse reaction to the drug
4. Prolongation of pregnancy (interval between randomization and birth)
5. Mode of birth
6. Number of prenatal hospital admissions
7. Satisfaction with therapy
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8. Use of tocolysis
Secondary Outcome Measures (Infant):
1. Birth before 37 complete weeks
2. Birth before 34 complete weeks
3. Birth before 32 complete weeks
4. Birth before 28 complete weeks
5. Birth weight below the third percentile for gestational age
6. Birth weight less than 2500 grams
7. Apgar score less than seven for five minutes
8. Respiratory distress syndrome
9. Use of mechanical ventilation
10. Duration of mechanical ventilation
11. Intraventricular hemorrhage - class III or IV
12. Periventricular leukomalacia
13. Retinopathy of prematurity
14. Retinopathy of prematurity - class III or IV
15. Chronic lung disease
16. Necrotizing enterocolitis
17. Neonatal sepsis
18. Fetal death
19. Neonatal death
20. Admission to the neonatal intensive care unit
21. Neonatal duration of hospital stay
22. Teratogenic effects (including virilization in female children)
Secondary Outcome Measures (Child):
1. Major sensorineural impairment (defined as any legal blindness, sensorineural deafness that requires hearing aids, moderate or severe cerebral palsy or developmental retardation or intellectual disability)
2. Development delay
3. Intellectual disability
4. Motor disability
5. Visual impairment
6. Blindness
7. Deafness
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8. Hearing impairment
9. Cerebral palsy
10. Child behavior
11. Child's temperament
12. Learning difficulties
13. Growth assessments during childhood follow-up (weight, head circumference, length, skin fold thickness)
In vitro fertilization
1. Primary outcome measures:
1.1. Pregnancy rate
1.2. Live birth
1.3. Ongoing pregnancy rate
1.4. Clinical pregnancy, defined as ultrasound evidence of fetal heart activity at 6-8 weeks of gestation
1.5. Fetal vitality measured by heartbeat
1.6. Complete abortion rate 24-48hrs after receiving medical treatment for early pregnancy loss.
2. Secondary Outcome Measures:
2.1. Clinical pregnancy
2.2. Cycle Cancellation Fees
2.3. Number of Oocytes Generated
2.4. Number of Embryos Generated
2.5. Serum hormonal evaluation
2.6. Evaluation of follicular fluid
2.7. Peak estradiol level
2.8. Gonadotropin ampoules required during ovarian stimulation
2.9. Number of days of ovarian stimulation
2.10. Number of oocytes recovered
2.11. Number of embryos transferred
2.12. Number of frozen embryos
2.13. Embryo class
2.14. Deployment rate
2.15. Rate of miscarriage
2.16. Pregnancy outcome
2.17. Complete abortion rate in one week, time for expulsion of conception products, correlation of abortion rates to 17 levels
16/69 serum hydroxyprogesterone and type of pregnancy loss, number of bleeding days and patient satisfaction
2.18. Ovarian Response [assessed after the completion of controlled ovarian stimulation and egg collection procedures]
Miscarriage
1. Primary outcomes
1.1. Miscarriage
1.2. Early miscarriage up to 12 weeks
1.3. Miscarriage after 12 weeks and before 23 weeks
1.4. IFN / IL-10 cytokine ratio
1.5. Clinical pregnancy rate at 8 weeks and 12 weeks pregnant
2. Secondary outcomes
2.1. Mom
The. Pain relief (threatened miscarriage)
B. Severity of 'morning sickness' - headache intensified
ç. nausea, breast tenderness
d. thromboembolic events reported
and. Thrombolytic events
f. depression;
g. admission to the special therapy unit
H. subsequent fertility.
i. PIBF level
j. Frequency of uterine contraction
2.2. Kid
The. Premature birth;
B. stillborn;
ç. neonatal death;
d. low birth weight less than 2500 g
and. fetal genital abnormalities;
f. teratogenic effects (impairing normal fetal development);
g. admission to the special therapy unit.
2.3. General
The. Intrauterine fetal death
B. Stillborn
ç. Fetal
d. Exploratory analysis of pregnancy outcome by monitoring
17/69 biochemical and clinical parameters of pregnancy, weekly assessment of serum progesterone
and. live birth rate, cycle cancellation rate, spontaneous abortion rate, biochemical pregnancy rate, ectopic pregnancy rate
Several biomarkers have been implicated in predicting premature birth (PTB). Among symptomatic women, the probability ratio (LR +) for predicting PTB is known to be greater than 10 using interleukin-6 (IL-6) from amniotic fluid (AF), Ureaplasma urealyticum from AF, as well as a multi-marker consisting of cervical IL-6, cervical IL-8 and cervical length (CL). LR + is also known to be between 5 and 10 for C-reactive whey protein (CRP). An LR + between 2.5 and 5 was recorded for serum corticotropin releasing hormone (CRH), cervical IL-6, serum relaxin.
In asymptomatic women, AFU urealyticum and a multi-marker consisting of five individual markers [fFN, CL, serum alpha-fetoprotein (AFP), serum alkaline phosphatase and granulocyte colony stimulating factor (GCSF)] predict PTB with an LR + greater than 10. A LR + was between 5 and 10 for relaxin and serum CL. The LRs + registered for serum alkaline phosphatase, salivary estriol, serum CRH, serum G-CSF, cervical IL-6, AF IL-6, cervical fFN, AFP and chlamydia, all ranged between 2.5 and 5. Finally, one LR + below 2.5 has been documented for serum ferritin, serum CRP, BV and cervical ferritin.
Spontaneous abortions and possible spontaneous abortions can be classified in several ways: A) possible or threatened miscarriage when any bleeding from the uterus occurs before 20 weeks, but the cervix is closed and the fetus is alive; B) Inevitable abortion or spontaneous abortion (inevitable - meaning it cannot be stopped, particularly if there is bleeding from the uterus and the cervix is opening before 20 weeks, but neither the fetus nor the placenta has passed out of the woman's body ) - the membranes around the fetus may or may not have been broken (broken); C) Miscarriage or incomplete miscarriage - when a portion of the fetus or placenta has passed out of the uterus before 20 weeks of gestation, while remains of the placenta or fetus remain in the uterus; D) Complete miscarriage - complete expulsion of all membranes around the fetus and the placenta and cervix close before 20 weeks; E) Miscarriage or miscarriage - death of the fetus before 20 weeks of gestation without the fetus or the placenta having been expelled from the uterus; F) Recurrent spontaneous abortion a woman is said to have a recurrent spontaneous abortion after she has already had two
18/69 or more consecutive spontaneous abortions; G) Malformed egg or anembryonic gestation - occurs when a gestational sac is formed inside the uterus, but no fetus is present after seven weeks.
Threatened miscarriage, as demonstrated by low endogenous progesterone or 17-hydroxyprogesterone, or vaginal bleeding with or without abdominal cramps within 26 weeks of conception, is a common pregnancy complication. This occurs in about 20% of recognized pregnancies. Risk of spontaneous abortion is higher in older women and in those with a history of spontaneous abortion.
Low serum levels of progestogen (progesterone or 17 HP) or human chorionic gonadotropin (hCG) have been shown to be a risk factor for miscarriage. Threatened miscarriage causes considerable stress and anxiety for a pregnant woman. Since 17-hydroxyprogesterone esters interact with the progesterone receptor, it is believed that treatment with 17-hydroxyprogesterone esters can be designed based on progesterone levels. A diagnostic criterion is low serum progesterone, but levels vary widely during early pregnancy and any further decline can be attributed to a dysfunctional placenta. However, luteal support is widely used for the maintenance of threatened spontaneous abortion. The first trimester of pregnancies shows a risk of miscarriage with declining serum progesterone levels. Levels of <5 ng / ml were associated with miscarriage in 86% of cases, compared with only 8% at levels of 20-25 ng / ml. A limit value of 14 ng / ml has been reported to differentiate between viable and non-continuous pregnancies. Other maternal serum biomarkers, such as tumor marker CA-125, Inibine A, Anandamide and progesterone-induced blocking factor (PIBF) are also good indicators of the risk of miscarriage.
In one embodiment, the compositions of the present invention are designed to provide an increase in the base endogenous progesterone and / or in the hydroxyprogesterone. In a particular embodiment, the increase in base endogenous progesterone may be greater than 10%. Progestogens also have a direct pharmacological effect by reducing the synthesis of prostaglandins, thereby relaxing uterine smooth muscle and avoiding inappropriate contractions that can result in spontaneous abortion.
Although the oral dosage forms and methods of the present invention can be used in most female subjects, the most suitable patients
19/69 to receive the oral 17-hydroxyprogesterone ester of this invention are those who have one or more of the following conditions, symptoms and / or needs: 1) need an anti-inflammatory; 2) are progesterone deficient with a baseline progesterone in early pregnancy (first trimester) of C _m d <14 ng / ml or baseline progesterone levels, C _m less than 50 ng / ml at the end of pregnancy ( second and third quarter); 3) they have genetic variation of the SEKPINH1 gene that causes a reduced amount of the protein, collagen, which can lead to weakened fetal membranes to be produced; 4) have a genetic variant of the Prolylcarboxypeptidase gene associated with preeclampsia; 5) have certain bacterial infections (bacterial vaginosis), including species of Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella vaginalis and Peptostreptococcus and Bacteroides; 6) have an abnormal amniotic fluid metabolome (the sum of all metabolic processes that occur in the amniotic fluid), indicating a risk of prematurity; 7) had exposure to phthalate above the total average; 8) body mass index of abnormal pregnancy; 9) have an inflammatory vagina in early pregnancy; 10) have increased maternal plasma urocortin levels; 11) show increased uterine activity, as observed by the Monitoring of Home Uterine Activity; 12) positive test for salivary estriol levels that predict premature delivery; 13) show alarming fetal Fibronectin Screening (STI) results; 14) show unusual cervical shortening related to gestational age, as measured by cervical ultrasound, or transvaginal ultrasound or digital examination with / without the use of Cervilenz ™; 15) show unusual maternal serum biomarkers, such as tumor marker CA-125, or Inibine A, or Anandamide or Progesterone-Induced Blocking Factor (PIBF); 16) have an unbalanced ratio between Th-1 cytokines and Th-2 cytokines, such as IFN for IL-10.
In addition to maintaining pregnancy, other potential uses of the ester of the 17-hydroxyprogesterone-containing oral dosage forms of the present invention include, but are not limited to: a) preventing estrogenic predominance; b) stimulation of new bone formation and prevention / reversal of osteoporosis; c) supply of the precursor to adrenal cortex hormones (corticosteroids); d) treatment of a variety of skin problems, such as acne in adult women, seborrhea, rosacea, psoriasis and keratosis; e) promoting the production of the myelin sheath to protect nerve fibers and accelerate nerve signals; f) management of the depression that accompanies PMS, menopause, postpartum depression, etc .; g) protection from spinal cord / brain injury, stroke and / or
20/69 hemorrhage.
In one embodiment, the present invention provides oral dosage forms containing 17-hydroxyprogesterone esters, as well as related methods. Oral dosage forms can be formulated to support pregnancy and can include a therapeutically effective amount of a 17-hydroxyprogesterone ester and a pharmaceutically acceptable carrier. The oral dosage form, when measured using a USP Type-ll dissolution apparatus in 900 mL of deionized water with 0.5 (w / v) sodium lauryl sulfate at 50 RPM at 37 ° C, can release at least 20 % by weight of the dose of the 17-hydroxyprogesterone ester after 60 minutes. In yet another modality, the oral dosage form, when measured using a USP Type-ll dissolution apparatus in 900 mL of deionized water with 0.5 (w / v) sodium lauryl sulfate at 50 RPM at 37 ° C, it can release at least 20% by weight plus 17hhydroxyprogesterone ester after 60 minutes than an equivalent oral dosage form without the carrier.
A series of 17-hydroxyprogesterone esters can be used in the oral compositions and dosages of the present invention. Examples of specific acceptable 17-hydroxyprogesterone esters include, without limitation, 17-hydroxyprogesterone acetate esters, 17-hydroxyprogesterone caproate esters, 17-hydroxyprogesterone undecanoate esters and the like and combinations thereof. Other pharmacologically active and acceptable esters of 17-hydroxyprogesterone can also be prepared and used according to the modalities of the present invention, as long as they provide the desired support for the conditions of pregnancy and / or non-pregnancy.
The 17-hydroxyprogesterone ester can be present in the oral compositions and dosage forms of the present disclosure in a variety of forms. In one embodiment, the 17-hydroxyprogesterone ester can be present in particulate form. In one embodiment, the 17-hydroxyprogesterone ester can be present in particulate form. The particulate form can have an average diameter of about 50 pm or less. The particulate form can have an average diameter of about 25 pm or less. In another embodiment, the particulate form may have an average diameter of about 1 pm or less. In another embodiment, the 17-hydroxyprogesterone ester can be present in a fully solubilized form. In another embodiment, the 17-hydroxyprogesterone ester may be present in a partially solubilized form. In another embodiment, a portion of the 17-hydroxyprogesterone ester present as a composition and / or
21/69 in dosage form may be present in particulate or unsubstituted form. In some embodiments, the 17-hydroxyprogesterone ester may be present in solubilized form, as well as in particulate form.
In some embodiments, the carrier of the oral compositions or dosage forms of the present invention can act to facilitate the distribution, release and / or bioavailability of the 17-hydroxyprogesterone ester. In some respects, the carrier may be one or a mixture of two or more compounds. The carrier can include at least one of a lipophilic and / or hydrophilic component additive. The lipophilic and hydrophilic additives that can be used in the compositions of the invention can be selected from a variety of pharmaceutical aid classes including, but not limited to, absorbents, acids, adjuvants, anti-caking agents, anti-caking agents, anti-caking agents, anticoagulants, antimicrobials, antioxidants, antiphlogists, astringents, antiseptics, bases, binders, buffers, chelating agents, sequestrants, celluloses, coagulants, coating agents, colorants, dyes, pigments, complexing agents, crystal growth regulators, denaturants, desiccants, agents drying, dehydrating agents, diluents, disintegrants, dispersants, emollients, emulsifiers, encapsulants, enzymes, extenders, fillers, flavor masking agents, flavorings, fragrances, gelling agents, glidant hardeners, hardening agents, humectants, lubricants, moisturizers, agents from c pH control, plasticizers, soothing agents, demulcent agents, retarding agents, dispersing agents, stabilizers, suspending agents, sweeteners, thickening agents, consistency regulators, surfactants, opacifiers, polymers, preservatives, antifreeze, rheology control agents, softeners , solubilizers; toning solvents, UV absorbers, viscosity modulators or combinations thereof. In some embodiments, additives of multiple classes or types can be used.
Non-limiting examples of compounds that can form all or part of the carrier are presented in the following lists that have been organized into general categories. It should be understood that the categories are not intended to limit the compounds of the particular carrier, but are present simply to facilitate organization and presentation. With this in mind, sample carrier compounds can include one or more of the following:
Triglycerides, such as Aceituno oil; almond oil; Arachis oil;
Babassu oil; blackcurrant seed oil; borage oil; canola oil (Lipex 108 (Abitec)); Castor oil; cocoa butter; coconut oil (Pureco 76 (Abitec)); coffee seed oil; corn oil; cottonseed oil; Crambe oil; oil of Cuphea species; evening primrose oil; grape seed oil; peanut oil; hemp seed oil; llipê butter; kapok seed oil; linseed oil; Menhaden oil; Mowrah butter; mustard seed oil; Oiticica oil; olive oil; Palm oil; palm kernel oil; peanut oil; poppy seed oil; rapeseed oil; rice bran oil; safflower oil; salt fat; Sesame oil; shark liver oil; Shea nut oil; soy oil; Stillingia oil; Sunflower oil; Tall oil; tea oil; tobacco seed oil; tung oil (wood oil from China); vernonia oil; wheat germ oil; hydrogenated castor oil (Castorwax); hydrogenated coconut oil (Pureco 100 (Abitec)); hydrogenated cottonseed oil (Dritex C (Abitec)); hydrogenated palm oil (Dritex PST (Abitec); Softisan154 (Huls)); hydrogenated soybean oil (Sterotex HM NF (Abitec); Dritex S (Abitec)); hydrogenated vegetable oil (Sterotex NF (Abitec): Hydrokote M (Abitec)); hydrogenated cottonseed and castor oil (Sterotex K (Abitec)); partially hydrogenated soybean oil (Hydrokote APS (Abitec)); partially cottonseed and soybean oil (Apex B (Abitec)); glyceryl tributyrate (Sigma); glyceryl tricaproate (Sigma); glyceryl tricaprilate (Sigma); glyceryl tricaprate (Captex 1000 (Abitec)); glyceryl undecanoate (8227 Captex (Abitec)); glyceryl trilaurate (Sigma); glyceryl trimyristate (Dynasan 114 (Huls)); glyceryl tripalmitate (Dynasan 11 16 (Huls)); glyceryl tristearate (Dynasan 118 (Huls)); glyceryl triarcidate (Sigma); glyceryl trimiristoleate (Sigma); Glyceryl tripalmitoleate (Sigma); glyceryl trioleate (Sigma); glyceryl trilinoleate (Sigma); glyceryl tricaprilat / caprate (Captex 300 (Abitec); Captex 355 (Abitec); Miglyol 810 (Huls); Miglyol 812 (Huls)); tricaprilat / caprate / glyceryl laurate (Captex 350 (Abitec)); glyceryl tricaprilat / caprate / linoleate (Captex 810 (Abitec); Miglyol 818 (Huls)); glyceryl tricaprtlate / caprate / stearate (Softisan 378 (Huls); (Larodan); glyceryl tricaprilate / laurate / stearate (Larodan); glyceryl 1,2-caprylate-3-linoleate (Larodan); 1,2-caprate- Glyceryl 3-stearate (Larodan); Glyceryl 1,2-laurate-3-myristate (Larodan); Glyceryl 1,2-myristate3-Larry (Larodan); Glyceryl 1,3-palmitate-2-butyrate (Larodan) ); Glyceryl 1,3-stearate-2-caprate (Larodan); glyceryl 1,2-linoleate-3-caprylate (Larodan), their mixtures and derivatives. Fractionated triglycerides, triglycerides
23/69 modified, synthetic triglycerides and mixtures of triglycerides are also within the scope of the invention.
PEG_ Fatty Acid Monoester Surfactants (listed as compound name (name of common commercial product (supplier) (HLB)): PEG 4-100 monolaurate (Crodet L series (Croda) (> 9)); PEG 4-100 oleate (Crodet O series (Croda) (> 8)); PEG 4-100 monostearate (Crodet S series (Croda), Myrj series (Atlas / ICI) (> 6)); distearate PEG 400 (Cithrol 4DS (Croda) series (> 10)); PEG 100, 200, 300 monolaurate (Cithrol ML (Croda) series (> 10)); PEG 100, 200, 300 mono-oleate ( Cithrol MO series (Croda) (> 10)); PEG 400 dioleate (Cithrol 4DO series (Croda) (> 10)); PEG 400-1000 monostearate (Cithrol MS series (Croda) (10)); PEG-1 stearate (Nikkol MYS-1 EX (Nikko), Coster K1 (Condea) (2)); PEG-2 stearate (Nikkol MYS-2 (Nikko) (4)); PEG-2 oleate (Nikkol MYO-2 (Nikko) (4,5)); PEG-4 laurate (Mapeg © 200 ML (PPG), Kessco © PEG 200 ML (Stepan), LIPOPEG 2 L (LiPO Chem.) (9.3)); oleate PEG-4 (Mapeg © 200 MO (PPG), Kessco © PEG 200 MO (Stepan) (8.3)); PEG-4 stearate (Kessco © PEG 200 MS (Stepan), Hodag 20 S (Calgene), Nikkol MYS-4 (Nikko) (6.5)); PEG-5 stearate (Nikkol TMGS-5 (Nikko) (9.5)); PEG-5 oleate (Nikkol TMGO-5 (Nikko) (9.5)); PEG-6 oleate (Algon OL 60 (Auschem SpA), Kessco® PEG 300 MO (Stepan), Nikkol MYO-6 (Nikko), A6 emulgante (Condea) (8.5)); PEG-7 oleate (Algon OL 70 (Auschem SpA) (10.4)); PEG-6 laurate (Kessco © PEG300 ML (Stepan) (11.4)); PEG-7 laurate (Lauridac 7 (Condea) (13)); PEG-6 stearate (Kessco © PEG300 MS (Stepan) (9.7)); PEG-8 laurate (Mapeg © 400 ML (PPG), LIPOPEG 4DL (Lipo Chem.) (13)); PEG-8 oleate (Mapeg © 400 MO (PPG), Emulgante A8 (Condea) (12)); PEG-8 stearate (Mapeg © 400 MS (PPG), Myrj 45 (12)); PEG-9 oleate (A9 emulgante (Condea) (> 10)); PEG-9 stearate (Cremophor S9 (BASF) (> 10)); PEG-10 laurate (Nikkol MYL-10 (Nikko), Lauridac 10 (Croda) (13)); PEG-10 oleate (Nilvkol MYO-10 (Nikko) (11)); PEG-12 stearate (Nikkol MYS-10 (Nikko), Coster K100 (Condea) (11)); PEG-12 laurate (Kessco® PEG 600 ML (Stepan) (15)); PEG-12 oleate (Kessco © PEG 600 MO (Stepan) (14)); Peg-12 ricinoleate (CAS # 9004-97-1) (> 10)); PEG-12 stearate (Mapeg © 600 MS (PPG), Kessco © PEG 600 MS (Stepan) (14)); PEG-15 stearate (Nikkol TMGS-15 (Nikko), K15 Rosier (Condea) (14)); PEG-15 oleate (Nikkol TMGO-15 (Nikko) (15)); PEG-20 laurate (Kessco © PEG 1000 ML (Stepan) (17)); PEG-20 oleate (Kessco® PEG 1000 MO (Stepan) (15)); PEG-20 stearate (Mapeg® 1000 MS (PPG),
24/69
Kessco® PEG 1000 MS (Stepan), Myrj 49 (16)); PEG-25 stearate (Nikkol MYS-25 (Nikko) (15)); PEG-32 laurate (Kessco® PEG 1540 ML (Stepan) (16)); PEG-32 oleate (Kessco® PEG 1540 MO (Stepan) (17)); PEG-32 stearate (Kessco® PEG 1540 MS (Stepan) (17)); PEG-30 stearate (Myrj 1 (> 10)); PEG-40 laurate (Crodet L40 (Croda) (17.9)); PEG-40 oleate (Crodet 040 (Croda) (17.4)); PEG-40 stearate (Myrj 52, Emerest® 2715 (Henkel), Nikkol MYS-40 (Nikko) (> 10)); PEG-45 stearate (Nikkol MYS-45 (Nikko) (18)); PEG-50 stearate (Myrj 53 (> 10)); PEG-55 stearate (Nikkol MYS-55 (Nikko) (18)); PEG-100 oleate (Crodet 0-100 (Croda) (18.8)); PEG-100 stearate (Myrj 59, Ariacel 165 (ICS) (19)); PEG-200 oleate (Albunol 200 MO (Taiwan Surf.). (> 10)); PEG-400 oleate (LACTQMUL (Henkel), Albunol 400 MO (Taiwan Surf.). (> 10)); PEG-600 oleate (Albunol 600 MO (Taiwan Surf.). (> 10)); and their combinations.
PEG Fatty Acid Diesters (listed as compound name (common commercial product name (supplier)) (HLB)): PEG-4 dilaurate (Mapeg® 200 DL (PPG), Kessco® PEG 200 DL (Stepan), LIPOPEG 2-DL (Lipo Chem.) (7)); PEG-4 dioleate (Mapeg® 200 DO (PPG), (6)); PEG-4 distearate (Kessco® 200 DS (Stepan) (5)) ; PEG-6 dilaurate (Kessco® PEG 300 DL (Stepan) (9.8)); PEG-6 dioleate (Kessco® PEG 300 DO (Stepan) (7.2)); PEG-6 distearate (Kessco ® PEG 300 DS (Stepan) (6.5)); PEG-8 dilaurate (Mapeg® 400 DL (PPG), Kessco® PEG 400 DL (Stepan), LIPOPEG 4 DL (Lipo Chem.) (11)); PEG-8 dioleate (Mapeg® 400 DO (PPG), Kessco® PEG 400 DO (Stepan), LIPOPEG 4 DO (Lipo Chem.) (8.8)); PEG-8 distearate (Mapeg® 400 DS (PPG ), CDS 400 (Nikkol) (11)); PEG-10 dipalmitate (Polyaldo 2PKFG (> 10)); PEG-12 dilaurate (Kessco® PEG 600 DL (Stepan) (11.7)); PEG distearate -12 (Kessco® PEG 600 DS (Stepan) (10.7)); PEG-12 dioleate (Mapeg® 600 DO (PPG), Kessco® 600 DO (Stepan) (10)); d PEG-20 ilaurate (Kessco® PEG 1000 DL (Stepan) (15)); PEG-20 dioleate (Kessco® PEG 1000 (Stepan) (13)); PEG-20 distearate (Kessco® PEG 1000 DS (Stepan) (12)); PEG-32 dilaurate (Kessco® PEG 1540 DL (Stepan) (16)); PEG-32 dioleate (Kessco® PEG 1540 (Stepan) (15)); PEG-32 distearate (Kessco® PEG 1540 DS (Stepan) (15)); PEG-400 dioleate (Cithrol 4DO series (Croda) (> 10)); PEG-400 distearate (Cithrol 4DS series (Croda) (> 10)); and their combinations.
Mixtures of PEG Fatty Acid Mono and Diesters (listed as compound name (name of common commercial product (supplier) (HLB));
25/69
PEG-150 4 mono, dilaurate (Kessco® PEG 200-6000 mono, dilaurate (Stepan))); PEG 4-150 mono, dioleate (Kessco® PEG 200-6000 mono, dioleate (Stepan))); PEG 4-150 mono, distearate (Kessco © 200-6000 mono, distearate (Stepan)) and their combinations.
Polyethylene Glycerol Glycerol Fatty Acid Esters (listed as compound name (common commercial product name (supplier) (HLB)): PEG-20 glyceryl laurate (Tagat® L (Goldschmidt) (16)); glyceryl PEG-30 (Tagat® L2 (Goldschmidt) (16)); glyceryl laurate PEG-15 (Glycerox L series (Croda) (15)); glyceryl laurate PEG-40 (Glycerox L series ( Croda) (15)); PEG-20 glyceryl stearate (Capmul © EMG (ABITEC), (13)); (Aldo © MS-20 KFG (Lonza)); PEG-20 glyceryl oleate (Tagat® O (Goldschmidt) (> 10)); PEG-30 glyceryl oleate (Tagat® 02 (Goldschmidt) (> 10)); and their combinations.
Alcohol-Oil Transesterification Products: _ (listed as compound name (common commercial product name) (supplier) (HBL)): PEG-3 castor oil (Nikkol CO-3 (Nikko) (3)); PEG-5, 9 and 16 castor oil (ACCONON CA (ABITEC) series (6-7)); PEG-20 castor oil (Emalex C-20 (Nihon Emulsion), Nikkol CO-20 TX (Nikko) (11)); PEG-23 castor oil (EL23 emulsifier (> 10)); PEG-30 castor oil (Emalex C-30 (Nihon Emulsion), Alkamuls® EL 620 (Rhone - Poulenc), Incrocas 30 (Croda) (11)); PEG-35 castor oil (Cremophor EL and EL-P (BASF), Emulphor EL, lncrocas-35 (Croda), Emulgin RO 35 (Henkel))); PEG-38 castor oil (Emulgante EL 65 (Condea))); PEG-40 castor oil (Emalex C-40 (Nihon Emulsion), Alkamuls® EL 719 (Rhone - Poulenc) (13)); PEG-50 castor oil (Emalex C-50 (Nihon Emulsion) (14)); PEG-56 castor oil (Eumulgin® PRT 56 (Pulcra SA) (> 10)); PEG-60 castor oil (Nikkol CO-60TX (Nikko) (14)); PEG100 castor oil (Thornley (> 10)); PEG-200 castor oil (Eumulgin® PRT 200 (Pulcra SA) (> 10)); hydrogenated PEG-5 castor oil. (Nikkol. HCO-5 (Nikko) (6)); hydrogenated PEG-7 castor oil (Simusol® 989 (Seppic), Cremophor W07 (BASF) (6)); hydrogenated PEG-10 castor oil (Nikkol HCO-10 (Nikko) (6.5)); hydrogenated PEG-20 castor oil (Nikkol HCO-20 (Nikko) (11)); hydrogenated PEG-25 castor oil (Simulsol® 1292 (Seppic), Cerex ELS 250 (Auschem SpA) (11)); hydrogenated PEG-30 castor oil (Nikkol HCO-30 (Nikko) (11)); hydrogenated PEG-40 castor oil (Cremophor RH 40 (BASF), Croduret (Croda), Emulgin HRE 40 (Henkel) (13)); hydrogenated PEG-45 castor oil (Cerex ELS 450 (Auschem Spa) (14)); hydrogenated castor oil from
26/69
PEG-50 (Emalex HC-50 (Nihon Emulsion) (14)); hydrogenated PEG-60 castor oil (Nikkol HCO-60 (Nikko); Cremophor RH 60 (BASF) (15)); hydrogenated PEG-80 castor oil (Nikkol HCO-80 (Nikko) (15)); hydrogenated PEG-100 castor oil (Nikkol HCO-100 (Nikko) (17)); PEG-6 corn oil (Labrafil® M 2125 CS (Gattefosse) (4)); PEG-6 almond oil (Labrafil® M 1966 CS (Gattefosse) (4)); PEG-6 apricot kernel oil (Labrafil® M 1944 CS (Gattefosse) (4)); PEG-6 olive oil (Labrafil® M 1980 CS (Gattefosse) (4)); PEG-6 peanut oil (Labrafil © M 1969 CS (Gattefosse) (4)); hydrogenated palm kernel oil from PEG-6 (Labrafil® M 2130 BS (Gattefosse) (4)); PEG-6 palm kernel oil (Labrafil® M 2130 CS (Gattefosse) (4)); PEG-6 triolein (Labrafil® M 2735 CS (Gattefosse) (4)); PEG-8 corn oil (Labrafil® WL 2609 BS (Gattefosse) (6-7)); corn glycerides from PEG-20 (Crovol M40 (Croda) (10)); almond glycerides from PEG-20 (Crovol A40 (Croda) (10)); PEG-25 trioleate (TAGAT® TO (Goidschmidt) (11)); PEG-40 palm kernel oil (Crovol PK-70 (> 10)); corn glycerides from PEG-60 (Crovol M70 (Croda) (15)); almond glycerides of PEG-60 (Crovol A70 (Croda) (15)); PEG-4 capillary / capric triglycerides (Labrafac® Hydro (Gattefosse), (4-5)); caprylic / capric glycerides of PEG-8 (Labrasol (Gattefosse), Labrafac CM 10 (Gattefosse) (> 10)); caprylic / capric glycerides from PEG-6 (SOFTIGEN® 767 (Huis), Glycerox 767 (Croda) (19)); glyceride from Lauroil macrogol-32 (GELUCIRE 44/14 (Gattefosse) (14)); macrogol stearoyl glyceride (GELUCIRE 50/13 (Gattefosse) (13)); Mono, di, tri, tertresters of vegetable oils and sorbitol (SorbitoGlyceride (Gattefosse) (<10)); pentaerythrityl tetraisostearate (Crodamol PTIS (Croda) (<10)); pentaerythrityl distearate (Albunol DS (Taiwan Surf.). (<10)); pentaerythryl tetraoleate (Liponate PO-4 (Lipo Chem.) (<10)); pentaerythrityl tetrastearate (Liponate PS-4 (Lipo Chem.) (<10)); tetracaprilat / pentaerythrityl tetracaprate (Liponate PE-810 (Lipo Chem.), Crodamol PTC (Croda) (<10)); pentaerythrityl tetraoctanoate (Nikkol Pentarate 408 (Nikko))); and their combinations.
Polyglycolized Fatty Acids: (listed as compound name (name of common commercial product (supplier) (HLB)): Polyglyceryl-2 stearate (Nikkol DGMS (Nikko) (5-7)); polyglyceryl-2 oleate (Nikkol DGMO (Nikko) (5-7)); polyglyceryl-2 isostearate (Nikkol DGMIS (Nikko) (5-7)); polyglyceryl-3 oleate (Caprol® 3GO (ABITEC), Drewpol 3-1-0 (Stepan) (6.5); polyglyceryl-4 oleate (Nikkol Tetraglyn 1-0 (Nikko) (5-7)); polyglyceryl-4 stearate (Nikkol Tetraglyn 1S (Nikko) (5-6)); polyglyceryl oleate 6 (Drewpol 6-1-0 (Stepan), Nikkol Hexaglyn (Nikko) 1-0 (9)); polyglyceryl laurate-10 (Nikkol Decaglyn 1-L (Nikko) (15)); oleate
27/69 polyglyceryl-10 (Nikkol Decaglyn 1-10 (Nikko) (14); polyglyceryl-10 stearate (Nikkol Decaglyn 1-S (Nikko) (12)); polyglyceryl-6 ricinoleate (Nikkol Hexaglyn PR-15 (Nikko) (> 8)); polyglyceryl-10 linoleate (Nikkol Decaglyn 1-LN (Nikko) (12)); polyglyceryl-6 pentaoleate (Nikkol Hexaglyn 5-0 (Nikko) (<10 »; polyglyceryl dioleate -3 (Cremophor G032 (BASF) (<10)); polyglyceryl-3 distearate (Cremophor GS32 (BASF) (<10)); polyglyceryl-4 pentaoleate (Nikkol Tetraglyn 50 (Nikko) (<10)); dioleate polyglyceryl-6 (Caprol® 6G20 (ABITEC); Hodag PGO62 (Calgene), PLUROL OLEIQUE CC 497 (Gattefosse) (8.5)); polyglyceryl-2 dioleate (Nikkol DGDO (Nikko) (7)); polyglyceryl-10 (Nikkol Decagiyn 3-0 (Nikko) (7); polyglyceryl-10 pentaoleate (Nikkol Decagiyn 5-0 (Nikko) (3.5)); polyglyceryl septaoleate-10 (Nikkol Decagiyn (Nikko) 7- 0 (3)); polyglyceryl-10 tetraoleate (Caprol © 10G4O (ABITEC); Hodag PGO-62 (CALGENE), Drewpol 10-4-0 (Stepan) (6.2)); decaisoe polyglyceryl-10 stearate (Nikkol Decagiyn 10-IS (Nikko) (<10)); polyglyceryl-10 decaoleate (Drewpol 10-10-0 (Stepan), Caprol 10G10O (ABITEC), Nikkol Decaglyn-10-O (3,5)); polyglyceryl-10 mono, dioelate (Caprol © PGE 860 (ABITEC) (11)); polyglyceryl polyrricinoleate (Polymuls (Henkel) (3-20)); and their combinations.
Propylene glycol fatty acid esters: (listed as compound name (common commercial product name (supplier) (HLB)): Propylene glycol monocaprilate (Capryol 90 (Gattefosse), Nikkol Sefsol 218 (Nikko) (<10>); monolaurate propylene glycol (Lauroglycol 90 (Gattefosse), Lauroglycol FCC (Gattefosse) (<10)); propylene glycol oleate (Lutrol CP2000 (BASF) (<10)); propylene glycol myristate (Mirpyl (<10)); propylene glycol monostearate (Mirpyl (<10)); ADM PGME-03 (ADM), LIPO PGMS (Lipo Chem.), Aldo © PGHMS (Lonza) (3-4)); propylene glycol hydroxystearate (<10)); propylene glycol ricinoleate (PROPYMULS (Henkel) (<10) ); propylene glycol isostearate (<10)); propylene glycol monooleate (Myverol P-06 (Eastman) (<10)); Dicaprilato / Propilenoglicol Dicaprato (Captex® 200 (ABITEC), Miglyol © 840 (Huis), Neobee © M-20 (Stepan) (> 6)); propylene glycol dioctanoate (Captex © 800 (ABITEC) (> 6)); propylene glycol caprylate / caprate (LAB RAF AC PG (Gattefosse) (> 6)); propylene glycol dilaurate (> 6)); propylene glycol distearate (Kessco © PGDS (Stepan) (> 6)); propylene glycol tipprilat (Nikkol Sefsol 228 (Nikko) (> 6)); propylene glycol tip (Nikkol PDD (Nikko) (> 6)); and their combinations.
Mixtures of Propylene Glycol Esters and Glycerol Esters: (listed as compound name (common commercial product name (supplier)) (HLB)): Oleic (ATMOS 300, ARLACEL 186 (ICI) (3-4)); Stearic (ATMOS 150
28/69 (3-4)); and their combinations.
Mono and Diglycerides: (listed as compound name (name of common commercial product (supplier) (HLB)) :): Monopalmitolein (C 16: 1) (Larodan) (<10)); Monoelaidin (C 18: 1) (Larodan) (<10)); Monocaproin (C6) (Larodan) (<10)); Monocapriline (Larodan) (<10)); Monocaprine (Larodan) (<10)); Monolaurin (Larodan) (<10)); glyceryl monomiristate (C14) (Nikkol MGM (Nikko) (3-4)); Glyceryl monooleate (018: 1) (PECEOL (Gattefosse), Hodag OGM-D, Nikkol MGO (Nikko) (3-4)); Glyceryl monooleate (RYLO series (Danisco), DIMODAN series (Danisco), EMULDAN (Danisco), ALDO ® MO FG (Lonza), Kessco GMO (Stepan), MONOMULS® series (Henkel), TEGIN O.DREWMULSE GMO (Stepan) , Atlas G-695 (ICI), GMOrphic 80 (Eastman), ADM DMG-40, 70 and 100 (ADM), Myverol (Eastman) (3-4)); glycerol monooleate / linoleate (OLICINE (Gattefosse) (3-4)); Glycerol monolinoleate (Maisine (Gattefosse), MYVEROL 18-92, Myverol (Eastman) (3-4) 18-06); glyceryl ricinoleate (Softigen® 701 (Huls), HODAG GMR-D (Calgene), ALDO® MR (Lonza) (6)); Glyceryl monolaurate (ALDO ® MLD (Lonza), Hodag GML (Calgene) (6.8)); Glycerol monopalmitate (Emalex GMS-P (Nihon) (4)); Glycerol monostearate (Capmul® GMS (ABITEC), Myvaplex (Eastman), IMWITOR® 191 (Huls), CUTINAGMS, Aldo® MS (Lonza), Nikkol MGS (Nikko) series (5-9)); Glyceryl mono-, dioleate (Capmul® OGM-K (ABITEC) (<10)); glyceryl palmitic / stearic (CUTINA MD-A, ESTAGEL-G18 (<10)); Glyceryl acetate (Lamegin ® EE (Grunau GmbH) (<10)); Glyceryl laurate (Imwitor® 312 (Huls), Monomuls® 90-45 (Grunau GmbH), Aldo® MLD (Lonza) (4)); glyceryl citrate / lactate / oleate / linoleate (Imwitor ® 375 (Huls) (<10)); Glyceryl caprylate (Imwitor ® 308 (Huls), Capmul ® MCMC8 (ABITEC) (5-6)); glyceryl caprylate / caprate (Capmul® MCM (ABITEC) (5-6)); Mono, caprylic acid diglycerides (Imwitor ® 988 (Huls) (5-6)); Caprylic / capric glycerides (Imwitor ® 742 (Huls) (<10)); Mono- and diacetylated monoglycerides (Myvacet® 9-45, Myvacet® 9-40, Myvacet® 9-08 (Eastman), Lamegin® (Grunau) (3,8-4)); Glycerin monostearate (Aldo ® MS, Arlacel 129 (ICI), LIPO GMS (Lipo Chem.), Imwitor ® 191 (Huls), Myvaplex (Eastman) (4.4)); Lactic acid esters of mono, diglycerides (LAMEGIN GLP (Henkel) (<10)); Dicaproin (C6) (Larodan) (<10); Dicaprine (C10) (Larodan) (<10); Dioctanoin (C8) (Larodan) (<10); Dimiristin (C14) (Larodan) (<10); Dipalmitin (C16) (Larodan) (<10); Distearin (Larodan) (<10); Glyceryl dilaurate (C12) (Capmul ® GDI. (ABITEC) (3-4)); Glyceryl dioleate (Capmul ® GDO (ABITEC) (3-4)); Glycerol esters of fatty acids (GELUCIRE 39/01
29/69 (Gattefosse), GELUCIRE 43/01 (Gattefosse) GELUCIRE 37/06 (Gattefosse) (16)); Dipalmitolein (C16: 1) (Larodan) (<10); 1,2 and 1,3-diolein (C18: 1) (Larodan) (<10); Dielaidin (018: 1) (Larodan) (<10); Dilinolein (Cl 8: 2) (Larodan) (<10); and their combinations.
Sterol and Sterol Derivatives: (listed as compound name (common commercial product name (supplier) (HLB)) cholesterol, sitosterol, lanosterol (<10)); cholesterol ether of PEG-24 (Solulan C-24 (Amerchol) (> 10)); cholestanol from PEG-30 (Nikkol DHC (Nikko) (> 10)); Phytosterol (GENEROL (Henkel) series (<10)); PEG-25 phytosterol (Nikkol BPSH-25 (Nikko) (> 10)); PEG-5 soy sterol (Nikkol BPS-5 (Nikko) (<10)); PEG-10 soy sterol (Nikkol BPS-10 (Nikko) (<10)); PEG-20 soy sterol (Nikkol BPS-20 (Nikko) (<10)); PEG-30 soy sterol (Nikkol BPS-30 (Nikko) (> 10)); and their combinations.
Sorbitan Fatty Acid Esters Polyethylene Glycol: (listed as compound name (common commercial product name (supplier)) (HLB)): PEG-10 sorbitan laurate (Liposorb L-10 (Lipo Chem.) (> 10) ); PEG-20 sorbitan monolaurate (Tween-20 (Atlas / ICI), Crillet 1 (Croda), DACOL MLS 20 (Condea) (17)); PEG-4 sorbitan monolaurate (Tween-21 (Atlas / ICI), Crillet 11 (Croda) (13)); Sorbitan monolaurate PEG-80 (Hodag PSML-80 (Calgene); T-Maz 28 (> 10)); PEG-6 sorbitan monolaurate (Nikkol GL- 1 (Nikko) (16)); PEG-20 sorbitan monopalmylate (Tween-40 (Atlas / ICI), Crillet 2 (Croda) (16)); PEG-20 sorbitan monostearate (Tween-60 (Atlas / ICI), Crillet 3 (Croda) (15)); PEG-4 sorbitan monostearate (Tween-61 (Atlas / ICI), Crillet 31 (Croda) (9.6)); Sorbitan monostearate PEG-8 (DACOL MSS (Condea) (> 10)); PEG-6 sorbitan monostearate (Nikkol TS106 (Nikko) (1-1)); PEG-20 sorbitan tristearate (Tween-65 (Atlas / ICI), Crillet 35 (Croda ) (11)); PEG-6 sorbitan tetrastearate (Nikkol GS-6 (Nikko) (3)); PEG-60 sorbitan tetrastearate (Nikkol GS-460 (Nikko) (13)); PEG-5 sorbitan monooleate (Tween-81 (Atlas / ICI), Crillet 41 (Croda) (10)); PEG-6 sorbitan monooleate (Nikkol TO-106 (Nikko) (10)); PEG-20 sorbitan monooleate (Tween-80 (Atlas / ICI), Crillet 4 (Croda) (15)); PEG40 sorbitan oleate (Emalex ET 8040 (Nihon Emulsion) (18)); PBG-20 sorbitan trioleate (Tween-85 (Atlas / ICI), Crillet 45 (Croda) (11)); PEG-6 sorbitan tetraoleate (Nikkol GO-4 (Nikko) (8.5)); PEG-30 sorbitan tetraoleate (Nikkol GO-430 (Nikko) (12)); PEG-40 sorbitan tetraoleate (Nikkol GO-440 (Nikko) (13)); PEG-20 sorbitan monoisostearate (Tween-120 (Atlas / ICS), Crillet 6 (Croda) (> 10)); PEG sorbitol hexaoleate (Atlas G-1086 (ICI) (10)); PEG-6
30/69 sorbitol hexastearate (Nikkol GS-6 (Nikko) (3)); and their combinations.
Polyethylene Glycol Alkyl Ethers: (listed as compound name (name of common commercial product (supplier) (HLB)): PEG-2, oleto-2 oleyl ether (Brij 92/93 (Atlas ICI) (4.9)) ; PEG-3 oleyl ether, oleto-3 (Volpo 3 (Croda) (<10)); PEG-5 oleyl ether, 5-oleto (Volpo 5 (Croda) (<10)); PEG- oleyl ether 10, oleto-10 (10 Volpo (Croda), Brij 96/97 (Atlas ICI) (12)); PEG-9 lauryl ether (> 10), PEG-20 oleyl ether, 20-oleto (Volpo 20 ( Croda), Brij 98/99 (Atlas / ICI) (15)); PEG-4 lauryl ether, lauret-4 (Brij 30 (Atlas / ICI) (9.7))); Lauryl ether from PEG-23, lauret-23 (Brij 35 (Atlas / ICI) (17)); PEG-2 cetyl ether (Brij 52 (ICI) (5.3)); PEG-10 cetyl ether (Brij 56 (ICI) (13)); PEG-20 cetyl ether (BriJ 58 (ICI) (16)); stearyl ether of PEG-2 (Brij 72 (ICI) (4.9)); stearyl ether of PEG-10 (Brij 76 (ICI) (12)); stearyl ether of PEG-20 (Brij 78 (ICT) (15)); stearyl ether of PEG-100 (Brij 700 (ICI) (> 10)); and their combinations.
Sugar esters: (listed as compound name (name of common commercial product (supplier) (HLB)): Sucrose distearate (SUCROESTER 7 (Gattefosse), Crodesta F-10 (Croda) (3)); Distearate / monostearate of sucrose (SUCROESTER 11 (Gattefosse), Crodesta F-110 (Croda) (12)); Sucrose dipalmitate (7.4)); Sucrose monostearate (Crodesta F-160 (Croda) (15)); Sucrose monopalmitate (SUCROESTER 15 (Gattefosse) (> 10)); Sucrose monolaurate (1695 sucrose monolaurate (Mitsubisbi-asei) (15)); and their combinations.
Polyethylene Glycol Alkyl Phenols: (listed as compound name (common commercial product name (supplier) (HLB)): PEG-10- 100 of nonyl phenol (Triton X series (Rohm & Haas), Igepal CA series (GAF, USA), Antarox CA series (> 10)); (GAF, UK); PEG-15-100 octyl phenol ether (Triton N series (Rohm & Haas), Igepal CO series (GAF, USA), Antaro CO series (GAF, United Kingdom) (> 10)), and their combinations.
Polyethylene-Polyoxypropylene Block Copolymers (known as poloxamer): These polymers have the formula:
HO (C <2> H <4> 0) <a> (C <3> H <6> 0) <b> (C <2> H <4> 0) <a> H where a and b represent the number of polyoxyethylene and polyoxypropylene units, respectively. The compounds are listed by the generic name, with the corresponding a and b values. POE-POP block copolymers)); (values a, b in)); (HO (C <2> H <4> 0) <a>)); (COMPOUND (C <3> H <6> 0) <b> (C <2> H <4> 0) <a> H (HLB)); (Poloxamer 105 (a = 11 (b = 16 (8)); (Poloxamer 108 (a = 46 (b = 16 (> 10)); (Poloxamer 122 (a = 5 (b = 21 (3)); ( Poloxamer 123 (a = 7 (b = 21 (7));
31/69 (Poloxamer 124 (a = 11 (b = 21 (> 7)); (Poloxamer 181 (a = 3 (b = 30));
(Poloxamer 182 (a = 8 (b = 30 (2)); (Poloxamer 183 (a = 10 (b = 30));
(Poloxamer 184 (a = 13 (b = 30)); (Poloxamer 185 (a = 19 (b = 30));
(Poloxamer 188 (a = 75 (b = 30 (29)); (Poloxamer 212 (a = 8 (b = 35));
(Poloxamer 215 (a = 24 (b = 35)); (Poloxamer 217 (a = 52 (b = 35));
(Poloxamer 231 (a = 16 (b = 39)); (Poloxamer 234 (a = 22 (b = 39));
(Poloxamer 235 (a = 27 (b = 39)); (Poloxamer 237 (a = 62 (b = 39 (24)); (Poloxamer 238 (a = 97 (b = 39)); (Poloxamer 282 (a = 10 (b = 47));
(Poloxamer 284 (a = 21 (b = 47)); (Poloxamer 288 (a = 122 (b = 47 (> 10));
(Poloxamer 331 (a = 7 (b = 54 (0.5)); (Poloxamer 333 (a = 20 (b = 54));
(Poloxamer 334 (a = 31 (b = 54)); (Poloxamer 335 (a = 38 (b = 54));
(Poloxamer 338 (a = 128 (b = 54)); (Poloxamer 401 (a = 6 (b = 67));
(Poloxamer 402 (a = 13 (b = 67)); (Poloxamer 403 (a = 21 (b = 67));
(Poloxamer 407 (a = 98 (b = 67)); and their combinations.
Sorbitan Fatty Acid Esters: (listed as compound name (common commercial product name (supplier)) (HLB)): Sorbitan monolaurate (Span-20 (Atlas / ICI), Crill 1 (Croda), Arlacel 20 (ICI ) (8.6)); Sorbitan monopalmitate (Span-40 (Atlas / ICI), Crill 2 (Croda), Nikkol SP-10 (Nikko) (6.7)); Sorbitan monooleate (Span-80 (Atlas / ICI), Crill 4 (Croda), Crill 50 (Croda) (4.3)); Sorbitan monostearate (Span-60 (Atlas / ICI), Crill 3 (Croda), Nikkol SS-10 (Nikko) (4.7)) ; Sorbitan trioleate (Span-85 (Alias Crill 45 (Croda), Nikkol SO-30 (Nikko) (4.3)); Sorbitan sesquioleate (Arlacel-C (ICI), Crill 43 (Croda), Nikkol SO-15 ( Nikko) (3.7)); Sorbitan tristearate (Span-65 (Atlas / ICI) Crill 35 (Croda), Nikkol SS-30 (Nikko) (2.1)); Sorbitan monoisostearate (Crill 6 (Croda), Nikkol SI- 10 (Nikko) (4.7)); Sorbitan sesquistearate (Nikkol SS-15 (Nikko) (4.2)); and their combinations.
Lower Alcohol Fatty Acid Esters: (listed as compound name (common commercial product name (supplier)) (HLB)): Ethyl oleate ((Crodamol EO (Croda), Nikkol EOO (Nikko) (<10)); isopropyl myristate (Crodamol IPM (Croda) (<10)); isopropyl palmitate (Crodamol IPP (Croda) (<10)); Ethyl linoleate (Nikkol VF-E (Nikko) (<10)); Isopropyl linoleate (Nikkol VF-IP (Nikko) (<10)); and their combinations
Lonic surfactants: (listed as compound name (HLB) Fatty acid salts (> 10)); Sodium caproate; Sodium caprylate; Sodium caprate; Sodium laurate; Sodium myristate)); Sodium myristolate; Sodium palmitate; Sodium palmitoleate; Sodium oleate (18); Sodium ricinoleate)); Linoleate
32/69 sodium; Sodium linolenate; Sodium stearate; Sodium lauryl sulfate (40); Sodium tetradecyl sulfate; Sodium lauryl sarcosinate; Sodium dioethyl sulfosuccinate; Bile salts (> 10); Sodium cholate; Sodium taurocholate; Sodium glycocholate; Sodium deoxycholate; Sodium taurodeoxycholate; Sodium glycodeoxycholate; Ursodeoxycholic sodium; Sodium kenodeoxycholate; Sodium tauroquenodeoxycholate; Sodium glyco-chene deoxycholate; Sodium colylsarcosinate; Sodium methyl taurocholate; and their combinations.
Phospholipids: such as egg / soy lecithin (Epikuron ™; Ovothin ™); Soy / egg lysolecithin; Hydroxylated lecithin; Lysophosphatidylcholine; Cardiolipin; Sphingomyelin; Phosphatidylcholine; Phosphatidyl ethanolamine; Phosphatidic acid; Phosphatidyl glycerol; Phosphatidyl serine and its combinations.
Phosphoric Acid Esters: Polyoxyethylene-10 phosphate oleyl ether diethanolammonium; Products for the esterification of fatty acids or ethoxylated fatty alcohols with phosphoric acid or anhydride.
Carboxylates, such as: Carboxylate ether (by oxidation of the OH terminal group of ethoxylated fatty alcohols) Succinylated monoglycerides; Stearyl sodium fumarate; stearoyl propylene glycol hydrogen succinate; Mono / diacetylated tartaric acid esters of mono and diglycerides; Mono-diglyceride citric acid esters; Fatty acid glycerol lactic esters; and their combinations.
Acyl lactylates, such as: lactyl fatty acid esters; calcium / sodium stearoyl-2-lactylate; calcium / sodium stearoyl lactylate; alginate salts such as sodium alginate, calcium alginate and others; and their combinations.
Hydrophilic polymers, such as: carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, methacrylic acid copolymers, macrogol, starch, gelatin, dextrin, pullulan, agar, acacia, poly (ethylene glycol), poly (ethylene) oxide, poly (ethylene) oxide vinyl), poly (ethylene-co-vinyl alcohol), poly (acrylic) acid, poly (ethylene-co-acrylic acid), poly (ethyloxazoline), poly (vinyl pyrrolidone), poly (ethylene-vinyl pyrrolidone), poly acid (maleic), poly (ethylene-co-maleic acid), poly (acrylamide) or poly (ethylene oxide) -co-poly (propylene oxide); Block copolymers, lactic acid graft copolymers, glycolic acid, epsiloncaprolactone, lactic-co-glycolic acid oligomers, trimethylene carbonate, amino acid anhydrides and acrylates, benzoquinones, naphthoquinones and the like; N-vinylpyrrolidone-co-vinyl alcohol, poly (ethylene-co-vinyl alcohol); acrylic or methacrylic acid copolymers; carbomers, chitosan, methacrylates (Eudragits) and their combinations.
33/69
Acids, such as: acetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, an amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromo phenyl sulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, its salts and mixtures thereof.
Bases, such as: amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, aluminum and magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine and mixtures of their combinations.
Chelating agents, such as: sodium EDTA, sodium dieditate and their mixtures or combinations. Complexing agents, such as: Hydroxypropyl cyclodextrin, Hydroxypropyl beta cyclodextrin, sulfobutyl ether cyclodextrin and their mixtures and combinations. Salts, such as: acid salts, bases, fatty acid salts, fatty acid glycerides, bile acid salts and their mixtures and combinations.
Amides, such as: for example 2-pyrrolidone, 2-piperidone, epsiloncaprolactam, N-alkyl-pyrrolidone, N-hydroxyalkyl-pyrrolidone, N-alkyl-piperidone, N-alkyl-caprolactam, dimethyl acetamide, polyvinylpyrrolidone and the like.
Alcohols such as: ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, glycerol, sorbitol, mannitol, dimethyl Isosorbide, polyethylene glycol, fatty acid alcohol, polypropylene glycol vinyl alcohol, polyvinyl alcohol, tocopherols, cyclodextrin cellulose, others derivatives, forms, mixtures of the same or similar.
Glycerols and Propylene Glycols, such as: glycerin, propylene glycol, polypropylene glycol, polypropylene oxides and their mixtures. Polyethylene Glycol (PEG), such as: PEG 300, PEG 400, PEG 4000 PEG 6000, PEG 8000, PEG 20000 and their combinations.
Esters, such as: ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate,
34/69 triacetin, propylene glycol monoacetate, propylene glycol diacetate, epsiloncaprolactone and its isomers, delta-valerolactone and its isomers, betabutyrolactone and its isomers, dimethyl acetamide, dimethyl isosorbide, diethylene monoolethine, N-methyl pyrrolidine similar.
Bile acids, such as: cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, uenodeoxycholate, glycodeoxycholate, glycoquenodeoxycholate, tauroquenodeoxycholate, ursodeoxycholate, litocolate, tauroursodeoxycholate, glycodesodeoxycholate, colyl sarcosine).
Cellulose, such as: microcrystalline cellulose, ethyl cellulose (CE), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethyl cellulose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CPr), cellulose butyrate (CB), cellulose butyrate acetate (CAB), cellulose acetate phthalate (CAP), cellulose trimellate acetate (CAT), hydroxypropyl methylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP), succinate acetate hydroxypropylmethylcellulose (HPMCAS), hydroxypropylmethylcellulose trimellite (HPCAT) and ethylhydroxyethylcellulose (EHEC), varying degrees of low viscosity (MW less than or equal to 50,000 daltons) and high viscosity (MW greater than 50,000 daltons) HPMC, and combinations thereof .
Cellulose esters, such as: Cellulose acetate, Cellulose Butyrate Acetate, Cellulose phthalate acetate, Hydroxypropyl methylcellulose phthalate and combinations thereof.
Mucoadhesive polymers, such as tocopherols, for example, tocopherol, tocopherol acetate, tocopherol succinate and combinations thereof.
Amino acids and Modified Amino acids, such as: derivatives of aminoboronic acid, n-acetylcysteine and their mixtures.
Sugars, such as: maltose, sucrose, glucose, lactose, fructose, marmitol, sucralose, fructose, trehalose, dextrose, maltodextrose and their combinations.
Sugar alcohols, such as: mannitol, xylitol, sorbitol, their combinations and the like.
Osmotic agents, such as: Hydrophilic vinyl and acrylic polymers, polysaccharides, such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly ( acrylic), poly (methacrylic) acid, polyvinylpyrrolidone (PVP) and crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers and PVA / PVP copolymers with hydrophobic monomers, such as methyl methacrylate, acetate
35/69 vinyl and the like, hydrophilic polyurethanes containing large blocks of PEO, croscarmellose sodium, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxycellulose (sodium), alginate , polycarbophil, gelatin, xanthan gum and sodium starch glycolate and the like.
Other carriers, such as: dibasic calcium phosphate, croscarmellose sodium, sodium starch glycolate, sodium alginate, phospholipids, lecithins, proteins (for example, collagen, gelatin, Zein, gluten, mussel protein, lipoprotein); carbohydrates (for example, alginates, carrageenan, cellulose derivatives, pectin, starch); gums (eg, xanthan gum, gum arabic, tragacanth gum, acacia gum); spermaceti; natural or synthetic waxes; carnauba wax; fatty acids (for example, stearic acid, hydroxystearic acid); Magnesium stearate, calcium stearate, titanium dioxide, polyacrylic acid, silicates, aluminum and magnesium silicates, siloxanes, dimethicones, paraffins, fatty alcohols; dibutyl phthalate; dibutyl sebacate; diethyl phthalate; dimethyl phthalate; triethyl citrate; butyl esters and fatty acid glycol; mineral oil; cetyl alcohol; stearyl alcohol; camphor oil; triethyl citrate, shellacs, benzalkonium chloride, methyl paraben, propyl paraben, sodium benzoate and the like.
In one embodiment, the pharmaceutical composition or oral dosage form can be formulated to include at least one of the following preferred carriers: citric acid, maleic acid, tartaric acid, ascorbic acid, lactic acid and salts thereof, potassium hydroxide, hydroxide sodium, sodium hydrogen carbonate, calcium carbonate, silicon dioxide, aluminum and magnesium silicate, triethylamine, fatty acid glycerides, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, triethylcitrate, benign triethylene , bile acids, bile acid salts, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose esters, carbomer, methacrylates, polyvinyl alcohol, gelatin, distearine, monopalmitolein tocopherol, corn oil, olive oil, peanut oil, olive oil, peanut oil safflower, sesame oil, soybean oil, hydrogenated castor oil, glyceryl tricaprate, gas trilinoleate lyceryl, glyceryl tricaprilate / caprate, glyceryl tricaprilat / caprate / glycolate, saturated polyglycolated glycerides, linoleic glycerides, caprylic / capric glycerides, capric acid, caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, oleic acid arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid,
36/69 glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl palmitate, glyceryl laurate, glyceryl caprylate, PEG-6 corn oil, PEG apricot seed oil -6, stearoyl macrogol glyceride, PEG-20 sorbitan monostearate, PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate , polyglyceryl-3 oleate, polyglyceryl-10 oleate, polyglyceryl-6 dioleate, polyglyceryl-10 mono, dioleate, poloxamer 188, poloxamer 108, poloxamer 182, propylene glycol monocaprylate, propylene glycol monolaurate, tipprilate / propylate propylate glycol, propylene glycol caprylate / caprate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate, maltose fructose, mannitol, xylitol and their combinations.
In one embodiment, the pharmaceutical compositions or oral dosage forms of the present invention can be formulated to include a hydrophilic additive. In another embodiment, the hydrophilic additive can be a hydrophilic surfactant. In one embodiment, when the hydrophilic additive includes a hydrophilic surfactant, the hydrophilic surfactant does not significantly solubilize the 17-hydroxyprogesterone ester. Non-limiting examples of hydrophilic additives include salts of citric acid, maleic acid, tartaric acid, acetic acid, ascorbic acid, benzoic acid and lactic acid, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, carbon dioxide silicon, aluminum and magnesium silicate, hydroxypropyl cyclodextrin, fatty acid glycerides, bile acid salts, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, carbamide, carbomethane polyvinyl alcohol, gelatin, PEG-8 caprylic / capric glycerides, macrogol-32 lauroyl glyceride, macrogol stearoyl glyceride, PEG-40 hydrogenated castor oil, PEG35 castor oil, sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, PEG-10 laurate, PEG-20 oleate, PEG30 stearate, PEG-40 laurate, gl laurate PEG-20 iceryl, PEG-20 glyceryl loomate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, sorbitan monooleate of PEG-20, polyglyceryl-10 oleate, mono-polyglyceryl-10, dioleate, poloxamer 188, poloxamer 108, maltose, sucrose, fructose, mannitol, xylitol, and combinations thereof.
37/69
In another specific modality, the carrier can be a hydrophilic surfactant and can be an ionic or non-ionic surfactant. Non-limiting examples of hydrophilic surfactants include protein salts, gelatin, bile acid salts, caprylic / capric PEG-8 glycerides, macrogol-32 lauroyl glyceride, macrogol stearoyl glyceride, PEG40 hydrogenated castor oil, castor oil PEG-35, sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, PEG-10 laurate, PEG-20 oleate, PEG-30 stearate, PEG-40 laurate, glycerol laurate PEG20, PEG-20 glyceryl loomate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate , polyglyceryl-10 oleate, mono polyglyceryl-10, dioleate, poloxamer 188, poloxamer 108, and combinations thereof.
In one embodiment, the hydrophilic additive may be free of hydrophilic surfactants, and may be citric acid, maleic acid, tartaric acid, acetic acid, ascorbic acid, benzoic acid, lactic acid, potassium hydroxide, sodium hydroxide, hydrogen carbonate of sodium, calcium carbonate, silicon dioxide, aluminum and magnesium silicate, hydroxypropyl cyclodextrin, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, cellulose esters, carbamide, carbones methacrylates, polyvinyl alcohol, gelatin, maltose, sucrose, fructose, mannitol, xylitol and their combinations.
In another embodiment, the carrier of pharmaceutical compositions or oral dosage forms may include a lipophilic additive. Non-limiting examples of lipophilic additives include tributyl citrate, triethyl citrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, methyl cellulose hydroxypropyl phthalate, tocopherol, tocopherol acetate, toccinolate succinate , corn oil, olive oil, peanut oil, safflower oil, sesame oil, soy oil, hydrogenated castor oil, glyceryl tricaprate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoleate, tricaprilate / caprate glyceryl, tricaprilat / caprate / glyceryl laurate, tricaprilat / caprate / glyceryl linoleate, tricaprilat / caprate / glyceryl stearate, saturated polyglycolated glycerides, linoleic glycerides, caprylic / capric glycerides, capric acid, caprylic acid, palmitic acid, lactic acid stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, monooleate glyceryl monoxide, glyceryl monolinoleate, glyceryl monolaurate,
38/69 glycerol, glyceryl distearate, glyceryl palmitostearate, glyceryl laurate, glyceryl caprylate, diestearin, monopalmitolein, monolaurine, ethyl oleate, PEG-6 corn oil, PEG-6 apricot seed oil, triglycerides caprylic / capric PEG-4, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poloxamer 182, propylene glycol monocaprilate, propylene glycol monolaurate , propylene glycol tip / propylate, propylene glycol caprate / caprate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate and their combinations. In one embodiment, the carrier of the present invention can include at least 50% by weight of lipophilic additive.
In a given embodiment, the lipophilic additive is at least one agent selected from tributyl citrate, triethyl citrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, methyl cellulose hydroxypropyl phthalate, tocopherol, tocopherol acetate, tocopherol succinate, triglycerides, corn oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, hydrogenated castor oil, glyceryl tricaprate, glyceryl trilaurate, glyceryl trioleate , glyceryl trilinoleate, glyceryl tricaprilat / caprate, tricaprilat / glyceryl laurate / caprate / glyceryl tracylacrylate / caprate / glyceryl triacylate, glyceride glycerides, saturated glycerides, glycerides, glycerides, glycerides, glycerides, caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicos acid apentaenoic, docosahexaenoic acid, glyceryl distearate, glyceryl palmitostearate, distestin, tristearin, paraffin oil, beeswax, animal fat, phytosterol, cholesterol, shellac and their combinations.
In a specific embodiment, the lipophilic additive is a triglyceride. Non-limiting examples of triglycerides suitable for this invention include corn oil, olive oil, peanut oil, palm oil, coconut oil, arachis oil, safflower oil, sesame oil, soybean oil, castor oil, evening primrose oil, cottonseed oil, vegetable oil, borage oil, linseed oil, linseed oil, omega oils, partially or fully hydrogenated castor oil, fish oil, shark oil, whale oil, seal, glyceryl tricaprate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoleate, glyceryl tricaprilat / caprate, glyceryl tricaprilat / caprate / glyceryl tricaprilate trate / caprine / linylate / capricylate / caprolate
39/69 saturated polyglycolated glycerides, linoleic glycerides, caprylic / capric glycerides, tristearin and the like, and combinations thereof.
In one embodiment, the lipophilic additive can be free of lipophilic surfactants. In a given modality, the carrier is a lipophilic surfactant. Non-limiting examples of lipophilic surfactants suitable for the present invention include tributyl citrate, triethyl citrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetate butyrate, benzyl benzoate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, tocopherol, tocopherol acetate, tocopherol succinate, corn oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, hydrogenated castor oil, glyceryl tricaprate, glyceryl trilaurate, glyceryl trioleate , glyceryl trilinoleate, glyceryl tricaprilat / caprate, tricaprilat / glyceryl laurate / caprate / glyceryl tracylacrylate / caprate / glyceryl triacylate, glyceride glycerides, saturated glycerides, glycerides, glycerides, glycerides, glycerides, caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl laurate, glyceryl oil, diestearin, monopalycin, monopalate PEG-6 corn, PEG-6 apricot seed oil, PEG-4 caprylic / capric triglycerides, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate , polyglyceryl-6 dioleate, poloxamer 182, propylene glycol monocaprilate, propylene glycol monolaurate, propylene glycol tip / acrylate, propylene glycol caprylate / caprate, sorbitan monolaurate, sorbitan sorbitan monopalmitate, sorbitan, sorbitan monopalmitate, sorbitan monate sorbitan sesquistearate and its combinations.
In another particular form, the compositions or dosage form of the present invention can be free of triglycerides, or substantially free of triglycerides. Thus, in one embodiment, the present invention does not include a lipophilic or hydrophilic additive that contains triglycerides as an intended or added component. However, it should be appreciated that the present invention does not exclude the use of lipophilic or hydrophilic additives that contain small amounts of triglycerides as impurities or unreacted raw materials. The expectation is that when such a lipophilic additive or
40/69 hydrophilic is used in the compositions of the present invention, the total content of triglycerides does not exceed 5% by weight of the composition or dosage form. Thus, substantially triglyceride free (s) should be understood as free of added triglycerides, and the triglyceride impurity of lipophilic or hydrophilic additives constitutes about 5%, or less than 5%, less than 2%, or preferably 0% (triglyceride free) by weight of the composition. In addition, the present invention does not exclude lipophilic or hydrophilic additives that are derived from triglycerides, such as, for example, derivatives of polyethylene glycol or triglyceride propylene glycol; while these triglyceride derivatives may have surfactant properties, triglycerides are not surfactants in themselves.
Non-limiting examples of such lipophilic additives include tributyl citrate, triethyl citrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, methyl cellulose hydroxypropyl phthalate, tocopherol, tocopherol acetate, succinate tocopherol, saturated polyglycolated glycerides, linoleic glycerides, caprylic / capric glycerides, capric acid, caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, benzyl benzoate, docosahexaenoic acid, monoolea glyceryl, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl laurate, glyceryl caprylate, diestearin, monopalmitoline, monolaurine, ethyl oleate, 6-P oil, corn oil apricot seed PEG-6, caprylic / capric triglycerides PEG-4, monoeste PEG-20 sorbitan arate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poloxamer 182, propylene glycol monocaprilate, propylene glycol monolaurate, tipprilate / propylate glycolprate and glycolate / propylene glycol caprate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate and their combinations.
In some embodiments, the carrier of the present invention may be a control release agent. In a given embodiment, the control release agent is selected from the group consisting of such hydrophilic additives or lipophilic additives, or a mixture thereof. In another particular embodiment, the compositions or dosage forms of the present invention can be free of lipophilic surfactant. In another particular embodiment, the compositions or dosage forms of the present invention can
41/69 be free of lipophilic additives.
As discussed above, in some embodiments, the pharmaceutical compositions and oral dosage forms of the present disclosure can include at least one hydrophilic additive and at least one lipophilic additive. In one embodiment, when a hydrophilic additive and a lipophilic additive are present, they can be present in a lipophilic to hydrophilic additive ratio of about 99: 1 to about 1:99. In one embodiment, the ratio of lipophilic additive to hydrophilic additive can be from about 95: 5 to about 5: 95. In another embodiment, the ratio of lipophilic additive to hydrophilic additive can be from about 90:10 to about 10:90. In one embodiment, the ratio of lipophilic additive to hydrophilic additive can be from about 90:10 to about 1:99. In another specific embodiment, the ratio of lipophilic additive to hydrophilic additive can be from about 80:20 to about 20:80. In another specific embodiment, the ratio of lipophilic additive to hydrophilic additive can be from about 70:30 to about 30:70. In another specific embodiment, the ratio of lipophilic additive to hydrophilic additive can be from about 60:40 to about 40:60. In another specific embodiment, the ratio of lipophilic additive to hydrophilic additive can be about 50:50.
In a separate embodiment, when a hydrophilic surfactant and a lipophilic additive are present, they can be present in amounts such that when 1 part by weight of the mixture of the hydrophilic surfactant and lipophilic additive is mixed 99 parts of an aqueous diluent, the dispersion thus obtained it can be colloidal, cloudy or unclear. For example, the aqueous diluent used for dispersion is water or 0.5% w / v sodium lauryl sulfate in water. In a specific embodiment, the dispersion may have an absorbance greater than 0.1 when determined using a spectrophotometer at 400 nm. In another specific modality, the absorbance is greater than 0.3 to 400 nm. In another embodiment, the average particle size of the dispersion is about 60 nm or more. In another specific embodiment, the average particle size of the dispersion is about 100 nm or more. In another specific embodiment, the average particle size of the dispersion is about 150 nm or more. In yet another specific embodiment, the average particle size of the dispersion is about 200 nm or more. In yet another specific embodiment, the average particle size of the dispersion is about 250 nm or more. For example, the aqueous diluent used for dispersion is water or 0.5% w / v sodium lauryl sulfate in water. For the purposes of the present invention, dispersion is considered clear if
42/69 appear clear to the naked eye. In one embodiment, the dispersion can be clear.
The carrier may be present in sufficient quantity to solubilize the hydroxyprogesterone ester. In some respects, the carrier of the present invention assists in the solubilization of a significant amount of the 17-hydroxyprogesterone ester in the composition. In one embodiment, the carrier can solubilize 20% by weight or more of the amount of the 17-hydroxyprogesterone ester. In another embodiment, the carrier can assist in the load greater than about 10% w / w / of the ester in the composition and / or dosage form. In another embodiment, the load achieved by the carrier can be greater than about 12% w / w of the composition and / or dosage form. In another embodiment, the load achieved by the carrier can be greater than about 15% w / w of the composition and / or dosage form. In another embodiment, the load achieved by including the carrier may be greater than about 18% w / w of the composition and / or dosage form. In other modalities, the load achieved by the inclusion of the carrier can be greater than about 20%; greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 75% or greater to about 90%, with each percentage based on w / w of the composition and / or dosage form.
In one embodiment, the carrier may include benzyl alcohol, benzyl benzoate, mixtures thereof. In another embodiment, the carrier can include benzyl alcohol, benzyl benzoate, or mixtures thereof, and the amount of the hydroxyprogesterone ester can be between about 5 to about 80% w / w of the total composition. In one embodiment, when the carrier includes benzyl alcohol, benzyl benzoate or mixtures thereof, the amount of the 17-hydroxyprogesterone ester can be between about 5 to about 80% w / w of the total composition, in one incarnation, the amount of the 17-hydroxyprogesterone ester can be between about 5% to about 60% w / w of the total composition. In another specific embodiment, when the carrier includes benzyl alcohol, benzyl benzoate or mixtures thereof, the amount of the 17-hydroxyprogesterone ester can be between about 5 to about 40% w / w of the total composition. In another specific embodiment, when the carrier includes benzyl alcohol, benzyl benzoate or mixtures thereof, the amount of the 17-hydroxyprogesterone ester can be between about 5 to about 30% w / w of the total composition. In another specific embodiment, when the carrier includes benzyl alcohol, benzyl benzoate or mixtures thereof, the amount of the 17-hydroxyprogesterone ester can be between about 5 to about 25% w / w of the total composition. In a modality
43/69 specific, when the carrier includes benzyl alcohol, benzyl benzoate or mixtures thereof, the 17-hydroxyprogesterone ester can be totally solubilized in the composition and / or in the dosage form. In a specific embodiment, the 17-hydroxyprogesterone ester can be partially solubilized in the dosage form. In another specific embodiment, the 17-hydroxyprogesterone ester can be 17-hydroxyprogesterone caproate.
In one embodiment, the ratio of the amount of the hydroxyprogesterone ester to the sum of the amounts of benzyl alcohol and benzyl benzoate present in the composition or oral dosage form can be approximately 1: 0.01 (w / w) to about 1 : 5 (w / w). In another embodiment, the ratio can be from about 1: 0.01 (w / w) to about 1: 3.5 (w / w). In another embodiment, the ratio of the amount of the 17-hydroxyprogesterone ester to the sum of the amounts of benzyl alcohol and benzyl benzoate present in the composition or oral dosage form can be approximately 1: 0.01 (w / w) to about of 1: 2.5 (w / w). In another embodiment, the ratio of the amount of the hydroxyprogesterone ester to the sum of the amounts of benzyl alcohol and benzyl benzoate present in the composition or oral dosage form can be approximately 1: 0.01 (w / w) to about 1 : 2 (w / w).
Pharmaceutical compositions and oral dosage forms can be formulated and delivered in a variety of solid or liquid dosage forms. Non-limiting examples of such dosage forms include powder, granules, particulates, granules, pellets (pellets), sprays, suspensions, solutions, tablets, capsules and combinations thereof. In one embodiment, the pharmaceutical composition or oral dosage form can be in the form of a capsule. In another embodiment, the pharmaceutical compositions or oral dosage form can be in the form of a tablet. In one embodiment, the dosage form is a hard or soft capsule. The capsule may be made of conventional capsule coating materials known in the art; these materials may include, but are not limited to, gelatin, cellulose, starches, methacrylates, carrageenans, polyvinyl alcohols and the like. In another embodiment, the capsule is an immediate release dosage form. In another embodiment, the capsule is a controlled release dosage form. In another embodiment, the tablet is an immediate release dosage form. In another embodiment, the tablet is a controlled release dosage form.
In one embodiment, the volume of the capsule can be about 1.5 ml or
44/69 less. In another embodiment, the volume of the capsule can be about 1.2 ml or less. In a given embodiment, the volume of the capsule can be about 0.8 mL or less. In another embodiment, the ratio of the weight of the encapsulated filler material within the capsule to the volume of the capsule can be between about 0.3 g / ml to about 3.5 ml. In a given embodiment, the ratio can be between 0.6 g / ml to about 2.5 g / ml. In a given embodiment, the ratio can be between 0.6 g / ml to about 1.2 g / ml.
In another embodiment, the oral pharmaceutical capsule dosage form of the present invention can have a ratio between the amount of the 17-hydroxyprogesterone ester in the composition and the capsule filling volume between about 0.02 g / ml to about 0.8 g / ml. In another embodiment, the ratio can be between about 0.02 g / ml to about 0.7 g / ml. In a specific embodiment, the ratio can be between 0.02 g / ml to about 0.5 g / ml. In another specific embodiment, the ratio can be between 0.05 g / ml to about 0.5 g / ml. In another specific embodiment, the ratio can be between 0.05 g / ml to about 0.35 g / ml.
In another specific embodiment, the ratio can be between 0.05 g / ml to about 0.3 g / ml. In another specific embodiment, the ratio can be between 0.1 g / ml to about 0.25 g / ml.
The oral dosage forms of the present invention can be formulated to include an amount of a 17-hydroxyprogesterone ester equivalent to about 10 mg to about 800 mg of 17-hydroxyprogesterone. In one embodiment, the oral dosage form can be formulated to include an amount of 17-hydroxyprogesterone ester equivalent to 20 mg to about 400 mg of 17-hydroxyprogesterone. The pharmaceutical composition and oral dosage forms of the present invention can be formulated to be administered to a subject in order to provide a daily dose of the 17-hydroxyprogesterone ester that is equivalent to about 40 mg of about 3200 mg of 17-hydroxyprogesterone. In one embodiment, the oral dosage form can be a capsule and the capsule includes about 10 mg to about 300 mg of 17-hydroxyprogesterone caproate. In another embodiment, the oral dosage form can be a tablet and the tablet includes about 20 mg to about 800 mg of 17-hydroxyprogesterone caproate.
In order to provide a desired daily dose, oral pharmaceutical compositions and dosage forms can be formulated to be administered at various dosage intervals. In one embodiment, oral compositions or dosage forms can be formulated for administration approximately
45/69 every 8 hours. In another embodiment, oral compositions or dosage forms can be formulated for administration to a subject, such as a human subject, once every 6 hours. In another embodiment, oral compositions or dosage forms can be formulated for administration approximately every 12 hours. In yet another embodiment, oral compositions or dosage forms can be formulated for administration approximately every 24 hours.
In one aspect, the oral dosage forms of the present invention can be used to treat pregnant female subjects who are at risk of premature birth. Treatment methods can include the step of administering orally to the female subject of the oral pharmaceutical composition. In another modality, oral dosage forms can be administered to subjects in need. Administration of the oral dosage form can treat at least one selected condition of premature labor, premature birth, infertility and miscarriage. In one embodiment, the subject receiving the administration of the pharmaceutical composition or oral dosage form may be experiencing or at risk for at least two of: single-stage pregnancy, history of premature labor and / or premature delivery, history of premature birth , shortened cervix and cervical effacement, history of abortion, at least one or more, and history of multifetal pregnancy. Conditions and relative treatment can be based on your measurements of primary and secondary outcomes associated with administration of the 17-hydroxyprogesterone ester.
In one embodiment, after single administration to a human subject, the pharmaceutical compositions or oral dosage forms of the present invention comprising a 17-hydroxy ester can provide a C _me d-24 equivalent to 17-hydroxyprogesterone greater than about 0, 7 ng / ml. In another embodiment, the oral dosage form or composition can provide _me d-C 24 equivalents of 17-hydroxyprogesterone greater than about 10 ng / ml. In another embodiment, the oral dosage form or composition can provide a C _m -d-24h of 17-hydroxyprogesterone equivalents greater than about 30 ng / ml. In another embodiment, the oral dosage form or composition can provide éd24h C _m of equivalents of 17-hydroxyprogesterone greater than about 50 ng / ml. In yet another embodiment, the oral dosage form or composition can provide C- _m -24h of 17-hydroxyprogesterone equivalents greater than about 100 ng / ml. In one modality, said C _m d- 24h equivalent of 17
46/69 hydroxyprogesterone is determined by an HPLC-MS / MS method of analyzing blood, serum or plasma samples collected after oral administration.
In one embodiment, after single administration to a human subject, the pharmaceutical compositions or oral dosage forms of the present invention comprising a 17-hydroxyprogesterone caproate can provide a 17 _m -hydroxyprogesterone caproate equal to about 1.0 ng / mL or more. In another embodiment, the oral dosage form or composition may provide 17 _m hydroxyprogesterone caproate equal to about 20 ng / ml or more. In another embodiment, the oral dosage form or composition may provide 17 _m hydroxyprogesterone caproate equal to about 50 ng / ml or more. In another embodiment, the oral dosage form or composition can provide d24h C _m is of 17-hydroxyprogesterone caproate equal to about 100 ng / mL or more. In one embodiment, said C- _m -24h of 17-hydroxyprogesterone caproate is determined by an HPLC-MS / MS method of analyzing blood, serum or plasma samples collected after oral administration.
Surprisingly, it was found that the compositions and / or dosage forms of this invention provided significantly increased bioavailability of 17 hydroxyprogesterone caproate as a function of the oral dose of 17 hydroxyprogesterone caproate administered to a subject. Therefore, the compositions or dosage forms of this invention provide, by oral administration of a single dose, a ratio between AUC (o-24h> and dose of about 10 or less, where the dose is the amount in mg of caproate 17-hydroxyprogesterone administered In one embodiment, the ratio between the AUC ₍ o24h> 17-hydroxyprogesterone caproate and the administered 17 hydroxyprogesterone caproate dose may be about 0.2 ng * h mL ' ¹ mg' ¹ to about 10 ng * h mL ' ¹ mg' ^1. In another embodiment, the AUC ratio (0.24 h of 17 hydroxyprogesterone caproate and the dose of 17-hydroxyprogesterone caproate administered can be about 0.3 ng * h mL ' ¹ mg ' ¹ to about 7 ng * h mL' ¹ mg ' ^1. In a specific embodiment, the ratio between AUC (o-24h) and dose is between 0.5 and about 6 ng * h mL' ¹ mg ' ¹ .
In a specific embodiment, after single administration of the pharmaceutical compositions or oral dosage forms containing caproate 17-hydroxyprogesterone of the present invention to a human subject in power state, pharmaceutical compositions , or oral dosage forms can provide a C _m éd -24h 17-hydroxyprogesterone caproate greater than about 1.0 ng / ml or more. In another specific modality, the compositions
47/69 pharmaceutical or oral 17-hydroxyprogesterone-containing dosage forms of the present invention can provide a steady-state 17 _m hydroxyprogesterone ca-24h greater than about 1.0 ng / mL when administered to a human subject in a steady state. food. In one embodiment, said C _m éd-24h is determined by an HPLC-MS / MS method of analyzing blood, serum or plasma samples collected after oral administration. In another embodiment, the compositions and oral dosage forms disclosed in this document can be administered orally with food or without considering the food or the content of the food. In a specific embodiment, compositions and oral dosage forms containing 17-hydroxyprogesterone caproate ester, as disclosed in this document, can be administered orally with food or without regard to food content.
In one embodiment, the oral dosage form can be administered orally with food or after feeding. In another embodiment, the composition or oral dosage form can be administered with a normal or standard meal. In a specific embodiment, the composition or oral dosage form can be administered with a food or meal, such as a meal that provides about 200 calories to about 1000 calories of energy. In another specific embodiment, the composition or oral dosage form can be administered with a meal that provides about 50% of the calories from fat. In another embodiment, the composition or oral dosage form can be administered with a meal that is high in fat and calories. In another embodiment, the composition or oral dosage form can be administered with a standard meal that provides about 500 calories to about 1000 calories of energy. The compositional characterization of meals that are administered can vary depending on a subject's tastes and dietary needs. However, in some situations it may be beneficial to administer oral compositions and dosage forms with meals that provide no fat or even about 50 g of fat. In one embodiment, the meal can provide about 3 g to about 50 g of fat. In yet another embodiment, the meal can provide from 10g to about 50g of fat. In another embodiment, the meal can provide about 15g to about 35g of fat. In one embodiment, when the oral dosage form is administered to a human female, this can be done without considering the presence of or the nutritional composition of a meal. In another modality, when
48/69 administers the oral dosage form, the total daily dose of the 17 HP ester administered to the female human subject with food or after feeding is about 20% to about 80% of the total daily dose administered without meals, for a similar therapeutic benefit. In a specific embodiment, the daily dose in the fed state is about 20% to about 60% of the total daily dose administered without meals, for a similar therapeutic benefit. In another embodiment, the composition or oral dosage form can be administered orally without food or on an empty stomach.
The oral bioavailability of the 17-hydroxyprogesterone ester can be enhanced by using the ester in the form of fine particles, for example, ground, micronized or nanodimensioned, etc., in the composition and / or in the dosage form of the present invention. In addition, oral bioavailability can be enhanced using the ester along with a carrier that assists in the release of at least 20% more of the ester from the composition or dosage form when exposed to aqueous medium, compared to an equivalent dose of the ester without the carrier of the present invention. In a specific embodiment, the oral bioavailability of the 17-hydroxyprogesterone caproate ester can be enhanced through the use of such ester in the form of fine particulate, for example, ground, micronized or nanodimensioned or their combinations in the composition and / or in the form of dosage of the present invention.
Likewise, in one embodiment, the oral bioavailability of the 17-hydroxyprogesterone ester is at least 10% higher for the compositions or dosage forms of the present invention that release at least 20% of the ester in aqueous medium compared to an equivalent dose. of the ester present in an untreated particulate form, for example, as unground or non-micronized particulate forms. In another embodiment, the oral bioavailability of the 17-hydroxyprogesterone ester is at least 10% higher for the compositions or dosage forms of the present invention that release at least 20% more of the ester of the composition or dosage form when exposed to the aqueous medium compared to an equivalent dose of the ester without the carrier of the present invention. In a specific embodiment, said ester is 17-hydroxyprogesterone caproate.
The 17-hydroxyprogesterone ester can be a substrate for P-glycoproteins (P-gp) efflux transport systems. Therefore, in one embodiment, oral bioavailability can be enhanced by at least 10% by co-administering the 17-hydroxyprogesterone ester of the present invention.
49/69 with an effective amount of P-gp and / or CYP3A4 inhibiting agents, for example, star fruit, grapefruit juice, bergamotine, cafestol (as in unfiltered coffee), ketoconazole, erythromycin, mibefradil, loperamide, etc.
In another aspect, oral pharmaceutical compositions or oral 17-hydroxyprogesterone ester dosage forms according to the present invention can be used to provide luteal support to a subject who needs it. In one embodiment, the oral composition or oral dosage form can be formulated to allow modulation or dose titration and / or the 17-hydroxyprogesterone ester dosing regimen to provide effective luteal support for a subject who needs it. In a given embodiment, the dose of the 17-hydroxyprogesterone ester in the form of oral compositions or dosage forms of the present invention can be modulated or titrated to provide effective luteal support as needed during early pregnancy. In another particular embodiment, the 17-hydroxyprogesterone ester dose in the form of oral compositions or dosage forms of the present invention can be modulated or titrated to provide effective luteal support as needed based on the subject's body mass index (BMI). In another particular embodiment, the 17-hydroxyprogesterone ester dose in the form of oral compositions or dosage forms of the present invention can be modulated or titrated to provide effective luteal support as needed based on the subject's race or ethnicity.
An example of dose modulation or titration may be based on the total daily dose and may include the administration of a dose with a higher initial load or a bolus dose, followed by a lower effective standard dose. Likewise, dose modulation or titration can be based on the total dose per week and may include the administration of a dose with a higher initial load or a bolus dose on the initial days of the week, followed by a lower effective standard dose on days end of the week. The dosage regimen may include increasing (ie, progressive increases), the daily dose in line with the progression of the pregnancy. In another specific embodiment, the ester is 17 hydroxyprogesterone caproate (17-hydroxyprogesterone caproate).
In another embodiment, the daily oral dose administered with 17-hydroxyprogesterone caproate foods is about 40 mg to about 5000 mg. In another embodiment, the daily oral dose is about 40 mg to about 4000 mg. In another embodiment, the daily oral dose is about 80 mg to about 4000 mg. In another embodiment, the daily oral dose is about 150 mg to about 4000 mg.
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In another embodiment, the daily oral dose is about 250 mg to about 4000 mg. In another embodiment, the daily oral dose is about 500 mg to about 4000 mg. In another embodiment, the daily oral dose is about 750 mg to about 4000 mg. In another embodiment, the daily oral dose is about 1000 mg to about 4000 mg. In another embodiment, the daily oral dose is about 1200 mg to about 4000 mg. In another embodiment, the daily oral dose is about 1500 mg to about 4000 mg. In another embodiment, the daily oral dose is about 1500 mg to about 3000 mg. In another embodiment, the daily oral dose is about 1000 mg to about 2000 mg. In another embodiment, the daily oral dose is about 200 mg to about 2000 mg. In another embodiment, the daily oral dose is about 400 mg to about 2000 mg. In another embodiment, the daily oral dose is about 800 mg to about 2000 mg.
In a particular embodiment, the oral dosage form of the present invention comprises a therapeutically effective amount of a 17-hydroxyprogesterone ester, where, when measured using a USP Type II dissolution apparatus in 900 ml of 0.5% deionized water ( w / v) sodium lauryl sulfate at 50 RPM at 37 ° C, the oral dosage form releases at least 20% by weight of the 17-hydroxyprogesterone ester dose after 60 minutes. In another particular embodiment, the dosage form releases at least about 40% by weight of the dose of the 17-hydroxyprogesterone ester after 60 minutes. In another particular embodiment, the dosage form releases at least about 50% by weight of the dose of the 17-hydroxyprogesterone ester after 60 minutes. In another particular embodiment, the dosage form releases at least about 70% by weight of the dose of the 17-hydroxyprogesterone ester after 60 minutes. In a specific embodiment, the ester is 17-hydroxyprogesterone caproate. In another embodiment, the dosage form is administered with food.
After oral administration of the 17-hydroxyprogesterone ester (e.g., 17-hydroxyprogesterone caproate) in the form of the composition or dosage form of the present invention, its concentration in the subject's serum, plasma or blood can be determined by analytical techniques based on in radioimmunoassay (RIA), high performance liquid chromatography coupled to Mass Spectrometry (HPLC-MS / MS) and similar. Consequently, the plasma or blood levels for the ester may be different. It should be understood that any relative comparison of the blood plasma levels of any compound must be made using the same assay methodology, or corrections must be made to adjust the discrepancy for the specificity of the
51/69 essay.
Likewise, in one embodiment, the 17-hydroxyprogesterone caproate compositions or dosage forms of the present invention can provide an average stable state of 17max hydroxyprogesterone average C _max from about 10 ng / mL to about 800 ng / mL, in which the plasma 17-hydroxyprogesterone caproate is determined by the HPLC-MS / MS method. In a given embodiment, the compositions or dosage forms provide an average steady state of mean C _max of 17 hydroxyprogesterone caproate of about 10 ng / ml to about 400 ng / ml.
In a further embodiment, the compositions or oral dosage forms of 17-hydroxyprogesterone caproate the present invention can provide a mean steady state C _m j _{n-hydroxyprogesterone} caproate 17 of about 1 ng / ml or more. The plasma concentrations of the 17 hydroxyprogesterone caproate can be determined by the HPLC-MS / MS method. In one embodiment, the oral compositions or dosage forms can provide an average stable state of 17 _m -hydroxyprogesterone caproate greater than about 10 ng / ml. In another embodiment, the oral composition or dosage forms may provide an average stable Cmin status of 17-hydroxyprogesterone caproate greater than 20 ng / ml, or greater than about 40 ng / ml, greater than about 60 ng / ml , or greater than about 80 ng / ml. In a specific embodiment, the composition or oral dosage form can provide a mean steady state C _m j _n from about 1 to about 60 ng / ml. In another specific embodiment, the composition or dosage form can provide an average Cmin steady state of about 1 ng / ml to about 20 ng / ml.
Thus, the oral 17 hydroxyprogesterone caproate dosage form of the present invention can be an immediate release dosage form. In a separate embodiment, the oral 17-hydroxyprogesterone caproate dosage form of the present invention can be a controlled release dosage form. In another specific embodiment, the dosage form may include 17-hydroxyprogesterone caproate in the form of immediate and controlled release fractions, preferably prolonged or delayed release.
Therefore, the controlled release of 17-hydroxyprogesterone caproate compositions or dosage forms of the present invention can provide a fluctuation in 17-hydroxyprogesterone caproate levels of less than about 795 ng / mL, where the fluctuation is determined by the difference in
52/69 mean stable state C _max and mean steady state Cmin of 17 hydroxyprogesterone caproate in plasma, or serum, or blood after oral administration.
In another specific aspect, the pharmaceutical compositions and / or oral 17-hydroxyprogesterone caproate dosage forms of the present invention can be used to treat one or more of the conditions selected from the group consisting of habitual abortion, recurrent abortion, threat abortion, postpartum pain, endometrial cancer, management of primary and secondary amenorrhea, infertility due to insufficient corpus luteum, progestogen deficiency, cervical insufficiency, cervical incompetence and abnormal uterine bleeding. In an additional embodiment, the pharmaceutical compositions and / or oral 17-hydroxyprogesterone caproate dosage forms of the present invention can be used to test the production of endogenous estrogen and for the production of secretory and desquamation endometrium.
In another embodiment, the pharmaceutical compositions and / or oral 17-hydroxyprogesterone caproate dosage forms of the present invention can be used in conjunction with omega-3 fatty acid supplementation to treat symptomatic premature delivery patients. In a given embodiment, the compositions and / or dosage forms of the present invention can include at least one omega fatty acid. In another particular modality, the compositions and / or dosage form of the present present may include omega-3, omega-6 or omega-9 fatty acids or mixtures thereof.
EXAMPLES
The following examples are provided to promote a clearer understanding of certain embodiments of the present invention and are not intended to be in any way a limitation thereof. Unless otherwise specified or mentioned, all compositions provided in the examples are with respect to% w / w of the final composition. Note that, with the exception of the compositions listed in Examples 1, 7, 10, 17 and 36, the 17-hydroxyprogesterone caproate of all other example compositions can be either treated (milled, micronized, or nanodimensioned) or untreated. The 17-hydroxyprogesterone caproate in compositions 1,7, 10, 17 and 36 is not treated for size reduction (ie, unground, non-micronized, or nano-sized), and has an average particle size greater than 50 micrometers. The dosage forms of the corresponding Examples were tested for the release of 17h hydroxyprogesterone caproate using a USP Type II apparatus, at 50 rpm in 900 mL of simulated intestinal fluid with 0.5% w / w sodium lauryl sulfate at 37 ° C . THE
53/69 percentage of 17-hydroxyprogesterone caproate released from each composition was analyzed using HPLC.
EXAMPLES 1-6 - 17-hydroxyprogesterone caproate compositions
17-hydroxyprogesterone caproate compositions, as recited in Examples 1 to 6, are prepared using the respective components shown in Table I. Example 1 is the treated crystalline form of the 17-hydroxyprogesterone caproate filled in hard gelatin capsules. Example 2 is micronized 17-hydroxyprogesterone caproate without a carrier filled in hard gelatin capsules. Examples 3-6 are prepared as follows: The required quantities of each component of the respective composition, except 17-hydroxyprogesterone caproate are collected in a clean stainless steel container and mixed at about 50 ° C to 70 ° C , using a shaker. A fused mixture of clear to nebula is obtained. The required amount of 17-hydroxyprogesterone caproate is added to the clear to nebulous mixture and stirred to form a homogeneous liquid mixture. A predetermined weight of the resulting liquid mixture is deposited in capsules of suitable size, according to the required 17-hydroxyprogesterone caproate dose. The capsules are allowed to solidify at room temperature and then arranged and packaged in HDPE bottles and sealed with a lid.
The 17-hydroxyprogesterone caproate released from each of the compositions using the above-mentioned dissolution test parameters is shown in Table I. Note that Examples 1 and 2 (17h hydroxyprogesterone caproate without a carrier) and Examples 3 to 6 (17-hydroxyprogesterone caproate mixed with at least one carrier) can be used for comparison purposes to help illustrate the advantages of the compositions and dosage forms of the present invention.
TABLE I
Example No. 1 2 3 4 5 6 Ingredients Composition in% w / w 17h hydroxyprogesterone caproate 100 15 11 18 Lipophilic Additive: Hydrogenated Castor Oil, NF - -- 48 - Lipophilic Additive: Lauroglycol FCC - -- 32 - Lipophilic Additive: - - - 63 - 75
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glyceryl monolinoleate, NF Hydrophilic additive: Polyoxyl 40 Hydrogenated Castor Oil, NF- - 16 Hydrophilic additive: PEG 8000 USP - - - 6 9 7 % of release in60 min <10 > 70 > 70 > 70 > 70 > 70
Micronized 17-hydroxyprogesterone caproate (approximate particle size distribution: d100% <25pm; d50% <15 pm)
The aqueous dispersion of the mixture that includes a lipophilic additive and hydrophilic surfactant, if present, from Examples 3 to 6 of Table I can be unclear nebula when seen with the naked eye. Its absorbance at 400 nm may be greater than 0.1, or greater than 0.3, and / or the dispersion particle size may be greater than 100 nm. In some respects, the average dispersion particle size can be greater than 250 nm. Each of the aqueous dispersions is prepared by mixing 1 part of the additive mixture of the corresponding example and 99 parts of an aqueous diluent. The compositions of Example 3-6 can be prepared by mixing 17-hydroxyprogesterone caproate additives to obtain a homogeneous suspension or solution. If necessary, the mixture can be heated (for example, at about 40 ° C to about 80 ° C) to obtain a solution or to obtain a homogeneous suspension. The mixture can be placed in a capsule. The dosage form of Example 1 and 2 has 17-hydroxyprogesterone caproate as non-micronized and micronized solid particles, respectively. The 17-hydroxyprogesterone caproate can be fully solubilized (as in the case of Example 3) or partially solubilized (as in the case of Examplos6 and 6). The formulations in Table I, if liquid, can also be formulated to be a solid dosage form by filling or mixed with a solidification tool inside a capsule. Alternatively, they can be formulated into tablets using appropriate tablet tools.
EXAMPLES 7 - 10 - 17h hydroxyprogesterone caproate compositions
The 17-hydroxyprogesterone caproate compositions of Examples 7 to 10 can be prepared using the ingredients shown in Table II and achieve the indicated release performance.
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TABLE II
Example No. 7 8 9 10 Ingredients Composition in% w / w 17- caproatehydroxyprogesterone(particle size> 50pm) 90-99 - - 90-99 17- caproatehydroxyprogesteronamicronized * - 70-80 - - 17- caproatehydroxyprogesterone (ground) - - 70-80 - Lactose 1-10 1-20 1-20 30 Povidona K30 3-6 3-6 3-6 3-6 Organic granulation solvent - 0 orq.s ** *** 0 orq.s *** 0 orq.s *** % of release in 60 min <15 > 50 > 50 > 50
* can be replaced with milled 17-hydroxyprogesterone caproate and scaled to billionth part ** removed substantially during the drying process *** Sufficient amount for the wet granulation process or for the in situ formation / precipitation of rapid caproate release 17h solid hydroxyprogesterone
It should be noted that the compositions of Examples 7 to 10 can be formulated to provide granules for compression into a tablet or filler in a capsule, sachet etc., with the inclusion of suitable pharmaceutical tools such as diluents, binders, disintegrants, lubricants, flavors etc.
Unlike Examples 1 and 7, the 17-hydroxyprogesterone caproate release profile of Examples 8, 9 and 10, shown in Table II, illustrates the advantages of the smaller 17-hydroxyprogesterone caproate particle size. These examples further illustrate the advantages of various manufacturing processes, such as granulation, which yield solid compositions with suitable 17-hydroxyprogesterone caproate release profiles. In some embodiments, the caproate ester in the example compositions in Table II can be replaced with other 17-hydroxyprogesterone esters, such as acetate or undecanoate.
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EXAMPLE 11 - 17h hydroxyprogesterone caproate coated tablets
The 17-hydroxyprogesterone caproate tablets of Example 7 to 10 can be coated with a coating solution of the typical composition set out in Table III, using conventional tablet coating procedures known in the art for a weight gain of about 3 to 6 %.
TABLE III
Ingredients Composition in% w / w Polymer (eg Hypromellose, Metocel E 5) 8.0 Plasticizer (eg Polyethylene Glycol, NF 8000) 0.6 Coating Solvent (eg Ethanol) 54.8 Coating SolventWater 36.6
The coating polymer can be selected based on the need for a specific functionality to be transmitted to the dosage form. For example, film coating, flavor masking, enteric coating protective coating, sustained release of the coating and so on, can all be used. Unlimited examples of polymers for use in such coatings include hypromellose, polyethylene glycol, povidone, sugars, ethyl cellulose, methacrylates, phthalates, cellulose etc. Many conventional coating tools such as talc, starch, plasticizers, opacifiers, colors, flavors, etc. they can also be used together with coating polymers or sugars. The coating solvents can be conveniently varied based on the coating polymer or sugar being applied.
EXAMPLES 12-17 - 17-hydroxyprogesterone caproate compositions
Table IV shows the 17-hydroxyprogesterone caproate compositions of Examples 12/17 that can be prepared using the components defined therein and the method similar to that described for Examples 3-6. The release of 17-hydroxyprogesterone caproate from the dosage form is also shown in Table IV.
TABLE IV
Example No. 12 13 14 15 16 17 Ingredients Composition in% w / w 17- caproate 15 15 14 15 22 25
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hydroxyprogesterone Lipophilic additive ... (e.g.Glycerol Caprylate / Caprate (Capmul ®MCM)85 Lipophilic additive (eg capric acid) 85 - - - - - Lipophilic additive (eg glycerol monolinoleate) - - 73 65 3 5 Hydrophilic additive (eg polyoxyl 40 Hydrogenated Castor Oil) 13 15- Hydrophilic additive (eg polyoxyl 35 Hydrogenated Castor Oil)- - -22 Lipophilic additive (eg glyceryl palmitostearate; glyceryl distearate, Precirol® ATO 5) 5 Hydrophilic additive (eg tocopherol polyethylene glycol succinate)- - - 22Lipophilic additive (eg vitamin E; d, 1-atocopherol) - - - - 35 48 Hydrophilic additive (eg hypromellose (4,000 cPs) - - - - 18% of release in60 min > 40 > 40 > 40 > 40 > 30 > 40
The aqueous dispersion of the mixture of the lipophilic additive and the hydrophilic surfactant, if present, in the examples shown in Table-VI may be unclear nebula when seen with the naked eye. Its absorbance at 400 nm may be greater than 0.1, or greater than 0.3, and / or the dispersion particle size 5 may be greater than 100 nm. In some respects, the average dispersion particle size can be greater than 250 nm. Each of the aqueous dispersions is prepared by mixing 1 part of the additive mixture of the corresponding example and 99 parts of an aqueous diluent.
The compositions in Table IV, if liquid, can be formulated to be
58/69 a solid dosage form by filling or mixed with a solidification tool such as polyethylene glycol, glyceryl distearate, wax and the like. It should be noted that these compositions can also be formulated to obtain granules for compression in a tablet or filling in a capsule, sachet etc., with the inclusion of suitable pharmaceutical tools such as diluents, binders, disintegrants, lubricants, flavors, etc.
The 17-hydroxyprogesterone caproate in the compositions of the examples in Table IV may, in some embodiments, be substituted with other 17-hydroxyprogesterone esters, such as 17-hydroxyprogesterone acetate or 10 17-hydroxyprogesterone undecanoate.
EXAMPLES 18-23 - 17-hydroxyprogesterone caproate compositions Table V shows several 17 hydroxyprogesterone caproate compositions as mentioned in Examples 18-23 that can be prepared using the components set out there.
TABLE V
Example No. 18 19 20 21 22 23 INGREDIENT Composition in% w / w 17h hydroxyprogesterone caproate 9 7 6 8 8 6 Hydrophilic surfactant (Tween 80) 1 1 1 4 1 1 Hydrophilic surfactant (eg sodium lauryl sulfate) 4 4 3 1 4 3 Hydrophilic polymer (eg HPMC) - 15 26 5 - 25 Enteric polymer (eg Eudragit) - - - - - 4 Hydrophobic polymer (eg ethyl cellulose) - - - - 5 - Processing Tools / Thinners 86 73 64 82 82 61 Total 100 100 100 100 100 100
Table VI shows several specific modalities of different dosage forms (DF-1-9-DF) containing 17-hydroxyprogesterone caproate which can be obtained from various combinations of the compositions shown in Table V.
TABLE VI
Example of Dosage form DF-1 DF-2 DF-3 DF-4 DF-5 DF-6 DF-7 DF-8 DF-9 Composition N ° Composition% w / w
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18 100 50 50 50 30 - - 30 50 19 - 50 - - - - - - - 20 - • 50 - - - - 30 - 21 - - - 50 • - - 40 50 22 - - - • - - 100 - - 23 - - • - 70 - - - - Total 100 100 100 100 100 100 100 100 100
Additional tablet methods known in the art that can be used can be applied to the compositions exemplified above.
The excipients shown are examples of the classes of 5 excipients that can be used
The form of the drug can be changed with other forms such as micronized, sieved, bleached, amorphous, nano etc.
The above dosage forms DF-1 to DF-9 can be single or multiple particle units in a capsule or as single or multiple particle units compressed into a single tablet or multilayer tablets.
EXAMPLES 24 - 28- - 17h hydroxyprogesterone caproate compositions
Table VII shows several 1715 hydroxyprogesterone caproate compositions as mentioned in Examples 24-28 that can be prepared using the components established therein and their release performance.
TABLE VII
Example No. 24 25 26 27 28 INGREDIENT Composition (mg per dosage form) 17-hydroxyprogesterone 50 50 50 50 50 Hydrophilic surfactant (Tween 80) 2.5 2.5 2.5 2.5 2.5 Hydrophilic surfactant (eg sodium lauryl sulfate) 12.5 12.5 12.5 12.5 12.5 Hydrophilic polymer (eg HPMC) 125 65 90 - 3 Enteric polymer (eg Eudragit) - - - - 5 Processing Tools - - - - 2
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Coating (eg plasticizer, non-stick agent)Processing Tools / Thinners (eg binder, disintegrant, thinner, glidant, lubricant) 25 25 35 35 35 Total 215 155 190 100 110 % of release in 60 min > 25 > 40 > 40 > 100 > 30
Additional tablet methods known in the art that can be used can be applied to the compositions exemplified above.
The excipients shown are examples of the classes of excipients that can be used, adjuvants such as binders, disintegrants, diluents, fluidizers, lubricants and coating tools commonly known in the art can be used.
• The form of the drug can be changed with other forms such as micronized, sieved, bleached, amorphous, nano, etc.
The above dosage forms can be units of single or multiple particles in a capsule or as units of single or multiple particles compressed into a monolithic tablet / mold or multilayer tablets.
In Example 28, the dosage form is exposed first to about 250 ml of simulated gastric fluid (SGF) without enzyme for the first 30 minutes, followed by exposure to 900 ml of 0.5% by weight of SLS in water with pH of about 6.8.
EXAMPLES 29-35 - 17-hydroxyprogesterone caproate compositions
Table VIII shows the 17 hydroxyprogesterone caproate compositions and release data from Examples 29-35 that can be prepared using the components defined therein and the method similar to that described for Examples 12-17.
TABLE VIII
Example No. 29 30 31 32 33 34 35 Ingredients With % w / w position 17h hydroxyprogesterone caproate 25 20 7 7 8 16 25
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Lipophilic additive (ex. Benzoate ofbenzyl) 48 45 - 29 53 Hydrophilic additive (eg alcoholbenzyl) 2 2 2 Lipophilic additive (eg castor oil) 25 23 - - - - - Lipophilic additive (eg corn oil) - - - - 67 - - Lipophilic additive (eg glyceryl caprylate / caprate; Capmul®MCM) 51 4817Lipophilic additive (eg capric acid) - - - - - - - Hydrophilic additive (eg Polyoxyl 40 castor oilhydrogenated)10 42 40 25 38 10 Hydrophilic additive (eg polyethyleneglycol 8000) 5 - - 10 % of release in60 min > 25 > 25 > 90 * > 80 > 60 > 60 > 25
*% released in 30 minutes
The above compositions can be formulated to display immediate or controlled release profiles. The aqueous dispersion of the mixture of the lipophilic additive and the hydrophilic surfactant, if present, in the examples shown in Table-VIII may be unclear nebula when seen with the naked eye. Its absorbance at 400 nm is greater than 0.1, in some cases, greater than 0.3 and / or the average dispersion particle size may be greater than 100 nm in some respects. In other respects, the average dispersion particle size can be greater than 250 nm. Each of the aqueous dispersions is prepared by mixing 1 part of the mixture of the additives and surfactants in the example
62/69 and 99 parts of an aqueous diluent.
As can be seen in Examples 29, 30 and 35 above using benzyl benzoate and / or benzyl alcohol, a larger drug load (e.g.,> 20% w / w 17-hydroxyprogesterone caproate) with desired release characteristics can be achieved. The 17-hydroxyprogesterone caproate can remain fully solubilized (Examples 29, 30, 31 and 33) or can be partially solubilized (Examples 32, 34 and 35) in the compositions. In addition, when seen with the naked eye, the aqueous dispersion of the mixtures with lipophilic additive and the hydrophilic surfactant, if present, as shown in Examples 29-31 and 3335 can be unclear nebula when seen with the naked eye. In some cases, its absorbance at 400 nm is greater than 0.1 or even greater than 0.3. In addition, the average dispersion particle size can be greater than 100 nm or even greater than 250 nm. Each of the aqueous dispersions is prepared by mixing 1 part of the mixture of the additives and surfactants of the corresponding example and 99 parts of an aqueous diluent.
The 17-hydroxyprogesterone caproate in the compositions of the examples in Table VIII can, in some respects, be substituted with other 17-hydroxyprogesterone esters, such as 17-hydroxyprogesterone acetate or 17-hydroxyprogesterone undecanoate.
The compositions of example 3, 31, 32, 33 and 34 can, in some respects, also be administered as an oral liquid. These compositions can also be administered orally, after adequate mixing / dilution with diluent, such as water, milk, fruit juices, drinks and the like just before administration.
In certain embodiments, the contents of the above compositions can be adsorbed on some additional diluents and excipients and can be compressed into a tablet.
EXAMPLE 36 - 17-hydroxyprogesterone caproate tablets
17-hydroxyprogesterone caproate containing granules for tablet with the components set out in Table IX can be prepared by wet granulation methods. Therefore, 17 hydroxyprogesterone caproate, macrocrystalline cellulose and croscarmellose sodium are passed through a # 40 ASTM mesh sieve and mixed in a low shear granulator to form a uniform mixture. A 1500 starch agglutinating solution in deionized water can be used to granulate the dry powder mixture to a granulation endpoint
63/69 typical. Dry wet granules using a tray dryer or fluid air dryer can be sized / selected, lubricated with Aerosil 200 and magnesium stearate and compressed into tablets.
TABLE IX
Ingredients Composition in% w / w 17-hydroxyprogesterone caproate (untreated) 28 Microcrystalline Cellulose (Avicel PH 102) 52.5 Croscarmellose sodium 10 Pregelatinized starch (Amidol 500) 8 Colloidal silicon dioxide 0.5 Magnesium stearate 1
The tablets of Example 36 have less than 20% 17-hydroxyprogesterone caproate released in the first 60 minutes, when tested using a USP Type II device, 50 rpm in 900 mL of simulated intestinal fluid, with 0.5% w / w of sodium lauryl sulfate at 37 ° C. Whereas, when micronized 17-hydroxyprogesterone caproate (with particle size d 100% being 50pm or less) with or without surfactant is used in the above formula, at least 40% released 17-hydroxyprogesterone caproate can be observed after 60 minute determined.
EXAMPLES 37-42 - 17-hydroxyprogesterone caproate compositions
Examples 37-39 of Table X have hydrophilic additives as carriers. Examples 37, 38 and 39 are prepared by the wet granulation process with organic solvents such as ethyl alcohol or ethanol-water as the granulation liquid. Partial or complete amounts of some of the hydrophilic additives in it (eg, povidones, pluronics, surfactants etc.) can be dissolved in the granulation liquid. Optionally, the 17-hydroxyprogesterone ester (eg, 17-hydroxyprogesterone caproate can be solubilized or suspended in the granulation liquid. This granulation liquid can then be poured onto the hydrophilic adsorption carriers (eg cellulose, Lactose etc.) with low mixing shear. The granules can be dried under a gentle air current at room temperature. The dried granules are passed through the # 40 ASTM mesh and filled into appropriately sized capsules or compressed into tablets according to the caproate strength of 17-hydroxyprogesterone required by unit dosage form, the 17-hydroxyprogesterone caproate compositions of the
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Examples 40-42 can be prepared using the components set out in Table X and according to the following method: The required amounts of the respective inactive component and the 17-hydroxyprogesterone caproate are taken in a clean stainless steel container and mixed gently in about from 50 ° C to 70 ° C, using a shaker, to obtain a homogeneous mixture. A pre-determined weight of the resulting mixture is placed in hard gelatin capsules and allowed to solidify at room temperature.
The dosage forms of each Example 37-42 are tested for the release of 17-hydroxyprogesterone caproate using a USP Type II apparatus, at 50 rpm in 900 mL of simulated intestinal fluid with 0.5% w / w lauryl sulfate sodium at 37 ° C. The percentage of 17-hydroxyprogesterone caproate released from each composition is analyzed using HPLC. The results of the release tests are also shown in Table X.
Note that the compositions of Examples 37-42 can be formulated to achieve tablet dosage forms with the inclusion of appropriate conventional tablet tools, such as diluents, binders, disintegrants, lubricants, etc., as needed.
TABLE X
Example No. 37 38 39 40 41 42 Ingredients Composition in% w / w 17h hydroxyprogesterone caproate 45 40 40 75 34 60 PEG 8000 USP - - - 10 29 40 Sodium lauryl sulfate 10 9 9 10 - - CelluloseMicrocrystalline * 45 40 37 - - - Pluronic F 68 0 11 11 - - - Polyvinylpyrrolidone (povidone K 30) 0 0 3 5 37 - % of release in60 min > 40 > 40 > 40 > 40 > 40 > 30
* Magnesium aluminum metasilicate (Neuslin®), lactose and other similar substances can be used / calcium silicate.
The performance of 17-hydroxyprogesterone caproate release in vitro
65/69 of Examples 37 to 42 can be seen superior to the release performance of Example 36. It should be noted that in the above compositions, adequate amounts of typical pharmaceutical tools, such as glidants, lubricants, non-stick, disintegrators and the like, can be incorporated as needed. In addition, suitable amounts of hydrophilic modifying agents (e.g., hypromellose, Eudragits etc.) can also be incorporated as necessary in the compositions of Examples 37 to 42, also, in some special cases, when the dosage form of Examples 37 to 42 is a tablet, appropriate functional coatings can be applied as needed. It should also be noted that, in some respects, the example compositions in Table X can be replaced with other 17-hydroxyprogesterone esters (for example, 17-hydroxyprogesterone acetate, 17-hydroxyprogesterone undecanoate, etc.)
EXAMPLES 43 and 44 - 17-hydroxyprogesterone caproate compositions
17-hydroxyprogesterone caproate compositions as mentioned in Examples 43 and 44 were prepared using the components set out there in Table XI. Each of the compositions was prepared by incorporating 17-hydroxyprogesterone caproate in the molten mixture of the corresponding inactive components taken in a stainless steel container, at about 35 ° C to 70 ° C, with gentle agitation to obtain a liquid flow mixture free. A predetermined weight of the resulting liquid mixture is placed in shells of hard or soft gelatin capsules and allowed to solidify at room temperature. It should be noted that the liquid mixture can also be allowed to solidify at room temperature to obtain solid aggregates that can be sized through an ASTM # 30 mesh to obtain granular particles, which can be filled in hard gelatin capsules or condensed in pills.
Each of the compositions is tested for the release of the 17 hydroxyprogesterone caproate using a USP Type II device, at 50 rpm in 900 ml of simulated intestinal fluid with 0.5% w / w sodium lauryl sulfate at 37 ° C. The percentage of 17-hydroxyprogesterone caproate released from each composition is analyzed using HPLC. The results of the release tests are also shown in Table XI.
TABLE XI
Example No. 43 44 Ingredients Composition in% w / w
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17-hydroxyprogesterone caproate 20 80 Lipophilic additive: (eg glycerol esters of C ^ -Cie fatty acids) 80 20 % of release in 60 min > 30% > 30%
EXAMPLE 45 - Spray-dried Multiparticulates of 17h hydroxyprogesterone caproate
17-hydroxyprogesterone caproate multiparticulates can be prepared as follows: 15g of 17-hydroxyprogesterone caproate and milled or micronized lactose mixture (95: 5 w / w), passed through a # 60 ASTM mesh sieve and added under mixing to about 250 mL of an 8% w / v solution of povidone K17 in water. The resulting suspension can be spray dried using conventional spray drying equipment with configurations, for example, at a heat inlet temperature of about 60-75 ° C and an outlet temperature of about 30-38 ° C , 90-100% aspirator, the pump fixed at about 8 to 12 mL / min, and the flow rate fixed at about 500-600 L / h. The final solid composition of 17-hydroxyprogesterone caproate multiparticulate may have a compositional makeup of about 53% by weight of 17-hydroxyprogesterone caproate, approximately 2.8% by weight of lactose and about 44.2% by weight of povidone K17 .
EXAMPLE 46-50 - 17-hydroxyprogesterone caproate compositions
A mixture of 17-hydroxyprogesterone caproate and the corresponding components can be melted together to obtain sufficient thermo stiffness to be placed in the capsule. Alternatively, the mixture can be fed into an extruder melter, for example, a single screw extruder (Kiliion, model KLB 100) equipped with a screw about 1 inch in diameter and a flexible opening mold of about 6 inches and the mold opening set to about 0.005 inches and the screw speed is fixed at about 50 rpm. The residence time of the materials inside the extruder can be defined for about 2 to 8 minutes. The extruded filaments can be cooled to room temperature, passing over a refrigerated roll. The filaments can then be sized through an ASTM # 40 mesh and the powder placed in capsules. Exemplary melt-extrusion compositions are shown in Table XII. These dosage forms can release 40% or more 17-hydroxyprogesterone caproate in approximately the first 60 minutes. It should be noted that the 17-hydroxyprogesterone caproate compositions in Table XII can be further formulated to include one or more other substances such as
67/69 such as lactose, starch, hydroxypropylmethylcellulose, methacrylate, etc. in different concentrations of about 12% to about 88% by weight of the total composition before melting-extrusion or after dimensioning the melted-extruded composition, in order to prepare solid multiparticulates for tablets.
TABLE XII
Example No. 46 47 48 49 50 IngredientsWith position in % w / w17h hydroxyprogesterone caproate 70 40 50 80 60 Polyethylene glycol 8000 USP 10 - 20 15 20 (Glyceryl distearate GDS, Precirol ATO 5) 10 40 20 - - Stearic acid 10 20 10 -Cholesterol - - - 5 20
Example 51 - 17-hydroxyprogesterone caproate compositions produced by co-milling
A 17-hydroxyprogesterone caproate containing composition can be prepared by co-grinding (or co-grinding) 80g 17hhydroxyprogesterone caproate together with 15g of PVP K 17 and 5g of sodium lauryl sulfate for a period of about 12 hours at about 24 hours using a ceramic ball mill maintained at about 20 ± 5 ° C. The eaten composition can provide a superior in vitro drug release profile that could be at least 20% more compared to the in vitro release profile of Example 1 when tested using a USP Type II apparatus, 50 rpm in 900 mL of intestinal fluid simulated with 0.5% w / w sodium lauryl sulfate at 37 ° C.
EXAMPLE 52 - 17-hydroxyprogesterone caproate charged pellets
17-hydroxyprogesterone caproate coated pellets are prepared with the ingredients set out in Table XIII. A spray solution of the coating materials can be prepared by dissolving 25g of 17-hydroxyprogesterone caproate, 6g of Pluronic F 68 and 5g of PVP K 30 in about 250mL of dehydrated alcohol. The spray solution can be sprayed intermittently onto a 64 g ball bearing bed of commercially available microcrystalline cellulose (for example, with an average particle size in the range of about 250pm to about 600pm) taken in a coating reservoir conventional. After the entire spray solution is loaded onto the spheres, it can be dried under a gentle
68/69 air for at least 1 hour to remove the solvent. Thus, by adjusting the reservoir speed, spray rate and air inlet flow and temperature, 17-hydroxyprogesterone caproate loaded with pellets or granules can be obtained, which can be placed inside a capsule. Auxiliary pharmaceutical process tools such as talc, starch, etc., can be dusted during the spraying process to prevent pellet agglomeration.
It should be noted that similar or appropriate equipment known in the art can be used for the purpose. Also, by varying the amount of spray solution sprayed on the beads or by varying the 17-hydroxyprogesterone caproate concentration in the spray solution, different drug loading pellets can be achieved.
TABLE XIII
Ingredients Composition in% w / w 17-hydroxyprogesterone caproate 25 Pluronic F 68 6 Polyvinylpyrrolidone K 30 5 Dehydrated Alcohol 250 mL Celsphere® Microcrystalline Cellulose Spheres 64
EXAMPLE 53 - Suspension Compositions of 17h hydroxyprogesterone caproate
The homogeneous suspension of 17-hydroxyprogesterone caproate prepared in a liquid vehicle with at least one non-solvent can be made by conventional processes known in the art. The suspension can be dosed as a conventional oral liquid or a known volume of the suspension can be encapsulated. Pharmaceutical tools such as suspending agents, thickening agents or viscosity modifiers, wetting agents, etc. known in the art can be used to achieve homogeneous suspension of the drug in the liquid vehicle.
EXAMPLE 54 - In vivo evaluation of the 17 hydroxyprogesterone caproate composition:
A preliminary evaluation of pharmacokinetic studies after oral administration of 17-hydroxyprogesterone caproate of the current invention was performed in male dogs. A single oral dose of 30 mg / kg and 5 mg / kg of 17-hydroxyprogesterone caproate, formulated in accordance with the exemplary formulations of the present invention were used for the study of relative bioavailability in a feeding state, compared to
69/69 an intramuscular dose of 6.4 mg / kg (composition similar to the commercially available Intramuscular injection, Makena®) as a positive control.
Post-dose blood levels of 17-hydroxyprogesterone caproate were monitored for 24 hours after the oral dose and 192 hours after the intramuscular injection of the dose. About 2mL of blood was drawn from the jugular, cephalic or saphenous veins just before the dose was administered and at the postdose at predetermined intervals. At each time point, the blood sample was collected in a vacutainer tube and centrifuged at about 3200 rpm for approximately 10 minutes, at about 5 ° C. The obtained serum was analyzed by HPLC-MS / MS for 17-hydroxyprogesterone caproate. The results of the 17-hydroxyprogesterone caproate concentration in the samples are shown in Table-XIV below:
Table-XIV
Exemplary Oral Dose Formulations of the Present Invention IM injection Administered dose 30 mg / kg 5 mg / kg 6.4 mg / kg Average End (ng / mL) 4.51 0.28 2.54 Medium (ng / mL) 74 2.5 8 AUC Medium O-final (ng * h / mL) 1767 60 1546 AUC (ng * h mL ' ¹ ) o-24h / Dose (MG) Ratio 5.8 1.0 -
Contrary to reports in the literature, we surprisingly found that oral compositions of the present invention provided significant levels of blood (medium) of 17-hydroxyprogesterone caproate after oral administration.
Numerous alternative modifications and arrangements can be designed by those skilled in the art without departing from the spirit and scope of the present invention and the added claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity and detail in relation to what is currently considered to be the most practical and preferred modalities of the invention, it will be evident to those of skill in the art that variations including, among others, variations in size , material, form, shape, function and mode of operation, assembly and use can be made without departing from the principles and concepts established here.
1/1

权利要求:
Claims (7)
[1]
1. Oral pharmaceutical composition, characterized by the fact that it is in the form of a capsule or a tablet comprising:
from 20 mg to 800 mg of 17-hydroxyprogesterone caproate and a pharmaceutically acceptable carrier;
wherein 17-hydroxyprogesterone caproate is present in the oral pharmaceutical composition in particulate form with an average particulate diameter of 50 pm or less; and wherein the carrier includes a hydrophilic surfactant which is a poloxamer, a polyethylene glycol sorbitan fatty acid ester, a sorbitan fatty acid ester, a polyethylene glycol glycerol fatty acid ester, a sodium lauryl sulfate, a dioctyl sodium sulfosuccinate or a bile salt, where the hydrophilic surfactant is a hydrophilic additive that has a hydrophilic lipophilic balance value of more than 10.
[2]
2. Pharmaceutical composition according to claim 1, characterized by the fact that, when measured using a USP Type-II dissolution apparatus in 900 mL of simulated intestinal fluid with 0.5% w / w sodium lauryl sulfate at 50 RPM at 37 ° C, the oral dosage form releases at least 20% by weight of 17-hydroxyprogesterone caproate after 60 minutes.
[3]
Pharmaceutical composition according to claim 1 or 2, characterized by the fact that the composition is formulated to support pregnancy.
[4]
Pharmaceutical composition according to claim 1 or 2, characterized by the fact that the capsule or the tablet is a controlled-release oral dosage form.
[5]
Pharmaceutical composition according to claim 1 or 2, characterized by the fact that the capsule or the tablet is an oral dosage form of immediate release.
[6]
Pharmaceutical composition according to any one of claims 1 to 5, characterized in that it is formulated for release once every 6, 8, 12 or 24 hours.
[7]
7. Use of a pharmaceutical composition defined in any one of claims 1 to 6, characterized by the fact that it is in the manufacture of a medicament for the treatment of a pregnant female subject at risk of premature birth.
Petition 870190127031, of 12/02/2019, p. 16/21
1/2

Time (hours) ______________________________

Time (hours)
2/2% of 17 average HPC

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law|

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2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2019-03-19| B07E| Notice of approval relating to section 229 industrial property law|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-05-21| B06T| Formal requirements before examination|

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2019-09-03| B07A| Technical examination (opinion): publication of technical examination (opinion)|

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2020-02-27| B09A| Decision: intention to grant|

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2020-04-22| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 27/07/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US13/193,571|US8951996B2|2011-07-28|2011-07-28|17-hydroxyprogesterone ester-containing oral compositions and related methods|

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PCT/US2012/048708|WO2013016697A2|2011-07-28|2012-07-27|17-hydroxyprogesterone ester-containing oral compositions and related methods|

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