NZ620698B2 - 17-hydroxyprogesterone ester-containing oral compositions and related methods - Google Patents

Abstract

Provided are oral dosage forms comprising esters of 17-hydroxyprogesterone and a pharmaceutically acceptable carrier. The carrier may be benzyl benzoate and/or benzyl alcohol. The carrier may improve the solubility of 17-hydroxyprogesterone and subsequently its bioavailability, or enhance the dissolution of the dosage form. ution of the dosage form.

Description

-HYDROXYPROGESTERONE ESTER-CONTAINING ORAL COMPOSITIONS AND RELATED METHODS FIELD OFTHE INVENTION The present invention relates to 17-hydroxyprogesterone ester containing compositions, oral dosage forms thereof, and associated methods. Accordingly, this invention involves the fields of chemistry, pharmaceutical sciences, medicine and other health sciences.

BACKGROUND OF THE INVENTION 17-alpha hydroxyprogesterone (alternatively hereinafter referred to as 17- hydroxyprogesterone or "17HP") is a C-21 endogenous steroid hormone produced during the syntheses of glucocorticoids and sex steroids. Like progesterone, 17HP is anatural progestagen. It has been isolated from both adrenal glands and corpora lutea. Esters of 7HP are reported tohave progestogenic effects and hence, can beused for indications related topregnancy support aswell asnon-pregnancy support in both pre- andpost menopausal women. Itis reported that 17HP,without esterification, has noprogestational activity. However, the synthetic esters of 17HP such 17-hydroxyprogesterone acetate or 17- alpha-hydroxyprogesterone caproate (also referred hereafter as 7 hydroxyprogesterone caproate or 17 HPC) have been shown to exhibit marked progestational activity when administered intramuscularly in animal experiments. 7- Hydroxyprogesterone caproate is a commonly used progestin available for mtramuscular injection toprevent Preterm Birth (alternatively hereinafter referred to as "PTB"). This synthetic caproate ester isreportedly inactive when given by mouth but works as along-acting progestin when administered intramuscularly. The metabolism of 17HP and the metabolism of 17-hydroxyprogesterone caproate in the human femaleare not yet fully established. Data from humans and animals indicate that intramuscularly administered 7-hydroxyprogesterone caproate has more potent progestational effect on endometrium and is longer lasting than progesterone (alternatively hereinafter referred to as "P"). This may be due tomore avid binding of 7- hydroxyprogesterone caproate tothe progesterone receptors (alternatively referred to hereinafter as "PR") and placental glucocorticoid receptors (alternatively referred to hereinafter as "GR") that could prevent an increase ofplacental corticotropin releasing hormone which is associated with onset of labor. 7-hydroxyprogesterone caproate is reportedly effective in providing luteal support in patients undergoing IVF-Embryo Transfer Cycles.

PTB is medically defined as delivery from 20 to 36weeks of gestation. According to the 2009 Center for Disease Control Report, PTB occurs in about 12.3% ofbirths in the US alone translating to about half a million PTBs annually. Spontaneous PTB accounts for approximately 70-80% of PTB. Of all the pregnancies in the US, one out of ever}' eight live- born infants isbom preterm representing an increase of>18% since 1990. Late pre-term birth between 35-36 weeks of gestation contributes to more than half ofalPTBs. PTB isthe primary cause ofneonatal morbidity and mortality. Mortality risk isthree fold higher at 35- 36 weeks and morbidities such asrespiratory distress requiring oxygen, temperature instability, hypoglycemia, jaundice, attention deficit disorders, cerebral palsy, developmental delay, etc. are quite common, PTB related time and costs in intensive care are a major health, social and economic issue with an average cost ofPTB delivery amounting toup to Ox that ofnormal delivery.

Major risk factors implicated in PTB are as follows: Histor ofprevious spontaneous PTB (past obstetrics history), cervical length (< 2.5 cm at mid pregnancy), presence of fetal fibronectin in vaginal secretions; multiple gestation, low maternal Body Mass Index (BMI), maternal race; maternal age (<17 and >35 years), and smoking. The prior history of at least one PTB is a good indicator of future occurrence potential with 17-50% recurrence potential and 28-70% recurrence potential with two previous PTBs. Benefits ofprolonging pregnancy to full term with therapeutic intervention include improved child survival as a function of gestational age, and reduced neonatal hospital stay.

Intramuscular injection of 17-hydroxyprogesterone caproate is available for reducing the ris of PTB in women with singleton pregnancy and history of single spontaneous PTB.

The injection marketed asMakena (250mg 17-hydroxyprogesterone caproate in lmL) mandates regular visits to the doctor's office, asthe typical treatment cycle consists of 16-20 weeks of injection repeated every week. This therapy regimen could result increasing the patient's distress and/or anxiety in addition to increasing the repeated travel risks for the patient and fetus. The injection therapy's interferences with the personal and family activities and disruption in professional life are also a major disadvantage.

In addition, adverse events with injection of 17-hydroxyprogesterone caproate (e.g.

Makena ) at once weekly (every 7 days) the injection site reactions (—45%) such asurticaria, HAS510341NZPR 304003925 pruritis, swelling, nodule formation and pain at the site of injection have been reported as significant.

Esters of hydroxy progesterone such as acetate, caproate, undecanoate are more lipophilic than hydroxy progesterone. The active substance (17-hydroxyprogesterone caproate) in Makena is known to be extremely insoluble in water (<20ng/mL), and very lipophilic with ClogP of about 5.7. Moreover, 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 overly expressed in pregnant women (~40% upregulation). Due to its extremely low water solubility and a potential to be susceptible for first pass hepatic inactivation oral delivery of long chain esters of 17HP has remained a challenge. It is reported that there is no oral activity with 17 hydroxyprogesterone caproate, an ester of 17 HP, (Saxton DJ et.al. Reproductive Biology and Endocrinology 2004, 2:80; Greene MF, NJEM 348:2453-2455). This could be likely due to very poor or no oral bioavailability of 17 HPC. Although much desired, to date the development of an orally active composition of long chain ester of hydroxyl progesterone remains a significant unmet need. In addition, development of dosage forms that enable administration of lesser number of dosage units per dose and/or at reduced frequency per day is most often desirable.

OBJECT It is an object of the present invention to provide an pharmaceutical composition, a method of treating a pregnant non-human female, a use of a pharmaceutical composition in the manufacture of a medicament, a pharmaceutically acceptable oral dosage form and/or a use of an oral dosage form in the manufacture of a medicament that overcomes or ameliorates at least one of the disadvantages of the prior art and/or meets one of the foregoing needs. It is a further alternate object of the invention to at least provide the public with a useful choice.

SUMMARY OF THE INVENTION It has now been surprisingly found that esters of 17HP can be effectively delivered orally to mammals. The pharmaceutical oral compositions and dosage forms of the present inventions can provide effective bioavailability of an ester of 17HP. Further, the compositions and/or dosage forms disclosed herein provide effective release enhancement for 17 HP esters. We have also surprisingly found that an ester of 17HP can be formulated into oral compositions and oral dosage forms thereof with higher percent w/w loading of the ester.

For example, we have found that when one or more solubilizing agents such as for example, benzyl alcohol, benzyl benzoate etc., is incorporated in the composition, a significant amount HAS510341NZPR 304003925 (i.e. greater than 12% w/w) of the ester of 17HP can be solubilized in the composition or dosage form. The increased drug loading in the compositions and dosage forms of the current inventions, can provide avid advantages including but not limited to reduced size or volume of the unit dosage (i.e. tablet, capsule, syrup, elixir, beverage, etc.), reduced number of dosage units to be taken per single administration, improved patient compliance etc., because patients typically can take fewer number of dosage units per day in order to get a sufficient dose to provide the desired efficacy. In a separate aspect, it was also surprisingly found that an effective bioavailability of the ester of 17HP can be provided by the compositions of the current inventions which when dispersed in an aqueous medium, provide clear or colloidal to hazy or unclear dispersions having partially or fully solubilized drug in the dispersions.

It was also found that the compositions of current invention enable production of solid dosage forms such as tablets, caplets, granules, beads, particulates etc., which can solve the drawbacks of having the 17HP ester in a liquid solution form in the dosage unit. This eliminates a number of undesirable inconveniences, such as specialized manufacturing process and/or equipment, poor chemical and/or physical stability of the ester typical to liquid solutions due to the nature of the ester or solvents used, and so-on.

All the oral dosage forms of the present inventions have the drug in the form of solution, suspension, particulates, etc., can be produced by conventional methods of processing and manufacture known in the art.

The present invention provides for compositions and oral dosage forms containing esters of 17HP as well as related methods. The compositions and oral dosage forms can be formulated to include a therapeutically effective amount of an ester of 17HP and a pharmaceutically acceptable carrier. In one embodiment, a pharmaceutically acceptable oral dosage form for pregnancy support and non-pregnancy support is provided. The pharmaceutically acceptable oral dosage can include a therapeutically effective amount of an ester of 17HP and a pharmaceutically acceptable carrier. The oral dosage form can, when measured using a USP Type-II dissolution apparatus in 900 mL of deionized water with 0.5 %(w/v) of sodium lauryl sulfate at 50 RPM at 37°C, release at least 20 wt% of the dose of the ester of 17HP after 60 minutes.

In yet a further embodiment, a pharmaceutically acceptable oral dosage form for pregnancy or non-pregnancy support is provided. The pharmaceutically acceptable oral dosage can include a therapeutically effective amount of an ester of 17HP and a HAS510341NZPR 304163055 pharmaceutically acceptable carrier. The oral dosage form can, when measured using a USP Type-II dissolution apparatus in 900 mL of deionized water with 0.5 %(w/v) of sodium lauryl sulfate at 50 RPM at 37°C, release at least 20 wt% more 17HP ester after 60 minutes than an equivalently dosed oral dosage form without the carrier.

In some aspects, the oral dosage forms of the present invention can be used to treat pregnant female subjects who are at risk of preterm birth. Such methods of treatment may include the step of orally administering to the female subject the oral pharmaceutical composition. In some aspects, the dosage amount is an amount sufficient to provide an intended therapeutic effect. In another embodiment, the oral dosage forms can be administered to subjects in need thereof. The administration of the oral dosage form can treat at least one condition selected from preterm labor, preterm birth, infertility and miscarriage.

The conditions and the relative treatment can be based on their primary and secondary outcome measurements associated with the administration of the ester of 17HP.

In a first particular aspect the invention provides a pharmaceutical composition comprising: a therapeutically effective amount of 17-hydroxyprogesterone caproate, and a pharmaceutically acceptable carrier; wherein the pharmaceutical composition is in the form of a powder, granulate, particulate, bead, pellet, sprinkle, suspension, solution, tablet, capsule or combination thereof; wherein the 17-hydroxyprogesterone caproate is present in the composition in particulate form having a mean particulate diameter of about 50 μm or less; and wherein the pharmaceutical composition is formulated for oral administration.

In a second particular aspect the invention provides a method of treating a pregnant non-human female subject at risk of preterm birth, comprising administering to the non- human female subject the pharmaceutical composition of the first particular aspect.

In a third particular aspect the invention provides a use of the pharmaceutical composition of the first particular aspect in the manufacture of a medicament for use in the treatment of a pregnant female subject at risk of preterm birth.

In a fourth particular aspect the invention provides a pharmaceutically acceptable oral dosage form comprising the pharmaceutical composition of the first particular aspect, wherein, when measured using a USP Type-II dissolution apparatus in 900 mL of simulated intestinal fluid having 0.5% w/w sodium lauryl sulfate at 50 RPM at 37°C, the oral dosage HAS510341NZPR 304163055 form releases at least 20 wt% of 17-hydroxyprogesterone caproate more after 60 minutes than an equivalently dosed oral dosage form without the carrier.

In a fifth particular aspect the invention provides a method of treating a pregnant non- human female subject at risk of preterm birth, comprising administering to the female subject the oral dosage form of the fourth particular aspect.

In a sixth particular aspect the invention provides a use of the oral dosage form of the fourth particular aspect in the manufacture of a medicament for use in the treatment of a pregnant female subject at risk of preterm birth.

In a seventh particular aspect the invention provides a pharmaceutically acceptable oral dosage form comprising the pharmaceutical composition of the first particular aspect, wherein, when measured using a USP Type-II dissolution apparatus in 900 mL of simulated intestinal fluid having 0.5% (w/v) of sodium lauryl sulfate at 50 RPM at 37°C, the oral dosage form releases at least 20 wt% of the dose of 17-hydroxyprogesterone caproate after 60 minutes.

In an eighth particular aspect the invention provides a method of treating a pregnant non-human female subject at risk of preterm birth, comprising administering to the female subject the oral dosage form of the seventh particular aspect.

In a ninth particular aspect the invention provides a use of the oral dosage form of the seventh particular aspect in the manufacture of a medicament for use in the treatment of a pregnant female subject at risk of preterm birth.

In a tenth particular aspect the invention provides a pharmaceutically acceptable oral dosage form comprising: a therapeutically effective amount of 17-hydroxyprogesterone caproate wherein, upon single oral administration to a human subject, the dosage form provides a ratio of 17- hydroxyprogesterone caproate AUC to the dose of 17-hydroxyprogesterone (0-24h) -1 -1 caproate ratio of about 0.2 to about 10 ng*h mL mg wherein, the dose is the amount in mg of the 17-hydroxyprogesterone caproate administered and wherein the 17- hydroxyprogesterone caproate is present in the composition in particulate form having a mean particulate diameter of about 50 μm or less.

In an eleventh particular aspect the invention provides a method of treating a pregnant non-human female subject at risk of preterm birth, comprising administering to the female subject the pharmaceutically acceptable oral dosage form of the tenth particular aspect.

HAS510341NZPR 304163055 In a twelfth particular aspect the invention provides a use of the pharmaceutically acceptable oral dosage form of the tenth particular aspect in the manufacture of a medicament for use in the treatment of a pregnant female subject at risk of preterm birth.

BRIEF DESCRIPTION OF THE DRAWINGS is a plot of the in vitro release profile of a 17-hydroxyprogesterone caproate containing oral dosage form in accordance with a certain embodiment of the present invention compared to a carrier-free dose of 17-hydroxyprogesterone caproate. is a plot of the in vitro release profiles of 17-hydroxyprogesterone containing oral dosage forms in accordance with a certain embodiment of the present invention. is a plot of the in vitro release profiles of 17-hydroxyprogesterone containing oral dosage forms in accordance with a certain embodiment of the present invention.

Reference will now be made to the exemplary embodiments illustrated, and specific language will be used herein to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended.

DETAILED DESCRIPTION OF EXAMPLE EMBODIMENT(S) Before the present oral dosage forms and methods for the delivery and use of 17- hydroxyprogesterone esters are disclosed and described, it is to be understood that this invention is not limited to the particular process steps and materials disclosed herein, but is extended to equivalents thereof, as would be recognized by those ordinarily skilled in the relevant arts. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.

It should be noted that, the singular forms “a,” “an,” and, “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” includes reference to one or more of such excipients, and reference to “the carrier” includes reference to one or more of such carriers.

Definitions As used herein, "drug," "active agent," "bioactive agent," "pharmaceutically active agent," "therapeutically active agent" and "pharmaceutical," may be used interchangeably to refer to an agent or substance that has measurable specified or selected physiologic activity when administered to a subject in a significant or effective amount It istobeunderstood that the term "drug" is expressly encompassed by the present definition as many drugs and prodrugs are known to have specific physiologic activities. These terms of art are well- known inthe pharmaceutical andmedicinal arts. Further, when theseterms are used, orwhen a particular active agent is specifically identified by name or category, it is understood that such recitation is intended to include the active agent per se, as well as pharmaceutically acceptable salts, esters or compounds significantly related thereto, including without limitation, prodrugs, active metabolites, isomers, andthe like.

Asused herein, the term "recurrent" is used to refer to a repeat or re-occurrence of at least one incidence like "miscarriage", "preterm birth" or "preterm labor" or "multifetal gestation" or any like medical situation in reference with or without same partner, with or without previous livebirth.

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 esterto subjects who are either asymptomatic or symptomatic. In other words, "treatment" can refer to the act ofreducing or eliminating a condition (i.e. symptoms manifested), or it can refer to prophylactic treatment, (i.e. administering to a subject not manifesting symptoms in ordertoprevent their occurrence). Suchprophylactic treatment can also bereferred to as prevention ofthe condition, preventative action, preventative measures, etc.

Asused herein, the term "ester" represents compounds produced by reaction between acids and alcohols with the elimination of water. As described herein, the term "ester" can also represent the class of organic compounds corresponding to the inorganic salts formed from an organic acid and an alcohol. In one aspect, the "ester of 17-hydroxyprogesterone" can be the caproate ester, but can also represent esters of the longer chain fatty acids such as undecanoic acid and higher, that typically get lymphatically absorbed and avoid first pass hepatic metabolism for improved efficacy 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 n some aspects the terras "formulation" and "composition"ray he used to refer to a raixture of one or more active agents with a carrier or other excipients Furthermore, the term "dosage form" can include one or more formulation(s) or composition(s) provided in a format for administration to a subject. When any ofthe above terms is modified by the term "oral" such terms refer to compositions, formulations, or dosage forms formulated and intended for oral administration to subjects.

Theterms "pharmaceutically acceptable carrier" or "carrier" areused interchangeably andrefer toapharmaceutically acceptable substance that enables apharmaceutical composition and/or a dosage form of an ester of 17-hydroxyprogesterone. Further in some aspects, the carrier is an element or ingredient that canbevaried forthe alteration ofrelease rate and/or extent ofthe active agent, for example an ester of 17-hydroxyprogesterone, from the composition and/or the dosage form. In one aspect of the invention, apharmaceutically acceptable carrier is a compound, or amixture ofcompounds, that determines, controls, or contributes atleast inpart, to therelease ofan ester of 17-hydroxyprogesterone from a pharmaceutical oral composition and/or dosage form, when tested using aUSP Type II apparatus in about 900 rnL ofsimulated intestinal fluid (according toUSP SIF,without enzyme) having 0.5% w/w sodium lauryl sulfate at about 37°C and50 rpm.

In another embodiment, the composition or dosage formprovides arelease ofthe ester of 7-hydroxyprogesterone such that when tested using aUSPType II apparatus in about 900 rnL of simulated intestinal fluid having 0.5% w/w sodium lauryl sulfate at about 37°C and 50rpm, at least 20% more the ester of 17-hydroxyprogesterone isreleased afterthe first 60 minutes compared toan equivalent dose an ester of 17-hydroxyprogesterone oral dosage form without the pharmaceutically acceptable carrier. In anotherparticular embodiment, the composition or the dosage form releases at least40% more ofthe ester of 17-hydroxyprogesterone after the first 60 minutes compared to an equivalent dose an ester of 17-hydroxyprogesterone oral dosage formwithout the pharmaceutically acceptable carrier.

It should benoted that the release ofthe ester of 17-hydroxyprogesterone fromthe composition orthe dosage form ca betested in asuitable solubiliz gmedium or ano - solubilizing aqueous medium at about 37°C, in aUSP Type IIapparatus at 50rpm. For example, aqueous medium can be water, simulated gastric fluid (SGF) with or without enzyme, simulated intestinal fluid (SIF)with orwithout enzyme, ahydro-alcoholic solution, a surfactant solution and the ike. The aqueous medium canbe used for thepurpose of determining the release rate and/or extent ofthe ester of 7-hdroxyprogesterone fromthe compositions or the dosage forms. The aqueous medium can be anon-solubilizing aqueous medium (for example, having ow orno surfactant in the medium) forthe entire amount of the esterpresent in the composition or the dosage form In one embodiment, the non- solubilizing aqueous medium can solubilize about 90% or less ofthe amount of esterpresent in the composition or dosage form. In another embodiment, the non-solubilizing aqueous medium can solubilize about 80% or ess,about 70% or less, about 60°/» or less, about 50% or less, about 30% or less, or about 20% or less of the total amount ofthe esterpresent inthe composition or dosage form.

Conversely, in another embodiment the aqueous medium is capable ofsoiubilizing substantially all ofthe ester of 7-hydroxyprogesterone present in the composition or dosage form. In one embodiment, the aqueous medium can solubilize at least about 90% ofthe amount of the ester of 7-hydroxyprogesterone present in the composition or dosage form. In aparticular embodiment the aqueous medium can solubilize about 5 times ormore, about 3 times ormore, 5times or more of the amount ofthe ester 17-hydroxyprogesteron present in the composition or dosage form.

Asused herein, "subject" refers toamammal that maybenefit fromthe administration of a drug composition 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 one specific aspect, a subject is a human. In another aspect, the subject is a female. In yet another aspect, the oral dosage form ofthe current invention is for afemale requiring pregnancy support.

The term "oral administration" represents any method of administration in which an 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 deliver the active agent in the gastrointestinal tract beyond the mouth and/or buccal cavity. Examples of solid dosage forms include conventional tablets, multi-layer tablets capsules, caplets, etc., which do not substantially release the drug in the mouth or in the oral cavity.

As used herein, the terms "release" and "release rate" are used interchangeably to refer to the discharge or liberation of a substance, including without limitation a drug, from the dosage form into a surrounding environment such as an aqueous medium either in vitro or in vivo.

As used herein, the terra 'lipophilic" when used in combination with both solid and liquid lipophilic additives (alternatively referred to hereinafter as "LA"), refers to additives that "love oil" and generally have poor or no solubility in water. "Lipophilic surfactants" (alternatively referred to hereinafter as "LS") refer to lipophilic additives that have HLB values of 10 or less, preferably between 2 to 10 Conversely the term "hydrophilic," when used in combination with both solid and liquid hydrophilic additives (alternatively referred to hereinafter as "HA"), refers to additives that "love water", and generally have average or good solubility in water. "Hydrophilic surfactants" (alternatively referred to hereinafter as "HS") are hydrophilic additives that have significant surface active property and that have HLB values ofmore 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 chain length greater than C ) or fatty acid esters or glycerides of fatty acid esters, mixtures thereof and derivativesthereof, althoughnot including salts thereof.

In some aspects of the present invention, the release of the drug may be controlled release. As used herein, the term "controlled release" represents the release of the drug from the dosage form according to a predetermined profile. In some aspects, the controlled release selected can be, intermediate, delayed, extended, sustained, pulsatile, gastric, enteric or colonic. In another aspect, combinations of the aforementioned release profiles may be used in orderto achieve specific delivery results, such as an immediate release followed by a delayed and/or asustainedrelease ofthe active agent.

As used herein, a composition or dosage form provides "immediate release" when greater than about 90% of the drug is released after the first 30 minutes, in a USP simulated gastric fluid (SGF) with orwithout enzyme.

Asused herein the term "pregnancy support" when usedto describe the functionality of the oral compositions or dosage forms of the present invention, can refer to providing exogenous progestational support from inception through birth including, but not limited to preterm birth, preterm labor, and miscarriage. The pregnancy support can provide improved quality of the pregnancy for the pregnant woman, the fetus, or both. Further, pregnancy support can also include increased fertility for awoman trying tobecome pregnant.

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 exogenous supplementation of a progestogen agent to a non-pregnant subject, suc as a non-pregnant woman, including but not limited to, delaying or preventing the occurrence of undesirable pregnancy, preventing or treating conditions due to progesterone deficiencies such as amenorrhea, fibroids, contraception, postpartum lactation suppression, treatment of dysfunctional uterine bleeding, endometriosis, endometrial hyperplasia, cervical hyperplasia, hormone replacement therapy, treatment of hypoventilation, prevention and treatment of osteoporosis, management of breast, hypothyroidism, migraine headaches, pemporomaiidibular joint syndrome, catamenial epilepsy, endometrial, and/or renal carcinomas. n one embodiment, the term "non- pregnancy" support when used to describe the functionality of the oral compositions or dosage forms of the present invention ca refer to conditions that require exogenous supplementation of the progestogen agent of the invention to a male human for example, to effect contraception, to counter estogenic activity, etc. It should be noted that the present compositions and dosage forms of the ester of the 17-hydroxyprogesterone may be administered alone or in combination with other therapy. In another embodiment, the current invention compositions and dosage forms ofthe ester ofthe 17-hydroxyprogesterone may be used to supplement, augment, mitigate, treat, cure or prevent, or forproviding prophylaxis in a subject inneed thereof.

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 achieve therapeutic results in treating a condition for which the drug is known tobe effective. It isunderstood that various biological factors may affect the ability ofa substance to perform its intended task. Therefore, an "effective amount" or a "therapeutically effective amount" may be dependent in some instances on such biological factors. Further, while the achievement of therapeutic effects may be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a somewhat subjective decision. The determination of an effective amount is well within the ordinary skill in the art of pharmaceutical sciences and medicine. See, for example, Meiner and Tonascia, "Clinical Trials: Design, Conduct, and Analysis," Monographs in Epidemiology and Biostattstics, Vol. 8(1986), incorporated herein by reference.

As used herein, the term "about" is used to provide flexibility to a numerical range endpoint by providing that a given value may be "a little above" or " little below" the endpoint. As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed asthough each member ofthe list is individually identified as a separate and unique member Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indicationsto the contrary.

Concentrations, amounts, levels and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of "about 1to about 5 should be interpreted to include not only the explicitly recited values of about 1to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3 and4and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4, and 5, individually. This same principle applies to ranges reciting only one numerical value as a minimum or a maximum. Furthermore, such an interpretation should apply regardless of the breadth ofthe range orthe characteristics being described.

Invention Reference will now be made in detail to preferred embodiments of the invention.

While the invention will be described in conjunction with the preferred embodiments, it will beunderstood that it isnot intendedtolimitthe inventiontothose preferred embodiments. To the contrary it is intended to cover alternatives, variants, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.

Duringpregnancy, it hasbeen shownthat serum progestogen, including progesterone and 17-hydroxyprogesterone levels are decreased in thepregnant female in cases of intrauterine death,premature labor, threatened premature labor,premature rupture of membranes, aninionitis and abruption ofplacenta. Asdiscussed above, it hasbeen discovered that esters of 17-hydroxyprogesterone have potential for use in pregnancy totreat and or prevent the following conditions or occurrences: spontaneous abortion inwomen who have hadprevious spontaneous abortion, history ofrecurrent spontaneous abortion previous stillbirth, previous premature delivery (<37 weeks), previous premature (<37weeks) rupture ofmembranes or PROM, previous pregnancy related hypertension or toxemia, previous abruption ofplacenta, threatened premature labor or cerclage, multiple pregnancy, primary or secondary infertility, congenital uterine anomaly or any other condition where endogenous progestogen (e.g. progesterone) levels are lowerthan in normal pregnancy.

Primary and secondary outcome measures can be used to determine the need for and/or the effectiveness of ester of 7-hydroxyprogesterone supplementation therapy for pregnancy related support to a particular subject and its direct or indirect effect on the neonates. Typical primary and secondary outcome measures for preterm birth and preterm labor include, without limitation, Primar Outcome Mensures (Maternal) 1. Perinatal mortality 2. Preterm birth (less than 32weeks' gestation) 3. Preterm birth(less than 34weeks' gestation) 4. Preterm birth (less than 37weeks' gestation) . Majorneuro-developmental handicap at childhood follow up Secondary Outcome Measures (Maternal): . Threatened preterm labor 2. Pre-labor spontaneous rupture ofmembranes 3. Adverse drugreaction 4. Pregnancy prolongation (interval between randomization andbirth) . Mode ofbirth 6. Number ofantenatal hospital admissions 7. Satisfaction with the therapy 8. Use oftoco!ysis Secondary Outcome Measures (Infant): . Birth before 37 completed weeks 2. Birth before 34 completed weeks 3. Birthbefore 32 completed weeks 4. Birthbefore 28completed weeks . Birth weight less thanthe third centile for gestational age 6. Birth weight lessthan 2500 grams 7. Apgar score ofless than seven atfiveminutes 8. Respirator)' distress syndrome 9. Use ofmechanical ventilation 0.Duration ofmechanical ventilation . ntraventricular hemorrhage -grades III or V .Periventricular leucomalacia 13. Retinopathy ofprematurity 14. Retinopathy ofprematurity -grades III or V . Chronic lung disease 6.Necrotizing enterocolitis 7.Neonatal sepsis 8. Fetal death 19. Neonatal death . Admission toneonatal intensive care unit 2 .Neonatal length ofhospital stay 22. Teratogenic effects (including virilisation in female infants) Secondary' Outcome Measures (Child): . Major sensorineural disability (defined as any oflegal blindness, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy, or developmental delay or intellectual impairment) 2. Developmental delay 3. Intellectual impairment 4. Motor impairment . Visual impairment 6. Blindness 7. Deafness 8. Hearing impairment 9. Cerebral palsy . Child behavior .Child temperament 12. Learning difficulties 3.Growth assessments at childhood follow up (weight, head circumference, length, skin foldthickness) 1. Primar Outcome Measures: 1.1.Pregnancy Rate 1.2. Livebirth 1.3. Ongoing pregnancy rate 1.4. Clinical pregnancy, defined asultrasoundevidence offetal heartactivity at 6-8 week ofgestation 1.5. Fetus Vitalitymeasured by heartbeat 1.6. Rate of complete abortion 24-48hrs afterreceiving medical treatment forearly pregnancy failure. 2. Secondary Outcome Measures: 2.1.Clinical pregnancy 2.2. Cycle Cancellation Rates 2.3. Number of Oocytes Generated 2.4. Number of Embryos Generated 2.5. Serumhormonal evaluation 2.6. Follicularfluid evaluation 2.7. Peak estradiol level 2.8. Ampules ofgonadotropins required during ovarian stimulation 2.9. Number ofdays ofovarian stimulation 2.10. Number ofoocytes retrieved 2.1 . Number ofembryos transferred 2.12. Number ofembryos frozen 2.13. Embryo grade 2.14. Implantation rate 2.15. Miscarriage rate 2.16. Pregnancy outcome 2.17. rate ofcomplete abortion at oneweek, timeto expulsion ofproducts ofconception, correlation ofabortion rates to serum 7-hydroxyprogesterone levels andtype of pregnancy failure, number ofbleeding days and patient satisfaction 2.18. Ovarian Response [assessedupon completion ofthe controlled ovarian stimulation and the egg collection procedures] Miscarriage /. Primary Outcomes 1.1.Miscarriage 1.2. Early miscarriage upto 12 weeks 1.3. Miscarriage laterthan 12 weeks and lessthan 23weeks 1.4. Cytokine ratio IFN/IL-10 1.5. Clinicalpregnancy rate at 8weeks and 12 weeks ofpregnancy Secondary Outcomes 2.1.Mother a. Painrelief (threatened miscarriage) b. Severity of 'morning sickness' -intensified headache c. nausea, breast tenderness d. reported thromboembolic events e. Thrombolytic events f. depression; g. admissiontospecial careunit h. subsequent fertility. i. PIBF level j. Uterine contraction frequency 2.2. Child a. Preterm birth; b. stillbirth; c. neonatal death; d. lowbirthweight less than 2500 g e. fetal genital abnormalities; f. teratogenic effects (impairingnormal fetal development); g. admission to special care unit. 2.3. General a. Intrauterine fetal death b. Stillbirth c. Fetal d. Exploratory analysis ofpregnancy outcome by monitoring biochemical and clinical pregnancy parameters, weekly evaluation of serum progesterone e. livebirthrate, cycle cancellation rate, rate ofspontaneous abortion, rate of biochemical pregnancy, rate ofectopicpregnancy Several biomarkers have been implicated in predicting preterm birth (PTB) Among symptomatic women, the likelihood ratio (LR+) for the prediction of PTB is known to be greater than 10 using amniotic fluid (AF) interleukin-6 (IL-6), AF Ureaplasma ureaiyticum, as well as a multi-marker consisting of cervical IL-6, cervical IL-8, and cervical length (CL).

The LR+ is also known tobebetween 5 and 0 for serum C-reactive protein (CRP). An LR+ between 2.5 and 5 was recorded for serum corticotropin-releasing hormone (CRH), cervical IL-6, serumrelaxin.

In asymptomatic women, AFU ureaiyticum and a multimarker consisting of five individual markers [fFN, CL, serum aipha-fetoprotein (AFP), serum alkaline phosphatase, and serum granulocyte colony-stimulating factor (G-CSF)j predict PTB with an LR+ greater than 0. The LR+ was between 5 and 10 for serumrelaxin and CL. LRs+ recorded 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, an LR+ below 2.5 hasbeen documented for serum ferritin, serum CRP, BV, and cervical ferritin.

Miscarriages and possible miscarriages can be categorized in several ways: A) threatened or possible 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 miscarriage (inevitable - meaning it cannot be stopped, particularly if there is bleeding from the uterus and the cervix is opening prior to 20 weeks, but neither the fetusnor placenta have passed out of the woman's body) - the membranes around the fetus may or may not have ruptured (broken); C) Incomplete abortion or miscarriage - when a portion ofthe fetus or placenta has passed out of the uterus prior to 20 weeks gestation while some of the placenta or fetus remains in the uterus; D) Complete miscarriage - complete expulsion of ail the membranes around the fetus andthe placenta and the cervix closes prior to20 weeks; E) Missed abortion or miscarriage - death of the fetus prior to 20 weeks gestation with neither the fetus nor the placenta havingbeen expelled from the uterus; F) Recurrent miscarriage - awoman is said to have recurrent miscarriage after she has already had two or more miscarriages in a row; G) Blighted ovum or an-embryonic gestation - occurs when a gestational sac forms inside the uterus, butnofetus ispresent after sevenweeks.

Threatened miscarriage, as demonstrated by low endogenous progesterone or 7- hydroxyprogesterone, orvaginal bleeding with orwithout abdominal cramps within 26weeks of conception, is a common complication ofpregnancy. Itoccurs in about 20% ofrecognized pregnancies. Risk of miscarriage is increased in older women and those with a history of miscarriage It has been shown that lo serum levels of progestogen (progesterone or 17 HP) or human chorionic gonadotropin (hCG) are a risk factor for miscarriage. Threatened miscarriage causes considerable stress and anxiety for a pregnant woman. Because esters of 7-hydroxypxOgesterone interact with the progesterone receptor, it is believed that treatment with esters of 7-hydroxyprogesterone can be designed based on progesterone levels. One diagnostic criterion is low seaim progesterone, but levels vary widely during early pregnancy and any later decline may be attributed to a dysfunctioning placenta. Nevertheless, luteal support is widely used for the management of threatened miscarriage. First trimester pregnancies show risk of miscarriage with declining serum progesterone levels. Levels of <5 ng/ml were associated with a spontaneous miscarriage in 86% of cases compared with only 8% at levels of20-25 ng/ml. Athreshold value of 14 ng/ml has been reported to differentiate between the viable and non-continuing pregnancies. Other maternal serum biomarkers such as Tumor marker CA-125, InhibinA,Anandamide and progesterone induced blocking factor (PIBF) are also good indicators ofmiscarriage risk.

In one embodiment, the compositions of the present invention are intended toprovide an increase in the baseline endogenous progesterone and/or 7-hydroxyprogesterone. In a particular embodiment the increase in the baseline endogenous progesterone can be greater than 10% Progestogens also have a direct pharmacological effect by reducing the synthesis of prostaglandins, thereby relaxing uterine smooth musculature and preventing inappropriate contractions that may result in miscarriage.

Although the oral dosage forms and methods of the present invention can be used in most female subjects, patients most suitable for receiving oral 7-hydroxyprogesterone ester of this invention are the ones that have one or more of the following conditions symptoms, and/or needs: ) are in need of an anti-inflammatory; 2) are progesterone deficient with base line progesterone in early (first trimester) pregnancy of C <14 ng/ml or baseline progesterone levels, C of less than 50 ng/ml in late (second and third trimester) pregnancy; 3) have genetic variation of the SEKPINH1 gene that cause to produce a reduced amount of the protein, collagen, which may lead to weakened fetal membranes; 4) have a genetic variant of the Proiylcarboxypeptidase gene associated with preeclampsia; 5) have certain bacterial infections (bacterial vaginosis) including Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella vaginalis, and Peptostreptococcus and Bacteroides species; 6) have abnormal amniotic fluid metabolome (the sum of all metabolic processes occurring in the amniotic fluid) indicating risk for prematurity; 7) have had above average total phthalate exposure; 8) abnormal prepregnancy body mass index; 9) have inflammatory milieu of the vagina in early pregnancy; 10) have increased maternal plasma urocortin levels; 11) show increased uterine activity as noted by Home Uterine Activity Monitoring; 12) test positive to salivary estriol levels predicting preterm deliver}; 13) show alarming fetal Fibronectin Screening (ITS) results; 14) show unusual cervical shortening relative to gestational age as measured by cervical ultrasonography, or transvaginal ultrasound or digital examination with/without use of Cervilenz™; 1) show unusual maternal serum bio markers such as Tumour marker CA- 125, or Inhibin A, or Anandamide or Progesterone Induced Blocking factor (PIBF); 16) haveunbalanced ratio ofTh-1 cytokines to Th-2 cytokines such asIFN toIL-10.

Besides maintaining pregnancy, other potential uses of the ester of 7- hydroxyprogesterone containing oral dosage forms of the present invention include, but are not limited to: a) preventing estrogen dominance; b) stimulating new bone formation and prevent/reverse osteoporosis; c) providing the precursor for adrenal cortex hormones (corticosteroids); d) treating variety ofskin problems such as acne in adult women, seborrhea, rosacea, psoriasis, and keratosis; e) promoting myelin sheath production to protect nerve fibers and speed nerve signals; f) managing depression that accompany PMS, menopause, postpartum depression, etc; g) protecting from brain/spinal cord injury, stroke, and/or hemorrhage.

In one embodiment, the present invention provides for oral dosage forms containing esters of 7-hydroxyprogesterone aswell asrelated methods. The oral dosage forms can be formulated forpregnancy support and can include atherapeutically effective amount ofan ester of 7-hydroxyprogesterone and apharmaceutically acceptable carrier. The oral dosage form can, when measured using aUSP Type-II dissolution apparatus in 900 mL ofdeionized water with 0.5 (w/v) ofsodium lauryl sulfate at 50 RPM at 37°C, release at least 20wt% of the dose ofthe ester of 7-hydroxyprogesterone after 60 minutes. Inyet a further embodiment, the oral dosage form can, when measured using aUSP Type-II dissolution apparatus in 900 mL ofdeionized water with 0.5 (w/v) ofsodium lauryl sulfate at 50 RPM at 37°C, release at least 20 wt% more 7-hydroxyprogesterone ester after 60minutes than an equivalently dosed oral dosage form without the carrier A number of 7-hydroxyprogesterone esters canbeused in the compositions and oral dosages ofthe present invention. Examples of specific acceptable esters of 17- hydroxyprogesierone include without limitation, acetate esters of 7-hydroxyprogesterone, caproate esters of 17-hydroxyprogesterone, iradecanoate esters of 7-hydroxyprogesterone, and the like and combinations thereof Other pharmacologically active and acceptable esters of 17-hydroxyprogesterone may also beprepared andused in accordance with the embodiments ofthe present invention so long as theyprovide the desired support in pregnancy and/or non-pregnancy conditions.

The ester of 17-hydroxyprogesterone canbepresent inthe compositions and oral dosage forms ofthe present disclosure in avariety of forms. n one embodiment, the ester of 7-hydroxyprogesterone canbepresent inparticulate form. .In one embodiment the ester of 7-hydroxyprogesterone canbe present inparticulate form. The particulate form can have amean diameter ofabout 50 μ or less. Theparticulate form can have amean diameter of about 25 μιη or less. In another embodiment, the particulate form can have amean diameter ofabout 1 μη or less in another embodiment, the ester of 17-hydroxyprogesterone can be present in a fully solubiiized form. In another embodiment the ester of 17- hydroxyprogesterone can bepresent in apartially solubiiized form. In another embodiment, aportion ofthe ester of 17-hydroxyprogesterone present in the composition and/or dosage form canbepresent in particulate or unsolubilzied form. In some embodiments, the ester of 17-hydroxyprogesterone canbepresent inboth solubiiized form aswell as in particulate form.

In some embodiments, the carrier ofthe compositions or oral dosage forms ofthe present invention can acttofacilitate the delivery, release, and/or bioavailability of the ester of 17-hydroxyprogesterone. In certain aspects, the carrier canbeone or amixture oftwo or more compounds. The carrier can include atleast one ofa lipophilic and/or ahydrophilic component additive. The lipophilic andhydrophilic additives that can be used in the compositions ofthe invention canbe selected from avariety ofclasses ofthe pharmaceutical aids including, but not limitedto, absorbents, acids, adjuvants, anticaking agent, antitacking agents, antifoamers, anticoagulants antimicrobials, antioxidants, antiphiogistics, astringents, antiseptics, bases, binders, bufferants, chelating agents, sequestrants, celluloses, coagulants, coating agents, colorants, dyes, pigments, complexing agents, crystal regulators, denaturants, desiccants, drying agents, dehydrating agents, diluents, disintegrants, dispersants, emollients, emulsifiers, encapsulants, enzymes, extenders, fillers, flavor masking agents, flavorants, fragrances, gelling agents, glidants hardeners, stiffening agents, humectants, lubricants, moisturizers, pH control agents, plasticizers, soothing agents, demulcents, retarding agents, spreading agents, stabilizers, suspending agents, sweeteners, thickening agents, consistency regulators, surfactants, opacifiers, polymers, preservatives, antigellants, rheology control agents, softeners, solubilizers; solvents toniciflers, viscosity modulators UV absorbers, or combinations thereof. In some embodiments additives from multiple classes ortypes canbe used.

Non-limiting examples of compounds that can form all or a art ofthe carrier are set forth in the following lists which have been organized in general categories. Itis tobe understood that the categories arenot intended to limitthe particular carrier compounds, but are simply present for ease oforganization andpresentation. With this in mind, example carrier compounds can include one or more ofthe following: Triglycerides such asAceituno 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; Cuphea species oil; Evening primrose oil; Grapeseed oil; Groundnut oil; Hemp seed oil; Illipebutter; 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; Sal fat; Sesame oil; Shark liver oil; Sheanut oil; Soybean oil; Stillingia oil; Sunflower oil; Tall oil; Tea sead oil; Tobacco seed oil; Tung oil (China wood oil); Vernonia oil; Wheat germ oil; Hydrogenated castor oil (Castorwax); Hydrogenated coconut oil (Pureco 00 (Abitec)); Hydrogenated cottonseed oil (Dritex C (Abitec)); Hydrogenated palm oil (Dritex PST (Abitec); Softisanl54 (Huls)); Hydrogenated soybean oil (Sterotex HMNF (Abitec); Dritex S(Abitec)); Hydrogenated vegetable oil (Sterotex NF (Abitec): Hydrokote M (Abitec)); Hydrogenated cottonseed and caster oil (Sterotex K (Abitec)); Partially hydrogenated soybean oil (Hydrokote APS (Abitec)); Partially soy and cottonseed oil (Apex B (Abitec)); Glyceryl tributyrate (Sigma); Glyceryl tricaproate (Sigma); Glyceryl tricaprylate (Sigma); Glyceryl tricaprate (Captex 000 (Abitec)); Glyceryl trundecanoate (Captex 8227 (Abitec)); Glyceryl trilaurate (Sigma); Glyceryl trimyristate (Dynasan 114 (Huls)); Glyceryl tripalmitate (Dynasan 6 (Huls)); Glyceryl tristearate (Dynasan 118 (Huls)); Glyceryl triarcidate (Sigma); Glyceryl trimyristoleate (Sigma); Glyceryl tripalmitoleate (Sigma); Glyceryl trioleate (Sigma); Glyceryl trilinoleate (Sigma); Glyceryl tricaprylate/caprate (Captex 300 (Abitec); Captex 355 (Abitec); Miglyol 810 (Huls); Miglyol 812 (Huls)); Glyceryl tricaprylate/caprate/ laurate (Captex 350 (Abitec)); Glyceryl tricaprylate/caprate/ linoleate (Captex 810 (Abitec); Miglyol 818 (Huls)); Glyceryl tricaprylate/caprate/ stearate (Softisan 378 (Huls); (Larodan); Glyceryl trieaprylate/laurate/ stearate (Larodan); Glyceryl l,2-caprylate linoleate (Larodan); Glyceryl l,2-caprate stearate (Larodan); Glyceryl ,2-lauratemyristate (Larodan); Glyceryl l,2~myristate laurate (Larodan); Glyceryl l,3-palmitate butyrate (Larodan); Glyceryl l,3-stearate caprate (Larodan); Glyceryl l,2-linoleate caprylate (Larodan), mixtures and derivatives thereof. Fractionated triglycerides, modified triglycerides, synthetic triglycerides, and mixtures of triglycerides are also within the scope of the invention.

PEG-Fatty Acid Monoester Surfactants_(listed as compound name (common commercial product name (supplier) (HLB)): PEG 4-100 monolaurate (Crodet L series (Croda) (> 9)); PEG 4- 00monooieate (Crodet series (Croda) (> 8)); PEG 4- 00 monostearate (Crodet Sseries (Croda), Myrj Series (Atlas/ICI) (> 6)); PEG 400 distearate (Cithrol 4DS series (Croda) (> 10)); PEG 100,200, 300 monolaurate (Cithrol ML series (Croda) (> 10)); PEG 100,200, 300 monooieate (Cithrol MO series (Croda) (> 10)); PEG 400 dioleate (Cithrol 4DO series (Croda) (> 10)); PEG 400-1000 monostearate (Cithrol MSseries (Croda) ( 0)); PEG-1 stearate (Nikkol MYS-1EX (Nikko), Coster K! (Condea) (2)); PEG- 2 stearate (Nikkol MYS-2 (Nikko) (4)); PEG-2 oieate (Nikkol MYO-2 (Nikko) (4.5)); PEG-4 laurate (Mapeg ©200 ML(PPG), Kessco © PEG 200 ML (Stepan), LIPOPEG 2 L(L P Chem.) (9.3)); PEG-4 oleate (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), Emulgante A6 (Condea) (8.5)); PEG-7 oleate (Algon OL 70 (Auschem SpA) (10.4)); PEG-6 laurate (Kessco ©PEG300 ML (Stepan) ( .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 (Emulgante A9 (Condea) (> 10)); PEG-9 stearate (Cremophor S9 (BASF) (> 10)); PEG-10 laurate (Nikkol MYL-10 (Nikko), Lauridac 10 (Croda) (13)); PEG-10 oleate (NilvkolMYO-10 (Nikko) (11)); PEG-12 stearate (Nikkol MYS-10 (Nikko), Coster KiOO (Condea) (1i)); PEG-12 laurate (Kessco ® PEG 600 ML (Stepan) (15)); PEG-12 oleate (Kessco ©PEG 600 MO (Stepan) (14)); PEG-12 ricinoleate (CAS # 90041) (> 10)); PEG-12 stearate (Mapeg © 600 MS(PPG), Kessco © PEG 600 MS(Stepan) (14)); PEG-15 stearate (Nikkol TMGS-15 (Nikko), Rosier K15 (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- stearate (Mapeg ® 1000 MS (PPG), 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 O40 (Croda) (17.4)); PEG-40 stearate (Myrj 52, Emerest ® 27 5 (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 O-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 combinations thereof.

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.) ( 1)); 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 ( 1)); PEG- 0 dipalmitate (Polyaldo 2PKFG (> 10)); PEG- 2 dilaurate (Kessco ® PEG 600 DL (Stepan) ( 1.7)); PEG- 12 distearate (Kessco ® PEG 600 DS (Stepan) (10.7)); PEG-12 dioleate (Mapeg ® 600 DO (PPG), Kessco ® 600 DO (Stepan) (10)); PEG-20 dilaurate (Kessco ® PEG 1000 DL (Stepan) (15)); PEG-20 dioleate (Kessco ® PEG 1000 DO (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 DO (Stepan) (15)); PEG-32 distearate (Kessco ® PEG 1540 DS (Stepan) (15)); PEG-400 dioleate (Cithrol 4DO series (Croda) (> )); PEG-400 distearate (Cithrol 4DS series (Croda) (> 10)); and combinations thereof.

PEG-Fatty Acid Mono- and Di-ester Mixtures (listed as compound name (common commercial product name (supplier) (HLB)); PEG 4-150 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, disiearate (Kessco © 200-6000 mono, distearate (Stepan)), and combinations thereof.

Polyethylene Glycol Glygerol Fatty Acid Esters (listed as compound name (common commercial product name (supplier) (HLB)J: PEG-20 glyceryl iaurate (Tagat ® L (Goldschmidt) (16)); PEG-30 glyceryl Iaurate (Tagat ® L2 (Goldschmidt) (16)); PEG- 15 glyceryl Iaurate (Glycerox L series (Croda) (15)); PEG-40 glyceryl Iaurate (Glycerox L series (Croda) (15)); PEG-20 glyceryl stearate (Capmul © EMG (ABITEC), (13)); (Aldo © MS-20 KFG (I. n/a))}; PEG-20 glyceryl oleate (Tagat ® O (Goldschmidt) (> 10)); PEG-30 glyceryl oleate (Tagat ® 2 (Goldschmidt) (> 10)); and combinations thereof.

Alcohol-oil Transesteif r i cation Products:_(listed as compound name (common commercial product name (supplier) (HLB)): PEG-3 castor oil (Nikkol CO-3 (Nikko) (3)); PEG-5, 9, and 16 castor oil (ACCONON CA series (ABITEC) (6-7)); PEG-20 castor oil (Emalex C-20 (Nihon Emulsion), Nikkol CO-20 TX (Nikko) ( 1)); PEG-23 castor oil (Emulgante EL23 (>10)); PEG-30 castor oil (Emalex C-30 (Nihon Emulsion), Alkamuls ® EL620 (Rhone- Poulenc), Incrocas 30 (Croda) (1 )); PEG-35 castor oil (Cremophor EL and EL-P (BASF), Emulphor EL, Incrocas-3 5(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)); PEG-100 castor oil (Thornley (>10)); PEG-200 castor oil (Eumulgin ® PRT 200 (Pulcra SA) (>10)); PEG-5 hydrogenated castor oil (Nikkol HCO- (Nikko) (6)); PEG-7 hydrogenated castor oil (Simusol @989 (Seppic), Cremophor W07 (BASF) (6)); PEG-10 hydrogenated castor oil (Nikkol HCO-10 (Nikko) (6.5)); PEG-20 hydrogenated castor oil (Nikkol HCO-20 (Nikko) (11)); PEG-25 hydrogenated castor oil (Simulsoi ® 1292 (Seppic), Cerex ELS 250 (Auschem SpA) (11)); PEG-30 hydrogenated castor oil (Nikkol HCO-30 (Nikko) ( 1)); PEG-40 hydrogenated castor oil (Cremophor RH 40 (BASF), Croduret (Croda), Emulgin HRE 40 (Henkel) (13)); PEG-45 hydrogenated castor oil (Cerex ELS 450 (Auschem Spa) (14)); PEG-50 hydrogenated castor oil (Emalex HC-50 (Nihon Emulsion) (14)); PEG-60 hydrogenated castor oil (Nikkol HCO-60 (Nikko); Cremophor RH 60 (BASF) (15)); PEG-80 hydrogenated castor oil (Nikkol HCO-80 (Nikko) (15)); PEG-100 hydrogenated 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)); PEG-6 hydrogenated pa mkernel oi (Labrafil M 2130 BS(Gattefosse) (4)); PEG-6 palmkernel oil (Labrafil ® M2130 CS (Gattefosse) (4)); PEG-6 triolein (Labrafil ® M 2735 CS(Gattefosse) (4)); PEG-8 corn oil (Labrafil ® WL2609BS (Gattefosse) (6-7)); PEG-20 corn glycerides (Crovol M40 (Croda) (10)); PEG-20 almond glycendes (Crovol A40 (Croda) (10)); PEG-25 trioleate (TAGAT ®TO(Goidschmidt) ( )); PEG-40 palm kernel oil (Crovol PK-70 (>10)); PEG-60 com glycerides (Crovol M70(Croda) (15)); PEG-60 almond glycerides (Crovol A70 (Croda) (15)); PEG-4 captylic/capric triglyceride (Labrafac ®Hydro (Gattefosse), (4-5)); PEG-8 capryiic/capric glycerides (Labrasol (Gattefosse),Labrafac CM 10 (Gattefosse) (>10)); PEG-6 capryiic/capric glycerides (SOFTIGEN ® 767 (Huls), Glycerox 767 (Croda) (19)); Lauroyl macrogol-32 glyceride (GELUCIRE 44/14 (Gattefosse) (14)); Stearoyl macrogol glyceride (GELUCIRE 50/13 (Gattefosse) (13)); Mono, di, tri, tetra esters ofvegetable oils and sorbitol (SorbitoGlyceride (Gattefosse) (<10)); Pentae hrity tetraisostearate (Crodamol PTIS (Croda) (<10)); Pentaerythrityl distearate (Alhunol DS(Taiwan Surf.) (<10)); Pentaen4hrityi tetraoleate (Liponate PO-4 (Lipo Chem.) (<10)); Pentaerythrityl tetrastearate (Liponate PS-4 (Lipo Chem.) (<10)); Pentaerythrityl tetracaprylate /tetracaprate (Liponate PE-810 (Lipo Chem.), Crodamol PTC (Croda) (<10)); Pentaerythrityl tetraoctanoate (Nikkol Pentarate 408 (Nikko))); and combinations thereof Polyglycolized FattyAcids: (listed as compound name (common commercial product name (supplier) (RLB)): 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 30 (Stepan) (6.5)); Polyglyceryl-4 oleate (Nikkol Tetraglyn 1-0 (Nikko) (5-7)); Polyglyceryl-4 stearate (Nikkol Tetraglyn 1-S (Nikko) (5-6)); Polyglyceryl-6 oleate (Drewpol 60 (Stepan), NikkolHexaglyn 1-0 (Nikko) (9)); Polyglyceryl-10 laurate (Nikkol Decaglyn 1-L (Nikko) (15)); Polyglyceryl-10 oleate (Nikkol Decaglyn 1-0 (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-3 dioleate (Cremophor G032 (BASF) (< 10)); Polyglyceryl-3 distearate (Cremophor GS32 (BASF) (< )); Polyglyceryl-4 pentaoleate (Nikkol Tetraglyn 5-0 (Nikko) (< 10)); Polyglyceryl-6 dioleate (Caprol ® 6G20 (ABITEC); Hodag PGO-62 (Caigene), PLUROL OLEIQUE CC 497 (Gattefosse) (8.5)); Polyglyceryl-2 dioleate (Nikkol DGDO (Nikko) (7)); Polyglyceryl- trioleate (Nikkol Decagiyn 3-0 (Nikko) (7)); Polyglyceryl-10 pentaoleate (Nikkol Decagiyn 5-0 (Nikko) (3.5)); Polyglyceryl-10 septaoleate (Nikkol Decagiyn 7-0 (Nikko) (3)); Polyglyceryl-10 tetraoleate (Caprol © 10G4O (ABITEC); Hodag PG0-62 (CALGENE), Drewpol 10O (Stepan) (6.2)); Polyglyceryl-10 decaisostearate (Nikkol Decagiyn 10- S (Nikko) (< 10)); Polyglyceryl-10 decaoleate (Drewpol 10O (Stepan), Caprol 10G10O (ABITEC), Nikkol Decagiyn 10-O (3.5)); Polyglyceryl-10 mono, dioleate (Caprol ©PG 860 (ABITEC) ( )); Polyglycery! polyricinoleate (Polymu!s (Henkel) (3- )); and combinations thereof.

Propylene Glycol Fatty Acid Esters: (listed as compound name (common commercial product name (supplier) (HLB)): Propylene glycol monocaprylate (Capryol 90 (Gattefosse}, Nikkol Sefsol 218 (Nikko) (< 10)); Propylene glycol monolaurate (Lauroglycol 90 (Gattefosse), Lauroglycol FCC (Gattefosse) (< 10)); Propylene glycol oleate (Lutrol OP2000 (BASF) (< 10)); Propylene glycol myristate (Mirpyl (< 10)); Propylene glycol monostearate (ADM PGME-03 (ADM), LIPO PGMS (Lipo Chem.), A do © PGHMS (Lonza) (3-4)); Propylene glycol hydroxy stearate (< 10)); Propylene glycol ricinoleate (PROPYMULS (Henkel) (< ));Propylene glycol isostearate (< )); Propylene glycol monooleate (Myverol P-06 (Eastman) (< 10)); Propylene glycol dicaprylate/dicaprate (Captex ® 200 (ABITEC), Miglyol © 840 (Huis), Neobee ©M-20 (Stepan) (> 6)); Propylene glycol dioctanoate (Captex © 800 (ABITEC) (> 6)); Propylene glycol caprylate/caprate (L BRAFACPG (Gattefosse) (> 6)); Propylene glycol dilaurate (> 6)); Propylene glycol distearate (Kessco © PGDS (Stepan) (> 6)); Propylene glycol dicaprylate (Nikkol Sefsol 228 (Nikko) (> 6)); Propylene glycol dicaprate (Nikkol PDD (Nikko) (> 6)); and combinations thereof.

Mixtures ofPropylene 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 (3-4)); and combinations thereof Mono- and Diglycerides: (listed as compound name (common commercial product name (supplier) (HLB)): Monopalmitolein (C16:1) (Larodan) (< 10)); Monoelaidin (C18: 1) (Larodan) (< 0));Monocaproin (C6) (Larodan) (< 10)); Monocaprylin (Larodan) (< 0)); Monocaprin (Larodan) (< 10)); Monolaurin (Larodan) (< 10)); Glyceryl monomyristate (C14) (Nikkol MGM (Nikko) (3-4)); Glyceryl monooleate (C18:l) (PECEOL (Gattefosse), Hodag GMO-D, Nikkol MGO (Nikko) (3-4)); Glyceryl monooleate (RYLO series (Danisco), DIMODAN series (Danisco), EMULDAN (Danisco), ALDO ® MOFG (Lonza), Kessco GMO (Stepan), MONOMULS ®series (Henkel), TEGIN O,DREWMULSE GMO (Stepan), Atlas G-695(C),GMOrphic 80 (Eastman), ADM DMG-40, 70, and 100 (ADM), Myverol(Eastman) (3-4)); Glycerol monooieate/linoleate (OLICINE (Gattefosse) (3-4)); Glycerol n o oli oleate (Maisine (Gattefosse), MYVEROL 18-92, Myverol 18-06 (Eastman) (3-4)); Glyceryl ricinoieate (Softigen ® 701 (Huis), HODAG GMR-D (Caigene), ALDO ® MR (Lonza) (6)); Glyceryl monolaurate (ALDO ®MLD (Lonza), Hodag GML (Caigene) (6.8)); Glycerol monopalmitate (Emalex GMS-P (Nihon) (4)); Glycerol monostearate (Capmul ® GMS (ABITEC), Myvaplex (Eastman), IMWITOR ® 191 (Huls), CUTINA GMS, Aldo ® MS (Lonza), Nikkol MGS series(Nikko) (5-9)); Glyceryl mono-,dioleate (Capmul ® GMO-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 capryiate (imwitor ® 308 (Huls), Capmul ® MCMC8 (ABITEC) (5-6)); Glyceryl caprylate/caprate (Capmul ®MCM (ABITEC) (5-6)); Caprylic acidmono.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));Glyceryl monostearate (Aldo ®MS, Arlacel 29 (ICI), LIPO GMS (Lipo Chem.), Imwitor ® 191 (Huls), Myvaplex (Eastman) (4.4)); Lactic acid esters ofmono, iglycerides (LAMEGIN GLP (Henkel) (< 10)); Dicaproin (C6) (Larodan) (< 0);Dicaprin (CIO) (Larodan) (< 10); Dioctanoin (C8) (Larodan) (< 10); Dimyristin (CI4) (Larodan) (< 10); Dipalmitin (CI6) (Larodan) (< 0);Distearm (Larodan) (< 10); Glyceryl dilaurate (CI2) (Capmul ®GDI. (ABITEC) (3-4)}; Glyceryl dioleate (Capmul ® GDO (ABITEC) (3-4)); Glycerol esters offatty acids (GELUCIRE 39/01 (Gattefosse), GELUCIRE 43/01 (Gattefosse) GELUCIRE 37/06 (Gattefosse) (1 6)); Dipalmitolein (C16:l) (Larodan) (< 10); 2 and 3-diolein (CI8:I) (Larodan) (< 10); Dielaidin (CI8:1) (Larodan) (< 10); Dilinolein (CI8:2) (Larodan) (< 10); and combinations thereof.

Sterol and Sterol Derivatives: (listed as compound name (common commercial product name (supplier) (HLB)): Cholesterol, sitosterol, lanosterol (< 10)); PEG-24 cholesterol ether (Solulan C-24 (Amerchol) (> 10)); PEG-30 cholestanol (Nikkol DHC (Nikko) (> 10}); Phytosterol (GENEROL series (Henkel) (< 10)); PEG-25 phyto sterol (Nikkol BPSH-25 (Nikko) (> 10)); PEG-5 soya sterol (Nikkol BPS-5 (Nikko) (< 10)); PEG- soya sterol (Nikkol BPS- 0 (Nikko) (< 10)); PEG-20 soya sterol (Nikkol BPS-20 (Nikko) (< 10)); PEG-30 soya sterol (Nikkol BPS-30 (Nikko) (> 10)); and combinations thereof.

Polyethylene Glycol Sorbitan Fatty Acid Esters: (listed as compound name (common commercial product name (supplier) (HLB)): PEG- 0 sorbitan laurate (Liposorb L-10 (Lipo Chem.) (> 10)); PEG-20 sorbitan monolaurate (Tween-20 (Atlas/ICI), Cnllet (Croda), DACOL MLS 20 (Condea) (17)); PEG-4 sorbitan monolaurate (Tween-21 (Atlas/ICI), Crillet (Croda) (13)); PEG-80 sorbitan monolaurate (Hodag PSML-80 (Ca!gene); T-Maz 28(> )); PEG-6 sorbitan monolaurate (Nikkol GL-1 (Nikko) (16)); PEG-20 sorbitan monopalmilate (Tween-40 (Atlas/ICI), Crillet 2(Croda) (16)); PEG-20 sorbitan moriostearate (Tween-60 (Atlas/ICI), Crillet 3(Croda) (15)); PEG-4 sorbitan moriostearate (Tween-61 (Atlas/ICI), Crillet 31(Croda) (9.6)); PEG-8 sorbitan moriostearate (DACOL MSS (Condea) (> 10)); PEG-6 sorbitan monostearate (Nikkol TS106 (Nikko) ( ));PEG-20 sorbitan tristearate (Tween-65 (Atlas/ICI), Crillet 35 (Croda) ( 1)); 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 4 (Croda) (10)); PEG-6 sorbitan monooleate (Nikkol TO-106 (Nikko) (10)); PEG-20 sorbitan monooleate (Tween-80 (Atlas/ICI), Crillet 4 (Croda) (15)); PEG-40 sorbitan oleate (Emalex ET 8040 (Nihon Emulsion) (18)); PBG-20 sorbitan trioleate (Tween-85 (Atlas/ICI), Crillet 45 (Croda) ( 1)); 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 ( C ) (10)); PEG-6 sorbitol hexastearate (Nikkol GS-6 (Nikko) (3)); and combinations thereof.

Polyethylene Glycol A ky Ethers: (listed as compound name (common commercial product name (supplier) (HLB)): PEG-2 oleyl ether,oleth-2 (Brij 92/93 (Atlas/ICI) (4.9)); PEG-3 oleyl ether,oieth-3 (Volpo 3(Croda) (< 10)); PEG-5 oleyl ether,oleth-5 (Volpo 5 (Croda) (< 10)); PEG-10 oleyl ether,oleth-10 (Volpo 10 (Croda), Brij 96/97 (Atlas/ICI) (12)); PEG-20 oleyl ether,oleth-20 (Volpo 20(Croda), Brij 98/99 (Atlas/ICI) (15)); PEG-4 lauryl ether, laureth-4 (Brij 30 (Atlas/ICI) (9.7)); PEG-9 lauryl ether (> 10)); PEG-23 lauryl ether, laureth-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)); PEG-2 stearyl ether (Brij 72 (ICI) (4.9)); PEG- 0 stearyi ether (Brij 76 ( C ) (12)); PEG-20 stearyi ether (Brij 78(CT) (15)); PEG-100 stearyi ether (Brij 700 (ICI) (> 10)); and combinations thereof.

Sugar Esters: (listed as compound name (common commercial product name (supplier) (HLB)): Sucrose distearate (SUCRO ESTER 7 (Gattefosse), Crodesta F-10 (Croda) (3)); Sucrose distearate/ monostearate (SUCRO ESTER (Gattefosse), Crodesta F- 0 (Croda) (12)); Sucrose dipaimitate (7.4)); Sucrose monostearate (Crodesta F-160 (Croda) (15)); Sucrose monopalmitate (SUCRO ESTER 5 (Gattefosse) (> 10)); Sucrose monolaurate (Saccharose monolaurate 695 (Mitsubisbi-Kasei) (15)); and combinations thereof.

Polyethylene Glycol A ky Phenols: (listed as compound name (common commercial product name (supplier) (HLB)): PEG 00 nonyl phenol (Triton X series (Rohm & Haas), Igepal CA series (GAF, USA), Antarox CA series (> 10)); (GAF, UK); PEG100 octyl phenoi ether (Triton N-series (Rohm & Haas), Igepal CO series (GAF, USA), Antaro CO series (GAF, UK) (> 10)); and combinations thereof.

Polyethyiene-Polyoxypropyieiie Block Copolymers (AKA - "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" denote the number ofpolyoxyethylene and poiyoxypropylene units, respectively. The compounds are listed by generic name, with the corresponding "a" and "b" values. POE-POP Block Copolymers)); (a, b values in)); HO(C<2>H<4>0)<a>)); (COMPOUND (C<3>H<6>0 )<b>(C<2>H<4>0)<a>H (HLB)); (Poloxamer 05 (a = (b = 16 (8)); (Poloxamer 108 (a= 46 (b = 16 (> 10)); (Poloxamer 122 (a = 5 (b=21(3)); (Poloxamer 123 (a =7 (b = 2 (7)); (Poloxamer 124 (a= 1(b = 21 (> 7j); (Poloxamer 181 (a= 3 (b = 30)); (Poloxamer 82 (a= 8 (b = 30 (2)); (Poloxamer 83 (a = 10 (b = 30)); (Poloxamer 184 (a= 13 (b = 30)); (Poloxamer 185 (a= 19 (b = 30)); (Poloxamer 88 (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= 3 (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 combinations thereof.

Sorbitan Fatty Acid Esters: (listed ascompound name (common commercial product name (supplier) (HLB)): Sorbitan monolaurate (Span-20 (Atlas/ICI), Crill 1(Croda), Arlacel (IC )(86)); Sorbitan monopalmitaie (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), Crill43 (Croda),Nikkol SO- 5(Nikko) (3.7)); Sorbitantristearate (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 combinations thereof.

Lower Alcohol Fatty Acid Esters: (listed ascompound 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 PP (Croda) (< 10)); Ethyl linoleate (Nikkol VF-E (Nikko) (< 0));Isopropyl linoleate (Nikkol VF-IP (Nikko) (< 10)); and combinations thereof Ionic Surfactants: (listed ascompound name (HLB) Fatty acid salts (> 10)); Sodium caproate; Sodium caprylate; Sodium caprate; Sodium laurate; Sodium myristate)); Sodium myristolate; Sodiumpalmitate; Sodiumpalmitoleate; Sodium oleate (18); Sodium ricinoleate)); Sodium linoleate; Sodium linolenate; Sodium stearate; Sodium lauryi sulfate (40); Sodiumtetradecyl sulfate; Sodium lauryi sarcosmate; Sodium dioetyl sulfosuccinate; Bile Salts (> 0); Sodium cholate; Sodiumtaurocholate; Sodium glycocholate; Sodium deoxycholate; Sodiumtaurodeoxycholate; Sodium glycodeoxycholate; Sodium ursodeoxycholic; Sodium chenodeoxycholate; Sodiumtaurochenodeoxycholate; Sodium glyeo cheno deoxycholate; Sodium cholyisarcosinate; Sodium -methyl taurocholate; and combinations thereof. lM lM Phospholipids: such asEgg/Soy lecithin (Epikuron ;Ovothin );Lyso egg/soy lecithin; Hydroxylated lecithin; Lysophosphatidylchoiiiie; Cardiolipin; Sphingomyelin; Phosphatidylcholine; Phosphatidyl ethanolamine; Phosphatidic acid; Phosphatidyl glycerol; Phosphatidyl serine, and combinations thereof.

Phosphoric AcidEsters: Diethanolammonium polyoxyethylene-10o ey ether phosphate; Esterification products offatty alcohols or fatty alcohol ethoxylates with phosphoric acid or anhydride.

Carboxylates, such as: Ether carboxylates (by oxidation ofterminal OH group of fatty alcohol ethoxylates) Succinylated monoglycerides; Sodium stearyl fumarate; Stearoyl propylene glycol hydrogen succinate; Morso/diacetylated tartaric acid esters of mono- and diglycerides; Citric acid esters of mono-, diglycerides; Glyceryl-lacto esters of fatty acids; and combinations thereof.

Acyl lactylates such as: lactylic esters of fatty acids; calcium/sodium stearoyl lactylate; calcium/sodium stearoyl lactyiate; alginate salts like sodium alginate, calcium alginate and others; and combinations thereof.

Hydrophilic Polymers such as: carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, methacrylic acid copolymers, maerogol, starch, gelatin, dextrin, pulluian, agar, acacia, poiyfethylene glycol), polyiethylene oxide), poly(vinyl alcohol), poiyiethylene- co-vinyl alcohol), poly(acrylic acid), polyCethylene-co-acrylic acid), poly(ethyioxazoline), polyfvinyi pyrrolidone), poly(ethylene-co-vinyl pyrrolidone), poiyfmaleic acid), poly(ethyiene-co-maieic acid), poly(acrylaniide), or poly(ethylene oxide)-co-poly(propyieiie oxide); block copolymers, graft copolymers of lactic acid, glycolic acid, epsilon- caprolactone, lactic-co-glycoiic acid oligomers trimethyiene carbonate, anhydrides, and amino acids acrylates, benzoquinones, naphthoquinones and the like; N-vinylpyrrolidone-co- vinyl alcohol, poly(ethylene-co-vinyl alcohol); acrylic or methacrylic acid copolymers; carhomers, Chitosan, methacrylates (Eudragits), and combinations thereof.

Acids such as: acetic acid, hydrochloric acid, hydrobromic acid, hydriodic 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 hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, salts thereof, 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, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrotaicite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethyleiiediamine, triethanolamine, triethyiamine, triisopropaiiolamine, and mixtures of combinations thereof.

Chelating Agents such as: Sodium EDTA,Dieditate Sodium, andmixtures or combinations thereof. Complexing Agents such as: Hydroxypropyl Cyclodextrin, Hydroxy propy beta Cyclodextrin, sulfabutyl ether cyclodextrin, andmixtures and combinations thereof Salts such as: salts ofacids,bases, salts offatty acids, fatty acid glycerides, Salts of bile acids, andmixtures and combinations thereof.

Amides such as: for example 2-pyrrolidone, 2-piperidone, .epsilon.-caprolactam, N- alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidoiie, N-alkylcaprolactam, dimethylacetamide, polyvinylpyrrolidone andthe like.

Alcohols such as: ethanol isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, glycerol, sorbitol, mannitol, dimethyl isosorbide, polyethylene glycol, fatty acid alcohol, vinyl alcohol polypropylene glycol, polyvinylalcohoi, tocopherols, cellulose cyclodextrins, other derivatives, forms, mixtures thereof, or the like.

Glycerols and Propylene Glycols such as: glycerine, propylene glycol, polypropylene glycol, polypropylene oxides and mixtures thereof. Polyethylene Glycol (PEG) such as: PEG 300, PEG 400, PEG 4000, PEG 6000, PEG 8000, PEG 20000, and combinations thereof.

Esters such as: ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, epsilon-caprolactone and isomers thereof, .delta.- vaierolactone and isomers thereof, beta-butyrolactone and isomers thereof; dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, orthe like.

Bile acids such as: cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxyeholate, glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate. lithocholate, tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine) Celluloses such as: microciystalline cellulose, ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethylcellulose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CPr), cellulose butyrate (CB), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose acetate trimellitate ( P CAT),and ethylhydroxy et ylce ose(EHEC), various grades of low viscosity (MW lessthan or equalto50,000 daltons) and high viscosity (MW greaterthan 50,000 daltons) HPMC, and combinations thereof.

Cellulose Esters such as: Cellulose acetate, Cellulose Acetate Butyrate, Cellulose acetate phthalate, Hydroxypropyl methylceilulose phthalate, and combinations thereof Mucoadhesive Polymers such as for exampletocopherols such as for example tocopherol, tocopherol acetate, tocopherol succinate, and combinations thereof.

Amino Acids and ModifiedAmino acids such as: aniinoboronic acid derivatives, n- acetylcysteine, and mixtures thereof.

Sugars such as: maltose, sucrose, dextrose, lactose, fructose, marmitol, sucraiose, fructalose, trehelose, dextrose, maltodextrose, and combinations thereof.

SugarAlcohols such as: mannitol, xylitol, sorbitol, combinations thereof, 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(acrylie) acid, poly(methacryiic) acid, polyvinylpyrrolidone (PVP) and crosslinked PVP,polyvinyl alcohol (PVA), PVA'PVP copolymers and PVA/PVP copolymers with hydrophobic monomers such asmethyl methacrylate, vinyl acetate, andthe like, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carbox cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate andthe like.

Other carriers such as: dibasic calcium phosphate, croscarmellose sodium, sodium starch glycolate, sodium alginate, phospholipids, lecithins, proteins (e.g., collagen, gelatin, Zein, gluten mussel protein, lipoprotein); carbohydrates (e.g., alginates, carrageenan cellulose derivatives, pectin, starch); gums (e.g., xanthan gum, gum Arabic, gumtragacanth, gum acacia); spermaceti; natural or synthetic waxes; carnuaba wax; fatty acids (e.g., stearic acid, hydroxystearic acid); Magnesium stearate, calcium stearate, titanium dioxide, polyacrylic acid, silicates, magnesium aluminum silicates, siloxanes, mimeticones, paraffins, fatty alcohols; dibutyl phthalate; dibutyl sebacate; diethyl phthalate; dimethyl phthalate; triethvl citrate; butyl and glycol esters offatty acids; mineral oil; cetyl alcohol; stearyl alcohol; camphor oil; triethvl citrate, shellacs, benzalkonium chloride methyl paraben, propyl paraben, sodiumbenzoate andthe like. n one embodiment, the pharmaceutical composition or oral dosage form can be formulated toinclude at least one ofthe following preferred carriers: citric acid, maleic acid, tartaric acid, ascorbic acid, lactic acid, and salts thereof,potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, silicon dioxide, magnesium aluminum silicate, triethyiamine, fatty acid glycerides, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, triethylcitrate, triacetin, benzyl benzoate, bile acid, salts ofbile acid, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose esters, carbomer, methacryiates, polyvinyl alcohol, gelatin, d stearin, monopalmitolein tocopherol, tocopherol succinate, com oil, olive oil. peanut oil. safflower oil, sesame oil, soybean oil, hydrogenated castor oil, glyceryl tricaprate, glyceryl trilinoleate, glyceryl tricaprylate/caprate, glyceryl tricapryiate/caprate/linoleate, saturated polyglycolized glycerides, linoleic glycerides, caprylic/capric glycerides, capric acid, caprylic acid, palmitic acid, Laurie acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, glyceryl monooleate, glyceryl monoiinoleate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl laurate, glyceryl caprylate, PEG-6 com oil, PEG-6 apricot kernel oil, 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, poygycer - oleate, polyglyceryl-6 dioleate, poygyce l-10mono, dioleate, poloxamer 188, poloxamer 108, poloxamer 182, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, propylene glycol caprylate/caprate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan sesquioieate, sorbitan sesquistearate, maltose, sucrose, fructose, mannitol, xylitol, and combinations thereof.

In one embodiment, thepharmaceutical compositions or oral dosage forms ofthe present invention can be formulated toinclude ahydrophilic additive. In another embodiment, the hydrophilic additive canbe ahydrophilic surfactant. In one embodiment, when the hydrophilic additive includes ahydrophilic surfactants, the hydrophilic surfactant does not appreciably solubilize the ester of 17-hydroxyprogesterone. Non-limiting examples ofhydrophilic 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, silicon dioxide, magnesium aluminum silicate, hydroxypropyl cyclodextrin, fatty acid glycerides, salts of bile acids, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol methyl cellulose, hydroxypropyl methyl cellulose, cellulose ssters, carbomer, chitosan, methacrylates,polyvinyl alcohol, gelatin, PEG-8 caprylic/capric glycerides, lauroyl macrogol- 32 glyceride, stearoyl macrogol glyceride, PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium oleate, sodium lauryl sulfate, sodium lau l sarcosinate, sodium dioctyl sulfosuccinate, PEG-10 laurate, PEG-20 oleate, PEG-30 stearate, PEG-40 laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl tearate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitart laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, polyglyceryl- 0 oleate, polyglyceryl-10 mono, dioleate, poloxamer 188, poloxamer 108 maltose, sucrose, fructose, mannitol, xylitol, and combinations thereof.

In another particular embodiment, the carrier canbe ahydrophilic surfactant and can be ionic or non-ionic surfactant. Non-limiting examples ofhydrophilic surfactants include proteins, gelatin, salts ofbile acids, PEG-8 caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, PEG-10 laurate, PEG-20 oleate, PEG-30 stearate, PEG-40 laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl tearate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate, poloxamer 188, poloxamer 08, and combinations thereof.

In one embodiment, the hydrophilic additive can be free of hydrophilic surfactants, and can becitric acid, maleic acid, tartaric acid, acetic acid, ascorbic acid, benzoic acid, lactic acid, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, silicon dioxide, magnesium aluminum silicate, hydroxypropyl cyciodextrin, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol propylene glycol, polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, cellulose esters, carbomer, chitosan, methacrylates, polyvinyl alcohol, gelatin, maltose, sucrose, fructose, mannitol, xylitol, and combinations thereof.

In another embodiment, the carrier ofthe pharmaceutical compositions or oral dosage forms can include a lipophilic additive. Non-limiting examples of lipophilic additives include tributylcitrate, triethylcitrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetates butyrate, cellulose acetate phthaiate, hydroxypropyl methylcellulose phthaiate, 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 tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate, saturated polyglycolized glycerides linoieic glycerides, caprylic/capric glycerides capric acid, capr ic acid, palmitic acid, lauric acid, stearic acid, linoieic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl laurate, glyceryl caprylate, distearin, monopainiitolein, nionolaurin, ethyl oleate, PEG-6 corn oil, PEG-6 apricot kernel oil, PEG-4 caprylic/capric triglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poloxamer 182, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, propylene glycol caprylate/caprate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate, and combinations thereof. In one embodiment, the carrier ofthe current invention can include at least 50wt% of lipophilic additive.

In aparticular embodiment, the lipophilic additive is at least one agent selected from tributylcitrate, triethylcitrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetates butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose 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 tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate, saturated polyglycolized glycerides linoieic glycerides, caprylic/capric glycerides, capric acid, caprylic acid, palmitic acid, lauric acid, stearic acid, linoieic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, glyceryl distearate, glyceryl palmitostearate, distearin, tristearin, paraffin oil, bess wax, anima fat, phytosterol, cholesterol, shellac and combinations thereof.

In a particular embodiment, the lipophilic additive is a triglyceride. Non-limiting examples of triglycerides suitable for this invention include com oil, olive oil, peanut oil, palm oil, coconut oil, arachis oil, safflower oil, sesame oil, soybean oil, castor oil, primrose oil, cotton seed oil, vegetable oil, borage oil, linseed oil, flax seed oil, omega oils, partially or fully hydrogenated castor oil, fish oil, shark oil, whale oil, seal oil, glyceryl tricaprate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilmoleate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricapryiate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate, saturated polyglycolized glycerides linoleic glycerid.es, caprylic/capric glycerides, tristearin and the like, and combinations thereof In one embodiment, the lipophilic additive can befree oflipophilic surfactants. In one particular embodiment, the carrier is a lipophilic surfactant. Non-limiting examples of lipophilic surfactants suitable forthis invention include tributyicitrate, triethylcitrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetates butyrate, benzyl benzoate, cellulose acetate phthalate, hydroxypropvl methvlcellulose phthalate. tocopherol, tocopherol acetate, tocopherol succinate, com oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, hydrogenated castor oil, glyceryl tricaprate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilmoleate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate, saturated polyglycolized glycerides linoleic glycerides, caprylic/capric glycerides capric acid, caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoieate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl laurate, glyceryl caprylate, distearin, monopalmitolein, monolaurin, ethyl oieate, PEG-6 com oil, PEG-6 apricot kernel oil, PEG-4 caprylic/capric triglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oieate, polyglyceryl-6 dioleate, poloxamer 182, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, propylene glycol caprylate/caprate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate, and combinations thereof.

In another particular embodiment, 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 lipophilic or hydrophilic additive which contain 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 which contain small amounts of triglycerides as impurities or as unreacted starting material.

It is expected that when such lipophilic or hydrophilic additive is used in the compositions of the present invention, the total triglyceride content does not exceed 5% by weight of the composition or dosage form. Thus, "substantially triglyceride-free" should be understood as meaning free of added triglycerides, and the triglyceride impurity from the lipophilic or hydrophilic additives constitute about 5%, or less than 5%, ess than 2%, or preferably 0% (triglyceride free), by weight of the composition. Further, the present invention does not exclude lipophilic or hydrophilic additives that are derivatives of triglycerides, such as for example polyethylene glycol or propylene glyocol derivatives of triglycerides; while these derivatized triglycerides may have surfactant properties, the triglycerides are not surfactants bythemselves.

Non-limiting examples ofsuch lipophilic additives include tributylcitrate, tnethylcitrate, triacetin, ethyl cellulose, cellulose esters, ceilulose acetate, cellulose acetates butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, tocopherol, tocopherol acetate, tocopherol succinate, saturated polyglycolized 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, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl laurate, glyceryl caprylate, distearin, monopalmitolein, monoiaurin, ethyl oleate, PEG-6 corn oil, PEG-6 apricot kernel oil, PEG-4 caprylic/capric triglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poloxamer 182, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, propylene glycol caprylate/caprate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate, and combinations thereof.

In some embodiments, the carrier ofthe current invention can be a control release agent. In aparticular embodiment, the control release agent is selected from the group consisting ofthe said hydrophilic additives or lipophilic additives or amixture thereof. In another particular embodiment, the compositions or dosage forms ofthepresent invention canbe free oflipophilic surfactant. Inanother particular embodiment, the compositions or dosage form ofthe present invention canbe free of lipophilic additive.

As discussed above, in some embodiments, the pharmaceutical compositions and the oral dosage forms ofthe present disclosure can include at least one hydrophilic additive and at least one lipophilic additive. In one embodiment, when both ahydrophilic additive and a lipophilic additive arepresent, they can be present at alipophilic additive to hydrophilic additive ratio ofabout 99: 1toabout :99. In one embodiment, the lipophilic additive to hydrophilic additive ratio can be about 95: 5to about 5:95. In another embodiment, the lipophilic additive tohydrophilic additive ratio canbeabout 90:10 toabout 10:90. In one embodiment, the lipophilic additive to hydrophilic additive ratio can be ofabout 90:10 to about 1:99. In another specific embodiment, the lipophilic additive tohydrophilic additive ratio can be ofabout 80:20 to about 20:80. In another specific embodiment, the lipophilic additive tohydrophilic additive ratio canbeof about 70:30 to about 30:70. In another specific embodiment, the lipophilic additive tohydrophilic additive ratio can be ofabout 60:40 to about 40:60. In another specific embodiment, the lipophilic additive tohydrophilic additive ratio can beabout 50:50.

In aseparate embodiment, when both a hydrophilic surfactant and a lipophilic additive are present, they canbepresent in amounts such that when 1part by weight ofthe mixture of the hydrophilic surfactant and lipophilic additive ismixed 99parts ofan aqueous diluent, the dispersion so obtained so obtained canbe colloidal, hazy or unclear. For example, the aqueous diluent used for dispersion is either water or 0.5% w/v sodium lauryl sulfate in water. In aspecific embodiment, the dispersion can exhibit an absorbance greater than 0.1 when determined using a spectrophotometer at 400 nm. In another specific embodiment, the absorbance isgreater than 0.3 at 400 nm. In another embodiment, the mean particle size of the dispersion is about 60nm or more. In another specific embodiment, the mean particle size ofthe dispersion isabout 100 nm or more. In another specific embodiment, the mean particle size ofthe dispersion is about 0 nm or more. In yet another specific embodiment, the mean particle size ofthe dispersion is about 200 nm or more. Inyet another specific embodiment, de mean particle size ofthe dispersion is about 250 nm ormore. For example, the aqueous diluent used for dispersion iseither water or 0.5% w/v sodium lauryl sulfate in water. For the purpose ofthis invention, the dispersion is deemed clear ifit appears clearto the naked eye. In one embodiment, the dispersion can be clear.

The carrier canbepresent in an amount sufficient to solubiiize de ester of 7 hydroxyprogesterone. In some aspects, the carrier ofthe present invention aids in solubilizing a significant amount ofthe ester of 17-hydroxyprogesterone inthe composition.

In one embodiment, the carrier can solubiiize 20wt% or more ofthe amount ofthe ester of 7-hydrxoyprogesterone. In another embodiment, the carrier can aid loading ofgreater than about 10% w/w/ ofthe ester in die composition and/or dosage form. In another embodiment, the loading achieved by the carrier can be greater than about 12% w/w ofthe composition and/or dosage form In another embodiment, the loading achieved by the carrier can be greater than about 15% w/w ofthe composition and/or dosage form. In another embodiment, the loading attained by inclusion ofthe carrier can be greater than about 18% w/w ofthe composition and/or dosage form. In further embodiments, the loading attained by inclusion of the carrier can begreater 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 than about 90%, with each percentage based onw/w ofthe composition and/or dosage form.

In one embodiment, the carrier can include benzyl alcohol, benzyl benzoate, mixtures thereof In another embodiment, the carrier can include benzyl alcohol, benzyl benzoate, or mixtures thereof andthe amount ofthe ester of 17-hydroxyprogesterone can bebetween about 5to about 80% w/w of the total composition. In one embodiment, when the carrier includes benzyi alcohol, benzyl benzoate, or mixtures thereof, the amount ofthe ester of 17- hydroxyprogesterone can bebetween about 5to about 80% w/w ofthe total composition In one embodiment, the amount ofthe ester of 17 hydroxyprogesterone can bebetween 5%to about 60% w/w ofthe total composition. In another specific embodiment, when the carrier includes benzyl alcohol, benzyl benzoate, or mixtures thereof, the amount ofthe ester of 17- hydroxyprogesterone can bebetween about 5toabout 40% w/w ofthe total composition. In another specific embodiment, when the carrier includes benzyl alcohol, benzyi benzoate, or mixtures thereof, the amount ofthe ester of 17-hydroxyprogesterone can bebetween about 5 to about 30% w/w of the total composition. In another specific embodiment, when the carrier includes benzyi alcohol, benzyl benzoate, or mixtures thereof, the amount ofthe ester of 17- hydroxyprogesterone can bebetween about 5to about 25% w/w ofthe total composition In one specific embodiment, when the carrier includes benzyi alcohol, benzyl benzoate, or mixtures thereof! the ester of 17-hydroxyprogesterone can be fully solubilized inthe composition and/or the dosage form. In another specific embodiment, the ester of 7- hydroxyprogesterone canbepartially solubilized inthe dosage form. In another specific embodiment, the ester of 17-hydroxyprogesterone can be 17-hydroxyprogesterone caproate.

In one embodiment the ratio ofthe amount ofthe ester of 17-hydroxyprogesterone to the sum ofthe amounts ofbenzy alcohol and benzyl benzoate present in the composition or oral dosage form can beabout 1:0.01 (W/W) to about :5 (W/W). In another embodiment, the ratio can be about 1: 0.0 (W/W) to about 1:3.5 (W/W). In another embodiment the ratio ofthe amount ofthe ester of 17-hydroxyprogesterone tothe sum ofthe amounts ofbenzyl alcohol and benzyl benzoate present in the composition or oral dosage form can be about : 001(WAV)to about 1:2.5 (WAV).In another embodiment, the ratio ofthe amount ofthe ester of 17-hydroxyprogesterone tothe sum ofthe amounts ofbenzyl alcohol andbenzyl benzoate present in the composition or oral dosage form can be about 1 0.01 to about 1:2 (WAV).

The pharmaceutical compositions and oral dosage forms can be formulated and delivered in avariety of solid or liquid dosage forms. Non-limiting examples of such dosage forms include powder, granulate, particulate, bead, pellet, sprinkle, suspension, solution, tablet, capsule and combinations thereof. In one embodiment, the pharmaceutical composition or oral dosage form ca beinthe form of acapsule. In another embodiment, the pharmaceutical composition or oral dosage form can be in the form of atablet. In one embodiment, the dosage form is ahard or a soft capsule. The capsule can bemade of conventional capsule shell materials known inthe art; such materials can include, but are not limited to gelatins, celluloses, starches, methacrylates, carrageenans. polyvinyl alcohols, and the like. In another embodiment, the capsule is an immediate release dosage form. In yet 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 ofthe capsule can be about 15 mL or less. In another embodiment, the volume of capsule can be about .2 mL or less. In one particular embodiment, the volume ofthe capsule can be about 0.8mLor less. In another embodiment, the ratio ofthe weight of fill material encapsulated within the capsule tothe capsule volume can bebetween about 0.3 g/mL to about 3.5 g mL. In aparticular embodiment, the ratio can bebetween 0.6 g/mL to about 2.5 g/mL. In another particular embodiment, the ratio can be between 0.6 g/mL to about 1.2 g/mL.

In another embodiment, the pharmaceutical capsule oral dosage form ofthe current invention can have aratio ofthe amount ofthe ester of 17-hydroxyprogesterone in the composition to the fill volume ofthe capsule between about 0.02gmL to about 0.8 g/mL. In another embodiment, the ratio can bebetween about 0.02 g/mL to about 0.7 g/mL. In a specific embodiment, the ratio can bebetween about 0.02 g mLto about 0.5gmL. In another specific embodiment, the ratio can bebetween about 0.05 g/mL to about05 g/mL. In another specific embodiment, theratio canbebetween about 0.05 g/mL to about 0.35 g/mL.

In another specific embodiment, the ratio canbebetween about 0.05 g/mL to about03 g/mL in another specific embodiment, the ratio canbebetween about 0.1 g/mL toabout 0.25 g/mL.

The oral dosage forms ofthe present invention canbeformulated toinclude an amount of an ester of 7-hydroxyprogesterone equivalent toabout 0 gto about 800 mgof 17-hydroxyprogesterone. In one embodiment the oral dosage form canbeformulated to include an amount ofester of 17-hydroxyprogesterone equivalentto20mgtoabout 400 mg of 17-hydroxyprogesterone. Thepharmaceutical composition and oral dosage forms ofthe present invention canbe formulated tobe administered to a subject in ordertoprovide adaily dose ofthe ester of 17-hydroxyprogesterone tha is equivalent toabout 40mgto about 3200 mg of 7-hydroxyprogesterone In one embodiment, the oral dosage for canbe acapsule andthe capsule includes from about 10 mgtoabout 300 mg17-hydroxyprogesterone caproate In another embodiment, the oral dosage form canbeatablet andthe tablet includes from about20mgtoabout 800 mg of 17-hydroxyprogesterone caproate.

In ordertoprovide a desired daily dose, thepharmaceutical compositions and ora dosage forms canbeformulated to beadministered at various dosing intervals. n one embodiment the compositions or oral dosage forms canbe formulated for administration about once ever 8hours. In another embodiment, the compositions or oral dosage forms can be formulated for administration to asubject, such as a human subject, once every 6 hours.

In another embodiment, the compositions or oral dosage forms canbe formulated for administration about once every 12 hours. In yet a further embodiment, the compositions or oral dosage forms can beformulated for administration about once every 24 hours.

In one aspect, the oral dosage forms ofthe present invention canbeused totreat pregnant female subjects who are at risk ofpreterm birth. The methods oftreatment include the step oforally administering tothe female subject the oral pharmaceutical composition. In another embodiment, the oral dosage forms canbeadministered tosubjects inneed thereof.

The administration ofthe ora dosage form cantreat at least one condition selected from preterm labor, preterm birth infertility and miscarriage. In one embodiment, the subject receiving administration ofthe pharmaceutical composition or oral dosage for canbe experiencing orbe atrisk of at leasttwo of: singleton pregnancy, history ofpreterm labor and/or preterm birth, history ofpreterm delivery, shortened cervix, and effaced cervix, history ofmore at least one miscarriage, and history ofmultifetal gestation. The conditions andthe relative treatment canbebased on their primary and secondary outcome measurements associated with the administration ofthe ester of 17-hydroxyprogesterone. n one embodiment, upon single administration to ahuman subject, the pharmaceutical compositions or oral dosage forms ofthe present invention comprising an ester of 17-hydroxyprogesterone can provide a 7-hydroxyprogesterone equivalent C ..24h greater than about 0.7 ng/mL. In another embodiment, the oral dosage form or the composition can provide a C of 17-hydroxyprogesterone equivalents greater than about ng/mL. n another embodiment, the oral dosage form orthe composition canprovide a 7-hydroxyprogesterone equivalents greater than about 30ng/mL. In another -2 h embodiment, the oral dosage form or the composition can provide a C of 7- g- h a 24 hydroxyprogesterone equivalents greater than about 50ng/mL. In yet afurther embodiment, the oral dosage form or the composition can provide a C of 7-hydroxyprogesterone g-24h equivalents greater than about 00 ng/mL. In one embodiment, the said 17- hydroxyprogesterone equivalent C is determined by an HPLC-MS/MS method of g- 4 analysis ofthe plasma, serum orblood samples collected following the oral administration.

In one embodiment, upon single administration to ahuman subject the pharmaceutical compositions or oral dosage forms ofthe present invention comprising 7- hydroxyprogesterone caproate, can provide a 7-hydroxyprogesterone caproate C equal -24h to about 1.0 ng/mL or more. In another embodiment, the oral dosage form or the composition can provide a 7-hydroxyprogesterone caproateCv equal to about 20ng/mL or more. In another embodiment, the oral dosage form or the composition can provide a 17- hydroxyprogesterone caproate C equal to about 50ng/mL or more. In another embodiment, the oral dosage form or the composition can provide a 7-hydroxyprogesterone caproate C equal to about 00 ng/mL or more. In one embodiment, the said 17- g-24h hydroxyprogesterone caproate C determined by an HPLC-MS/MS method of analysis -24h ofthe plasma, serum or blood samples collected following the oral administration.

It was surprisingly found that the compositions and/or dosage forms ofthis invention provided significantly enhanced bioavailability of 7 hydroxyprogesterone caproate as a function ofthe oral dose ofthe 17 hydroxyprogesterone caproate administered to a subject.

Accordingly, the compositions or dosage forms ofthis invention provide, upon single dose oral administration, an AUC(o to dose ratio of about 0 or less, wherein the dose isthe amount in mgof the 17-hydroxyprogesterone caproate administered I one embodiment, the ratio ofthe 7-hydroxyprogesterone caproate AUC(o-24h) dose ofthe 17- hydroxyprogesterone caproate administered can be about 0.2 ng*h mL^mg to about 0 ng*h mmg. In another embodiment, the ratio ofthe 7-hydroxyprogesterone caproate AUC( todose of the 17-hydroxyprogesterone caproate administered canbe about 0.3 ng*h ml. mg toabout 7ng*h m mg '. In a specific embodiment, the AUC o todose ratio is between about05 a dabout 6ng*h mL^mg .

In a specific embodiment, upon single administration ofthe pharmaceutical compositions or oral dosage forms containing 17-hydroxyprogesterone caproate ofthe present invention toahuman subject under fed condition, the oral dosage form or pharmaceutical composition canprovide a 7-hydroxyprogesterone caproate C of greater than about 1.0 ng/mL. In another specific embodiment, the pharmaceutical compositions or oral dosage forms containing 17-hydroxyprogesterone ofthepresent invention canprovide asteady state 17-hydroxyprogesterone caproate C g- hofgreater than about .0 ng/mL, when administered to ahuman subject under fed condition. In one embodiment, the said C - s determined by an HPLC-MS/MS method ofanalysis ofthe avg2h plasma, serum orblood samples collected following the administration. In another embodiment, the compositions and oral dosage forms disclosed herein canbeorally administered with food orwithout regards tothe food or food content. In a specific embodiment the compositions and oral dosage forms containing caproate ester of 17- hydroxyprogesterone asdisclosed herein can be orally administered with food orwithout regards tothe food or food content.

In one embodiment, the oral dosage form canbe orally administered with food or under fed condition. In another embodiment, the composition or oral dosage form canbe administered with anormal or standard meal. In aspecific embodiment, the composition or oral dosage form canbe administered with a food or meal, such as ameal that provides about 200 calories toabout 1000 calories ofenergy. In another specific embodiment, the composition or oral dosage form can be administered with ameal that provides about 50% of the calories fromthe fat. In another embodiment, the composition or oral dosage form canbe administered with ahigh-fat, high calorie meal. In another embodiment, the composition or oral dosage form canbe administered with a standard meal that provides about 500 calories to about 1000 calories ofenergy. The compositional make-up ofthe meals that are administered can vary depending onthe tastes and dietary needs ofa subject. However, in some situations itmay bebeneficial to administer the compositions and oral dosage forms with meals that provide no fatto about 50gof fat. In one embodiment, the meal can provide about 3gto about 50gof fat. Inyet a further embodiment, the meal canprovide 10 g to about 50gof fat. n yet another embodiment, the meal canprovide about 5gtoabout 35 g of fat. In one embodiment, when the oral dosage form is administered to ahuman female, it canbe done without regard tothe presence ofornutritional make-up ofameal. In another embodiment, when administering theoral dosage form, the total daily dose ofthe ester of 7 HPadministered tohuman female subject with food orunder fed condition is from about % to about 80% ofthetotal daily dose administered without meals, for a similar therapeutic benefit. In a specific embodiment, the daily doseunder fed condition is from about 20% toabout 60% of the total daily dose administered without meals, for asimilar therapeutic benefit. In another embodiment, the composition or oral dosage form canbe administered without food orunder fasted condition.

The oral bioavailability ofthe ester of 7-hydroxyprogesterone ca be enhanced by using the said ester inthe form offine particulate, for example milled, micronized or nanosized etc, in the composition and/or the dosage form ofthe current invention Further, the oralbioavailability canbe enhanced by using the ester along with a carrier that aidsthe release of at least 20% more ofthe esterfromthe composition or dosage formwhen exposed to an aqueous medium compared to an equivalent dose ofthe esterwithout the carrier ofthe current invention. In aspecific embodiment the oralbioavailability ofthe caproate ester of 7-hydroxyprogesterone canbe enhanced by using the said ester in the form offine particulate, for example milled, micronized ornanosized or combinations thereof inthe composition and/or the dosage for of the current invention Accordingly, in one embodiment, the oral bioavailability ofthe ester of 17- hydroxyprogesterone is atleast % more forthe compositions or adosage forms ofthe current invention that releases at least 20% ofthe ester in an aqueous medium compared to an equivalent dose ofthe esterpresent in a "untreated" particulate form such as forexample as unmiiled orunrnicronized particulate forms. In another embodiment, the oral bioavailability ofthe ester of 7-hydroxyprogesterone is at least 0% more forthe compositions or a dosage forms ofthe current invention that releases at least 20% more ofthe ester from the composition or dosage form when exposed to an aqueous medium compared to a equivalent dose ofthe esterwithout the carrier ofthe current invention. In a specific embodiment, the said ester is 17-hydroxyprogesterone caproate.

The ester of 17-hydroxyprogesterone canbe asubstrate tothe P-glycoproteins (P-gp) the efflux transporter systems. Hence, in one embodiment, the ora bioavailability can be enhanced by at least 0% by co-administering the ester of 7-hydroxyprogesterone ofthe current invention wi h an effective amount of P-gp and/or CYP3A4 inhibiting agents e.g., star fruit, grape fruitjuice, bergarnotiin, cafestol (as in unfiltered coffee), ketoconazole, erythromycin, mibefradil, loperamide etc.

In a further aspect, the oral pharmaceutical compositions or the oral dosage forms of the ester of 17-hydroxyprogesterone according tothe current invention canbeused for providing luteal support for a subject inneed thereof In one embodiment, the oral composition orthe oral dosage form canbe formulated to enable modulation ortitration of the dose and/or dosing regimen ofthe ester of 17-hydroxyprogesterone forproviding effective luteal support to a subject in need thereof. In oneparticular embodiment, the dose ofthe ester of 17-hydroxyprogesterone in the form oforal compositions or dosage forms of the present invention may bemodulated ortitrated toprovide effective luteal support as needed at the during early pregnancy. In another particular embodiment, the dose ofthe ester of 17-hydroxyprogesterone in the form of oral compositions or dosage forms ofthe present invention maybemodulated ortitrated toprovide effective luteal support asneeded based on thebody mass index (BMI) of the subject. In another particular embodiment, the dose ofthe ester of 7-hydroxyprogesterone inthe form of oral compositions or dosage forms of the present invention may bemodulated ortitrated toprovide effective luteal support asneeded based onthe race or ethnicity ofthe subject.

An example ofthe dose modulation or titration canbebased onthe total doseper day, and can include administration ofahigher initial loading dose orbolus dose, followed by alower effective standard dose. Similarly, the dose modulation ortitration canbebased onthe total doseper week and ca include administration ofahigher initial loading dose or bolus dose in the initial days ofthe week followed by a lower effective standard dose inthe later days ofthe week. The dosing regimen can include ramping up of(i.e. progressive increments) the daily dose in accordance with the progression ofpregnancy. In a specific embodiment the ester is 17-hydroxyprogesterone caproate (17-hydroxyprogesterone caproate).

In another embodiment, the daily oral dose administered with food of 17- hydroxyprogesterone caproate is from about 40mgto about 5000 g. In another embodiment, the daily oral dose is from about 40mgto about 4000 mg. In another embodiment, the daily oral dose is from about 80mgto about 4000 mg. In another embodiment, the daily oral dose is from about 50 mgto about 4000 mg. In another embodiment, the daily oral dose is from about 250 mgto about 4000 mg. In another embodiment, the daily oral dose ofis from about 500mg toabout 4000 mg. In another embodiment, the daily ora dose is from about 750 mgto about 4000 mg. In another embodiment, the daily oral dose is from about 1000 mgto about 4000 mg. In another embodiment, the daily ora dose is from about 00mgto about 4000 mg. In another embodiment, the daily oral dose is from about 1500 mgto about 4000 mg. n another embodiment, the daily oral dose is from about 1500 mgto about 3000 mg. In another embodiment, the daily oral dose is from about 1000 mgto about 2000 mg. In another embodiment the daily oral dose is from about 200 mgto about 2000 mg. In another embodiment, the daily oral dose is from about 400 mgto about 2000 mg. In another embodiment, the daily oral dose is from about 800 mgto about 2000 mg.

In one particular embodiment the oral dosage form ofthe current invention comprises atherapeutically effective amount of an ester of 17-hydroxyprogesterone, wherein, when measured using aUSP Type-II dissolution apparatus in 900 ml. of deionized water with 0.5% (w v) of sodium lauryl sulfate at 50 RPM at 37°C, the oral dosage form releases at least 20 wt% of the dose of the ester of 7-hydroxyprogesterone after 60minutes. In another particular embodiment, the dosage form releases at least about 40wt% ofthe dose ofthe ester of 7-hydroxyprogesterone after 60 minutes. In another particular embodiment, the dosage form releases at least about 50wt% of the dose ofthe ester of 17- hydroxyprogesterone after 60minutes. In another particular embodiment, the dosage form releases at least about 70 wt% of the dose of the ester of 7-hydroxyprogesterone after 60 minutes. In aspecific embodiment the ester is 7-hydroxyprogesterone caproate. In another embodiment, the dosage form is administered with food.

Following ora administration of the ester of 7-hydroxyprogesterone (e.g. 17- hydroxyprogesterone caproate) in the form of the composition or dosage form the present invention, its concentration in the serum, plasma or blood of the subject may be determined by analytical techniques based on radio-immunoassay (RIA), high performance liquid chromatography-Mass Spectroscopy (HPLC-MS/MS) and the like. Accordingly, the plasma or blood levels for the ester may be different. It has to be understood that any relative comparisons of blood plasma levels of any compound should be made with the same assay methodology, or corrections must bemade toadjust for discrepancy for assay specificity.

Accordingly, in one embodiment, the 7-hydroxyprogesterone caproate compositions or dosage forms of the present invention can provide a mean steady state 17- hydroxyprogesterone caproate mean C - from about 0 ng/niL to about 800 g/mL wherein the plasma 7-hydroxyprogesterone caproate is determined by HPLC-MS/MS method. n a particular embodiment, the compositions or dosage forms provides a mean steady state 17- hydroxyprogesterone caproate mean C x from about 10 ng/mLtoabout 400 ng/mL.

In further embodiment, the 7-hydroxyprogesterone caproate compositions or oral dosage forms of the present invention ca provide a 17-hydroxyprogesterone caproate mean steady state C of about 1 ngmL or more. The plasma concentrations of the 17- hydroxyprogesterone caproate can be determined by HPLC-MS/MS method. In one embodiment the compositions or oral dosage forms can provide a 17-hydroxyprogesterone caproate mean steady state C greater than about 0 ng/mL. In another embodiment, the composition or oral dosage forms can provide a 7-hydroxyprogesterone caproate mean steady state Cmm greater than about 20 ng/mL, or greater than about 40 ng/ , greater than about 60 ng/mL, or greater than about 80 ng/mL. In one specific embodiment, the composition or ora dosage form can provide a mean steady state C of about 1 to about 60 ng/mL in another specific embodiment, the composition or dosage form can provide amean steady state C ofabout 1ng mL toabout 20ng/mL.

Accordingly, the oral dosage form of 7-hydroxyprogesterone caproate of the present invention can be an immediate release dosage form. In a separate embodiment, the oral dosage form of the 17-hydroxyprogesterone caproate of the present invention can be a controlled release dosage form. In another specific embodiment, dosage form can include 7-hydroxyprogesterone caproate in the form of both immediate release and controlled release fractions, preferably extended or delayed release Consequently, the controlled release 7-hydroxyprogesterone caproate compositions or dosage forms of the present invention can provide a fluctuation i the 17- hydroxyprogesterone caproate levels less than about 795 ng/mL, wherein the fluctuation is determined by the difference of the mean steady state Cma and the mean steady state C.of 7-hydroxyprogesterone caproate in plasma or serum orblood, upon oral administration.

In a another particular aspect, the oral pharmaceutical compositions and/or dosage forms of 17-hydroxyprogesterone caproate of the current invention can be used for the treatment of one or more of the conditions selected from the group consisting of habitual abortion, recurrent abortion, threatened abortion, post-partum after pains, endometrial cancer, management of primary and secondary amenorrhea, infertility due to corpus luteum insufficiency, deficiency of progestogen, cervical insufficiency, cervical incompetency, and abnormal uterine bleeding. In a further embodiment the oral pharmaceutical compositions and/or dosage forms of 7-hydroxyprogesterone caproate ofthe current invention can be used in for testing endogenous estrogen production, and for the production of secretory endometrium and desquamation.

In another embodiment, the oral pharmaceutical compositions and/or dosage forms of 17-hydroxyprogesterone caproate of the current invention can be used along with omega-3 fatty acid supplementation to treat symptomatic preterm labor patients In a particular embodiment, the current mvention compositions and/or dosage forms may include at least one omega fatty acid. In another particular embodiment, the current invention compositions and/or dosage form may include omega-3, omega-6 or omega-9 fatty acid or mixtures thereof.

EXAMPLES The following examples are provided to promote a more clear understanding of certain embodiments of the present invention, and are in no way meant as a limitation thereon. Unless otherwise specified or mentioned, all the compositions provided in the examples are with respect to %w/w ofthe final composition. Note that with the exception of the compositions listed in Examples 1, 7 10, 17 and 36, the 17-hydroxyprogesterone caproate ofal other example compositions can be in either treated (milled, micronized, or nanosized) or untreated form. The 17-hydroxyprogesterone Caproate in compositions , 7, 0, 17 and 36 are untreated for size reduction (i.e. unmilled, non-micronized, un-micronized or non- nanosized), and have an average particle size greater than 50 micrometers. The dosage forms of corresponding Examples were tested for release of the 17-hydroxyprogesterone caproate using aUSP Type II apparatus, 50 rpm in 900 mL of "simulated intestinal fluid having 0.5% w/w sodium lauryl sulfate at 37°C. The percent of the 7-hydroxyprogesterone caproate released from each composition was analyzed using HPLC.

EXAMPLES 1-6 /7-hydroxyprogesteronecaproatecompositions 17-hydroxyprogesterone caproate compositions as recited in Examples 1 through 6 are prepared by using the respective components shown in Table I. Example 1 is the untreated crystalline form of 17-hydroxyprogesterone caproate filled into hard gelatin capsule. Example 2 is micronized 7-hydroxyprogesterone caproate without a carrier filled into hard gelatin capsule. Examples 3-6, are prepared as follows: The required quantities of each of the components of the respective composition, except 17-hydroxyprogesterone caproate are taken in a clean stainless steel container and mixed at about 50°C to 70°C using a stirrer A molten clear-to-hazy mixture is obtained The required amount of the 7- hydroxyprogesterone caproate is added to the clear-to-hazy mixture and stirred to form a homogenous liquid mixture A predetermined weight of the resulting liquid mixture is disposed into appropriate size capsules according to the 17-hydroxyprogesterone caproate dose required The capsules are allowed to solidify at room temperature and then banded, and packaged into DPE bottles and sealed with a lid.

The 17-hydroxyprogesterone caproate released from each of the compositions using the aforementioned dissolution testing parameters are shown in Table I. t should be noted that the Examples 1& 2 (17-hydroxyprogesterone caproate without a carrier) and Examples 3 to 6 ( 7-hydroxyprogesterone caproate admixed with at least one carrier) can be used for comparison purposes to help illustrate the advantages of the compositions and dosage forms ofthe current invention.

FABLE *micronized 7-hydroxyprogesterone caproate (approximate particle size distribution: dl00% < 25 m; d50% <15 m) The aqueous dispersion of the mixture that includes lipophilic additive and a hydrophilic surfactant, if present, of the Examples 3 to 6 of Table-I can be hazy to non-clear when viewed with a naked eye. Their absorbance at 400 n can be greater than 0.1, or greater than 0.3, and/or the particle size of the dispersion can be greater than 100 nm. In some aspects, the average particle size ofthe dispersion may be greater than 250 nm. Each of the aqueous dispersions is prepared by mixing 1part of the mixture of the additives of the corresponding example and 99 parts of an aqueous diluent. The compositions of Example 3- 6 may be prepared by mixing the additives the 17 hydroxvprogesterone caproate to get a homogenous solution or suspension. Ifrequired, the mixture may he heated (for example, to about 40°C to about 80°C) to get a solution or to achieve a homogenous suspension. The mixture canbe disposed into a capsule. The dosage form of Example 1 and 2 has 17- hydroxyprogesterone caproate in the solid unmicronized and micronized particulate form respectively. The 17-hydroxyprogesterone caproate can be fully solubilized (as i case of Example 3) or partially solubilized (as in case of ExamplesS and 6). The formulations of Table I, if liquid, can be also formulated to be a solid dosage form by filling either as is or admixed with a solidification aid, into a capsule. Alternatively, they can be formulated into tablets by using appropriate tableting aids.

EXAMPLES 7 17-hydroxyprogesteronecaproate compositions 17-hydroxyprogesterone caproate compositions of Examples 7 through 10 can be prepared by using the ingredients shown in Table II and attain the release performance indicated.

TABLE II ** removed substantially during drying process *** Quantity sufficient for wet granulation process or for in situ formation/precipitation offastreleasing solid 17-hydroxyprogesterone caproate It should be noted that the compositions of Examples 7 to 0 can be formulated to provide granules for compression into a tablet or filling in a capsule, sachet etc., with the inclusion of appropriate pharmaceutical aids such as diluents, binder, disintegrant, lubricants, flavor, etc.

Unlike Example 1 and 7, the 7-hydroxyprogesterone caproate release profile of Examples 8, 9 and 10, shown in Table II, illustrate the advantages ofthe smaller particle size of 7-hydroxyprogesterone caproate. These Examples further illustrate the advantages of various manufacturing processes, such as granulation, which yield solid compositions with appropriate 7-hydroxygprogesterone caproate release profiles. In some embodiments, the caproate ester inthe compositions ofexamples in Table II can be substituted with other esters of 17-hydroxyprogesterone, such as acetate orundecanoate.

EXAMPLE - 17-hydroxyprogesteronecaproate CoatedTablets 17-hydroxyprogesterone caproate tablets of Example 7 through 0 can be further coated with a coating solution having typical composition set forth in Table III, using conventional tablet coating procedures known inthe art to a weight gain ofabout 3to6%.

TABLE III The coating polymer can be selected based on the need for a specific functionality to be imparted to the dosage form. For example film coating, taste masking, enteric coating protective coating, sustained release coating and so on can all be used. Unlimited examples of the polymers for use in such coatings include hypromellose, polyethylene glycol, povidone, sugars, ethyl celluloses, methacrylates, cellulose phthalates etc. Many conventional coating aids such as talc, starch, plasticizers, opacifiers, colors, flavors etc. can also be used along with coating polymers or sugars. The coating solvents can be suitably varied based on the coating polymer or sugarbeing applied.

EXAMPLES 12-17 - 17-hydroxyprogesteronecaproatecompositions Table IV shows the 7-hydroxyprogesterone caproate compositions of Examples 2- that can be prepared by using the components set forth therein and the method similar to that described for Examples 3-6. The release of 7-hydroxyprogesterone caproate from the dosage form is also shown inTable IV.

TABLEIV The aqueous dispersion of the mixture of lipophilic additive and the hydrophilic surfactant, if present, in the examples shown in Tahle-IV can be hazy to non-clear when viewed with the naked eye. Their absorbance at 400 nm can be greater than 0.1, or greater than 0.3, and/or the particle size of the dispersion can be greater than 100 nm. n some aspects, the mean particle size of the dispersion may be greater than 250 nm. Each of de aqueous dispersions is prepared by mixing 1 part of the mixture of the additives of the corresponding example and 99parts ofan aqueous diluent.

The compositions of Table IV, if liquid, can be formulated to be solid dosage forms by filling into a capsule either as is, or admixed with a solidification aid such aspolyethylene glycol, glyceryl distearate, wa and the like.. It should benoted that these compositions can aso be formulated to obtain granules for compression into a tablet or filling into a capsule, sachet etc., with the inclusion of appropriate pharmaceutical aids such as diluents binders, disintegrants, lubricants, flavors, etc.

The 7-hydroxyprogesterone caproate i the compositions of examples in Table IV can in some embodiments be substituted with other esters of 7-hydroxyprogesterone, such as ]7-hydroxyprogesterone acetate or 17-hydroxyprogesterone undecanoate.

EXAMPLES 8 1 -hydroxyprogesteronecaproatecompositions Table V shows various 7-hydroxyprogesterone caproate compositions as recited in Examples 18-23 that can beprepared using the components set forth therein.

TABLE V Table VI shows various specific embodiments of different dosage forms (DF-1 to DF-9) containing 7-hydroxyprogesterone caproate that can be achieved by various combinations of the compositions shown in Table V.

TABLE V Dosage Form Composition DF-1 DF-2 DF~3 DF-4 DF-5 DF~6 DF-7 DF~8 DF-9 Example No.

Composition %w/w 8 100 50 50 50 30 -- 30 50 9 - -- 30 -- 40 50 - --- -- 100 23 -- -- - Total 100 100 100 100 100 100 100 00 00 Additional tableting methods known in the art canbe used canbe applied to the above exemplified compositions.

Excipients shown are exemplary ofclasses ofexcipients that can beused The form of the drug can be interchanged with other forms such as micronized, sieved milled, amorphous nano, etc.

The above dosage forms DF-1 to DF-9 canbe single or multiple particulate units in a capsule oras single or multiple particulate units compressed into a single tablet or multi-layer tablets.

EXAMPLES 24 -28 - -hydroxyprogesteronecaproatecompositions Table VII shows 17-hydroxyprogesterone caproate compositions as recited in Examples 24-28 that canbeprepared using the components set forth therein, and their release performance.

TABLE V I Additional tableting methods known inthe art can beused canbe applied tothe abov exemplifiedcompositios.

Excipients shown are exemplary of classes of excipients that can he used, processing aids like binders, disintegrants, diluents, glidants, lubricants and coating aids commonly known in the art canbe used.

The form of the drug can be interchanged with other forms such as micronized, sieved, milled, amorphous, nano, etc The above dosage forms can be single or multiple particulate units in a capsule or as single or multiple particulate units compressed as a monolithic/matrix tablet or multi layer tablets For Example 28 the dosage form is first exposed to about 250 mL simulated gastric fluid (SGF) without enzyme for the first 30 minutes, followed by exposure to 900 mL of 0.5 wt% SLS inwater at having pH about 6.8.

EXAMPLES 29-35 - 17-hydroxyprogesteronecaproate compositions TableVI shows 7-hydroxyprogesterone caproate compositions and release data for Examples 29-35 that can be prepared by using components set forth therein and the method similar tothat described for Examples 12-17.

TABLEVIII *%released in 30minutes The above compositions can be formulated to exhibit immediate or controlled release profiles. The aqueous dispersion ofthe mixture of the lipophilic additive and the hydrophiiic surfactant, ifpresent, in the examples of Table-VII can be hazy to non-clear when viewed with the naked eye. Their absorbance at 400 nm are greater than 0.1, in some cases greater than 0.3, and/or the average particle size of the dispersion may be greater than 100 nm in some aspects. In other aspects, the average particle size ofthe dispersion can be greater than 250 nm. Each of the aqueous dispersions is prepared by mixing 1part of the mixture of the additives and surfactants ofthe corresponding example and 99parts ofan aqueous diluent.

As can be seen from the above Examples 29, 30 and 35 by using benzyl benzoate and/or benzyl alcohol, a higher drug loading (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. Further, when viewed with the naked eye the aqueous dispersion of the mixtures having a lipophilic additive and the hydrophiiic surfactant, ifpresent, asrecited in Examples 29-31 and 33-35 can be hazytonon- clear. In some cases, their absorbance at400 nm is greater than 0.1, or even greater than 0.3.

Further the average particle size of the dispersion can be greater than 100 nm, or even greater than 250 nm. Each ofthe aqueous dispersions is prepared by mixing 1part ofthe 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 examples in Table VIII can in some aspects substituted with other esters of 17-hydroxyprogesterone, such as 17- hydroxyprogesterone acetate or 17-hydroxyprogesterone imdecanoate.

The compositions of example 3, 31, 32, 33, and 34 can in some aspects, also be administered as oral liquid. These compositions can also be administered orally after appropriate admixture / dilution with diluent such as water, milk, fruitjuices, beverages and the likejust before administration. n certain embodiments, the contents of the above compositions can be adsorbed on some diluents and additional excipients and can be compress into tablet.

EXAMPLE 36 - 17-hydroxyprogesteronecaproate Tablets 17-hydroxyprogesterone caproate containing granules for tableting having the components set forth in Table IX can beprepared by wet granulation methods. Accordingly, 7-hydroxyprogesterone caproate, macrocrystalline cellulose and croscarmellose sodium are passed through an ASTM mesh # 40 mesh sieve and mixed in a low shear granulator to form a uniform blend. A binder solution of Starch 1500 in deionized water can be used to granulate the dry powder blend to a typical granulation end-point. The wet granulate dried using a tray dryer or fluid air dryer can be sized/ screened, lubricated with Aerosil 200 and magnesium stearate, and compressed into tablets.

TABLE IX The tablets of Example 36 exhibit less than 20% 17-hydroxyprogesterone caproate released in the first 60 minutes when tested using a USP Type i apparatus, 50 rpm in 900 mL of simulated intestinal fluid having 0.5%w/w sodium lauryl sulfate at 37°C. Whereas, when the micronized 7-hydroxyprogesterone caproate (with particle size d!00% being about 50μη or less) with or without surfactant is used in the above formula, at least 40% release of 1- hydroxyprogesterone caproate may be observed afterthe 60 minute time-point.

EXAMPLES 37-42 - 17-hydroxyprogesteronecaproate compositions Examples 37-39 ofTable X have hydrophilic additives as carriers. The Examples 37, 38 and 39 therein are prepared by wet granulation process with organic solvent such as ethanol or ethanol-water as the granulating liquid. Partial or full amounts of some of hydrophilic additives therein (e.g. povidones, pluronics, surfactants etc.) can be dissolved in the granulating liquid. Optionally the ester of 7-hydroxyprogesterone (e.g. 17- hydroxyprogesterone caproate) ca be solubilized or suspended in the granulating liquid.

This granulating liquid can then be poured over the adsorbing hydrophilic carriers (e.g. celluloses, Lactose etc.) with low shear mixing. The granules can be dried under a gentle current of air at room temperature. The dried granules are passed through ASTM# 40 mesh and filled into appropriate size capsules or compressed into tablets according to the required 17-hydroxyprogesterone caproate strength per unit dosage form 7-hydroxyprogesterone caproate compositions of Examples 40-42 can be prepared by using the components set forth in Table X and according to the following method: The required quantities of the respective inactive component and the 17-hydroxyprogesterone caproate, aretaken in a clean stainless steel container and mixed gently at about 50°C to 70°C using a stirrer to get a homogenous mixture A predetermined weight of the resulting mixture is disposed into hard gelatin capsule and allowedto solidify at room temperature.

The dosage forms of each Example 37-42 are tested for release of the 17- hydroxyprogesterone caproate using a USP Type Π apparatus, at 50 rpm in 900 mL of simulated intestinal fluid having 0.5%ww sodium lauryl sulfate at 37°C. The percent ofthe 7-hydroxyprogesterone caproate released from each composition is analyzed using HPLC.

Theresults ofthe release testing are also shown in Table X It should be noted that the compositions of Examples 37-42 can be formulated to achieve tablet dosage formswith the inclusion ofappropriate conventional tableting aids such as diluents, binders, disintegrants, lubricants, etc. asneeded.

TABLE X * Magnesium alumnometasilicate (Neuslin®), lactose and other similar substances can be used/ calcium silicate The in vitro 7-hydroxyprogesterone caproate release performance of Examples 37to 42 can be seen to be superior over the release performance of the Example 36. It should be noted that in the above-recited compositions, appropriate amounts of typical pharmaceutical aids such as glidants, lubricants, anti-adherents, disintegrants and the like, can be incorporated as needed. Further, suitable amounts of hydrophilic release modifying agents (e.g. hypromellose, Eudragits etc.) may also be incorporated asneeded in the compositions of Examples 37to 42 Also, in some particular cases, when the dosage form ofthe Examples 37 to 42 is a tablet, appropriate functional coatings may be applied as required. It should also be noted that in some aspects the example compositions ofTable X can be substituted with other esters of 17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone acetate, 17- hydroxyprogesterone undecanoate, etc.) EXAMPLES 43 and 44 /7-hydroxyprogesterone caproatecompositions 17-hydroxyprogesterone caproate compositions as recited in Examples 43 and 44 were prepared by using the components set forth in Table XI. Each of the compositions was prepared by incorporating 17-hydroxyprogesterone caproate in the molten mixture of the corresponding inactive components taken i a stainless steel container at about 35°C to 70°C with gentle stirring to get a free-flowing liquid mixture. A predetermined weight of the resulting liquid mixture is disposed into hard or soft gelatin capsule shells and allowed to solidify at room temperature. t should be noted that the liquid mixture can also be allowed to solidify to room temperature to get solid aggregates which may be sized through an ASTM mesh # 30 to get granular particulates, which can be further filled in hard gelatin capsules or compressed into tablets.

Each ofthe compositions istested forrelease ofthe 17-hydroxyprogesterone caproate using aUSP Type IIapparatus, at 50 rpm in 900 mL ofsimulated intestinal fluid having05% w/w sodium lauryl sulfate at 37°C The percent of the 7-hydroxyprogesterone caproate released from each composition is analyzed using HPLC. The results of the release testing are also shown in TableXL TABLE Χ EXAMPLE 45- 17-hydroxyprogesteronecaproateSprayDriedMultiparticulates 17-hydroxyprogesterone caproate multiparticulates can beprepared as follows: 15g of amilled or niicronized 17-hydroxyprogesterone caproate and lactose, mixture (95:5 w/w), are passed through ASTM mesh # 60 sieve and added under mixing to about 250 mL of a solution of 8% w/v povidone K17 in water. The resulting suspension can be spray dried using a conventional spray drying equipment with settings, for example, at a heat inlet temperature ofabout 60-75°C and an outlet temperature ofabout 30-38°C, aspirator set at 90- 100%, thepump set at about 8- 12 mL/min, and the flow rate set atabout 500-600 L/hr The final solid multiparticulate 7-hydroxyprogesterone caproate composition can have a compositional makeup of about 53 wt% 17-hydroxyprogesterone caproate, about 2.8 wt% lactose and about 44.2 wt% povidone Kl7.

EXAMPLE 46- - 17-hydroxyprogesteronecaproatecompositions A mixture of 7-hydroxyprogesterone caproate and the corresponding components can be melted together to get thennosetting fill to be disposed into capsule. Alternatively, the mixture can be fed into a melt-extrader apparatus for example, a single-screw extruder (Kiliion, Model KLB 00) equipped with about 1inch diameter screw and about 6 inch flex lip die, and the die opening adjusted to about 0005 inches and the screw speed is set at about 50 rpm. The residence time of the materials within the extruder can be set for about 2 to 8 minutes. The extruded strands can be cooled to room temperature by passing over a chilled roll. The strands can then be sized through an ASTM mesh # 40 and the powder disposed into capsules. The exemplary compositions for melt-extrusion are indicated in Table XII.

These dosage forms can release 40% or more 17-hydroxyprogesterone caproate in about first 60 minutes. It should be noted that the 7-hydroxyprogesterone caproate compositions of Table XII can be further formulated to include one or more other substances such as lactose, starches, hydroxypropyl methyl cellulose, methacrylate, etc., at varying concentrations from about 12% to about 88%» by weight of the total composition either prior to melt-extrusion or after sizing the melt-extruded composition, in order to prepare solid m t -particulates for tablets.

Stearic acid 20 0 - Cholesterol -- - 5 20 EXAMPLE - /7-hydroxyprogesterone caproate Compositions produced by Co- milling A 1T-hydroxyprogesterone caproate containing composition can be prepared by co- milling (or co-grinding) 80g 17-hydroxyprogesterone caproate along with 15gPVPK 17 and 5g of sodium Iauryl sulfate for a period from about 12 hours to about 24 hours using a ceramic ball-mill maintained at about 20±5°C. The co-milled composition can provide a superior in vitro drug release profile which could be at least 20% more when compared tothe in vitro release profile of Example 1when tested using a USP Type II apparatus, 50 rpm in 900 mL ofsimulated intestinal fluidhaving 0.5% w/w sodium Iauryl sulfate at 37°C.

EXAMPLE 52- 17-hydroxyprogesterone caproate loaded pellets 17-hydroxyprogesterone caproate coated pellets are prepared using the ingredients set forth in Table XIII A spraying solution of the coating materials can be prepared by dissolving 25g of 7-hydroxyprogesterone caproate, 6g of Pluronic F 68 and 5g ofPVP K 30 in about 250 mL of dehydrated alcohol. The spray solution can be intermittently sprayed on to a rolling bed of 64 g commercially available microcrystalline cellulose spheres (for example, having amean particle size in the range of about 250 mto about 600μηι)taken in a conventional coating pan. After all the spray solution is loaded on the spheres, it canbe dried under a gentle current of air for at least 1hour to remove the solvent. Thus, by adjusting the pan speed, spray rate and the inlet air flow and temperature, the 7-hydroxyprogesterone caproate loaded pellets or beads can be obtained which can be disposed into a capsule.

Auxiliary pharmaceutical process aids such as talc, starch etc., may be dusted during the spraying process to avoid agglomeration ofthepellets.

It should be noted that appropriate similar or equivalent equipment known in the art may be used for the purpose. Also, by varying the quantity of spray solution sprayed on the spheres or by varying the concentration of 7-hydroxyprogesterone caproate in the spray solution, pellets ofdifferent drug loading canbe achieved.

TABLE Xlli EXAMPLE 53- 17-hydroxyprogesteronecaproate Suspension Compositions A homogenous suspension of 17-hydroxyprogesterone caproate prepared in a liquid vehicle having 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 may be encapsulated. Pharmaceutical aids such suspending agents, thickening agents or viscosity modifiers, wetting agents, etc., known in the art can be used to achieve homogenous suspension ofthe drug in the liquidvehicle.

EXAMPLE 54- 17-hydroxyprogesteronecaproate composition in vivo evaluation: A preliminary pharmacokinetic evaluation upon oral administration of 7- hydroxyprogesterone caproate ofthe current invention was carried out in male dogs. A single oral dose of30mg/kg and 5mg/ kgof 17-hydroxyprogesterone caproate formulated in a accordance with exemplar}'formulations ofthe present invention were used forrelative bioavailability study in afed state, compared with an intramuscular dose of 6.4 mg/kg (composition similartocommercially available Intramuscular injection, Makena^) aspositive control.

Thepost-dose blood levelsof 17-hydroxyprogesterone caproate weremonitored for 24 hours after oral dosing and for 192 hours after intramuscular injection dosing. About 2 mLof bloodwas drawn from thejugular, cephalic, or saphenous veins immediately before the dose was administered and atpre-determined intervals post-dose. At eachtime point, the blood sample was collected in a vaculainer tubes and centrifuged at about 3200 rpm for approximately 10 minutes at about 5°C. The serum obtained was analyzed by HPLC-MS/MS for 17-hydroxyprogesterone caproate. Theresults ofthe 17-hydroxyprogesterone caproate concentration in the samples are shown in Table-XIV below: HAS510341NZPR 304003925 Table-XIV Exemplary Oral Dosage IM Injection formulations of the present invention 6.4 mg/kg Dose Administered 30 mg/kg 5 mg/kg Mean C (ng/mL) last 4.51 0.28 2.54 C(ng/mL) 74 2.5 8 Mean AUC (ng*h/mL) 1767 60 1546 0-last AUC(ng*h mL ) /Dose 0-24h .8 1.0 - (mg) Ratio Contrary to reports in the literature we surprisingly found that oral compositions of the present invention provided significant blood levels (C ) of 17-hydroxyprogesterone caproate upon oral administration.

Numerous modifications and alternative arrangements may be devised by those skilled in the art without departing from the spirit and scope of the present invention and the appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity and detail in connection with what is presently deemed to be the most practical and preferred embodiments of the invention, it will be apparent to those of ordinary skill in the art that variations including, but not limited to, variations in size, materials, shape, form, function and manner of operation, assembly and use may be made without departing from the principles and concepts set forth herein.

Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like, are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of “including, but not limited to.

The reference to any prior art in the specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in New Zealand.

HAS510341NZPR 304161867

Claims (95)

1. A pharmaceutical composition comprising: a therapeutically effective amount of 17-hydroxyprogesterone caproate, and a pharmaceutically acceptable carrier; 5 wherein the pharmaceutical composition is in the form of a powder, granulate, particulate, bead, pellet, sprinkle, suspension, solution, tablet, capsule or combination thereof; wherein the 17-hydroxyprogesterone caproate is present in the composition in particulate form having a mean particulate diameter of about 50 μm or less; and 10 wherein the pharmaceutical composition is formulated for oral administration.

2. The pharmaceutical composition of claim 1, wherein the composition is formulated for pregnancy support. 15

3. The pharmaceutical composition of claim 1 or claim 2, wherein the carrier includes benzyl benzoate, benzyl alcohol, or mixtures thereof.

4. The pharmaceutical composition of claim 3, wherein the amount of the 17-hydroxyprogesterone caproate to the sum of the amounts of benzyl benzoate and/or 20 benzyl alcohol, in the composition is about 1:0.01 (W/W) to about 1:5 (W/W).

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the amount of the 17-hydroxyprogesterone caproate is from about 5% to about 80% w/w of the total composition.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the composition is in the form of a capsule and the capsule includes from about 30 mg to about 300 mg of 17-hydroxyprogesterone caproate. 30 7. The pharmaceutical composition of any one of claims 1 to 5, wherein the composition is in the form of a tablet and the tablet includes from about 20 mg to about 800 mg of 17-hydroxyprogesterone caproate.

HAS510341NZPR 304161867

8. The pharmaceutical composition of claim 6 or claim 7, wherein the capsule or tablet is a controlled release oral dosage form.

9. The pharmaceutical composition of claim 6 or claim 8 when in capsule form, wherein 5 the ratio of the amount of 17-hydroxyprogesterone caproate in the composition to the fill volume of the capsule is from about 0.02 g/mL to about 0.8 g/mL.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the carrier includes a hydrophilic additive.

11. The pharmaceutical composition of any one of claims 1 to 9, wherein the carrier includes a lipophilic additive.

12. The pharmaceutical composition of claim 10, wherein the carrier includes a compound 15 selected from the group consisting of 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, silicon dioxide, magnesium aluminum silicate, hydroxypropyl cyclodextrin, fatty acid glycerides, salts of bile acids, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, 20 polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, carbomer, chitosan, methacrylates, polyvinyl alcohol, gelatin, PEG-8 caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, PEG-10 laurate, PEG-20 oleate, PEG-30 25 stearate, PEG-40 laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl tearate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate, poloxamer 188, poloxamer 108, maltose, sucrose, fructose, mannitol, xylitol, and combinations thereof.

13. The pharmaceutical composition of claim 10, wherein the carrier includes a compound selected from the group consisting of salts of citric acid, maleic acid, tartaric acid, HAS510341NZPR 304161867 acetic acid, ascorbic acid, benzoic acid and lactic acid, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, silicon dioxide, magnesium aluminum silicate, hydroxypropyl cyclodextrin, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methyl 5 cellulose, hydroxypropyl methyl cellulose, cellulose esters, carbomer, chitosan, methacrylates, polyvinyl alcohol, gelatin, maltose, sucrose, fructose, mannitol, xylitol, and combinations thereof.

14. The pharmaceutical composition of claim 11, wherein the carrier includes a compound 10 selected from the group consisting of tributylcitrate, triethylcitrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetates butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, tocopherol, tocopherol acetate, tocopherol succinate, benzyl benzoate, corn oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, hydrogenated castor oil, glyceryl tricaprate, glyceryl

15 trilaurate, glyceryl trioleate, glyceryl trilinoleate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate, saturated polyglycolized glycerides linoleic glycerides, caprylic/capric glycerides capric acid, caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic 20 acid, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl laurate, glyceryl caprylate, distearin, monopalmitolein, monolaurin, ethyl oleate, PEG-6 corn oil, PEG-6 apricot kernel oil, PEG-4 caprylic/capric triglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, 25 poloxamer 182, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, propylene glycol caprylate/caprate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate, and combinations thereof. 30 15. The pharmaceutical composition of claim 11, wherein the carrier includes a compound selected from the group consisting of tributylcitrate, triethylcitrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetates butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, tocopherol, tocopherol HAS510341NZPR 304161867 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 tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl 5 tricaprylate/caprate/stearate, capric acid, caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, ethyl oleate, and combinations thereof.

16. The pharmaceutical composition of any one of claims 11, 14 or 15, wherein the carrier 10 includes at least 50 wt% of a lipophilic additive.

17. The pharmaceutical composition of any one of claims 1 to 9, wherein the carrier includes at least one hydrophilic additive and at least one lipophilic additive at a lipophilic additive to hydrophilic additive ratio of about 90:10 to about 1:99.

18. A method of treating a pregnant non-human female subject at risk of preterm birth, comprising, administering to the non-human female subject the pharmaceutical composition of any one of claims 1 to 17. 20

19. A use of the pharmaceutical composition of any one of claims 1 to 17 in the manufacture of a medicament for use in the treatment of a pregnant female subject at risk of preterm birth.

20. A pharmaceutically acceptable oral dosage form comprising the pharmaceutical 25 composition of claim 1 wherein, when measured using a USP Type-II dissolution apparatus in 900 mL of simulated intestinal fluid having 0.5% w/w sodium lauryl sulfate at 50 RPM at 37°C, the oral dosage form releases at least 20 wt% of 17- hydroxyprogesterone caproate more after 60 minutes than an equivalently dosed oral dosage form without the carrier.

21. The pharmaceutically acceptable oral dosage form of claim 20, wherein the oral dosage form is formulated for pregnancy support. HAS510341NZPR 304161867

22. The pharmaceutically acceptable oral dosage form of claim 20 or claim 21, wherein the carrier includes benzyl benzoate, benzyl alcohol, or mixtures thereof. 5 23. The pharmaceutically acceptable oral dosage form of claim 22, wherein the amount of the 17-hydroxyprogesterone caproate to the sum of the amounts of benzyl benzoate and/or benzyl alcohol, in the oral dosage form is about 1:0.01 (W/W) to about 1:5

(W/W). 10

24. The pharmaceutically acceptable oral dosage form of any one of claims 20 to 23, wherein the amount of the 17-hydroxyprogesterone caproate is from about 5% to 80% w/w of the total oral dosage form.

25. The pharmaceutically acceptable oral dosage form of any one of claims 20 to 24, 15 wherein the oral dosage form is a capsule and the capsule includes from about 10 mg to about 300 mg17-hydroxyprogesterone caproate.

26. The pharmaceutically acceptable oral dosage form of any one of claims 20 to 24, wherein the oral dosage form is a tablet and the tablet includes from about 20 mg to 20 about 800 mg of 17-hydroxyprogesterone caproate.

27. The pharmaceutically acceptable oral dosage form of any one of claims 20 to 25, wherein the oral dosage form is a capsule and the ratio of the amount of 17-hydroxyprogesterone caproate in the capsule to the fill volume of the capsule is 25 from about 0.02 g/mL to about 0.8 g/mL.

28. The pharmaceutically acceptable oral dosage form of any one of claims 20 to 27, wherein the carrier includes a hydrophilic additive. 30 29. The pharmaceutically acceptable oral dosage form of any one of claims 20 to 27, wherein the carrier includes a lipophilic additive.

HAS510341NZPR 304161867

30. The pharmaceutically acceptable oral dosage form of claim 28, wherein the carrier includes a compound selected from the group consisting of 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, silicon 5 dioxide, magnesium aluminum silicate, hydroxypropyl cyclodextrin, fatty acid glycerides, salts of bile acids, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol methyl cellulose, hydroxypropyl methyl cellulose, carbomer, chitosan, methacrylates, polyvinyl alcohol, gelatin, PEG-8 caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, 10 PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, PEG-10 laurate, PEG- 20 oleate, PEG-30 stearate, PEG-40 laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl tearate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, polyglyceryl-10 oleate, 15 polyglyceryl-10 mono, dioleate, poloxamer 188, poloxamer 108, maltose, sucrose, fructose, mannitol, xylitol, and combinations thereof.

31. The pharmaceutically acceptable oral dosage form of claim 28, wherein the carrier includes a compound selected from the group consisting of salts of citric acid, maleic 20 acid, tartaric acid, acetic acid, ascorbic acid, benzoic acid and lactic acid, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, silicon dioxide, magnesium aluminum silicate, hydroxypropyl cyclodextrin, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, cellulose esters, 25 carbomer, chitosan, methacrylates, polyvinyl alcohol, gelatin, maltose, sucrose, fructose, mannitol, xylitol, and combinations thereof.

32. The pharmaceutically acceptable oral dosage form of claim 29, wherein the carrier includes a compound selected from the group consisting of tributylcitrate, 30 triethylcitrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetates butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, tocopherol, tocopherol acetate, tocopherol succinate, benzyl benzoate, corn oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, hydrogenated castor oil, glyceryl HAS510341NZPR 304161867 tricaprate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoleate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate, saturated polyglycolized glycerides linoleic glycerides, caprylic/capric glycerides capric acid, 5 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 caprylate, distearin, monopalmitolein, monolaurin, ethyl oleate, PEG-6 corn oil, PEG-6 apricot kernel oil, 10 PEG-4 caprylic/capric triglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poloxamer 182, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, propylene glycol caprylate/caprate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan 15 sesquioleate, sorbitan sesquistearate, and combinations thereof.

33. The pharmaceutically acceptable oral dosage form of claim 29, wherein the carrier includes a compound selected from the group consisting of tributylcitrate, triethylcitrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose 20 acetates butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose 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 tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl 25 tricaprylate/caprate/stearate, capric acid, caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, ethyl oleate, and combinations thereof.

34. The pharmaceutically acceptable oral dosage form of any one of claims 29, 32 or 33, 30 wherein the carrier includes at least 50 wt% of a lipophilic additive. HAS510341NZPR 304161867

35. The pharmaceutically acceptable oral dosage form of claim 20 to 27, wherein the carrier includes at least one hydrophilic additive and at least one lipophilic additive at a lipophilic additive to hydrophilic additive ratio of about 90:10 to about 1:99. 5

36. The pharmaceutically acceptable oral dosage form of any one of claims 20 to 35, wherein the oral dosage form is formulated for administration to a subject once every 8 hours.

37. The pharmaceutically acceptable oral dosage form of any one of claims 20 to 35, 10 wherein the oral dosage form is formulated for administration to a subject once every 6 hours.

38. The pharmaceutically acceptable oral dosage form of any one of claims 20 to 35, wherein the oral dosage form is formulated for administration to a subject once every 15 12 hours.

39. The pharmaceutically acceptable oral dosage form of any one of claims 20 to 35, wherein the oral dosage form is formulated for administration to a subject once every 24 hours.

40. A method of treating a pregnant non-human female subject at risk of preterm birth, comprising, administering to the non-human female subject the oral dosage form of any one of claims 20 to 39. 25

41. A use of the oral dosage form of any one of claims 20 to 39 in the manufacture of a medicament for use in the treatment of a pregnant female subject at risk of preterm birth.

42. A pharmaceutically acceptable oral dosage form, comprising the pharmaceutical 30 composition of claim 1 wherein, when measured using a USP Type-II dissolution apparatus in 900 mL of simulated intestinal fluid having 0.5% (w/v) of sodium lauryl HAS510341NZPR 304161867 sulfate at 50 RPM at 37°C, the oral dosage form releases at least 20 wt% of the dose of 17-hydroxyprogesterone caproate after 60 minutes.

43. A method of treating a pregnant non-human female subject at risk of preterm birth, 5 comprising, administering to the non-human female subject the pharmaceutically acceptable oral dosage form of claim 42.

44. A use of the oral dosage form of claim 42 in the manufacture of a medicament for use in the treatment of a pregnant female subject at risk of preterm birth.

45. A pharmaceutically acceptable oral dosage form, comprising: a therapeutically effective amount of 17-hydroxyprogesterone caproate wherein, upon single oral administration to a human subject, the dosage form provides a ratio of 17-hydroxyprogesterone caproate AUC to the dose of (0-24h) -1 -1 15 17-hydroxyprogesterone caproate ratio of about 0.2 to about 10 ng*h mL mg ; wherein, the dose is the amount in mg of the 17-hydroxyprogesterone caproate administered; and wherein, the 17-hydroxyprogesterone caproate is present in the oral dosage form in particulate form having a mean particulate diameter of about 50 μm or less.

46. The pharmaceutically acceptable oral dosage form of claim 45, wherein the dosage form includes a pharmaceutically acceptable carrier selected from the group of hydrophilic additives, lipophilic additives, or combinations thereof. 25

47. The pharmaceutically acceptable oral dosage form of claim 45 or claim 46, wherein the carrier includes benzyl benzoate, benzyl alcohol, or mixtures thereof.

48. The pharmaceutically acceptable oral dosage form of any one of claims 45 to 47, wherein the oral dosage form is a tablet or a capsule.

49. The pharmaceutically acceptable oral dosage form of any one of claims 45 to 48, wherein the oral dosage form is a controlled release oral dosage form. HAS510341NZPR 304161867

50. The pharmaceutically acceptable oral dosage form of any one of claims 45 to 48, wherein the oral dosage form is an immediate release oral dosage form. 5

51. The pharmaceutically acceptable oral dosage form of any one of claims 46 to 50, wherein the carrier includes one or more hydrophilic additive selected from the group consisting of 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, silicon dioxide, magnesium aluminum silicate, 10 hydroxypropyl cyclodextrin, fatty acid glycerides, salts of bile acids, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, carbomer, chitosan, methacrylates, polyvinyl alcohol, gelatin, PEG-8 caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 hydrogenated 15 castor oil, PEG-35 castor oil, sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, PEG-10 laurate, PEG-20 oleate, PEG-30 stearate, PEG-40 laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl tearate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, polyglyceryl-10 oleate, polyglyceryl-10 20 mono, dioleate, poloxamer 188, poloxamer 108, maltose, sucrose, fructose, mannitol, xylitol, gums, and combinations thereof.

52. The pharmaceutically acceptable oral dosage form of any one of claims 46 to 50, wherein the carrier includes one or more lipophilic additive selected from the group 25 consisting of: tributylcitrate, triethylcitrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetates butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, tocopherol, tocopherol acetate, tocopherol succinate, benzyl benzoate, corn oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, hydrogenated castor oil, glyceryl tricaprate, glyceryl trilaurate, glyceryl trioleate, 30 glyceryl trilinoleate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate, saturated polyglycolized glycerides linoleic glycerides, caprylic/capric glycerides capric acid, HAS510341NZPR 304161867 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 caprylate, distearin, 5 monopalmitolein, monolaurin, ethyl oleate, PEG-6 corn oil, PEG-6 apricot kernel oil, PEG-4 caprylic/capric triglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poloxamer 182, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, propylene glycol caprylate/caprate, sorbitan monolaurate, 10 sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate, and combinations thereof.

53. A method of treating a pregnant non-human female subject at risk of preterm birth, comprising, administering to the non-human female subject the pharmaceutically 15 acceptable oral dosage form of any one of claims 45 to 52.

54. A use of the pharmaceutically acceptable oral dosage form of any one of claims 45 to 52 in the manufacture of a medicament for use in the treatment of a pregnant female subject at risk of preterm birth.

55. A pharmaceutical composition as claimed in claim 1, substantially as hereinbefore described with particular reference to any one or more of the examples and/or figures.

56. A method as claimed in claim 18, substantially as hereinbefore described with 25 particular reference to any one or more of the examples and/or figures.

57. A use as claimed in claim 19, substantially as hereinbefore described with particular reference to any one or more of the examples and/or figures. HAS510341NZPR 304161867

58. A pharmaceutically acceptable dosage form as claimed in claim 20, substantially as hereinbefore described with particular reference to any one or more of the examples and/or figures. 5

59. A method as claimed in claim 40, substantially as hereinbefore described with particular reference to any one or more of the examples and/or figures.

60. A use as claimed in claim 41, substantially as hereinbefore described with particular reference to any one or more of the examples and/or figures.

61. A pharmaceutically acceptable oral dosage form as claimed in claim 42, substantially as hereinbefore described with particular reference to any one or more of the examples and/or figures. 15

62. A method as claimed in claim 43, substantially as hereinbefore described with particular reference to any one or more of the examples and/or figures.

63. A use as claimed in claim44, substantially as hereinbefore described with particular reference to any one or more of the examples and/or figures.

64. A pharmaceutically acceptable oral dosage form as claimed in claim 45, substantially as hereinbefore described with particular reference to any one or more of the examples and/or figures. 25

65. A method as claimed in claim 53, substantially as hereinbefore described with particular reference to any one or more of the examples and/or figures.

66. A use as claimed in claim 54, substantially as hereinbefore described with particular reference to any one or more of the examples and/or figures. HAS510341NZPR 304161867

67. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable carrier comprises at least a hydrophilic surfactant; and the amount of the 17- hydroxyprogesterone caproate is from about 5% to about 80% w/w of the total composition.

68. The pharmaceutical composition of claim 67 wherein said hydrophilic surfactant comprises an ionic hydrophilic surfactant.

69. The pharmaceutical composition of claim 67 or claim 68 wherein said hydrophilic 10 surfactant comprises a non-ionic hydrophilic surfactant.

70. The pharmaceutical composition of claim 69 wherein said hydrophilic surfactant is a poloxamer, a polyethylene glycol sorbitan fatty acid ester, a sorbitan fatty acid ester, a polyethylene glycol glycerol fatty acid ester or a combination thereof.

71. The pharmaceutical composition of claim 68 wherein said hydrophilic surfactant is sodium lauryl sulfate, sodium dioctyl sulfosuccinate, a lecithin, a bile salt or a combination thereof. 20

72. The pharmaceutical composition of any one of claims 67 to 71 further comprising polyvinylpyrrolidone, croscarmellose, microcrystalline cellulose, magnesium stearate, silicon dioxide, stearic acid, mannitol, a polyvinyl alcohol copolymer, a polyvinylpyrrolidone copolymer, a polyethylene glycol copolymer, a methacrylic acid copolymer, or a combination thereof.

73. The pharmaceutical composition of any one of claims 67 to 72 formulated as a capsule.

74. The pharmaceutical composition of any one of claims 67 to 72 formulated as a tablet. HAS510341NZPR 304161867

75. The pharmaceutical composition of any one of claims 67 to 74 having an amount of 17- hydroxyprogesterone caproate equivalent to from about 20 mg to about 400 mg of 17- hydroxyprogesterone. 5

76. The pharmaceutical composition of any one of claims 67 to 75 having from about 20 mg to about 800 mg 17-hydroxyprogesterone caproate.

77. The pharmaceutical composition of any one of claims 67 to 75 having from about 10 mg to about 300 mg 17-hydroxyprogesterone caproate.

78. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable carrier comprises at least an ionic hydrophilic surfactant.

79. The pharmaceutical composition of claim 78 further comprising polyvinylpyrrolidone, 15 croscarmellose, microcrystalline cellulose, magnesium stearate, silicon dioxide, stearic acid, mannitol, a polyvinyl alcohol copolymer, a polyvinylpyrrolidone copolymer, a polyethylene glycol copolymer, a methacrylic acid copolymer, or a combination thereof. 20

80. The pharmaceutical composition of claim 78 wherein said ionic hydrophilic surfactant is sodium lauryl sulfate, sodium dioctyl sulfosuccinate, a lecithin, a bile salt or a combination thereof.

81. The pharmaceutical composition of any one of claims 78 to 80 formulated as a capsule.

82. The pharmaceutical composition of any one of claims 78 to 80 formulated as a tablet.

83. The pharmaceutical composition of any one of claims 78 to 82 having an amount of 17- hydroxyprogesterone caproate equivalent to from about 10 mg to about 800 mg of 17- 30 hydroxyprogesterone. HAS510341NZPR 304161867

84. The pharmaceutical composition of claim 1 whereinthe pharmaceutically acceptable carrier comprises at least a non-ionic hydrophilic surfactant. 5

85. The pharmaceutical composition of claim 84 further comprising polyvinylpyrrolidone, croscarmellose, microcrystalline cellulose, magnesium stearate, silicon dioxide, stearic acid, mannitol, a polyvinyl alcohol copolymer, a polyvinylpyrrolidone copolymer, a polyethylene glycol copolymer, a methacrylic acid copolymer, or a combination thereof.

86. The pharmaceutical composition of claim 84 wherein said non-ionic hydrophilic surfactant is a poloxamer, a polyethylene glycol sorbitan fatty acid ester, a sorbitan fatty acid ester, a polyethylene glycol glycerol fatty acid ester or a combination thereof. 15

87. The pharmaceutical composition of any one of claims 84 to 86 formulated as a capsule.

88. The pharmaceutical composition of any one of claims 84 to 86 formulated as a tablet.

89. The pharmaceutical composition of any one of claims 84 to 88 having an amount of 17- 20 hydroxyprogesterone caproate equivalent to from about 10 mg to about 800 mg of 17- hydroxyprogesterone.

90. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable carrier comprises at least a hydrophilic surfactant chosen from a poloxamer, a 25 polyethylene glycol sorbitan fatty acid ester, a sorbitan fatty acid ester, a polyethylene glycol glycerol fatty acid ester, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, a lecithin, a bile salt or a combination thereof; and the pharmaceutically acceptable carrier further comprises polyvinylpyrrolidone, croscarmellose, microcrystalline cellulose, magnesium stearate, silicon dioxide, stearic 30 acid, mannitol, a polyvinyl alcohol copolymer, a polyvinylpyrrolidone copolymer, a HAS510341NZPR 304161867 polyethylene glycol copolymer, a methacrylic acid copolymer or a combination thereof; the amount of the 17-hydroxyprogesterone caproate is from about 5% to about 80% w/w of the total composition.

91. The pharmaceutical composition of claim 90 formulated as a capsule.

92. The pharmaceutical composition of claim 90 formulated as a tablet. 10

93. The pharmaceutical composition of any one of claims 90 to 92 having an amount of 17- hydroxyprogesterone caproate equivalent to from about 10 mg to about 800 mg of 17- hydroxyprogesterone.

94. The pharmaceutical composition of any one of claims 90 to 92 having an amount of 17- 15 hydroxyprogesterone caproate equivalent to from about 20 mg to about 400 mg of 17- hydroxyprogesterone.

95. The pharmaceutical composition of any one of claims 90 to 92 having from about 10 mg to about 300 mg 17-hydroxyprogesterone caproate.