US20170035781A1 - 17-hydroxyprogesterone ester-containing oral compositions and related methods - Google Patents

17-hydroxyprogesterone ester-containing oral compositions and related methods Download PDF

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US20170035781A1
US20170035781A1 US15/190,109 US201615190109A US2017035781A1 US 20170035781 A1 US20170035781 A1 US 20170035781A1 US 201615190109 A US201615190109 A US 201615190109A US 2017035781 A1 US2017035781 A1 US 2017035781A1
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Prior art keywords
hydroxyprogesterone
pharmaceutical composition
peg
hpc
ester
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Chandrashekar Giliyar
Srinivasan Venkateshwaran
Basawaraj Chickmath
Satish Nachaegari
Nachiappan Chidambaram
Mahesh Patel
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Lipocine Inc
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Lipocine Inc
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Priority to US15/190,109 priority Critical patent/US20170035781A1/en
Publication of US20170035781A1 publication Critical patent/US20170035781A1/en
Assigned to LIPOCINE INC. reassignment LIPOCINE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHICKMATH, BASAWARAJ, CHIDAMBARAM, NACHIAPPAN, GILIYAR, CHANDRASHEKAR, NACHAEGARI, SATISH, PATEL, MAHESH, VENKATESHWARAN, SRINIVASAN
Priority to US16/055,594 priority patent/US20190275060A1/en
Priority to US16/927,891 priority patent/US11590147B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis

Definitions

  • 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.
  • 17-alpha hydroxyprogesterone is a C-21 endogenous steroid hormone produced during the syntheses of glucocorticoids and sex steroids. Like progesterone, 17HP is a natural progestagen. It has been isolated from both adrenal glands and corpora lutea. Esters of 17HP are reported to have progestogenic effects and hence, can be used for indications related to pregnancy support as well as non-pregnancy support in both pre- and post-menopausal women. It is reported that 17HP, without esterification, has no progestational activity.
  • 17HP such 17-hydroxyprogesterone acetate or 17-alpha-hydroxyprogesterone caproate
  • 17 HPC 17 hydroxyprogesterone caproate
  • PTB Preterm birth
  • This synthetic caproate ester is reportedly inactive when given by mouth but works as a long-acting progestin when administered intramuscularly.
  • the metabolism of 17HP and the metabolism of 17-hydroxyprogesterone caproate in the human female are not yet fully established.
  • 17-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 to more avid binding of 17-hydroxyprogesterone caproate to the progesterone receptors (alternatively referred to hereinafter as “PR”) and placental glucocorticoid receptors (alternatively referred to hereinafter as “GR”) that could prevent an increase of placental corticotropin releasing hormone which is associated with onset of labor. 17-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 36 weeks of gestation. According to the 2009 Center for Disease Control Report, PTB occurs in about 12.3% of births 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 every eight live-born infants is born preterm representing an increase of>18% since 1990. Late pre-term birth between 35-36 weeks of gestation contributes to more than half of all PTBs. PTB is the primary cause of neonatal morbidity and mortality.
  • Mortality risk is three fold higher at 35-36 weeks and morbidities such as respiratory 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 of PTB delivery amounting to up to 10 ⁇ that of normal delivery.
  • Major risk factors implicated in PTB are as follows: History of previous 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 of prolonging 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 risk of PTB in women with singleton pregnancy and history of single spontaneous PTB.
  • the injection marketed as Makena ® 250 mg 17-hydroxyprogesterone caproate in 1 mL
  • 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.
  • 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 ( ⁇ 20 ng/mL), and very lipophilic with ClogP of about 5.7.
  • 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).
  • 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.
  • 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 (i.e.
  • 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.
  • unit dosage i.e., tablet, capsule, syrup, elixir, beverage, etc.
  • reduced number of dosage units to be taken per single administration i.e., tablet, capsule, syrup, elixir, beverage, etc.
  • 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.
  • 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.
  • compositions of current invention facilitate 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.
  • All the oral dosage forms of the present inventions having the drug in the form of solution, suspension, particulates, etc., can be produced by conventional methods of processing and manufacture known in the art.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • FIG. 1 is a plot of the in vitro release profile of a 17-hydroxyprogesterone caproate containing oral dosage form in accordance with an embodiment of the present invention compared to a carrier-free dose of 17-hydroxyprogesterone caproate.
  • FIG. 2 is a plot of the in vitro release profiles of 17-hydroxyprogesterone containing oral dosage forms in accordance with an embodiment of the present invention.
  • FIG. 3 is a plot of the in vitro release profiles of 17-hydroxyprogesterone containing oral dosage forms in accordance with an embodiment of the present invention.
  • FIG. 4 is a plot of pharmacokinetics in accordance with embodiments described herein and Example 55.
  • FIG. 5 is a plot of XRD data in accordance with embodiments described here in and Example 56.
  • drug 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 is to be understood 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 in the pharmaceutical and medicinal arts.
  • 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 live birth.
  • treatment when used in conjunction with the administration of a 17-hydroxyprogesterone ester, refers to the administration of the 17-hydroxyprogesterone ester to subjects who are either asymptomatic or symptomatic.
  • treatment can refer to the act of reducing 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 order to prevent their occurrence).
  • prophylactic treatment can also be referred to as prevention of the condition, preventative action, preventative measures, etc.
  • esters represents compounds produced by reaction between acids and alcohols with the elimination of water.
  • esteer can also represent the class of organic compounds corresponding to the inorganic salts formed from an organic acid and an alcohol.
  • 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.
  • formulation and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules.
  • the terms “formulation” and “composition” may be used to refer to a mixture of one or more active agents with a carrier or other excipients.
  • dosage form can include one or more formulation(s) or composition(s) provided in a format for administration to a subject.
  • oral such terms refer to compositions, formulations, or dosage forms formulated and intended for oral administration to subjects.
  • pharmaceutically acceptable carrier or “carrier” are used interchangeably and refer to a pharmaceutically acceptable substance that enables a pharmaceutical composition and/or a dosage form of an ester of 17-hydroxyprogesterone.
  • the carrier is an element or ingredient that can be varied for the alteration of release rate and/or extent of the active agent, for example an ester of 17-hydroxyprogesterone, from the composition and/or the dosage form.
  • a pharmaceutically acceptable carrier is a compound, or a mixture of compounds, that determines, controls, or contributes, at least in part, to the release of an ester of 17-hydroxyprogesterone from a pharmaceutical oral composition and/or dosage form, when tested using a USP Type II apparatus in about 900 mL of simulated intestinal fluid (according to USP, SIF, without enzyme) having 0.5% w/w sodium lauryl sulfate at about 37° C. and 50 rpm.
  • the composition or dosage form provides a release of the ester of 17-hydroxyprogesterone such that when tested using a USP Type II apparatus in about 900 mL of simulated intestinal fluid having 0.5% w/w sodium lauryl sulfate at about 37° C. and 50 rpm, at least 20% more the ester of 17-hydroxyprogesterone is released after the first 60 minutes compared to an equivalent dose an ester of 17-hydroxyprogesterone oral dosage form without the pharmaceutically acceptable carrier.
  • the composition or the dosage form releases at least 40% more of the ester of 17-hydroxyprogesterone after the first 60 minutes compared to an equivalent dose an ester of 17-hydroxyprogesterone oral dosage form without the pharmaceutically acceptable carrier.
  • aqueous medium can be water, simulated gastric fluid (SGF) with or without enzyme, simulated intestinal fluid (SIF) with or without enzyme, a hydro-alcoholic solution, a surfactant solution and the like.
  • SGF simulated gastric fluid
  • SIF simulated intestinal fluid
  • hydro-alcoholic solution a surfactant solution and the like.
  • the aqueous medium can be used for the purpose of determining the release rate and/or extent of the ester of 17-hydroxyprogesterone from the compositions or the dosage forms.
  • the aqueous medium can be a non-solubilizing aqueous medium (for example, having low or no surfactant in the medium) for the entire amount of the ester present in the composition or the dosage form.
  • the non-solubilizing aqueous medium can solubilize about 90% or less of the amount of ester present in the composition or dosage form.
  • the non-solubilizing aqueous medium can solubilize about 80% or less, 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 of the ester present in the composition or dosage form.
  • the aqueous medium is capable of solubilizing substantially all of the ester of 17-hydroxyprogesterone present in the composition or dosage form.
  • the aqueous medium can solubilize at least about 90% of the amount of the ester of 17-hydroxyprogesterone present in the composition or dosage form.
  • the aqueous medium can solubilize about 1.5 times or more, about 3 times or more, 5 times or more of the amount of the ester 17-hydroxyprogesterone present in the composition or dosage form.
  • subject refers to a mammal that may benefit from the administration of a drug composition or method of this invention.
  • subjects include humans, and may also include other animals such as horses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals.
  • a subject is a human.
  • the subject is a female.
  • the oral dosage form of the current invention is for a female requiring pregnancy support.
  • 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.
  • 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.
  • 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.
  • 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 are hydrophilic additives that have significant surface active property and that have HLB values of more than 10.
  • lipid or lipid substance when used in connection, with various compounds, refers to fatty acid (unless otherwise specified, having chain length greater than C 6 ) or fatty acid esters or glycerides of fatty acid esters, mixtures thereof and derivatives thereof, although not including salts thereof.
  • the release of the drug may be controlled release.
  • controlled release represents the release of the drug from the dosage form according to a predetermined profile.
  • the controlled release selected can be, intermediate, delayed, extended, sustained, pulsatile, gastric, enteric or colonic.
  • combinations of the aforementioned release profiles may be used in order to achieve specific delivery results, such as an immediate release followed by a delayed and/or a sustained release of the active agent.
  • 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 or without enzyme.
  • SGF simulated gastric fluid
  • pregnancy support when used to 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 a woman trying to become pregnant.
  • 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, such as a non-pregnant woman, including but not limited to, delaying or preventing the occurrence of 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, pemporomandibular joint syndrome, catamenial epilepsy, endometrial, and/or renal carcinomas.
  • progesterone deficiencies such as amenorrhea, fibroids, contraception, postpartum lactation suppression, treatment of dysfunctional uterine bleeding, end
  • 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 the progestogen agent of the invention to a male human for example, to effect contraception, to counter estogenic activity, etc.
  • present compositions and dosage forms of the ester of the 17-hydroxyprogesterone may be administered alone or in combination with other therapy.
  • the current invention compositions and dosage forms of the ester of the 17-hydroxyprogesterone may be used to supplement, augment, mitigate, treat, cure or prevent, or for providing prophylaxis in a subject in need thereof.
  • 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 to be effective. It is understood that various biological factors may affect the ability of a 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 Biostatistics , Vol. 8 (1986), incorporated herein by reference.
  • 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 “a little below” the endpoint.
  • 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 as though each member of the 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 indications to the contrary.
  • serum progestogen including progesterone and 17-hydroxyprogesterone levels are decreased in the pregnant female in cases of intrauterine death, premature labor, threatened premature labor, premature rupture of membranes, amnionitis and abruption of placenta.
  • esters of 17-hydroxyprogesterone have potential for use in pregnancy to treat and or prevent the following conditions or occurrences: spontaneous abortion in women who have had previous spontaneous abortion, history of recurrent spontaneous abortion, previous stillbirth, previous premature delivery ( ⁇ 37 weeks), previous premature ( ⁇ 37 weeks) rupture of membranes or PROM, previous pregnancy related hypertension or toxemia, previous abruption of placenta, 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 lower than in normal pregnancy.
  • progesterone endogenous progestogen
  • Primary and secondary outcome measures can be used to determine the need for and/or the effectiveness of ester of 17-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,
  • LR+ likelihood ratio for the prediction of PTB is known to be greater than 10 using amniotic fluid (AF) interleukin-6 (IL-6), AF Ureaplasma urealyticum, as well as a multi-marker consisting of cervical IL-6, cervical IL-8, and cervical length (CL).
  • AF amniotic fluid
  • IL-6 interleukin-6
  • IL-8 AF Ureaplasma urealyticum
  • CL cervical length
  • the LR+ is also known to be between 5 and 10 for serum C-reactive protein (CRP).
  • An LR+ between 2.5 and 5 was recorded for serum corticotropin-releasing hormone (CRH), cervical IL-6, serum relaxin.
  • AFU urealyticum and a multimarker consisting of five individual markers [fFN, CL, serum alpha-fetoprotein (AFP), serum alkaline phosphatase, and serum granulocyte colony-stimulating factor (G-CSF)] predict PTB with an LR+ greater than 10.
  • the LR+ was between 5 and 10 for serum relaxin 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.
  • an LR+ below 2.5 has been 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 fetus nor 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 of the 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 all the membranes around the fetus and the placenta and the cervix closes prior to 20
  • progestogen progesterone or 17 HP
  • human chorionic gonadotropin hCG
  • esters of 17-hydroxyprogesterone interact with the progesterone receptor, it is believed that treatment with esters of 17-hydroxyprogesterone can be designed based on progesterone levels.
  • One diagnostic criterion is low serum 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 of 20-25 ng/ml. A threshold 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, Inhibin A, Anandamide and progesterone induced blocking factor (PIBF) are also good indicators of miscarriage risk.
  • Tumor marker CA-125 Tumor marker CA-125
  • Inhibin A Inhibin A
  • Anandamide progesterone induced blocking factor
  • compositions of the present invention are intended to provide an increase in the baseline endogenous progesterone and/or 17-hydroxyprogesterone.
  • 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.
  • patients most suitable for receiving oral 17-hydroxyprogesterone ester of this invention are the ones that have one or more of the following conditions, symptoms, and/or needs: 1) are in need of an anti-inflammatory; 2) are progesterone deficient with base line progesterone in early (first trimester) pregnancy of C avg ⁇ 14 ng/ml or baseline progesterone levels, C avg of less than 50 ng/ml in late (second and third trimester) pregnancy; 3) have genetic variation of the SERPINH1 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 Prolylcarboxypeptidase gene associated with preeclampsia; 5) have certain bacterial infections (bacterial vaginosis) including Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella vaginalis , and Peptostre
  • ester of 17-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 of skin 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.
  • the present invention provides for oral dosage forms containing esters of 17-hydroxyprogesterone as well as related methods.
  • the oral dosage forms can be formulated for pregnancy support and can include a therapeutically effective amount of an ester of 17-hydroxyprogesterone 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 17-hydroxyprogesterone after 60 minutes.
  • 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 17-hydroxyprogesterone ester after 60 minutes than an equivalently dosed oral dosage form without the carrier.
  • a number of 17-hydroxyprogesterone esters can be used in the compositions and oral dosages of the present invention.
  • specific acceptable esters of 17-hydroxyprogesterone include without limitation, acetate esters of 17-hydroxyprogesterone, caproate esters of 17-hydroxyprogesterone, undecanoate esters of 17-hydroxyprogesterone, and the like and combinations thereof.
  • Other pharmacologically active and acceptable esters of 17-hydroxyprogesterone may also be prepared and used in accordance with the embodiments of the present invention so long as they provide the desired support in pregnancy and/or non-pregnancy conditions.
  • the ester of 17-hydroxyprogesterone can be present in the compositions and oral dosage forms of the present disclosure in a variety of forms.
  • the ester of 17-hydroxyprogesterone can be present in particulate form.
  • the particulate form can have a mean diameter of about 50 ⁇ m or less.
  • the particulate form can have a mean diameter of about 25 ⁇ m or less.
  • the particulate form can have a mean diameter of about 1 ⁇ m or less.
  • the ester of 17-hydroxyprogesterone can be present in a fully solubilized form.
  • the ester of 17-hydroxyprogesterone can be present in a partially solubilized form.
  • a portion of the ester of 17-hydroxyprogesterone present in the composition and/or dosage form can be present in particulate or unsolubilzied form.
  • the ester of 17-hydroxyprogesterone can be present in both solubilized form as well as in particulate form.
  • the carrier of the compositions or oral dosage forms of the present invention can act to facilitate the delivery, release, and/or bioavailability of the ester of 17-hydroxyprogesterone.
  • the carrier can be one or a mixture of two or more compounds.
  • the carrier can include at least one of a lipophilic and/or a hydrophilic component additive.
  • the lipophilic and hydrophilic additives that can be used in the compositions of the invention can be selected from a variety of classes of the pharmaceutical aids including, but not limited to, absorbents, acids, adjuvants, anticaking agent, antitacking agents, antifoamers, anticoagulants, antimicrobials, antioxidants, antiphlogistics, astringents, antiseptics, bases, binders, bufferants, chelating agents, sequestrants, celluloses, coagulants, coating agents, colorants, dyes, pigments, complexing agents, crystal growth 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
  • Non-limiting examples of compounds that can form all or a part of the carrier are set forth in the following lists which have been organized in general categories. It is to be understood that the categories are not intended to limit the particular carrier compounds, but are simply present for ease of organization and presentation.
  • example carrier compounds can include one or more of the following:
  • Triglycerides such as Aceituno oil; Almond oil; Arachis oil; Babassu oil; Blackcurrant seed oil; Borage oil; Canola oil (Lipex 108 (Abitec)); Castor oil; Cocoa butter; Coconut oil (Pureco 76 (Abitec)); Coffee seed oil); Corn oil; Cottonseed oil; Crambe oil; Cuphea species oil; Evening primrose oil; Grapeseed oil; Groundnut oil; Hemp seed oil; Illipe butter; Kapok seed oil; Linseed oil; Menhaden oil; Mowrah butter; Mustard seed oil; Oiticica oil; Olive oil; Palm oil; Palm kernel oil; Peanut oil; Poppy seed oil; Rapeseed oil; Rice bran oil; Safflower oil; Sal fat; Sesame oil; Shark liver oil; Shea nut oil; Soybean oil; Stillingia oil; Sunflower oil; Tall oil; Tea sead oil; Tobacco seed oil; Tung oil (China wood oil): Vernonia
  • 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 4-100 monooleate (Crodet O series (Croda) (>8)); PEG 4-100 monostearate (Crodet S series (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 monooleate (Cithrol MO series (Croda) (>10)); PEG 400 dioleate (Cithrol 4DO series (Croda) (>10)); PEG 400-1000 monostearate (Cithrol MS series (Croda) (>10)); PEG-1 stearate (Ni
  • PEG-Fatty Acid Diesters listed as compound name (common commercial product name (supplier) (HLB): PEG-4 dilaurate (Mapeg® 200 DL (PPG), Kessco® PEG 200 DL (Stepan), LIPOPEG 2-DL (Lipo Chem.) (7)); PEG-4 dioleate (Mapeg® 200 DO (PPG), (6)); PEG-4 distearate (Kessco® 200 DS (Stepan) (5)); PEG-6 dilaurate (Kessco® PEG 300 DL (Stepan) (9.8)); PEG-6 dioleate (Kessco® PEG 300 DO (Stepan) (7.2)); PEG-6 distearate (Kessco® PEG 300 DS (Stepan) (6.5)); PEG-8 dilaurate (Mapeg® 400 DL (PPG), Kessco® PEG 400 DL (Stepan), LIPOPEG 4 DL (Lipo Chem.) (11));
  • PEG-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, distearate (Kessco® 200-6000 mono, distearate (Stepan)), and combinations thereof.
  • HLB common commercial product name
  • Polyethylene Glycol Glygerol Fatty Acid Esters listed as compound name (common commercial product name (supplier) (HLB)): PEG-20 glyceryl laurate (Tagat® L (Goldschmidt) (16)); PEG-30 glyceryl laurate (Tagat® L2 (Goldschmidt) (16)); PEG-15 glyceryl laurate (Glycerox L series (Croda) (15)); PEG-40 glyceryl laurate (Glycerox L series (Croda) (15)); PEG-20 glyceryl stearate (Capmul® EMG (ABITEC), (13)); (Aldo® MS-20 KFG (Lonza))); PEG-20 glyceryl oleate (Tagat ® 0 (Goldschmidt) (>10)); PEG-30 glyceryl oleate (Tagat ® 02 (Goldschmidt) (>10)); and combinations thereof.
  • PEG-20 glyceryl laurate
  • Alcohol-oil Transesterification 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) (11)); PEG-23 castor oil (Emulgante EL23 (>10)); PEG-30 castor oil (Emalex C-30 (Nihon Emulsion), Alkamuls® EL 620 (Rhone-Poulenc), Incrocas 30 (Croda) (11)); PEG-35 castor oil (Cremophor EL and EL-P (BASF), Emulphor EL, Incrocas-35(Croda), Emulgin RO 35 (Henkel))); PEG-38 castor oil (Emulgante EL 65 (Conde
  • Polyglycolized Fatty Acids (listed as compound name (common commercial product name (supplier) (HLB)): Polyglyceryl-2 stearate (Nikkol DGMS (Nikko) (5-7)); Polyglyceryl-2 oleate (Nikkol DGMO (Nikko) (5-7)); Polyglyceryl-2 isostearate (Nikkol DGMIS (Nikko) (5-7)); Polyglyceryl-3 oleate (Caprol ® 3GO (ABITEC), Drewpol 3-1-0 (Stepan) (6.5)); Polyglyceryl-4 oleate (Nikkol Tetraglyn 1-O (Nikko) (5-7)); Polyglyceryl-4 stearate (Nikkol Tetraglyn 1-S (Nikko) (5-6)); Polyglyceryl-6 oleate (Drewpol 6-1-O (Stepan), Nikkol Hexaglyn 1-O (Nikko) (9)); Poly
  • 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.), Aldo® PGHMS (Lonza) (3-4)); Propylene glycol hydroxy stearate ( ⁇ 10)); Propylene glycol ricinoleate (PROPYMULS (Henkel) ( ⁇ 10)); Propylene glycol isostear
  • Propylene Glycol Esters and Glycerol-Esters (listed as compound name (common commercial product name (supplier) (HLB)): Oleic (ATMOS 300, ARLACEL 186 (ICI) (3-4)); Stearic (ATMOS 150 (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) ( ⁇ 10)); Monocaproin (C6) (Larodan) ( ⁇ 10)); Monocaprylin (Larodan) ( ⁇ 10)); Monocaprin (Larodan) ( ⁇ 10)); Monolaurin (Larodan) ( ⁇ 10)); Glyceryl monomyristate (C14) (Nikkol MGM (Nikko) (3-4)); Glyceryl monooleate (C18:1) (PECEOL (Gattefosse), Hodag GMO-D, Nikkol MGO (Nikko) (3-4)); Glyceryl monooleate (RYLO series (Danisco), DIMODAN series (Danisco), EMULDAN (Danisco), ALDO® MO FG (Lonza), Kessco GMO (Stepan),
  • 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-10 soya sterol (Nikkol BPS-10 (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-10 sorbitan laurate (Liposorb L-10 (Lipo Chem.) (>10)); PEG-20 sorbitan monolaurate (Tween-20 (Atlas/ICI), Crillet 1 (Croda), DACOL MLS 20 (Condea) (17)); PEG-4 sorbitan monolaurate (Tween-21 (Atlas/ICI), Crillet 11 (Croda) (13)); PEG-80 sorbitan monolaurate (Hodag PSML-80 (Calgene); T-Maz 28 (>10)); PEG-6 sorbitan monolaurate (Nikkol GL-1 (Nikko) (16)); PEG-20 sorbitan monopalmitate (Tween-40 (Atlas/ICI), Crillet 2 (Croda) (16)); PEG-20 sorbitan mono
  • Polyethylene Glycol Alkyl Ethers (listed as compound name (common commercial product name (supplier) (HLB)): PEG-2oleyl ether, oleth-2(Brij 92/93 (Atlas/ICI) (4.9)); PEG-3 oleyl ether, oleth-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 lau
  • 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 11 (Gattefosse), Crodesta F-110 (Croda) (12)); Sucrose dipalmitate (7.4)); Sucrose monostearate (Crodesta F-160 (Croda) (15)); Sucrose monopalmitate (SUCRO ESTER 15 (Gattefosse) (>10)); Sucrose monolaurate (Saccharose monolaurate 1695 (Mitsubisbi-Kasei) (15)); and combinations thereof.
  • Polyethylene Glycol Alkyl Phenols (listed as compound name (common commercial product name (supplier) (HLB)): PEG-10-100 nonyl phenol (Triton X series (Rohm & Haas), Igepal CA series (GAF, USA), Antarox CA series (>10)); (GAF, UK); PEG-15-100 octyl phenol ether (Triton N-series (Rohm & Haas), Igepal CO series (GAF, USA), Antarox CO series (GAF, UK) (>10)); and combinations thereof.
  • HLB common commercial product name
  • Polyethylene-Polyoxypropylene Block Copolymers (AKA—“poloxamer”): These polymers have the formula: HO(C ⁇ 2>H ⁇ 4>O) ⁇ a>(C ⁇ 3>H ⁇ 6>O) ⁇ b>(C ⁇ 2>H ⁇ 4>O) ⁇ a>H where “a” and “b” denote the number of polyoxyethylene and polyoxypropylene units, respectively. The compounds are listed by generic name, with the corresponding “a” and “b” values.
  • Sorbitan Fatty Acid Esters (listed as compound name (common commercial product name (supplier) (HLB)): Sorbitan monolaurate (Span-20 (Atlas/ICI), Crill 1 (Croda), Arlacel 20 (ICI) (8.6)); Sorbitan monopalmitate (Span-40 (Atlas/ICI), Crill 2 (Croda), Nikkol SP-10 (Nikko) (6.7)); Sorbitan monooleate (Span-80 (Atlas/ICI), Crill 4 (Croda), Crill 50 (Croda) (4.3)); Sorbitan monostearate (Span-60 (Atlas/ICI), Crill 3 (Croda), Nikkol SS-10 (Nikko) (4.7)); Sorbitan trioleate (Span-85 (Atlas/ICI), Crill 45 (Croda), Nikkol SO-30 (Nikko) (4.3)); Sorbitan sesquioleate (Arlacel-C (ICI),
  • Lower Alcohol Fatty Acid Esters (listed as compound name (common commercial product name (supplier) (HLB)): Ethyl oleate ((Crodamol EO (Croda), Nikkol EOO (Nikko) ( ⁇ 10)); Isopropyl myristate (Crodamol IPM (Croda) ( ⁇ 10)); Isopropyl palmitate (Crodamol IPP (Croda) ( ⁇ 10)); Ethyl linoleate (Nikkol VF-E (Nikko) ( ⁇ 10)); Isopropyl linoleate (Nikkol VF-IP (Nikko) ( ⁇ 10)); and combinations thereof.
  • Ethyl oleate ((Crodamol EO (Croda), Nikkol EOO (Nikko) ( ⁇ 10)); Isopropyl myristate (Crodamol IPM (Croda) ( ⁇ 10)); Isopropyl palmitate (Croda
  • Ionic Surfactants (listed as compound name (HLB) Fatty acid salts (>10)); Sodium caproate; Sodium caprylate; Sodium caprate; Sodium laurate; Sodium myristate)); Sodium myristolate; Sodium palmitate; Sodium palmitoleate; Sodium oleate (18); Sodium ricinoleate)); Sodium linoleate; Sodium linolenate; Sodium stearate; Sodium lauryl sulfate (40); Sodium tetradecyl sulfate; Sodium lauryl sarcosinate; Sodium dioctyl sulfosuccinate; Bile Salts (>10); Sodium cholate; Sodium taurocholate; Sodium glycocholate; Sodium deoxycholate; Sodium taurodeoxycholate; Sodium glycodeoxycholate; Sodium ursodeoxycholate; Sodium chenodeoxycholate; Sodium taurochenodeoxychol
  • Phospholipids such as Egg/Soy lecithin (EpikuronTM; OvothinTM); Lyso egg/soy lecithin; Hydroxylated lecithin; Lysophosphatidylcholine; Cardiolipin; Sphingomyelin; Phosphatidylcholine; Phosphatidyl ethanolamine; Phosphatidic acid; Phosphatidyl glycerol; Phosphatidyl serine, and combinations thereof.
  • Egg/Soy lecithin EpikuronTM; OvothinTM
  • Lyso egg/soy lecithin Hydroxylated lecithin
  • Lysophosphatidylcholine Cardiolipin
  • Sphingomyelin Phosphatidylcholine
  • Phosphatidyl ethanolamine Phosphatidic acid
  • Phosphatidyl glycerol Phosphatidyl
  • Phosphoric Acid Esters Diethanolammonium polyoxyethylene-10 oleyl ether phosphate; Esterification products of fatty alcohols or fatty alcohol ethoxylates with phosphoric acid or anhydride.
  • Carboxylates such as: Ether carboxylates (by oxidation of terminal OH group of fatty alcohol ethoxylates) Succinylated monoglycerides; Sodium stearyl fumarate; Stearoyl propylene glycol hydrogen succinate; Mono/diacetylated tartaric acid esters of mono- and diglycerides; Citric acid esters of mono-, diglycerides; Glyceryl-lacto esters of fatty acids; and combinations thereof.
  • Ether carboxylates by oxidation of terminal OH group of fatty alcohol ethoxylates
  • Succinylated monoglycerides Succinylated monoglycerides
  • Sodium stearyl fumarate Stearoyl propylene glycol hydrogen succinate
  • Mono/diacetylated tartaric acid esters of mono- and diglycerides Citric acid esters of mono-, diglycerides
  • Glyceryl-lacto esters of fatty acids and
  • Acyl lactylates such as: lactylic esters of fatty acids; calcium/sodium stearoyl-2-lactylate; calcium/sodium stearoyl lactylate; alginate salts like sodium alginate, calcium alginate and others; and combinations thereof.
  • Hydrophilic Polymers such as: carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, methacrylic acid copolymers, macrogol, starch, gelatin, dextrin, pullulan, agar, acacia, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(ethylene-co-vinyl alcohol), poly(acrylic acid), poly(ethylene-co-acrylic acid), poly(ethyloxazoline), poly(vinyl pyrrolidone), poly(ethylene-co-vinyl pyrrolidone), poly(maleic acid), poly(ethylene-co-maleic acid), poly(acrylamide), or poly(ethylene oxide)-co-poly(propylene oxide); block copolymers, graft copolymers of lactic acid, glycolic acid, epsilon-caprolactone, lactic-co-glycolic acid oligomers, trimethylene carbonate, anhydrides, and amino acids acrylates,
  • 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 hydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, and mixtures of combinations thereof.
  • Chelating Agents such as: Sodium EDTA, Dieditate Sodium, and mixtures or combinations thereof.
  • Complexing Agents such as: Hydroxypropyl Cyclodextrin, Hydroxy propyl beta Cyclodextrin, sulfabutyl ether cyclodextrin, and mixtures and combinations thereof.
  • Salts such as: salts of acids, bases, salts of fatty acids, fatty acid glycerides, Salts of bile acids, and mixtures and combinations thereof.
  • Amides such as: for example 2-pyrrolidone, 2-piperidone, epsilon-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, polyvinylpyrrolidone and the like.
  • Alcohols such as: ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, glycerol, sorbitol, mannitol, dimethyl isosorbide, polyethylene glycol, fatty acid alcohol, vinyl alcohol polypropylene glycol, polyvinylalcohol, 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-valerolactone and isomers thereof, beta-butyrolactone and isomers thereof; dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, or the like.
  • Bile acids such as: cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate, glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate, lithocholate, tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine).
  • Celluloses such as: microcrystalline 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 (HPMCAT), and ethylhydroxy ethylcellulose (EHEC), various grades of low viscosity (MW less than or equal to 50,000 daltons) and high viscosity (
  • Cellulose Esters such as: Cellulose acetate, Cellulose Acetate Butyrate, Cellulose acetate phthalate, Hydroxypropyl methylcellulose phthalate, and combinations thereof.
  • Mucoadhesive Polymers such as for example tocopherols such as for example tocopherol, tocopherol acetate, tocopherol succinate, and combinations thereof.
  • Amino Acids and Modified Amino acids such as: aminoboronic acid derivatives, n-acetylcysteine, and mixtures thereof.
  • Sugars such as: maltose, sucrose, dextrose, lactose, fructose, mannitol, sucralose, fructalose, trehelose, dextrose, maltodextrose, and combinations thereof.
  • Sugar Alcohols 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(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP) and crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers and PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate, vinyl acetate, and the 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
  • 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, gum tragacanth, 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; tri
  • the pharmaceutical composition or oral dosage form can be formulated to include at least one of the following preferred carriers: citric acid, maleic acid, tartaric acid, ascorbic acid, lactic acid, and salts thereof,potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, silicon dioxide, magnesium aluminum silicate, triethylamine, fatty acid glycerides, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, triethylcitrate, triacetin, benzyl benzoate, bile acid, salts of bile acid, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose esters, carbomer, methacrylates, polyvinyl alcohol, gelatin, distearin, monopalmitolein tocopherol, tocopherol succinate, corn oil, olive oil, peanut oil
  • the pharmaceutical compositions or oral dosage forms of the present invention can be formulated to include a hydrophilic additive.
  • the hydrophilic additive can be a hydrophilic surfactant.
  • the hydrophilic surfactant when the hydrophilic additive includes a hydrophilic surfactant, the hydrophilic surfactant does not appreciably solubilize the ester of 17-hydroxyprogesterone.
  • Non-limiting examples of hydrophilic additives include salts of citric acid, maleic acid, tartaric acid, acetic acid, ascorbic acid, benzoic acid and lactic acid, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, 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
  • the carrier can include a hydrophilic surfactant that is an ionic or non-ionic surfactant.
  • hydrophilic surfactants include proteins, gelatin, salts of bile 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
  • the hydrophilic additive can be free of hydrophilic surfactants, and can be citric 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 cyclodextrin, 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.
  • hydrophilic surfactants can be citric acid, maleic acid, tartaric acid, acetic acid, ascorbic acid, benzoic acid, lactic acid,
  • the carrier of the pharmaceutical compositions or oral dosage forms can include a lipophilic additive.
  • lipophilic additives include tributylcitrate, triethylcitrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose 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 tricaprylate/caprate,
  • 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
  • the lipophilic additive is a triglyceride.
  • triglycerides suitable for this invention include corn oil, olive oil, peanut oil, palm oil, coconut oil, arachis oil, safflower oil, sesame oil, soybean oil, castor oil, 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 trilinoleate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate, saturated polyglycolized glycerides linoleic glycerides
  • the lipophilic additive can be free of lipophilic surfactants.
  • the carrier is a lipophilic surfactant.
  • lipophilic surfactants suitable for this invention include tributylcitrate, triethylcitrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetates butyrate, benzyl benzoate, 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,
  • compositions or dosage form of the present invention can be free of triglycerides, or substantially free of triglycerides.
  • the present invention does not include lipophilic or hydrophilic additive, which contain triglycerides as an intended or added component.
  • 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.
  • 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%, less than 2%, or preferably 0% (triglyceride free), by weight of the composition.
  • 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 by themselves.
  • Non-limiting examples of such lipophilic additives include tributylcitrate, triethylcitrate, triacetin, ethyl cellulose, cellulose esters, cellulose 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 mono
  • the carrier of the current invention can include a control release agent.
  • the control release agent can be selected from the group consisting of the said hydrophilic additives or lipophilic additives or a mixture thereof.
  • the compositions or dosage forms of the present invention can be free of lipophilic surfactant.
  • the compositions or dosage form of the present invention can be free of lipophilic additive.
  • the pharmaceutical compositions and the oral dosage forms of the present disclosure can include at least one hydrophilic additive and at least one lipophilic additive.
  • a hydrophilic additive and a lipophilic additive when both a hydrophilic additive and a lipophilic additive are present, they can be present at a lipophilic additive to hydrophilic additive ratio of about 99:1 to about 1:99.
  • the lipophilic additive to hydrophilic additive ratio can be about 95:5 to about 5:95.
  • the lipophilic additive to hydrophilic additive ratio can be about 90:10 to about 10:90.
  • the lipophilic additive to hydrophilic additive ratio can be of about 90:10 to about 1:99.
  • the lipophilic additive to hydrophilic additive ratio can be of about 80:20 to about 20:80. In another specific embodiment, the lipophilic additive to hydrophilic additive ratio can be of about 70:30 to about 30:70. In another specific embodiment, the lipophilic additive to hydrophilic additive ratio can be of about 60:40 to about 40:60. In another specific embodiment, the lipophilic additive to hydrophilic additive ratio can be about 50:50.
  • both a hydrophilic surfactant and a lipophilic additive when both a hydrophilic surfactant and a lipophilic additive are present, they can be present in amounts such that when 1 part by weight of the mixture of the hydrophilic surfactant and lipophilic additive is mixed 99 parts of an aqueous diluent, the dispersion so obtained so obtained can be colloidal, hazy or unclear.
  • the aqueous diluent used for dispersion is either water or 0.5% w/v sodium lauryl sulfate in water.
  • the dispersion can exhibit an absorbance greater than 0.1 when determined using a spectrophotometer at 400 nm. In another specific embodiment, the absorbance is greater than 0.3 at 400 nm.
  • the mean particle size of the dispersion is about 60 nm or more. In another specific embodiment, the mean particle size of the dispersion is about 100 nm or more. In another specific embodiment, the mean particle size of the dispersion is about 150 nm or more. In yet another specific embodiment, the mean particle size of the dispersion is about 200 nm or more. In yet another specific embodiment, the mean particle size of the dispersion is about 250 nm or more.
  • the aqueous diluent used for dispersion is either water or 0.5% w/v sodium lauryl sulfate in water. For the purpose of this invention, the dispersion is deemed clear if it appears clear to the naked eye. In one embodiment, the dispersion can be clear.
  • the carrier can be present in an amount sufficient to solubilize the ester of 17 hydroxyprogesterone. In some aspects, the carrier of the present invention aids in solubilizing a significant amount of the ester of 17-hydroxyprogesterone in the composition. In one embodiment, the carrier can solubilize 20 wt % or more of the amount of the ester of 17-hydrxoyprogesterone. In another embodiment, the carrier can aid loading of greater than about 10% w/w of the ester in the composition and/or dosage form. In another embodiment, the loading achieved by the carrier can be greater than about 12% w/w of the composition and/or dosage form.
  • the loading achieved by the carrier can be greater than about 15% w/w of the composition and/or dosage form. In another embodiment, the loading attained by inclusion of the carrier can be greater than about 18% w/w of the composition and/or dosage form. In further embodiments, the loading attained by inclusion of the carrier can be greater than about 20%; greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 75%, or greater than about 90%, with each percentage based on w/w of the composition and/or dosage form.
  • the carrier can include benzyl alcohol, benzyl benzoate, mixtures thereof. In another embodiment, the carrier can include benzyl alcohol, benzyl benzoate, or mixtures thereof and the amount of the ester of 17-hydroxyprogesterone can be between about 5 to about 80% w/w of the total composition. In one embodiment, when the carrier includes benzyl alcohol, benzyl benzoate, or mixtures thereof, the amount of the ester of 17-hydroxyprogesterone can be between about 5 to about 80% w/w of the total composition. In one embodiment, the amount of the ester of 17-hydroxyprogesterone can be between 5% to about 60% w/w of the total composition.
  • the amount of the ester of 17-hydroxyprogesterone can be between about 5 to about 40% w/w of the total composition. In another specific embodiment, when the carrier includes benzyl alcohol, benzyl benzoate, or mixtures thereof, the amount of the ester of 17-hydroxyprogesterone can be between about 5 to about 30% w/w of the total composition. In another specific embodiment, when the carrier includes benzyl alcohol, benzyl benzoate, or mixtures thereof, the amount of the ester of 17-hydroxyprogesterone can be between about 5 to about 25% w/w of the total composition.
  • the ester of 17-hydroxyprogesterone when the carrier includes benzyl alcohol, benzyl benzoate, or mixtures thereof, can be fully solubilized in the composition and/or the dosage form. In another specific embodiment, the ester of 17-hydroxyprogesterone can be partially solubilized in the dosage form. In another specific embodiment, the ester of 17-hydroxyprogesterone can be 17-hydroxyprogesterone caproate.
  • the ratio of the amount of the ester of 17-hydroxyprogesterone to the sum of the amounts of benzyl alcohol and benzyl benzoate present in the composition or oral dosage form can be about 1:0.01 (W/W) to about 1:5 (W/W). In another embodiment, the ratio can be about 1:0.01 (W/W) to about 1:3.5 (W/W). In another embodiment, the ratio of the amount of the ester of 17-hydroxyprogesterone to the sum of the amounts of benzyl alcohol and benzyl benzoate present in the composition or oral dosage form can be about 1:0.01 (W/W) to about 1:2.5 (W/W).
  • the ratio of the amount of the ester of 17-hydroxyprogesterone to the sum of the amounts of benzyl alcohol and benzyl benzoate present in the composition or oral dosage form can be about 1:0.01 to about 1:2 (W/W).
  • the pharmaceutical composition or unit dosage form described herein having an ester of 17-alpha-hydroxyprogesterone is particle size physically stable.
  • particle size physically stable means that, on storage, there is no evidence of substantial particle growth or agglomeration of the API particles.
  • Substantial particle growth or agglomeration refers to an increase in particle size of greater than 10%, 20%, 30%, 40%, 50%, 75%, 100%, 150%, 200%, or 300%.
  • One particular apparatus that can be used is the Sympatec Dry Dispersion Size Analyser.
  • particle agglomeration inhibitor refers to agents, which are used to stabilize an API in order to reduce or prevent the API from agglomerating or aggregating.
  • a stabilizing agent generally reduces the cohesion between particles and prevents fine particles becoming attached to each other.
  • Stabilizing agents include metal stearates such as magnesium stearate and calcium stearate, ionic and non-ionic surfactants, and polymers such as cellulose ethers, PVP or PVA.
  • a particle agglomeration inhibitor can be included in an amount to provide particle size stability.
  • particle agglomeration inhibitors include, but are not limited to, povidone, crosslinked PVP (crospovidone), cross linked carmellose (croscarmellose), sodium starch glycolate, Povidone (PVP), Povidone K12, Povidone K17, Povidone K25, Povidone K29/32 and Povidone K30, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium stearyl lactylate, zinc stearate, sodium stearate or lithium stearate, other solid state fatty acids such as oleic acid, lauric acid, palmitic acid, erucic acid, behenic acid, or derivatives (such as esters and salts), Amino acids such as leucine, isoleucine, lysine, valine, methionine, phenylalanine, aspartame or acesulfame K.
  • PVP crosslinked PVP
  • PVP cross linked car
  • the pharmaceutical composition or unit dosage form described herein having an ester of 17-alpha-hydroxyprogesterone is crystallization stable.
  • crystallization stable means that, on storage, there is no evidence of substantial crystallization of the API particles.
  • Substantial crystallization refers to an increase in crystalline particle size of greater than 10%, 20%, 30%, 40%, 50%, 75%, 100%, 150%, 200%, or 300%.
  • the pharmaceutical composition or unit dosage form described herein having an ester of 17-alpha-hydroxyprogesterone e.g., 17-hydroxyprogesterone caproate
  • has a crystallization inhibitor has a crystallization inhibitor.
  • crystallization inhibitor means an agent that facilitates prevention of crystallization of the API.
  • crystallization inhibitors include, but are not limited to polyvinylpyrrolidone (PVP or povidone), including homo- and copolymers of polyvinylpyrrolidone and homopolymers or copolymers of N-vinylpyrrolidone; crospovidone; gums; cellulose derivatives (e.g., HPMC polymers, hydroxypropyl cellulose, ethyl cellulose, hydroxyethylcellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose); dextran; acacia; homo- and copolymers of vinyllactam, and mixtures thereof; cyclodextrins; gelatins; hypromellose phthalate; sugars; sugar alcohols including mannitol; polyhydric alcohols; polyethylene glycol (PEG); polyethylene oxides; polyoxyethylene derivatives; polyvinyl alcohol; propylene glycol derivatives and the like, SLS, Tweens, Eudragit
  • the pharmaceutical compositions and oral dosage forms can be formulated and delivered in a variety of solid or liquid dosage forms.
  • Non-limiting examples of such dosage forms include powder, granulate, particulate, bead, pellet, sprinkle, suspension, solution, tablet, capsule, and combinations thereof.
  • the pharmaceutical composition or oral dosage form can be in the form of a capsule.
  • the pharmaceutical composition or oral dosage form can be in the form of a tablet.
  • the dosage form is a hard or a soft capsule.
  • the capsule can be made of conventional capsule shell materials known in the art; such materials can include, but are not limited to gelatins, celluloses, starches, methacrylates, carrageenans, polyvinyl alcohols, and the like.
  • the capsule is an immediate release dosage form.
  • the capsule is a controlled release dosage form.
  • the tablet is an immediate release dosage form.
  • the tablet is a controlled release dosage form.
  • the volume of the capsule can be about 1.5 mL or less. In another embodiment, the volume of capsule can be about 1.2 mL or less. In one particular embodiment, the volume of the capsule can be about 0.8 mL or less. In another embodiment, the ratio of the weight of fill material encapsulated within the capsule to the capsule volume can be between about 0.3 g/mL to about 3.5 g/mL. In a particular embodiment, the ratio can be between 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.
  • the pharmaceutical capsule oral dosage form of the current invention can have a ratio of the amount of the ester of 17-hydroxyprogesterone in the composition to the fill volume of the capsule between about 0.02 g/mL to about 0.8 g/mL. In another embodiment, the ratio can be between about 0.02 g/mL to about 0.7 g/mL. In a specific embodiment, the ratio can be between about 0.02 g/mL to about 0.5 g/mL. In another specific embodiment, the ratio can be between about 0.05 g/mL to about 0.5 g/mL. In another specific embodiment, the ratio can be between about 0.05 g/mL to about 0.35 g/mL. In another specific embodiment, the ratio can be between about 0.05 g/mL to about 0.3 g/mL. In another specific embodiment, the ratio can be between about 0.1 g/mL to about 0.25 g/mL.
  • the oral dosage forms of the present invention can be formulated to include an amount of an ester of 17-hydroxyprogesterone equivalent to about 10 mg to about 800 mg of 17-hydroxyprogesterone. In one embodiment, the oral dosage form can be formulated to include an amount of ester of 17-hydroxyprogesterone equivalent to 20 mg to about 400 mg of 17-hydroxyprogesterone.
  • the pharmaceutical composition and oral dosage forms of the present invention can be formulated to be administered to a subject in order to provide a daily dose of the ester of 17-hydroxyprogesterone that is equivalent to about 40 mg to about 3200 mg of 17-hydroxyprogesterone.
  • the oral dosage form can be a capsule and the capsule includes from about 10 mg to about 300 mg17-hydroxyprogesterone caproate.
  • the oral dosage form can be a tablet and the tablet includes from about 20 mg to about 800 mg of 17-hydroxyprogesterone caproate. In another embodiment, the oral dosage form includes from about 20 mg to about 1200 mg of 17-hydroxyprogesterone caproate. In another embodiment, the oral dosage form can be a tablet and the tablet includes from about 100 mg to about 1000 mg of 17-hydroxyprogesterone caproate. In another embodiment, the oral dosage form includes from about 200 mg to about 900 mg of 17-hydroxyprogesterone caproate. In another embodiment, the oral dosage form includes from about 300 mg to about 900 mg of 17-hydroxyprogesterone caproate.
  • the oral dosage form includes from about 350 mg to about 800 mg of 17-hydroxyprogesterone caproate. In another embodiment, the oral dosage form includes from about 400 mg to about 800 mg of 17-hydroxyprogesterone caproate. In another embodiment, the oral dosage form includes from about 100 mg to about 400 mg of 17-hydroxyprogesterone caproate. In another embodiment, the oral dosage form includes from about 150 mg to about 350 mg of 17-hydroxyprogesterone caproate. In another embodiment, the oral dosage form includes from about 200 mg to about 375 mg of 17-hydroxyprogesterone caproate. In another embodiment, the oral dosage form includes from about 200 mg to about 475 mg of 17-hydroxyprogesterone caproate.
  • the oral dosage form includes from about 525 mg to about 850 mg of 17-hydroxyprogesterone caproate.
  • the pharmaceutical compositions and oral dosage forms can be formulated to be administered at various dosing intervals.
  • the compositions or oral dosage forms can be formulated for administration about once every 8 hours.
  • the compositions or oral dosage forms can be formulated for administration about three times a day.
  • the compositions or oral dosage forms can be formulated for administration to a subject, such as a human subject, once every 6 hours.
  • the compositions or oral dosage forms can be formulated for administration about four times a day.
  • the compositions or oral dosage forms can be formulated for administration about once every 12 hours.
  • compositions or oral dosage forms can be formulated for administration about two times a day. In yet a further embodiment, the compositions or oral dosage forms can be formulated for administration about once every 24 hours. In one embodiment, the compositions or oral dosage forms can be formulated for administration about once a day.
  • the amount of 17 HPC per dosage form are as provided in the previous paragraph which can be administered as one, two, three, or four unit dosage forms per dose (e.g., each time).
  • the oral pharmaceutical compositions comprising 17 HPC and a pharmaceutically acceptable carrier when used to treat a female for one or more of the conditions described herein yields improved efficacy as compared to administration of placebo.
  • the oral dosage forms of the present invention can be used to treat pregnant female subjects who are at risk of preterm birth.
  • the methods of treatment include the step of orally administering to the female subject the oral pharmaceutical composition.
  • 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 subject receiving administration of the pharmaceutical composition or oral dosage form can be experiencing or be at risk of at least two of: singleton pregnancy, history of preterm labor and/or preterm birth, history of preterm delivery, shortened cervix, and effaced cervix, history of more at least one miscarriage, and history of multifetal gestation.
  • the conditions and the relative treatment can be based on their primary and secondary outcome measurements associated with the administration of the ester of 17-hydroxyprogesterone.
  • the pharmaceutical compositions or oral dosage forms of the present invention comprising an ester of 17-hydroxyprogesterone can provide a 17-hydroxyprogesterone equivalent C avg-24h greater than about 0.7 ng/mL.
  • the oral dosage form or the composition can provide a C avg-24h of 17-hydroxyprogesterone equivalent greater than about 10 ng/mL.
  • the oral dosage form or the composition can provide a C avg-24h of 17-hydroxyprogesterone equivalent greater than about 30 ng/mL.
  • the oral dosage form or the composition can provide a C avg-24h of 17-hydroxyprogesterone equivalent greater than about 50 ng/mL.
  • the oral dosage form or the composition can provide a C avg-24h of 17-hydroxyprogesterone equivalent greater than about 100 ng/mL.
  • the said 17-hydroxyprogesterone equivalent C avg-24h is determined by an HPLC-MS/MS method of analysis of the plasma, serum or blood samples collected following the oral administration.
  • the pharmaceutical compositions or oral dosage forms of the present invention comprising an ester of 17-hydroxyprogesterone can provide a 17-hydroxyprogesterone equivalent C avg-24h greater than about 0.05, 0.1, 0.5, 0.7, 1.0, 1.5, 1. 2.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 35.0, 40.0, 45.0, 50.0 60.0 or 75.0 ng/mL (or within a range defined by any two of these values).
  • the said 17-hydroxyprogesterone equivalent C avg-24h is determined by an HPLC-MS/MS method of analysis of the plasma, serum or blood samples collected following the oral administration.
  • the pharmaceutical compositions or oral dosage forms of the present invention comprising 17-hydroxyprogesterone caproate
  • the oral dosage form or the composition can provide a 17-hydroxyprogesterone caproate C avg-24h equal to about 20 ng/mL or more.
  • the oral dosage form or the composition can provide a 17-hydroxyprogesterone caproate C avg-24h equal to about 50 ng/mL or more.
  • the oral dosage form or the composition can provide a 17-hydroxyprogesterone caproate C avg-24h equal to about 100 ng/mL or more.
  • the said 17-hydroxyprogesterone caproate C avg-24h is determined by an HPLC-MS/MS method of analysis of the plasma, serum or blood samples collected following the oral administration.
  • the pharmaceutical compositions or oral dosage forms of the present invention comprising 17-hydroxyprogesterone caproate
  • the said 17-hydroxyprogesterone caproate C avg-24h is determined by an HPLC-MS/MS method of analysis of the plasma, serum or blood samples collected following the oral administration.
  • compositions and/or dosage forms of this invention provided significantly enhanced bioavailability of 17-hydroxyprogesterone caproate as a function of the oral dose of the 17 hydroxyprogesterone caproate administered to a subject. Accordingly, the compositions or dosage forms of this invention provide, upon single dose oral administration, an AUC (0-24h) to dose ratio of about 10 or less, wherein the dose is the amount in mg of the 17-hydroxyprogesterone caproate administered.
  • the ratio of the 17-hydroxyprogesterone caproate AUC (0-24h) to dose of the 17-hydroxyprogesterone caproate administered can be about 0.2 ng*h mL ⁇ 1 mg ⁇ 1 to about 10 ng*h mL ⁇ 1 mg ⁇ 1 . In another embodiment, the ratio of the 17-hydroxyprogesterone caproate AUC (0-24h) to dose of the 17-hydroxyprogesterone caproate administered can be about 0.3 ng*h mL ⁇ 1 mg ⁇ 1 to about 7 ng*h mL ⁇ 1 mg ⁇ 1 . In a specific embodiment, the AUC (0-24h) to dose ratio is between about 0.5 and about 6 ng*h mL ⁇ 1 mg ⁇ 1 .
  • compositions or dosage forms of this invention provide, upon single dose oral administration, an AUC (0-24h) to dose ratio of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 , wherein the dose is the amount in mg of the 17-hydroxyprogesterone caproate administered.
  • compositions or dosage forms of this invention provide, upon single dose oral administration, an AUC (0-24h) to dose ratio of greater than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1.75, 1.5, 1.25, 1 or 0.5, wherein the dose is the amount in mg of the 17-hydroxyprogesterone caproate administered.
  • the ratio of the 17-hydroxyprogesterone caproate AUC (0-24h) to dose of the 17-hydroxyprogesterone caproate administered can be about 0.01 ng*h mL ⁇ 1 mg ⁇ 1 to about 5.0 ng*h mL ⁇ 1 mg ⁇ 1 . In another embodiment, the ratio of the 17-hydroxyprogesterone caproate AUC (0-24h) to dose of the 17-hydroxyprogesterone caproate administered can be about 0.05 ng*h mL ⁇ 1 mg ⁇ 1 to about 3.0 ng*h mL ⁇ 1 mg ⁇ 1 .
  • the AUC (0-24h) to dose ratio is between about 0.1 and about 2.0 ng*h mL ⁇ 1 mg ⁇ 1 . In a specific embodiment, the AUC (0-24h) to dose ratio is between about 0.1 and about 1.5 ng*h mL ⁇ 1 mg ⁇ 1 . In a specific embodiment, the AUC (0-24h) to dose ratio is between about 0.1 and about 1.0 ng*h mL ⁇ 1 mg ⁇ 1 . In a specific embodiment, the AUC (0-24h) to dose ratio is between about 1.5 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 .
  • the AUC (0-24h) to dose ratio is between about 2.0 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 . In a specific embodiment, the AUC (0-24h) to dose ratio is between about 3.0 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 . In a specific embodiment, the AUC (0-24h) to dose ratio is between about 4.0 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 . In a specific embodiment, the AUC (0-24h) to dose ratio is between about 5.0 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 .
  • the AUC (0-24h) to dose ratio is between about 6.0 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 . In a specific embodiment, the AUC (0-24h) to dose ratio is between about 7.0 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 .
  • an oral dosage form having 17-hydroxyprogesterone caproate upon single dose administration to a human provides at least 10% of the bioavailability of an intramuscular injection of 17-hydroxyprogesterone caproate (e.g., 250 mg of 17-hydroxyprogesterone caproate in castor oil (1 or 5 mL) with or without benzyl alcohol or benzyl benzoate.)
  • 17-hydroxyprogesterone caproate e.g., 250 mg of 17-hydroxyprogesterone caproate in castor oil (1 or 5 mL) with or without benzyl alcohol or benzyl benzoate.
  • the oral dosage form or pharmaceutical composition upon single administration of the pharmaceutical compositions or oral dosage forms containing 17-hydroxyprogesterone caproate of the present invention to a human subject under fed conditions, can provide a 17-hydroxyprogesterone caproate C avg-24h of greater than about 1.0 ng/mL.
  • the pharmaceutical compositions or oral dosage forms containing 17-hydroxyprogesterone of the present invention can provide a steady state 17-hydroxyprogesterone caproate C avg-24h of greater than about 1.0 ng/mL, when administered to a human subject under fed condition.
  • the said C avg-24h is determined by an HPLC-MS/MS method of analysis of the plasma, serum or blood samples collected following the administration.
  • the compositions and oral dosage forms disclosed herein can be orally administered with food or without regards to the food or food content.
  • the compositions and oral dosage forms containing caproate ester of 17-hydroxyprogesterone as disclosed herein can be orally administered with food or without regards to the food or food content.
  • the pharmaceutical compositions or oral dosage forms containing 17-hydroxyprogesterone of the present invention can provide a steady state 17-hydroxyprogesterone caproate C avg-24h of greater than about 0.05, 0.1, 0.5, 0.7, 1.0, 1.5, 2.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 35.0, 40.0, 45.0, 50.0, 60.0 or 75.0 ng/mL, when administered to a human subject under fed conditions (or within a range defined by any two of these values).
  • the oral dosage form can be orally administered with food or under fed condition.
  • the composition or oral dosage form can be administered with a normal or standard meal.
  • the composition or oral dosage form can be administered with a food or meal, such as a meal that provides about 200 calories to about 1000 calories of energy.
  • the composition or oral dosage form can be administered with a meal that provides about 50% of the calories from the fat.
  • the composition or oral dosage form can be administered with a high-fat, high calorie meal.
  • the composition or oral dosage form can be administered with a standard meal that provides about 500 calories to about 1000 calories of energy.
  • the compositional make-up of the meals that are administered can vary depending on the tastes and dietary needs of a subject.
  • the meal can provide about 3 g to about 50 g of fat. In yet a further embodiment, the meal can provide 10 g to about 50 g of fat. In yet another embodiment, the meal can provide about 15 g to about 35 g of fat.
  • the oral dosage form when administered to a human female, it can be done without regard to the presence of or nutritional make-up of a meal.
  • the total daily dose of the ester of 17 HP administered to human female subject with food or under fed condition is from about 20% to about 80% of the total daily dose administered without meals, for a similar therapeutic benefit. In a specific embodiment, the daily dose under fed condition is from about 20% to about 60% of the total daily dose administered without meals, for a similar therapeutic benefit.
  • the composition or oral dosage form can be administered without food or under fasted condition.
  • the oral bioavailability of the ester of 17-hydroxyprogesterone can be enhanced by using the said ester in the form of fine particulate, for example milled, micronized or nanosized etc, in the composition and/or the dosage form of the current invention. Further, the oral bioavailability can be enhanced by using the ester along with a carrier that aids the release of at least 20% more of the ester from the composition or dosage form when exposed to an aqueous medium compared to an equivalent dose of the ester without the carrier of the current invention.
  • the oral bioavailability of the caproate ester of 17-hydroxyprogesterone can be enhanced by using the said ester in the form of fine particulate, for example milled, micronized or nanosized or combinations thereof in the composition and/or the dosage form of the current invention.
  • the oral bioavailability of the ester of 17-hydroxyprogesterone is at least 10% more for the compositions or a dosage forms of the current invention that releases at least 20% of the ester in an aqueous medium compared to an equivalent dose of the ester present in an “untreated” particulate form such as for example as unmilled or unmicronized particulate forms.
  • the oral bioavailability of the ester of 17-hydroxyprogesterone is at least 10% more for the compositions or a dosage forms of the current invention that releases at least 20% more of the ester from the composition or dosage form when exposed to an aqueous medium compared to an equivalent dose of the ester without the carrier of the current invention.
  • the said ester is 17-hydroxyprogesterone caproate.
  • the ester of 17-hydroxyprogesterone can be a substrate to the P-glycoproteins (P-gp) the efflux transporter systems.
  • the oral bioavailability can be enhanced by at least 10% by co-administering the ester of 17-hydroxyprogesterone of the current invention with an effective amount of P-gp and/or CYP3A4 inhibiting agents e.g., star fruit, grape fruit juice, bergamottin, cafestol (as in unfiltered coffee), ketoconazole, erythromycin, mibefradil, loperamide etc.
  • the oral pharmaceutical compositions or the oral dosage forms of the ester of 17-hydroxyprogesterone according to the current invention can be used for providing luteal support for a subject in need thereof.
  • the oral composition or the oral dosage form can be formulated to enable modulation or titration of the dose and/or dosing regimen of the ester of 17-hydroxyprogesterone for providing effective luteal support to a subject in need thereof.
  • the dose of the ester of 17-hydroxyprogesterone in the form of oral compositions or dosage forms of the present invention may be modulated or titrated to provide effective luteal support as needed at the during early pregnancy.
  • the dose of the ester of 17-hydroxyprogesterone in the form of oral compositions or dosage forms of the present invention may be modulated or titrated to provide effective luteal support as needed based on the body mass index (BMI) of the subject.
  • the dose of the ester of 17-hydroxyprogesterone in the form of oral compositions or dosage forms of the present invention may be modulated or titrated to provide effective luteal support as needed based on the race or ethnicity of the subject.
  • An example of the dose modulation or titration can be based on the total dose per day, and can include administration of a higher initial loading dose or bolus dose, followed by a lower effective standard dose.
  • the dose modulation or titration can be based on the total dose per week and can include administration of a higher initial loading dose or bolus dose in the initial days of the week followed by a lower effective standard dose in the later days of the week.
  • the dosing regimen can include ramping up of (i.e. progressive increments) the daily dose in accordance with the progression of pregnancy.
  • the ester is 17-hydroxyprogesterone caproate.
  • the daily oral dose administered with food of 17-hydroxyprogesterone caproate is from about 40 mg to about 5000 mg. In another embodiment, the daily oral dose is from about 40 mg to about 4000 mg. In another embodiment, the daily oral dose is from about 80 mg to about 4000 mg. In another embodiment, the daily oral dose is from about 150 mg to about 4000 mg. In another embodiment, the daily oral dose is from about 250 mg to about 4000 mg. In another embodiment, the daily oral dose of is from about 500 mg to about 4000 mg. In another embodiment, the daily oral dose is from about 750 mg to about 4000 mg. In another embodiment, the daily oral dose is from about 1000 mg to about 4000 mg. In another embodiment, the daily oral dose is from about 1200 mg to about 4000 mg.
  • the daily oral dose is from about 1500 mg to about 4000 mg. In another embodiment, the daily oral dose is from about 1500 mg to about 3000 mg. In another embodiment, the daily oral dose is from about 1000 mg to about 2000 mg. In another embodiment, the daily oral dose is from about 200 mg to about 2000 mg. In another embodiment, the daily oral dose is from about 400 mg to about 2000 mg. In another embodiment, the daily oral dose is from about 800 mg to about 2000 mg.
  • the total daily dose of 17 HPC administered to a human subject in milligrams is about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,
  • the 17 HPC is administered one, two or three times a day as one, two, three or four unit dosage forms (e.g., up to 12 unit dosage forms per day) to yield the total daily dose provided in this paragraph.
  • the total daily dose can provide a 17-hydroxyprogesterone caproate C avg-24h of greater than about 0.1, 0.5 or 1.0 ng/mL when admistered to a human subject (female or pregnant female) once, twice or three times daily as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms.
  • the daily dose is from 525 mg per day to about 1400 mg per day. In one aspect, the daily dose is from 800 mg per day to about 1400 mg per day.
  • the daily dose is from 900 mg per day to about 1200 mg per day.
  • the daily dose is provided by one or more unit dosage form, which is a tablet, capsule, solution, suspension, or sprinkle for oral administration.
  • the unit dosage form has a surfactant e.g., at least 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, or 50 mg of a non-ionic or ionic surfactant.
  • the unit dosage form has one or more of (1) a lipophilic additive, (2) a diluent (3) a binder (4) a disintegrant, (5) a lubricant and (6) one or more other pharmaceutically acceptable excipients.
  • the unit dosage form has a lipophilic additive, binder, a diluent, a disintegrant or a combination thereof individually or together in an amount of e.g., at least 10, 20, 30, 40, 50, 100, 150, 200, 300, 400, or 500 mg (or within a range defined by any two of these values.)
  • the total daily dose of 17 HPC administered to a human subject in milligrams is about 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 5
  • the 17 HPC is administered one, two or three times a day as one, two, three or four unit dosage forms (e.g., up to 12 unit dosage forms per day) to yield the total daily dose provided in this paragraph.
  • the total daily dose can provide a 17-hydroxyprogesterone caproate C avg-24h of greater than about 0.1, 0.5 or 1.0 ng/mL when admistered to a human subject (female or pregnant female) once, twice or three times daily as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms.
  • the daily dose is from 525 mg per day to about 1400 mg per day. In one aspect, the daily dose is from 800 mg per day to about 1400 mg per day.
  • the daily dose is from 900 mg per day to about 1200 mg per day.
  • the daily dose is provided by one or more unit dosage form, which is a tablet, capsule, solution, suspension, or sprinkle for oral administration.
  • the unit dosage form has a surfactant e.g., at least 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, or 50 mg of a non-ionic or ionic surfactant.
  • the unit dosage form has one or more of (1) a lipophilic additive, (2) a diluent (3) a binder (4) a disintegrant, (5) a lubricant and (6) one or more other pharmaceutically acceptable excipients.
  • the unit dosage form has a lipophilic additive, binder, a diluent, a disintegrant or a combination thereof individually or together in an amount of e.g., at least 10, 20, 30, 40, 50, 100, 150, 200, 300, 400, or 500 mg (or within a range defined by any two of these values.)
  • the total daily dose of 17 HPC administered to a human subject in milligrams is about 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 8
  • the 17 HPC is administered one, two or three times a day as one, two, three or four unit dosage forms (e.g., up to 12 unit dosage forms per day) to yield the total daily dose provided in this paragraph.
  • the total daily dose can provide a 17-hydroxyprogesterone caproate C avg-24h of greater than about 0.1, 0.5 or 1.0 ng/mL when admistered to a human subject (female or pregnant female) once, twice or three times daily as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms.
  • the daily dose is from 525 mg per day to about 1400 mg per day. In one aspect, the daily dose is from 800 mg per day to about 1400 mg per day.
  • the daily dose is from 900 mg per day to about 1200 mg per day.
  • the daily dose is provided by one or more unit dosage form, which is a tablet, capsule, solution, suspension, or sprinkle for oral administration.
  • the unit dosage form has a surfactant e.g., at least 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, or 50 mg of a non-ionic or ionic surfactant.
  • the unit dosage form has one or more of (1) a lipophilic additive, (2) a diluent (3) a binder (4) a disintegrant, (5) a lubricant and (6) one or more other pharmaceutically acceptable excipients.
  • the unit dosage form has a lipophilic additive, binder, a diluent, a disintegrant or a combination thereof individually or together in an amount of e.g., at least 10, 20, 30, 40, 50, 100, 150, 200, 300, 400, or 500 mg (or within a range defined by any two of these values.)
  • a unit dosage form (e.g., tablet, capsule, caplet etc.) having a milligram amount of 17 HPC of about 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284,
  • the oral dosage form or pharmaceutical composition can provide a 17-hydroxyprogesterone caproate C avg-24h of greater than about 0.1, 0.5 or 1.0 ng/mL when admistered to a human subject (female or pregnant female) once or twice daily as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms.
  • the release of of 17 HPC from the unit dosage form is tested using a USP Type II apparatus at 50 or 100 rpm in about 1000 mL of from about 2% to about 16% (e.g., 2%, 4%, 6%, 8%, 10%, 12%, 14% or 16%) Triton X-100 solution in water at a specific temperature e.g., 20.0, 37.0 or 40.0° C. ( ⁇ 0.5).
  • the unit dosage form release greater than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% at one hour.
  • the unit dosage form has a surfactant e.g., at least 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, or 50 mg of a non-ionic or ionic surfactant.
  • the unit dosage form has one or more of (1) a lipophilic additive, (2) a diluent (3) a binder (4) a disintegrant, (5) a lubricant and (6) one or more other pharmaceutically acceptable excipients.
  • the unit dosage form has a lipophilic additive, binder, a diluent, a disintegrant or a combination thereof individually or together in an amount of e.g., at least 10, 20, 30, 40, 50, 100, 150, 200, 300, 400, or 500 mg (or within a range defined by any two of these values.)
  • a unit dosage form (e.g., tablet, capsule, caplet etc.) having a milligram amount of 17 HPC of about 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381,
  • the oral dosage form or pharmaceutical composition can provide a 17-hydroxyprogesterone caproate C avg-24h of greater than about 0.1, 0.5 or 1.0 ng/mL when admistered to a human subject (female or pregnant female) once or twice daily as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms.
  • the release of of 17 HPC from the unit dosage form is tested using a USP Type II apparatus at 50 or 100 rpm in about 1000 mL of from about 2% to about 16% (e.g., 2%, 4%, 6%, 8%, 10%, 12%, 14% or 16%) Triton X-100 solution in water at a specific temperature e.g., 20.0, 37.0 or 40.0° C. ( ⁇ 0.5).
  • the unit dosage form release greater than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% at one hour.
  • the unit dosage form has a surfactant e.g., at least 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, or 50 mg of a non-ionic or ionic surfactant.
  • the unit dosage form has one or more of (1) a lipophilic additive, (2) a diluent (3) a binder (4) a disintegrant, (5) a lubricant and (6) one or more other pharmaceutically acceptable excipients.
  • the unit dosage form has a lipophilic additive, binder, a diluent, a disintegrant or a combination thereof individually or together in an amount of e.g., at least 10, 20, 30, 40, 50, 100, 150, 200, 300, 400, or 500 mg (or within a range defined by any two of these values.)
  • a unit dosage form (e.g., tablet, capsule, caplet etc.) having a milligram amount of 17 HPC of about 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529,
  • the oral dosage form or pharmaceutical composition can provide a 17-hydroxyprogesterone caproate C avg-24h of greater than about 0.1, 0.5 or 1.0 ng/mL when admistered to a human subject (female or pregnant female) once or twice daily as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms.
  • the release of of 17 HPC from the unit dosage form is tested using a USP Type II apparatus at 50 or 100 rpm in about 1000 mL of from about 2% to about 16% (e.g., 2%, 4%, 6%, 8%, 10%, 12%, 14% or 16%) Triton X-100 solution in water at a specific temperature e.g., 20.0, 37.0 or 40.0° C. ( ⁇ 0.5).
  • the unit dosage form release greater than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% at one hour.
  • the unit dosage form has a surfactant e.g., at least 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, or 50 mg of a non-ionic or ionic surfactant.
  • the unit dosage form has one or more of (1) a lipophilic additive, (2) a diluent (3) a binder (4) a disintegrant, (5) a lubricant and (6) one or more other pharmaceutically acceptable excipients.
  • the unit dosage form has a lipophilic additive, binder, a diluent, a disintegrant or a combination thereof individually or together in an amount of e.g., at least 10, 20, 30, 40, 50, 100, 150, 200, 300, 400, or 500 mg (or within a range defined by any two of these values.)
  • the oral dosage form of the current invention comprises a therapeutically effective amount of an ester of 17-hydroxyprogesterone, wherein, 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., the oral dosage form releases at least 20 wt % of the dose of the ester of 17-hydroxyprogesterone after 60 minutes, In another particular embodiment, the dosage form releases at least about 40 wt % of the dose of the ester of 17-hydroxyprogesterone after 60 minutes.
  • the dosage form releases at least about 50 wt % of the dose of the ester of 17-hydroxyprogesterone after 60 minutes. In another particular embodiment, the dosage form releases at least about 70 wt % of the dose of the ester of 17-hydroxyprogesterone after 60 minutes. In a specific embodiment the ester is 17-hydroxyprogesterone caproate. In another embodiment, the dosage form is administered with food.
  • the ester of 17-hydroxyprogesterone e.g., 17-hydroxyprogesterone caproate
  • its concentration in the serum, plasma or blood of the subject may be determined by analytical techniques based on radio-immunoassay (MA), 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 be made to adjust for discrepancy for assay specificity.
  • MA radio-immunoassay
  • HPLC-MS/MS high performance liquid chromatography—Mass Spectroscopy
  • the 17-hydroxyprogesterone caproate compositions or dosage forms of the present invention can provide a mean steady state 17-hydroxyprogesterone caproate mean C max from about 10 ng/mL to about 800 ng/mL, wherein the plasma 17-hydroxyprogesterone caproate is determined by HPLC-MS/MS method.
  • the compositions or dosage forms provides a mean steady state 17-hydroxyprogesterone caproate mean C max from about 10 ng/mL to about 400 ng/mL.
  • the 17-hydroxyprogesterone caproate compositions or oral dosage forms of the present invention can provide a 17-hydroxyprogesterone caproate mean steady state C min of about 1 ng/mL or more.
  • the plasma concentrations of the 17-hydroxyprogesterone caproate can be determined by HPLC-MS/MS method.
  • the compositions or oral dosage forms can provide a 17-hydroxyprogesterone caproate mean steady state C min greater than about 10 ng/mL.
  • the composition or oral dosage forms can provide a 17-hydroxyprogesterone caproate mean steady state C min greater than about 20 ng/mL, or greater than about 40 ng/ml, greater than about 60 ng/mL, or greater than about 80 ng/mL.
  • the composition or oral dosage form can provide a mean steady state of about 1 to about 60 ng/mL.
  • the composition or dosage form can provide a mean steady state C min of about 1 ng/mL to about 20 ng/mL.
  • the 17-hydroxyprogesterone caproate compositions or oral dosage forms or method described herein can provide a 17-hydroxyprogesterone caproate mean steady state C min of greater than about 0.001, 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 ng/mL (or within a range defined by any two of these values).
  • the plasma concentrations of the 17-hydroxyprogesterone caproate can be determined by HPLC-MS/MS method.
  • the Cmin range occurs for less than 4 hours, 3, hours, 2 hours or 0.5 hours per day.
  • the Cmin values in this paragraph are threshold values for which the patient does not have values lower than these values or ranges for more than 4 hours, 3, hours, 2 hours, 0.5 hours or 0.25 hours per day.
  • the oral dosage form of 17-hydroxyprogesterone caproate of the present invention can be an immediate release dosage form.
  • the oral dosage form of the 17-hydroxyprogesterone caproate of the present invention can be a controlled release dosage form.
  • dosage form can include 17-hydroxyprogesterone caproate in the form of both immediate release and controlled release fractions, preferably extended or delayed release.
  • the controlled release 17-hydroxyprogesterone caproate compositions or dosage forms of the present invention can provide a fluctuation in the 17-hydroxyprogesterone caproate levels less than about 795 ng/mL, wherein the fluctuation is determined by the difference of the mean steady state C max and the mean steady state C min of 17-hydroxyprogesterone caproate in plasma or serum or blood, upon oral administration.
  • 17-hydroxyprogesterone caproate compositions or dosage forms of the present invention can provide a fluctuation in the 17-hydroxyprogesterone caproate levels less than about 2000, 1500, 1000, 900, 800, 700, 600, 500, 400, 300, 200, 175, 150, 140, 130, 120, 110 or 100 ng/mL, wherein the fluctuation is determined by the difference of the mean steady state C max and the mean steady state C min of 17-hydroxyprogesterone caproate in plasma or serum or blood, upon oral administration.
  • 17-hydroxyprogesterone caproate compositions or dosage forms of the present invention can provide a fluctuation in the 17-hydroxyprogesterone caproate levels greater than about 1, 10, 15, 25, 50, 75, 100, 200, 300 or 400 ng/mL, wherein the fluctuation is determined by the difference of the mean steady state C max and the mean steady state C min of 17-hydroxyprogesterone caproate in plasma or serum or blood, upon oral administration.
  • the fluctuation falls within a range defined by any two of the values in the greater than and less than embodiments.
  • 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.
  • the oral pharmaceutical compositions and/or dosage forms of 17-hydroxyprogesterone caproate of the current invention can be used for testing endogenous estrogen production, and for the production of secretory endometrium and desquamation.
  • 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.
  • the current invention compositions and/or dosage forms may include at least one omega fatty acid.
  • the current invention compositions and/or dosage form may include omega-3, omega-6 or omega-9 fatty acid or mixtures thereof.
  • a method for treating a pregnant female based on gestational age involves treating a pregnant female with a pharmaceutically composition formulated for oral administration comprising 17 HPC and a pharmaceutically acceptable carrier with an initial gestational age daily dose of 17 HPC.
  • the initial gestational age daily dose of 17 HPC is selected or determined based on gestational age. For example, initiation of treatment of a pregnant female with a gestational age of 20 weeks involves a daily dose of 17 HPC appropriate for this gestational age. Initiation of treatment of a pregnant female with a gestational age of 26 weeks involves a daily dose appropriate for this gestational age.
  • the initial gestational age daily dose for 20 weeks gestational age and 26 weeks gestational age can be the same or differ (a non-limiting example is that a 20 week initial gestational age daily dose can be e.g., 550 mg 17 HPC per day orally whereas a 20 week initial gestational age daily dose can be e.g., 750 mg 17 HPC per day orally).
  • Gestational age can be determined by any appropriate method including directly calculating the days since the beginning of the last menstrual period, early obstetric ultrasound, and the like.
  • a pregnant female being treated with an initial gestational age daily dose of 17 HPC can be maintained on the same daily dose of 17 HPC throughout the pregnancy or have a daily dose alteration based on a later gestational age.
  • the initial gestational age daily dose can be between 10 mg to 1500 mg per day orally and after 1 day, 2 days, 3, days, 5 days, 7 days, 10 days, 14 days, 18 days, 21 days or more on the initial gestational age daily dose, the dose can be adjusted within plus/minus 5 mg to 1495 mg per day orally which is a referred to as a second gestational age daily dose.
  • the second gestational age daily dose can be adjusted after 1 day, 2 days, 3, days, 5 days, 7 days, 10 days, 14 days, 18 days, 21 days or more on the second gestational age daily dose, the dose can be adjusted within plus/minus 5 mg to 1495 mg per day orally of the second gestational age daily dose—this new daily dose is referred to as the third gestational age daily dose.
  • the gestational age treatment can be based on IM injection.
  • 17 HPC is formulated as an IM injection and the amount of 17 HPC administered via the IM route is based on the gestational age.
  • the oil can be castor oil or another suitable vegetable oil (e.g., corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil)).
  • the formulation can include one or more of benzyl benzoate, benzyl alcohol.
  • the formulation can include a surfactant (e.g., non-ionic surfactant) or more or more other optional additives.
  • the initial gestational dose and second gestational age doses of 17 HPC are within the range of about 50 mg to 1000 mg per week (or e.g., 100 mg to 2000 mg every two weeks or 200 mg to 4000 mg per month).
  • the dose is then adjusted based on gestational are as general described above although the dose changes correlate to about 25 mg or less, 50 mg or less, 100 mg or less or 200 mg or less per week of IM 17 HPC.
  • a method of administering 17 HPC to a female involves administering to or treating a female with a pharmaceutical composition formulated for oral administration comprising 17 HPC and a pharmaceutically acceptable carrier with an initial daily dose of 17 HPC.
  • the initial daily dose of 17 HPC is in the range of 10 mg to 1500 mg per day.
  • a biomarker from the female being treated is measured or the level of the biomarker is determined. If the biomarker is within a maintenance target range, then the female continues to receive the same daily dose.
  • the female is administered a second daily dose that is greater than the initial daily dose. If the biomarker is within a down-titration target range, then the female is administered a second daily dose that is less than the initial daily dose.
  • the daily dose changes between the initial and second daily doses are within plus/minus 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of each other.
  • an up-titration or down titration can be a change from the initial daily dose of about 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg 80-90 mg, 90-100 mg, 100-125 mg, 125-150 mg, 150-175 mg or 175-200 mg (or 200-225 mg, 225-250 mg, 250-300 mg, 300-325 mg, 325-350 mg, 350-400 mg, 400-425 mg, 425-450 mg, or 450-500 mg).
  • the biomarker used to determine titration can be any appropriate biomarker.
  • the biomarker can be an efficacy biomarker, a safety biomarker or a combination thereof.
  • the biomarker can be 17 HPC or a metabolite thereof.
  • 17 HPC or a metabolite thereof can be serum 17 HPC or metabolite thereof, urinary 17 HPC or a metabolite thereof, salivary 17 HPC or a metabolite thereof.
  • the biomarker can be a steroid e.g., progesterone or a metabolite thereof (serum, salivary, urinary).
  • the biomarker can be any biomarker specified in this application or otherwise useful for determining titrations.
  • the titration biomarker is serum 17 HPC (a pharmacokinetic parameter).
  • the daily dose of 17 HPC daily dose can be increased, if the serum 17 HPC is above a maximum target threshold, then the 17 HPC daily dose can be decreased, or if the serum 17 HPC is within a target range that is deemed sufficient, then the daily dose can be maintained.
  • the serum 17 HPC e.g., C avg , C min , C max or any other pharmacokinetic parameter and particularly described herein
  • the target is can provide a 17-hydroxyprogesterone caproate C avg-24h greater than about 0.05, 0.1, 0.5, 0.7, 1.0, 1.5, 2.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 35.0, 40.0, 45.0, 50.0 60.0, 75.0 or 100 ng/mL (or alternatively less than any of these values or alternatively within a range defined by any two of these values).
  • the said 17-hydroxyprogesterone caproate C avg-24h is determined by an HPLC-MS/MS method of analysis of the plasma, serum or blood samples collected following the oral administration.
  • the oral pharmaceutical composition comprises 17-hydroxyprogesterone caproate and a pharmaceutically acceptable carrier, 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., at least 20% of the 17-hydroxyprogesterone caproate is released from the oral composition at 60 minutes.
  • the oral pharmaceutical composition comprises: 17-hydroxyprogesterone caproate, and a pharmaceutically acceptable carrier including at least a hydrophilic surfactant.
  • the oral pharmaceutical composition comprises: 17-hydroxyprogesterone caproate having a mean particulate diameter of about 50 micron or less, and a pharmaceutically acceptable carrier including at least a hydrophilic surfactant.
  • the oral pharmaceutical composition comprises: 17-hydroxyprogesterone caproate having a mean particulate diameter of about 50 micron or less, and a pharmaceutically acceptable carrier including at least a hydrophilic surfactant 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., at least 20% of the 17-hydroxyprogesterone caproate is released from the oral composition at 60 minutes.
  • the oral pharmaceutical composition comprises: 17-hydroxyprogesterone caproate having a mean particulate diameter of about 50 micron or less, and a pharmaceutically acceptable carrier including at least a hydrophilic surfactant; wherein the amount of the 17-hydroxyprogesterone caproate is from about 5% to about 80% w/w of the total composition; and 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., at least 20% of the 17-hydroxyprogesterone caproate is released from the oral composition at 60 minutes.
  • the oral pharmaceutical composition comprises a hydrophilic surfactant, which is an ionic hydrophilic surfactant. In one aspect, the oral pharmaceutical composition comprises a hydrophilic surfactant, which is a non-ionic hydrophilic surfactant. In one aspect, the oral pharmaceutical composition comprises a hydrophilic surfactant, which is a poloxamer, a polyethylene glycol sorbitan fatty acid ester, a sorbitan fatty acid ester, a polyethylene glycol glycerol fatty acid ester or a combination thereof.
  • the oral pharmaceutical composition comprises a hydrophilic surfactant, which is sodium lauryl sulfate, sodium dioctyl sulfosuccinate, a lecithin, a bile salt or a combination thereof.
  • the oral pharmaceutical composition further comprises 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.
  • the oral pharmaceutical composition is formulated as a powder, granulate, particulate, bead, pellet, sprinkle, suspension, solution, tablet, capsule, or a combination thereof.
  • the oral pharmaceutical composition is formulated as a capsule.
  • the oral pharmaceutical composition is formulated as a tablet.
  • the oral pharmaceutical composition comprises an amount of 17-hydroxyprogesterone caproate equivalent to from about 20 mg to about 400 mg of 17-hydroxyprogesterone.
  • the oral pharmaceutical composition has from about 20 mg to about 800 mg 17-hydroxyprogesterone caproate.
  • the oral pharmaceutical composition has from about 10 mg to about 300 mg 17-hydroxyprogesterone caproate.
  • Example 58 There was a good correlation of C max to C avg and C avg to pre-dose C value which enables single point titration (e.g., based on serum or plasma 17 HPC levels at a single time point with 0-12 hours after single dose administration at steady state (e.g., at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, or 11.5 hours after single dose administration (or within a range defined by any two of these values, or within a range of within 0.5 h or 1 h of any one of these values))).
  • single point titration e.g., based on serum or plasma 17 HPC levels at a single time point with 0-12 hours after single dose administration at steady state (e.g., at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10,
  • a pregnant female at risk for preterm birth is administered orally, a pharmaceutical composition (e.g., as described herein), in an initial dosing regimen, until steady state is achieved (e.g., 5 or more days, 6 or more days, 7 or more days).
  • a pharmaceutical composition e.g., as described herein
  • steady state e.g., 5 or more days, 6 or more days, 7 or more days.
  • the initial dosing regimen (or alternatively after titration can be) can be e.g., 400 mg per day, 450 mg per day, 500 mg per day, 550 mg per day, 600 mg per day, 650 mg per day, 700 mg per day, 750 mg per day, 800 mg per day, 850 mg per day, 900 mg per day, 950 mg per day, 1000 mg per day, 1150 mg per day, 1200 mg per day, 1250 mg per day, 1300 mg per day, 1350 mg per day, 1400 mg per day, 1450 mg per day, 1500 mg per day, 1550 mg per day, 1600 mg per day, 1650 mg per day, 1700 mg per day, 1750 mg per day, 1800 mg per day, 1850 mg per day, 1900 mg per day, 1950 mg per day or 2000 mg per day (or within a range defined by any two of these values, or within a range of within 50 mg or 100 mg of any one of these values) e.g., on a once, twice, thrice, or four times a
  • the plasma or serum 17 HPC in the subject is determined and if the levels are too low, the daily dose is increased, if the levels are too high, the daily dose is increased or if they levels are appropriate, the daily dose is maintained.
  • the pharmaceutical composition can delivery the daily dose in e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 unit dosage forms per day.
  • the pharmaceutical compositions containing 17 HPC are for use in conditions associated with preterm labor.
  • a method for treating preterm labor or a condition associated with preterm labor involves orally administering a pharmaceutical composition comprising 17 HPC and a pharmaceutically acceptable carrier to a pregnant female experiencing preterm labor, at risk for preterm labor or after preterm labor.
  • the method and oral pharmaceutical composition can reduce the risk of preterm labor, reduce the risk of preterm birth as a result of preterm labor, provide tocolytic effect, improve tocolysis, provide maintenance tocolysis, reduce preterm birth, reduce the risk of miscarriage, improve neonatal outcome, prolong gestation, improve postnatal outcome, improve maternal outcome, improve Bayley Scales of Infant Development Scores (including one or more of motor (fine, gross or both), language (receptive, expressive or both), and cognitive development), improve scores on Social-Emotional Adaptive Behavior Questionnaire, or a combination thereof.
  • the pharmaceutical composition and method of this embodiment can improve neonatal outcomes including birth weight gestational age or both.
  • the pharmaceutical composition and method of this embodiment can improve maternal, infant and child outcomes as described elsewhere herein.
  • Preterm labor refers to regular contractions of the uterus that result in changes in the cervix that occur before 37 weeks of pregnancy. Changes in the cervix include effacement (e.g., the cervix thins out) and dilation (e.g., the cervix opens so that the fetus can enter the birth canal).
  • preterm labor is diagnosed by transvaginal ultrasound, fetal fibronectin in vaginal discharge or both.
  • a pregnant female experiencing preterm labor is administered an oral pharmaceutical composition having 17 HPC and a pharmaceutically acceptable carrier.
  • a method for improving one or more of maternal, infant and child outcomes is provided.
  • the method involves administering to a female that recently experienced preterm labor e.g., within 3 weeks, 2 weeks, 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day an oral pharmaceutical composition having 17 HPC and a pharmaceutically acceptable carrier.
  • the pregnant female can have had the preterm labor stop, subside or lessen without pharmaceutical intervention or alternatively the preterm labor was treated medically with a pharmaceutical intervention.
  • the pharmaceutical intervention is magnesium sulfate or a tocolytic.
  • the daily dose of 17 HPC and per unit dosage are as described herein.
  • the daily dose of 17 HPC ranges from about 550 mg to about 1600 mg.
  • the unit dosage forms comprise from about 250 mg to about 800 mg of 17 HPC.
  • a combination therapy comprising oral 17 HPC and a second agent.
  • the second agent can be a pharmaceutical agent, a vitamin, a mineral, supplement, etc.
  • a combination therapy comprising oral 17 HPC and a compound chosen from a progestogen, a corticosteroid, a tocolytic, an antibiotic, a vitamin D compound or a combination thereof.
  • the combination therapy in some aspects, involves a co-formulation of oral 17 HPC and a compound chosen from a progestogen, a corticosteroid, a tocolytic, an antibiotic, a vitamin D compound or a combination thereof.
  • the co-formulation is orally administered to a subject in need thereof.
  • a co-formulation of (1) 17 HPC, (2) one or more of a progestogen, a corticosteroid, a tocolytic, an antibiotic, a vitamin D compound and (3) a pharmaceutically acceptable carrier is administered to a pregnant female.
  • the combination therapy involves a co-administration of oral 17 HPC and a compound chosen from a progestogen, a corticosteroid, a tocolytic, an antibiotic, a vitamin D compound or a combination thereof.
  • Co-administration refers to oral administration of 17 HPC and enteral, parenteral or topical administration of one or more of a progestogen, a corticosteroid, a tocolytic, an antibiotic and a vitamin D compound.
  • a combination therapy comprising oral 17 HPC and a compound chosen from an antenatal corticosteroid, beta-adrenergic receptor agonist, a calcium channel blocker, magnesium sulfate, an NSAID, an oxytocin antagonist or a combination thereof.
  • the pharmaceutical compositions and methods of this embodiment can improve maternal, infant and child outcomes as described elsewhere herein.
  • compositions comprising 17 HPC and a pharmaceutically acceptable carrier can be co-formulated or co-administered with prenatal vitamins or supplements and the like.
  • the pharmaceutical compositions described herein can be co-administered or co-formulated with A, B3, B6, C, D, folic acid, calcium, iron, magnesium, manganese, phosphorus, potassium, sodium, zinc, omega-3, eicosapentaenoic acid (EPA), docosahexaenoic (DHA) or a combination thereof.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic
  • one or more of, 400 micrograms (mcg) of folic acid, 400 IU of vitamin D, 200 to 300 mg of calcium, 65-75 mg of vitamin C, 2-4 mg of thiamine, 1-3 mg of riboflavin, 14-25 mg of niacin, 4-8 mcg of vitamin B12, 8-12 mg of vitamin E, 13-17 mg of zinc, 15-19 mg of iron, 140-160 micrograms of iodine can be co-administered with the pharmaceutical compositions comprising 17 HPC and a pharmaceutically acceptable carrier described herein.
  • Co-administration does not necessarily mean that the compositions are administered at the same time.
  • the prenatal vitamins can be administered once-a-day (or more) and a different time of day than the 17 HPC containing compositions (which could be administered e.g., two time or three times daily).
  • compositions and methods for treating a pregnant female is provided.
  • a therapy comprising vitamin D and oral 17 HPC is provided.
  • the therapy comprises administration of oral 17 HPC and oral vitamin D to a pregnant female.
  • the daily dose of 17 HPC and per unit dosage are as described herein.
  • the daily dose of 17 HPC ranges from about 550 mg to about 1600 mg.
  • the unit dosage forms comprise from about 250 mg to about 800 mg of 17 HPC.
  • the daily dose of vitamin D is 200 IU per day or more.
  • the daily dose of vitamin D is 400 IU per day or more.
  • the daily dose of vitamin D is 600 IU per day or more.
  • the daily dose of vitamin D is 800 IU per day or more. In another aspect, the daily dose of vitamin D is 1000 IU per day or more. In another aspect, the daily dose of vitamin D is 1500 IU per day or more. In another aspect, the daily dose of vitamin D is 2000 IU per day or more. In another aspect, the daily dose of vitamin D is 3000 IU per day or more. In another aspect, the daily dose of vitamin D is 4000 IU per day or more. In another aspect, the daily dose of vitamin D is 5000 IU per day or more. In another aspect, the daily dose of vitamin D is 4000 IU per day or more. In another aspect, the daily dose of vitamin D is 6000 IU per day or more.
  • the daily dose of vitamin D is from 450 to 8000 IU per day or more. In another aspect, the daily dose of vitamin D is from 450 to 3000 IU per day or more. In another aspect, the daily dose of vitamin D is from 450 to 2000 IU per day or more. In another aspect, the daily dose of vitamin D is from 450 to 2000 IU per day or more. In one aspect, the daily dose of vitamin D is based at least in part on first, second, or third trimester serum vitamin D levels of the pregnant female. For example, in one aspect, the dose of vitamin D is chosen such that the level of serum vitamin D falls within the range of about 50 to about 75 nmol/L.
  • the dose of vitamin D is chosen such that the level of serum vitamin D is greater than about 50 nmol/L. In another aspect, the dose of vitamin D is chosen such that the level of serum vitamin D falls is greater than about 75 nmol/L. In another aspect, the dose of vitamin D is chosen such that the level of serum vitamin D is greater than about 100 nmol/L. In another aspect, the dose of vitamin D is chosen such that the level of serum vitamin D is greater than about 125 nmol/L. In another aspect, the dose of vitamin D is chosen such that the level of serum vitamin D is greater than about 150 nmol/L. In another aspect, the dose of vitamin D is chosen such that the level of serum vitamin D is greater than about 175 nmol/L.
  • the daily dose of vitamin D is chosen such that the level of serum vitamin D falls within a range of about 50 nmol/L to about 200 nmol/L. In another aspect, the dose of vitamin D is chosen such that the level of serum vitamin D is greater than about 500, 400, 300 or 200 nmol/L. In one aspect, the serum level of the pregnant female is titrated into a selected range or value. For example, the pregnant female is administered a dose of vitamin D, e.g., 200 IU per day and it is determined that this daily dose has not provided her with sufficient vitamin D.
  • the dose can then be increased, e.g., by 50 IU or more, 100 IU or more, 200 IU or more, 300 IU or more, until the desired target vitamin D level is reached.
  • the vitamin D daily dose can be down-titrated into the target range in a similar manner.
  • the serum vitamin D is 25-hydroxyvitamin D (the target serum vitamin D levels or ranges are for 25-hydroxyvitamin D).
  • the pharmaceutical composition that is administered comprises cholecalciferol or ergocalciferol.
  • the pharmaceutical composition that is administered comprises alfacalcidol, calcifediol, calcitriol, dihydrotachysterol or combination thereof.
  • the pharmaceutical composition that is administered comprises cholecalciferol, alfacalcidol, calcifediol, calcitriol, dihydrotachysterol or a combination thereof and 17 HPC.
  • the amount of vitamin D administered is in addition to that being provided by prenatal vitamins or supplements to the pregnant female.
  • the pharmaceutical composition that is administered comprises at least 50 IU cholecalciferol and at least 50 mg 17 HPC.
  • the pharmaceutical composition that is administered comprises 50 IU to 400 IU cholecalciferol and 100 mg to 450 mg 17 HPC.
  • the combination composition is formulated for parenteral administration. In another aspect, the combination composition is formulated for oral administration.
  • the daily comprises at least 200 IU cholecalciferol and at least 200 mg 17 HPC. In one aspect, the daily dose comprises 200 IU to 4000 IU cholecalciferol and 400 mg to 1600 mg 17 HPC. In one aspect, the daily dose comprises 200 IU to 4000 IU cholecalciferol and 550 mg to 1600 mg 17 HPC.
  • the method and composition according to this embodiment provide one or more of an improvement in maternal, infant and child outcomes with respect to a pregnant female.
  • pregnant female is at risk for preterm birth due to previous low birth weight or preterm delivery, multiple 2nd trimester spontaneous abortion, exposure to tobacco smoke or tobacco smoke residue, use of smokeless tobacco, substance use or abuse or dependence, alcohol use or abuse or dependence, stress, anxiety, depression, short stature, poor nutritional status, insufficient weight gain during pregnancy, low prepregnancy weight/low body mass index, advanced maternal age, low socio-economic status, prior first trimester induced abortion, familial and intergenerational factors, history of infertility, nulliparity, placental abnormalities, cervical and uterine anomalies, gestational bleeding, intrauterine growth restriction, in utero diethylstilbestrol exposure, multiple gestations, infant sex (e.g., fetal male), urogenital infections, preeclampsia or a combination thereof.
  • infant sex e.g., fetal male
  • urogenital infections preeclampsia or a combination thereof.
  • a therapy comprising intramuscular injection of vitamin D and 17 HPC to a pregnant female.
  • a pregnant female is administered from 100 mg/mL to 500 mg/mL of 17 HPC per week and from 10,000 IU to 300000 IU cholecalciferol per week.
  • a pregnant female is administered from 100 mg/mL to 500 mg/mL of 17 HPC per week and from 10,000 IU to 100000 IU cholecalciferol per week.
  • a pregnant female is administered from 100 mg to 500 mg of 17 HPC per week and from 10,000 IU to 50000 IU cholecalciferol per week.
  • the vitamin D and 17 HPC are coformulated for IM injection. In another aspect, the vitamin D and 17 HPC are formulated separately.
  • the values described in this embodiment can be for one week, two weeks, three weeks or more. For example, a two week dose can be provides which would be twice the dose of the one week dose.
  • a pregnant female is administered from a dose of about 200 mg to 300 mg (e.g., 1 mL of 250 mg/mL 17 HPC) of 17 HPC per week and a dose of from 10,000 IU to 50000 IU cholecalciferol per week.
  • the 17 HPC, cholecalciferol, or both can be formulated for IM injection in a vehicle having an oil suitable for IM injection and optionally a solubilizer.
  • the oil can be castor oil or another suitable vegetable oil (e.g., corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil)).
  • the formulation can include one or more of benzyl benzoate, benzyl alcohol.
  • the formulation can include a surfactant (e.g., non-ionic surfactant) or more or more other optional additives.
  • beta-adrenergic receptor agonist examples include, but are not limited to, fenoterol, terbutaline, salbutamol, and nifedipine.
  • NSAIDs include, but are not limited to, indomethacin, ketorolac and sulindac.
  • An example of a calcium channel blocker includes, but is not limited to, nifedipine.
  • An example of an oxytocin antagonist includes, but is not limited to, atosiban.
  • examples of antenatal corticosteroids examples include, but are not limited to, betamethasone and dexamethasone.
  • antibiotics examples include, but are not limited to ampicillin and penicillin.
  • vitamin D compounds examples include, but are not limited to, cholecalciferol and ergocalciferol.
  • progestogens examples include, but are not limited to, progesterone and dydrogesterone.
  • Nifedipine can be administered at e.g., an initial oral dose of 20 mg followed by 10-20 mg three to four times daily, adjusted according to uterine activity for up to 48 hours. Total doses above 60 mg appear to be associated with increased adverse events. Atosiban can be administered e.g., as an initial bolus dose of 6.75 mg over 1 minute, followed by an infusion of 18 mg/hour for 3 hours, then 6 mg/hour for up to 45 hours (to a maximum of 330 mg).
  • a method of treatment involves orally administering to a pregnant female a pharmaceutical composition having 17 HPC and a pharmaceutically acceptable carrier where the preganant female is at risk for preterm birth due to previous low birth weight or preterm delivery, multiple 2nd trimester spontaneous abortion, exposure to tobacco smoke or tobacco smoke residue, use of smokeless tobacco, substance use or abuse or dependence, alcohol use or abuse or dependence, stress, anxiety, depression, short stature, poor nutritional status, insufficient weight gain during pregnancy, low prepregnancy weight/low body mass index, advanced maternal age, low socio-economic status, prior first trimester induced abortion, familial and intergenerational factors, history of infertility, nulliparity, placental abnormalities, cervical and uterine anomalies, gestational bleeding, intrauterine growth restriction, in utero diethylstilbestrol exposure, multiple gestations, infant sex, urogenital infections, preeclampsia or a combination thereof.
  • the ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is provided herein which is crystalline.
  • the crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) can be a particular crystal form, a solvate of a crystal form, a polymorph, a pseudopolymorph, a pharmaceutically acceptable solvate, or a hydrate.
  • the crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is a crystal form substantially free of other crystal forms of ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • the crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is substantially free of amorphous ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • amorphous ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is provided which is substantially free of crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • Ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is provided herein having a particular size characteristic.
  • ester of 17-hydroxyprogesterone e.g., 17-hydroxyprogesterone caproate
  • ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is provided wherein the particle size is less than 200 nm (“nanometer”), from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 ⁇ m (“micrometer”), from 50 to 250 ⁇ m, from 250 to 500 ⁇ m, from 500 to 1000 ⁇ m, or greater than 1000 ⁇ m.
  • ester of 17-hydroxyprogesterone having a d 50 of greater than 1000 ⁇ m, from 355 to 1000 ⁇ m, from 180 to 355 ⁇ m, from 125 to 180 ⁇ m, 90 to 125 ⁇ m 1 to 90 ⁇ m, or less than 1 ⁇ m.
  • the mean particle size of ester of 17-hydroxyprogesterone is from 1 to 40 ⁇ m, from 1 to 30 ⁇ m, or from 1 to 25 ⁇ m.
  • the ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate has a D 10 , D 50 , or D 90 that is less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 ⁇ m, from 50 to 250 ⁇ m, from 250 to 500 ⁇ m, from 500 to 1000 ⁇ m, or greater than 1000 ⁇ m.
  • the ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) having a particular size or size characteristics is crystalline ester of 17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate).
  • the ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) having a particular size or size characteristics is a crystal form of the ester of 17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate) substantially free of other crystal forms of the ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • the ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) having a particular size or size characteristics is amorphous ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • the ester of 17-hydroxyprogesterone having a particular size or size characteristics is amorphous ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) substantially free of crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • compositions are provided herein having or prepared from ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) as described in the paragraphs above.
  • the pharmaceutical composition is prepared from or has ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) and one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical composition described herein can comprise or be prepared from crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate), amorphous ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate), or a combination thereof.
  • the pharmaceutical composition comprises or is prepared from a particular crystal form, a solvate of a crystal form, a polymorph, a pseudopolymorph, a pharmaceutically acceptable solvate, or a hydrate of crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • the pharmaceutical composition is prepared from or comprises amorphous ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • the pharmaceutical composition comprises or is prepared ester of 17-hydroxyprogesterone (e.g.
  • the pharmaceutical composition comprises or is prepared from an ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) wherein the mean particle size of the API is less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 ⁇ m, from 50 ⁇ m to 250 ⁇ m, from 250 ⁇ m to 500 ⁇ m, from 500 ⁇ m to 1000 ⁇ m, or greater than 1000 ⁇ m.
  • the mean particle size of ester of 17-hydroxyprogesterone is from 1 to 40 ⁇ m, from 1 to 30 ⁇ m, from 1 to 25 ⁇ m, from 1 to 20 ⁇ m, from 1 to 15 ⁇ m, or from 1 to 10 ⁇ m.
  • the pharmaceutical composition comprises or is prepared from an ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) having a d 50 of greater than 1000 ⁇ m, from 355 to 1000 ⁇ m, from 180 to 355 ⁇ m, from 125 to 180 ⁇ m, from 90 to 125 ⁇ m, from 1 to 90 ⁇ m, from 1 to 40 ⁇ m, from 1 to 30 ⁇ m, or from 1 to 25 ⁇ m, or less than 1 ⁇ m.
  • 17-hydroxyprogesterone e.g., 17-hydroxyprogesterone caproate
  • the pharmaceutical composition comprises or is prepared from ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) having a D 10 , D 50 , or D 90 that is less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 ⁇ m, from 50 to 250 ⁇ m, from 250 to 500 ⁇ m, from 500 to 1000 ⁇ m, or greater than 1000 ⁇ m.
  • the pharmaceutical composition of this paragraph is formulated for topical, enteral or parenteral administration.
  • the pharmaceutical composition of this paragraph is formulated for buccal, sublingual, or sublabial administration.
  • the pharmaceutical composition of this paragraph is formulated for nasal, rectal or vaginal administration. In some specific aspects, the pharmaceutical composition of this paragraph is formulated for intravenous, subcutaneous, intramuscular, intradermal, intraspinal, intrathecal, or intra-arterial administration. In some specific aspects, the pharmaceutical composition of this paragraph is formulated as a sprinkle liquid, solution, suspension, dispersion, solid, semi-solid, a gel, a lotion, paste, foam, spray, suspension, dispersion, syrup, or ointment. In some specific aspects, the pharmaceutical composition of this paragraph is formulated as a tincture, patch, injectable, or oral dosage form.
  • the pharmaceutical composition of this paragraph comprises solubilized or partially solubilized ester of 17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate).
  • the pharmaceutical composition or unit dosage forms is suitable for oral administration (e.g., capsule or tablet).
  • D values like D10, D50 or D90 refer the the size of particles e.g., a D10 of 5 micron refers to 10% of the particles having a size of 5 micron or less; a D90 of 17 micron refers to 90% of the particles having a particle size of less than 17 micron.
  • Solid state API e.g., solid state ester of 17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate) described herein, can exist in different crystalline forms as well as in non-crystalline forms.
  • a non-crystalline solid API is referred to herein as an “amorphous form,” which is a disordered arrangement of API molecules.
  • Different crystalline forms of the API e.g., of a specific ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) arise from different packing of the ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) molecules in the solid state, resulting in different crystal symmetries and/or unit cell parameters.
  • Crystalline forms are identified or characterized by any suitable methods e.g., x-ray diffraction (see, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa., p 173 (1990); The United States Pharmacopeia, 23rd ed., pp. 1843-1844 (1995)).
  • Such different crystalline forms are referred to herein as “polymorphic forms” or “non-solvated forms,” which means that they are essentially free of residual solvents e.g., organic solvents.
  • amorphous form as used herein in connection with ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) that is a non-crystalline solid (i.e not in a crystalline form), which is a disordered arrangements of ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) molecules.
  • amorphous ester of 17-hydroxyprogesterone e.g., 17-hydroxyprogesterone caproate
  • Amorphous ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) appears as a halo with no distinctive peaks.
  • Amorphous material for some compounds can be obtained by a number of methods known in the art, including, but not limited to, heating, melt cooling, rapid melt cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, grinding, cryo-grinding or freeze-drying.
  • crystal refers to a solid structure, typically formed by a solidification of an API, that generally has a regular atomic structure (characteristic shapes and cleavage planes formed by the arrangement of molecules in a pattern referred to as a “lattice”).
  • seeding refers to starting or promoting a crystallization event using a small amount of material.
  • Crystalline forms of a substance can be obtained by a number of techniques, as is known in the art.
  • Exemplary techniques for obtaining, producing, or manufacturing crystalline forms of ester of 17-hydroxyprogesterone include e.g., melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as, e.g., in nanopores or capillaries, recrystallization on surfaces or templates such as, e.g., on polymers, recrystallization in the presence of additives, such as, e.g., co-crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding and solvent-drop grinding.
  • additives such as, e.g., co-crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding and solvent-drop grinding.
  • the crystalline form of ester of 17-hydroxyprogesterone is generated from recrystallization of solid API from a solvent.
  • the solvent for crystallization or recrystallization
  • the solvent is an alcohol (e.g., ethanol, methanol, or propanol), fatty acid (e.g., oleic acid, linoleic acid, or linoleic acid), alkane (e.g., hexane, heptane, pentane, or halogenated alkane), oil (e.g., vegetable oil, castor oil, or hydrogeneated oil), an ester, or any other suitable solvent (e.g., pyridine, benzene, or toluene).
  • alcohol e.g., ethanol, methanol, or propanol
  • fatty acid e.g., oleic acid, linoleic acid, or linoleic acid
  • alkane e.g., he
  • the crystalline form of ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is generated from recrystallization of solid API from a solvent in the presence of a seeding agent.
  • the seeding agent is a steroid.
  • the seeding agent is a derivative of 17 HPC.
  • the seeding agent is an ester of 17-hydroxyprogesterone that is not the caproate ester.
  • crystalline forms of a specific ester of 17-hydroxyprogesterone can be distinguished from each other by one or more physical or analytical properties such as rate of dissolution, infrared or raman spectroscopy, x-ray diffraction techniques such as single crystal and powder diffraction techniques, solid state-NMR (SS-NMR), thermal techniques such as melting point, differential thermal analysis (DTA), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) and other methods as disclosed elsewhere in the specification or available to the skilled artisan.
  • physical or analytical properties such as rate of dissolution, infrared or raman spectroscopy, x-ray diffraction techniques such as single crystal and powder diffraction techniques, solid state-NMR (SS-NMR), thermal techniques such as melting point, differential thermal analysis (DTA), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) and other methods as disclosed elsewhere in the specification or available to the skilled artisan.
  • DTA differential thermal analysis
  • DSC differential scanning
  • an ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) which has one or more advantageous properties compared to other forms such as chemical, crystalline, or polymorphic purity, increased crystallinity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, specific surface and pycnometric density, bulk/tap density, stability (e.g., such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion), stability towards hydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvent(s) and advantageous processing and handling characteristics such as compressibility and bulk density.
  • advantageous properties compared to other forms such as chemical, crystalline, or polymorphic purity, increased crystallinity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, specific surface and pycnometric density, bulk/tap density, stability (e.g., such as chemical stability as well as thermal
  • the ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is crystalline, non-crystalline, or a mixture thereof.
  • the ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) in solid state form has unexpectedly improved dissolution, solubility, bioavailability, bioactivity, fluctuation index, processing, manufacturing, storage, taste, color, aggregates or granules.
  • solid state ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is provided.
  • the ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is crystalline or non-crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate), or a mixture thereof.
  • the solid state API is amorphous ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate). The solid state API is particularly suitable for administration to a human.
  • the solid state API is a specific crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) form (e.g., substantially similar to that characterized in the Examples and figures by XRD.
  • the solid state API is crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) having 50%, 40%, 30%, 20%, 10%, 5%, 2%, or 1% or less by total weight amorphous ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • the solid state API is a solvate or a pseudopolymorph of ester of 17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate). In another aspect, the solid state API is a polymorph of ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate). In another aspect, the solid state API is a hydrate of ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • the solid state API is crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) form having 50%, 40%, 30%, 20%, 10%, 5%, 2%, or 1% or less by total weight of API of other crystalline forms of ester of 17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate).
  • the solid state API is a crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) having a melting point in the range of 110 to 130° C., 115 to 125° C., 117 to 124° C., as determined by differential scanning calorimetry.
  • the solid state API has a melting point as determined by differential scanning calorimetry characteristic of a single crystal form or non-amorphous ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • the solid state API is crystalline ester of 17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate) having 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or more peaks as determined by XRD corresponding to those in FIG. 5 (one aspect, the peaks are chosen from the 7 tallest peaks in the reference spectrum).
  • the solid state API is ester of 17-hydroxyprogesterone (e.g.
  • 17-hydroxyprogesterone caproate having 50%, 40%, 30%, 20%, 10%, 5%, 2%, or 1% or less by total weight of crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • the solid state API is crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) which is not milled or is milled, micronized, or nanosized.
  • the solid state API is ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) having a D 50 of greater than 1000 ⁇ m, from 355 to 1000 ⁇ m, from 180 to 355 ⁇ m, from 125 to 180 ⁇ m, from 90 to 125 ⁇ m, from 1 to 90 ⁇ m, or less than 1 ⁇ m.
  • 17-hydroxyprogesterone e.g., 17-hydroxyprogesterone caproate
  • the solid state API is ester of 17hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) having a particle size of less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 ⁇ m, from 50 ⁇ m to 250 ⁇ m, from 250 ⁇ m to 500 ⁇ m, from 500 ⁇ m to 1000 ⁇ m, or greater than 1000 ⁇ m.
  • 17hydroxyprogesterone e.g., 17-hydroxyprogesterone caproate
  • the solid state API is ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) having a D 10 , D 50 , or D 90 that is less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 ⁇ m, from 50 to 250 ⁇ m, from 250 to 500 ⁇ m, from 500 to 1000 ⁇ m, or greater than 1000 ⁇ m.
  • 17-hydroxyprogesterone e.g., 17-hydroxyprogesterone caproate
  • the solid state ester of 17-hydroxyprogesterone is a composition having greater than 1 g, 2 g, 50 g, 500 g, 1 kg, 10 kg, 50 kg, 100 kg, 200 kg, 500 kg, 1000 kg, 2000 kg, 5000 kg, or 10,000 kg solid state ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • the release profile of the ester of 17-hydroxyprogesterone e.g., 17-hydroxyprogesterone caproate
  • API particularly ester of 17-hydroxyprogesterone (e.g 17-hydroxyprogesterone caproate).
  • ester of 17-hydroxyprogesterone e.g 17-hydroxyprogesterone caproate.
  • a number of different forms including crystalline forms of ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) may exist.
  • Crystalline ester of 17-hydroxyprogesterone e.g., 17-hydroxyprogesterone caproate
  • Crystalline ester of 17-hydroxyprogesterone may be produced according to the Figures and as described herein or by other methods available to the ordinary skilled artisan in view of this disclosure to obtain solid state forms having desirable properties.
  • Amorphous ester of 17-hydroxyprogesterone is another solid state API form.
  • a number of techniques are available for preparing amorphous ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate). For example, flash evaporation, lyophilization, quench cooling of the melt, spray drying, grinding, supercritical fluids are non-limiting techniques that can be used to make amorphous API.
  • the amorphous ester of 17-hydroxyprogesterone e.g., 17-hydroxyprogesterone caproate
  • FT-Raman Fourier Transform-Raman Spectroscopy
  • solid state ester of 17-hydroxyprogesterone e.g. 17-hydroxyprogesterone caproate
  • Fourier Transform-Raman Spectroscopy (“FT-Raman”) is useful for characterizing and identify solid state forms of (ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • FT-Raman Fourier Transform-Raman Spectroscopy
  • different solid API forms may be characterized using a Bruker RFS100 instrument, with Nd:YAG 1064 nm excitation, 300 mW laser power, Ge detector, using 64 scans over the range of 25-3500 cm ⁇ 1 , and with 2 cm ⁇ 1 resolution.
  • the parameters and instrumentation for FT-Raman may be modified depending on the instrument, the solid state API and goal(s) of the analysis.
  • XRD Power X-ray Diffraction
  • XRD can be performed with a Bruker D8 Advance X-ray diffractometer with CuK ⁇ -radiation.
  • the standard measuring conditions are e.g., tube power 35 kV/45 mA; step size 0.017° (2 ⁇ ); step time 105 ⁇ 5 sec; scanning range 2° -50° (2 ⁇ ); divergence slit equal to variable V12; sample rotation; a Vantec1 detector; the opening angle 3°; channel number 360 ⁇ 10; the y-axis shows the value intensity/number of active detector channels/sec; silicon single crystal sample holders; and the sample dimensions depth/diameter was 0.1 mm/ ⁇ 12 mm.
  • the parameters and instrumentation for PDXR may be modified depending on the instrument, the solid state API and goal(s) of the analysis.
  • the solid state ester of 17-hydroxyprogesterone e.g., 17-hydroxyprogesterone caproate
  • An example of an XRD spectra is shown in FIG. 6 for crystalline or substantially crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • FIG. 6 An example of an XRD spectra is shown in FIG. 6 for crystalline or substantially crystalline ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
  • the solid state API described herein has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more of the peaks that corresponds to those in FIG. 5 (in one aspect these peaks are chosen from the 7 tallest peaks in the reference spectrum).
  • Thermogravimetric-Fourier transform Infrared Spectroscopy (“TG-FTIR”) can also be used to characterize or analyze solid state API.
  • TG-FTIR can be performed with a Netzsch Thermo-Microbalance TG 209 coupled with a Bruker FT-IR Spectrometer Vector 22, using an aluminum crucible (open or with a microhole), under a nitrogen atmosphere, and e.g., at a heating rate of 10° C./min over the range of 25° C. to 350° C.
  • the parameters and instrumentation for TG-FITR may be modified depending on the instrument, the solid state API and goal(s) of the analysis.
  • Characterization/Analysis of API can also be performed using Differential Scanning calorimetry (“DSC”).
  • DSC Differential Scanning calorimetry
  • DSC can be performed with a Perkin Elmer Differential Scanning calorimeter, using closed gold crucibles, a heating rate of 10° C. min ⁇ 1 or 20° C. min ⁇ 1 over a range from 0° C. to 300° C. (or e.g., over a range from 5° C. to 250° C.).
  • the parameters and instrumentation for DSC may be modified depending on the instrument, the solid state API and goal(s) of the analysis.
  • a solid state API e.g., ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate), is provided which has a melting point in the range of about 50 to 300° C., as determined by DSC.
  • a solid state API is provided which has a melting point in the range of about 50 to 200° C., as determined by DSC.
  • a solid state API is provided which has a melting point in the range of about 100 to 150° C., as determined by DSC.
  • the melting point of the solid state API is characteristic of a single physical form of API e.g., a single crystalline form or amorphous API.
  • a pharmaceutical composition or unit dosage form having a solid state API e.g., ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is provided where the API in the pharmaceutical composition has a melting point in the range of about 50 to 150° C., as determined by DSC.
  • the pharmaceutical composition or unit dosage form of this embodiment comprises or is prepared from solid state API and one or more pharmaceutically acceptable carriers.
  • a pharmaceutical composition is provided having or prepared from solid state API where the solid state API starting material has a melting point in the range of about 85 to 145° C., as determined by DSC.
  • a pharmaceutical composition having or prepared from solid state API where the solid state starting material has a melting point in the range of about 110 to 130° C., 115 to 125° C., 117 to 124° C., as determined by DSC.
  • a pharmaceutical composition is provided having or prepared from solid state which has a melting point of API in the range of about 115 to 125° C., as determined by DSC.
  • the melting point of the pharmaceutical composition or unit dosage form does not have a peak corresponding to the melting point peak of the API from which it was prepared as determined by DSC.
  • the melting point of the starting solid state API is in the range of 115 to 125° C.
  • Dynamic Vapor Sorption (DVS) analysis is another technique for characterizing and analyzing API.
  • DVS can be performed with a Surface Measurement Systems DVS-1 water vapor sorption analyzer. The experiments can be run by placing the sample on a quartz holder on top of a microbalance, and allowing the sample to equilibrate at 50% relative humidity (r.h.) before starting the pre-defined humidity program. The program can proceed e.g., in the following steps: 1 hour at 50% r.h.; 50% to 0% r.h. at a rate of 5% r.h.
  • High performance liquid chromatography is also useful for analyzing or characterizing API.
  • the purity of the amorphous form of ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) as measured by high pressure liquid chromatography is greater than about 90%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9% total area under the curve as observed at a suitable wavelength e.g., about 240 nm or about 242 nm.
  • the amorphous form of ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is about 100.0% pure as measured by HPLC as area under the curve as observed at a suitable wavelength, e.g., at a wavelength of from about 200 nm to about 300 nm, e.g., about 240 nm or 242 nm.
  • the purity of a crystalline form of ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) as measured by HPLC is greater than about 90%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9% total area under the curve as observed at a suitable wavelength e.g., about 240 nm or about 242 nm.
  • a suitable wavelength e.g., about 240 nm or about 242 nm.
  • a crystalline form of ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is about 100.0% pure as measured by HPLC as area under the curve as observed at a suitable wavelength, e.g., at a wavelength of from about 200 nm to about 300 nm, e.g., about 240 nm or 242 nm.
  • solid state NMR and other techniques can be used to analyze or characterize solid API and forms thereof in view of this disclosure.
  • Composition having different particles sizes or distributions of particles sizes can be produced by any suitable method.
  • Micronization techniques can be based on friction to reduce particle size; such methods include milling, bashing and grinding.
  • Another technique of producing different sized API particles involves supercritical fluids where the API is dissolved in a solvent at high temperature and pressure and they sprayed out of a nozzle, causing the formation of API particles of particular sizes or within particular size ranges/distributions.
  • Some basic supercritical fluid techniques are RESS process (Rapid Expansion of Supercritical Solutions), the SAS method (Supercritical Anti-Solvent) and the PGSS method (Particles from Gas Saturated Solutions).
  • Solid state API particles can be analyzed by a number of techniques. For example, Particle size can analyzed by photon correlation spectroscopy (PCS) using a Malvern ZetaSizer 2000 HS (Malvern Instruments, Malvern, UK). The measuring mode applied can be e.g., Contin-Auto mode. PCS yields the mean diameter of the bulk population (z-average) and a polydispersity index (PI) ranging from 0 (monodisperse) through 0.10-0.20 (relatively monodisperse) to>0.5 for a broad size distribution. The measuring range of PCS is approximately 3 nm-3 ⁇ m. As is understood by the ordinary skilled artisan, the parameters and instrumentation for PCS may be modified depending on the instrument, the solid state API and goal(s) of the analysis.
  • PCS photon correlation spectroscopy
  • Solid state API can also be analyzed by electron microscopy. Solid particles are deposited on metallic stubs then placed in liquid nitrogen and dried under vacuum. The freeze-dried particles are coated uniformly with gold. All samples are examined for morphology and surface properties using a scanning electron microscope (e.g., Joel, SEM, JSM-25 SII, Tokyo, Japan). Particle size, polydispersity index and zeta potential were initially measured by a laser particle size analyser (Submicron Particle Size Analyser 90 plus, Brookhaven Instrument Co., Holtsville, N.Y., USA). An aliquot of solid state API particles can be diluted with e.g., 3 ml of deionized water.
  • the diluted API samples are loaded into a 4 ml cuvette and the particle size and zeta potential measurement can be conducted at e.g., ambient temperature.
  • the parameters and instrumentation for electron microscopy may be modified depending on the instrument, the solid state API and goal(s) of the analysis.
  • the particle size can also be estimated by XRD e.g., by applying the Sherrer equation which relates the size particles (e.g., crystal particles or crystallites), in a solid to the broadening of a peak in a diffraction pattern.
  • Sherrer equation which relates the size particles (e.g., crystal particles or crystallites), in a solid to the broadening of a peak in a diffraction pattern.
  • the release profile (e.g., a profile comprising 2, 3, 4, 5, or 6 or more time points each at least 5, 10, or 15 minutes apart or a single time point) of solid state ester of 17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate) API does not change substantially as a function of storage time.
  • the release profile of solid state 17-HPC does not substantially change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks.
  • the release profile of solid state 17-HPC does not substantially change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 months.
  • the release profiles is tested using a USP type 2 apparatus at 100 rpm in about 1000 mL 8%, 12% or 16% Triton X-100 solution in water at a specific temperature e.g., 20.0, 37.0 or 40.0° C. ( ⁇ 0.5).
  • a release profile that does not substantially change over a period of time refers to a release profile that changes by less than plus/minus 50%, 40%, 30%, 20%, or 10% or less of amount ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) released at one or more specific time point under specific conditions.
  • compositions and oral dosage forms prepared from or comprising solid ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) API can include a variety of pharmaceutically acceptable carriers or excipeints known in the art. Exemplary pharmaceutical compositions and unit dosage forms are given below in Tables A-E. These Tables describe various formulations containing 17 HPC.
  • the pharmaceutical composition or oral dosage form includes 17 HPC and a carrier.
  • the carrier can include a surfactant.
  • the surfactant is a lipophilic or hydrophilic surfactant.
  • the surfactant is an ionic or non-ionic surfactant.
  • the pharmaceutical composition includes 17 HPC and one or more of: a diluent, filler, binder, adhesive, disintegrant, lubricant, anti-oxidant, surfactant, colorant, flavorant, coating agent, solvent, and water.
  • the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a diluent and (3) one or more other pharmaceutically acceptable excipients.
  • the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a binder and (3) one or more other pharmaceutically acceptable excipients.
  • the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a disintegrant and (3) one or more other pharmaceutically acceptable excipients.
  • the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a lubricant and (3) one or more other pharmaceutically acceptable excipients.
  • the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a diluent (3) a binder and (4) one or more other pharmaceutically acceptable excipients.
  • the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a diluent (3) a disintegrant and (4) one or more other pharmaceutically acceptable excipients.
  • the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a diluent (3) a lubricant and (4) one or more other pharmaceutically acceptable excipients.
  • the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a binder (3) a disintegrant and (4) one or more other pharmaceutically acceptable excipients. In another aspect, the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a binder (3) a lubricant and (4) one or more other pharmaceutically acceptable excipients. In another aspect, the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a disintegrant (3) a lubricant and (4) one or more other pharmaceutically acceptable excipients. In another aspect, the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a diluent (3) a binder (4) a disintegrant and (5) one or more other pharmaceutically acceptable excipients.
  • the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a diluent (3) a binder (4) a lubricant and (5) one or more other pharmaceutically acceptable excipients.
  • the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a diluent (3) a disintegrant (4) a lubricant and (5) one or more other pharmaceutically acceptable excipients.
  • the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a binder (3) a disintegrant (4) a lubricant and (5) one or more other pharmaceutically acceptable excipients.
  • the pharmaceutical composition or unit dosage form includes (1) 17 HPC, (2) a diluent (3) a binder (4) a disintegrant, (5) a lubricant and (5) one or more other pharmaceutically acceptable excipients.
  • the pharmaceutical composition or oral dosage forms are as described below in Tables A-E.
  • the 17 HPC is present in the pharmaceutical composition or unit dosage form in an amount ranging from about 1 mg to about 1200 mg, In some aspects, the 17 HPC is present in the pharmaceutical composition or unit dosage form in an amount ranging from about 10 mg to about 1000 mg, In some aspects, the 17 HPC is present in the pharmaceutical composition or unit dosage form in an amount ranging from about 100 mg to about 900 mg, In some aspects, the 17 HPC is present in the pharmaceutical composition or unit dosage form in an amount ranging from about 200 mg to about 800 mg, In some aspects, the 17 HPC is present in the pharmaceutical composition or unit dosage form in an amount ranging from about 300 mg to about 700 mg, In some aspects, the 17 HPC is present in the pharmaceutical composition or unit dosage form in an amount ranging from about 350 mg to about 700 mg, In some aspects, the 17 HPC is present in the pharmaceutical composition or unit dosage form in an amount ranging from about 400 mg to about 700 mg, In some aspects, the 17 HPC is present in the pharmaceutical composition or unit dosage form in an amount ranging from about 450 mg to
  • the unit dosage forms e.g., tablet, caplet, capsule, etc.
  • the unit dosage forms have a total weight of from 10-100 mg, 100-200 mg, 200-300 mg, 300-400 mg, 500-600 mg, 600-700 mg, 700-800 mg, 800-900 mg, 900-1000 mg, 1000-1100 mg, 1100-1200 mg, 1200-1300 mg, 1300-1400 mg, 1400-1500 mg, 1500-1600 mg 1600-1700 mg, 1700-1800 mg, 1800-1900 mg, or 1900-2000 mg.
  • the loading of the 17 HPC in the pharmaceutical compositions and unit dosage forms described in the Tables below is greater than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 75%, 80%, 85%, 90%, or 95% (or within any range defined by any two of these value (e.g., 30%-75% or 45%-65%, etc.)).
  • Loading is the mg amount of 17 HPC/total mg amount of the unit dosage form or pharmaceutical composition multiplied by 100.
  • the 17 HPC is present in particulate form, partially solubilized, fully solubilized, or amorphous form.
  • the 1 HPC is present as crystalline particulate form.
  • the crystalline particulate form of 17 HPC has a D 50 of from 1000-750, 750-500, 500-250, 250-200, 200-150, 150-100, or 100-50 microns. In one aspect, the crystalline particulate form of 17 HPC has a D 50 of from 50-40, 40-30, 30-20, 20-10, or 10-1 microns. In one aspect, the crystalline particulate form of 17 HPC has a D 50 of from 1000-750, 750-500, 500-250, 250-200, 200-150, 150-100, or 100-50 nanometers.
  • the pharmaceutical composition or unit dosage form is a powder, granulate, particulate, bead, pellet, sprinkle, suspension, solution, tablet, caplet, capsule, or a combination thereof.
  • the pharmaceutical composition or unit dosage form is a matrix tablet.
  • the pharmaceutical composition or unit dosage form is a coated or uncoated tablet.
  • the pharmaceutical composition or unit dosage form is immediate release or controlled release.
  • the controlled release selected can be, intermediate, delayed, extended, sustained, pulsatile, gastric, enteric or colonic.
  • the pharmaceutical composition of unit dosage form is administered once, twice or three time a day to an individual in need of treatment (e.g., a pregnant female).
  • the pharmaceutical composition or dosage form is administered with food.
  • the oral dosage form or pharmaceutical composition can provide a 17-hydroxyprogesterone caproate C avg -24h of greater than about 0.1, 0.5 or 1.0 ng/mL when admistered to a human subject (female or pregnant female) once or twice daily as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms.
  • the 17-hydroxyprogesterone caproate compositions or dosage forms can provide a fluctuation in the 17-hydroxyprogesterone caproate levels less than about 2000, 1500, 1000, 900, 800, 700, 600, 500, 400, 300, 200, 175, 150, 140, 130, 120, 110 or 100 ng/mL, or greater than about 1, 10, 15, 25, 50, 75, 100, 200, 300 or 400 ng/mL (or within a range as defined by any two of these values) wherein the fluctuation is determined by the difference of the mean steady state C max and the mean steady state C min of 17-hydroxyprogesterone caproate in plasma or serum or blood, upon oral administration.
  • the AUC (0-24h) to dose ratio is between about 1.5 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 . In a specific aspect, the AUC (0-24h) to dose ratio is between about 2.0 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 . In a specific aspect, the AUC (0-24h) to dose ratio is between about 3.0 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 . In a specific aspect, the AUC (0-24h) to dose ratio is between about 4.0 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 .
  • the AUC (0-24h) to dose ratio is between about 5.0 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 . In a specific aspect, the AUC (0-24h) to dose ratio is between about 6.0 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 . In a specific aspect, the AUC (0-24h) to dose ratio is between about 7.0 and about 10.0 ng*h mL ⁇ 1 mg ⁇ 1 .
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • Carrier component carriers % w/w
  • Diluent/filler 1-50 e.g. lactose, starch, glucose, magnesium salt, potassium chloride
  • Binder/adhesive e.g. cellulose derivatives, starch, 1-50 gelatin
  • Disintegrant e.g. cellulose derivatives, 1-20 crospovidone, starch
  • Lubricant/glidant e.g.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • Binder + Carriers Except Binders Composition (% w/w) Ingredients A2B B2B C2B 17-a-Hydroxyprogesterone 1-99 — — Caproate (particle size >50 ⁇ m) 17-a-Hydroxyprogesterone — 1-99 — Caproate (micronized: ⁇ 15 ⁇ m or nanosized: ⁇ 1 ⁇ m) 17-a-Hydroxyprogesterone — — 1-99 Caproate (milled, ⁇ 50 ⁇ m) Binder/adhesive (e.g.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • Disintegrant Carriers Except Disintegrants Composition (% w/w) Ingredients A2C B2C C2C 17-a-Hydroxyprogesterone 1-99 — — Caproate (particle size >50 ⁇ m) 17-a-Hydroxyprogesterone — 1-99 — Caproate (micronized: ⁇ 15 ⁇ m or nanosized: ⁇ 1 ⁇ m) 17-a-Hydroxyprogesterone — — 1-99 Caproate (milled, ⁇ 50 ⁇ m) Disintegrant (e.g.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • Binder/adhesive e.g. cellulose 1-50 1-50 1-50 derivatives, starch, gelatin
  • Disintegrant e.g. cellulose 1-20 1-20 1-20 derivatives, crospovidone, starch
  • Lubricant/Glidant e.g. 0-5 0-5 0-5 magnesium stearate, colloidal silicon dioxide
  • the formulations e.g., unit dosage forms in the above table have from about 100 to 495 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • compositions or unit dosage forms described herein can release greater than 20% of the 17 HPC at one hour when tested under appropriate conditions.
  • the selection of conditions depends on a number of factors that the skilled artisan is aware of
  • the release of 17 HPC is tested with a USP Type II Dissolution Apparatus using a specific aqueous media.
  • the specific aqueous media is one in which provides sink conditions for the amount of 17 HPC in the pharmaceutical composition or unit dosage form. Sink conditions refers to the ability of the aqueous media to completely dissolve all of the 17 HPC and is determined by the solubility of 17 HPC in that particular aqueous media.
  • the release is determined in 2 ⁇ , 3 ⁇ , 4 ⁇ , 5 ⁇ , 6 ⁇ , 7 ⁇ , 8 ⁇ , or 10 ⁇ or more sink conditions.
  • 2 ⁇ refers to the ability of the media to dissolve twice the total amount of the 17 HPC in the pharmaceutical composition or unit dosage form (if the solubility of 17 HPC was 1 mg/mL in a particular aqueous media and 1000 mL than that would be 2 ⁇ for 500 mg of 17 HPC; 4 ⁇ for 250 mg 17 HPC, etc.).
  • the aqueous media has 0.5% (w/w) sodium lauryl sulfate.
  • the aqueous media is simulated intestinal fluid having 0.5% w/w sodium lauryl sulfate.
  • the aqueous media is 900 mL simulated intestinal fluid having 0.5% w/w sodium lauryl sulfate.
  • the release is tested using a USP Type II apparatus at 50 or 100 rpm in about 1000 mL 8%, 12% or 16% Triton X-100 solution in water at a specific temperature e.g., 20.0, 37.0 or 40.0° C. ( ⁇ 0.5).
  • compositions 1, 7, 10, 17 and 36 are with respect to %w/w of the final composition.
  • the 17-hydroxyprogesterone caproate of all other example compositions can be in either treated (milled, micronized, or nanosized) or untreated form.
  • the 17-hydroxyprogesterone Caproate in compositions 1, 7, 10, 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 a USP 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 17-hydroxyprogesterone caproate released from each composition was analyzed using HPLC.
  • 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 17-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 17-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 HDPE bottles and sealed with a lid.
  • FIG. 1 shows the comparative release of Examples 1 and 2 over a duration of 2 hours. It should be noted that the Examples 1 & 2 (17-hydroxyprogesterone caproate without a carrier) and Examples 3 to 6 (17-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 of the current invention.
  • Example No. 1 2 3 4 5 6
  • Castor Oil NF Lipophilic additive: — — 35 — 32 —
  • Lauroglycol FCC Lipophilic additive: — — — 63 — 75 Glyceryl Monolinoleate
  • NF Hydrophilic additive — — — 16 — — Polyoxyl 40 Hydrogenated Castor Oil
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 mg
  • the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the aqueous dispersion of the mixture that includes a 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 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. In some aspects, the average particle size of the dispersion may be greater than 250 nm.
  • Each of the aqueous dispersions is prepared by mixing 1 part of the mixture of the additives of the corresponding example and 99 parts of an aqueous diluent.
  • compositions of Example 3-6 may be prepared by mixing the additives the 17 hydroxyprogesterone caproate to get a homogenous solution or suspension. If required, the mixture may be heated (for example, to about 40° C. to about 80° C.) to get a solution or to achieve a homogenous suspension. The mixture can be 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 in case of Example 3) or partially solubilized (as in case of Examples 5 and 6).
  • the formulations of Table I 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.
  • 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.
  • Example No. 7 8 9 10 Ingredients Composition in % w/w. 17-hydroxyprogesterone 90-99 — — 90-99 caproate (particle size >50 ⁇ m) 17-hydroxyprogesterone — 70-80 — — caproate micronized* 17-hydroxyprogesterone — — 70-80 — caproate (milled) Lactose 1-10 1-20 1-20 30 Povidone K30 3-6 3-6 3-6 3-6 3-6 3-6 Organic granulating — 0 or 0 or q.s*** solvent (example, q.s*** q.s***- alcohol)** % release in 60 mins ⁇ 15 >50 >50 >30 *may be substituted with nanomilled or nanosized 17-hydroxyprogesterone caproate. **removed substantially during drying process ***Quantity sufficient for wet granulation process or for in situ formation/precipitation of fast releasing solid 17-hydroxyprogesterone caproate
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 mg to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • compositions of Examples 7 to 10 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.
  • the 17-hydroxyprogesterone caproate release profile of Examples 8, 9 and 10, shown in Table II illustrate the advantages of the smaller particle size of 17-hydroxyprogesterone caproate. These Examples further illustrate the advantages of various manufacturing processes, such as granulation, which yield solid compositions with appropriate 17-hydroxygprogesterone caproate release profiles.
  • the caproate ester in the compositions of examples in Table II can be substituted with other esters of 17-hydroxyprogesterone, such as acetate or undecanoate.
  • 17-hydroxyprogesterone caproate tablets of Example 7 through 10 can be further coated with a coating solution having typical composition set forth in Table III, using conventional tablet coating procedures known in the art to a weight gain of about 3 to 6%.
  • 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 sugar being applied.
  • Table IV shows the 17-hydroxyprogesterone caproate compositions of Examples 12-17 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 17-hydroxyprogesterone caproate from the dosage form is also shown in Table IV.
  • Lipophilic Additive e.g Glyceryl — — — 5 — — Palmitostearate; Glyceryl distearate, Precirol ® ATO 5
  • Hydrophilic Additive e.g. — — — — 22 — Tocopherol Polyethylene Glycol Succinate
  • Lipophilic Additive e.g Vitamin E; — — — — 35 48 d,l- ⁇ -tocopherol
  • Hydrophilic Additive e.g. Hypromellose — — — — 18 — (4,000 cPs) % release in 60 mins >40 >40 >40 >30 >40
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 mg to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • the aqueous dispersion of the mixture of lipophilic additive and the hydrophilic surfactant, if present, in the examples shown in Table-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. In some aspects, the mean particle size of the dispersion may be greater than 250 nm.
  • Each of the aqueous dispersions is prepared by mixing 1 part of the mixture of the additives of the corresponding example and 99 parts of an aqueous diluent.
  • compositions of Table IV can be formulated to be solid dosage forms by filling into a capsule either as is, or admixed with a solidification aid such as polyethylene glycol, glyceryl distearate, wax and the like. It should be noted that these compositions can also be formulated to obtain granules for compression 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.
  • a solidification aid such as polyethylene glycol, glyceryl distearate, wax and the like.
  • the 17-hydroxyprogesterone caproate in the compositions of examples in Table IV can in some embodiments be substituted with other esters of 17-hydroxyprogesterone, such as 17-hydroxyprogesterone acetate or 17-hydroxyprogesterone undecanoate.
  • Table V shows various 17-hydroxyprogesterone caproate compositions as recited in Examples 18-23 that can be prepared using the components set forth therein.
  • Ethyl Cellulose Diluents/Processing Aids 86 73 64 82 82 61 Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 Table VI shows various specific embodiments of different dosage forms (DF-1 to DF-9) containing 17-hydroxyprogesterone caproate that can be achieved by various combinations of the compositions shown in Table V.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 mg to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • Table VII shows 17-hydroxyprogesterone caproate compositions as recited in Examples 24-28 that can be prepared using the components set forth therein, and their release performance.
  • Example No. 24 25 26 27 28 INGREDIENT Composition (mg per dosage form) 17-hydroxyprogesterone 50 50 50 50 50 50 Hydrophilic Surfactant 2.5 2.5 2.5 2.5 2.5 (e.g. Tween 80) Hydrophilic Surfactant 12.5 12.5 12.5 12.5 (e.g. Sodium Lauryl Sulfate) Hydrophilic Polymer 125 65 90 — 3 (e.g. HPMC) Enteric Polymer — — — — 5 (e.g. Eudragit) Coating Processing Aids — — — — 2 (e.g. Plasticizer, Anti-sticking agent) Diluents/Processing Aids 25 25 35 35 35 (e.g. binder, disintegrant, diluent, glidant, lubricant) Total 215 155 190 100 110 % Release in 60 minutes >25 >40 >40 100 >30
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 mg to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • Table VIII shows 17-hydroxyprogesterone caproate compositions and release data within 60 min for Examples 29-35 that can be prepared by using components set forth therein and the method similar to that described for Examples 12-17. Furthermore, FIGS. 2 and 3 show the release profile over the course of two hours for Examples 31 and 34 in comparison to Example 1 respectively.
  • Example No. 29 30 31 32 33 34 35 Ingredients Composition % w/w 17-hydroxyprogesterone caproate 25 20 7 7 8 16 25 Lipophilic Additive 48 45 — — — 29 53 (e.g. Benzyl benzoate) Hydrophilic Additive 2 2 — — — — 2 (e.g. Benzyl alcohol) Lipophilic Additive (e.g. Castor Oil) 25 23 — — — — — — Lipophilic Additive — — — — 67 — (e.g. Corn glycerides) Lipophilic Additive (e.g.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 mg to 495 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • compositions can be formulated to exhibit immediate or controlled release profiles.
  • the aqueous dispersion of the mixture of the lipophilic additive and the hydrophilic surfactant, if present, in the examples of Table-VIII 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 of the dispersion can be greater than 250 nm.
  • Each of the aqueous dispersions is prepared by mixing 1 part of the mixture of the additives and surfactants of the corresponding example and 99 parts of an aqueous diluent.
  • a higher drug loading e.g.>20% w/w 17-hydroxyprogesterone caproate
  • 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.
  • the aqueous dispersion of the mixtures having a lipophilic additive and the hydrophilic surfactant, if present, as recited in Examples 29-31 and 33-35 can be hazy to non-clear.
  • each of the aqueous dispersions is prepared by mixing 1 part of the mixture of the additives and surfactants of the corresponding example and 99 parts of an aqueous diluent.
  • the 17-hydroxyprogesterone caproate in the compositions of examples in Table VIII can in some aspects substituted with other esters of 17-hydroxyprogesterone, such as 17-hydroxyprogesterone acetate or 17-hydroxyprogesterone undecanoate.
  • 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, fruit juices, beverages and the like just before administration.
  • diluent such as water, milk, fruit juices, beverages and the like just before administration.
  • the contents of the above compositions can be adsorbed on some diluents and additional excipients and can be compress into tablet.
  • 17-hydroxyprogesterone caproate containing granules for tableting having the components set forth in Table IX can be prepared by wet granulation methods. Accordingly, 17-hydroxyprogesterone caproate, microcrystalline 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.
  • Example 36 exhibit less than 20% 17-hydroxyprogesterone caproate released in the first 60 minutes when tested using a USP Type II apparatus, 50 rpm in 900 mL of simulated intestinal fluid having 0.5% w/w sodium lauryl sulfate at 37° C.
  • the micronized 17-hydroxyprogesterone caproate with particle size d100% being about 50 ⁇ m or less
  • surfactant is used in the above formula, at least 40% release of 17-hydroxyprogesterone caproate may be observed after the 60 minute time-point.
  • Examples 37-39 of Table 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.
  • the ester of 17-hydroxyprogesterone e.g. 17-hydroxyprogesterone caproate
  • 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.
  • 17-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, are taken 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 allowed to solidify at room temperature.
  • Example 37-42 The dosage forms of each Example 37-42 are tested for release of the 17-hydroxyprogesterone caproate using a USP Type II apparatus, at 50 rpm in 900 mL of simulated intestinal fluid having 0.5% w/w sodium lauryl sulfate at 37° C.
  • the percent of the 17-hydroxyprogesterone caproate released from each composition is analyzed using HPLC. The results of the release testing are also shown in Table X.
  • compositions of Examples 37-42 can be formulated to achieve tablet dosage forms with the inclusion of appropriate conventional tableting aids such as diluents, binders, disintegrants, lubricants, etc. as needed.
  • the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • Example 37 to 42 The in vitro 17-hydroxyprogesterone caproate release performance of Examples 37 to 42 can be seen to be superior over the release performance of the Example 36.
  • appropriate amounts of typical pharmaceutical aids such as glidants, lubricants, anti-adherents, disintegrants and the like, can be incorporated as needed.
  • suitable amounts of hydrophilic release modifying agents e.g. hypromellose, Eudragits etc.
  • appropriate functional coatings may be applied as required.
  • compositions of Table X can be substituted with other esters of 17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone acetate, 17-hydroxyprogesterone undecanoate, etc.)
  • 17-hydroxyprogesterone e.g. 17-hydroxyprogesterone acetate, 17-hydroxyprogesterone undecanoate, etc.
  • 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 in 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. It 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.
  • compositions are tested for release of the 17-hydroxyprogesterone caproate using a USP Type II apparatus, at 50 rpm in 900 mL of simulated intestinal fluid having 0.5% w/w sodium lauryl sulfate at 37° C.
  • the percent of the 17-hydroxyprogesterone caproate released from each composition is analyzed using HPLC. The results of the release testing are also shown in Table XI.
  • Example No. 43 44 Ingredients Composition in % w/w 17-hydroxyprogesterone caproate 20 80 Lipophilic additive: 80 20 (e.g., Glycerol esters of C 12 -C 18 fatty acids) % release in 60 mins >30% >30%
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 mg to 495 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • 17-hydroxyprogesterone caproate multiparticulates can be prepared as follows: 15 g of a milled or micronized 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 of about 60-75° C. and an outlet temperature of about 30-38° C., aspirator set at 90-100%, the pump set at about 8-12 mL/min, and the flow rate set at about 500-600 L/hr.
  • the final solid multiparticulate 17-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 K17.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 mg to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • a mixture of 17-hydroxyprogesterone caproate and the corresponding components can be melted together to get thermosetting fill to be disposed into capsule.
  • the mixture can be fed into a melt-extruder apparatus for example, a single-screw extruder (Killion, Model KLB 100) equipped with about 1 inch diameter screw and about 6 inch flex lip die, and the die opening adjusted to about 0.005 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 17-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 multi-particulates for tablets.
  • the 17-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 s
  • Example No. 46 47 48 49 50 Ingredients Composition in %w/w 17-hydroxyprogesterone caproate 70 40 50 80 60 Polyethylene glycol 8000 USP 10 — 20 15 20 (Glyceryl distearate GDS, 10 40 20 — — Precirol ATO 5) Stearic acid 10 20 10 — Cholesterol — — — 5 20
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 mg to 495 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • a 17-hydroxyprogesterone caproate containing composition can be prepared by co-milling (or co-grinding) 80 g 17-hydroxyprogesterone caproate along with 15 g PVP K 17 and 5 g of sodium lauryl 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 to the in vitro release profile of Example 1 when tested using a USP Type II apparatus, 50 rpm in 900 mL of simulated intestinal fluid having 0.5% w/w sodium lauryl sulfate at 37° C.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 mg to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • 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 25 g of 17-hydroxyprogesterone caproate, 6 g of Pluronic F 68 and 5 g of PVP 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 a mean particle size in the range of about 250 ⁇ m to about 600 ⁇ m) taken in a conventional coating pan. After all the spray solution is loaded on the spheres, it can be dried under a gentle current of air for at least 1 hour to remove the solvent.
  • the 17-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 of the pellets.
  • pellets of different drug loading can be achieved.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 mg to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC.
  • the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • 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 of the drug in the liquid vehicle.
  • the formulations (e.g., unit dosage forms) in the above table have from about 100 mg to 495 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 150 to 450 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 200 mg to 490 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 505 mg to 850 mg of 17 HPC. According to another aspect, the formulations (e.g., unit dosage forms) in the above table have from about 400 mg to 600 mg of 17 HPC.
  • a preliminary pharmacokinetic evaluation upon oral administration of 17-hydroxyprogesterone caproate of the current invention was carried out in male dogs.
  • a single oral dose of 30 mg/kg and 5 mg/kg of 17-hydroxyprogesterone caproate formulated in a accordance with exemplary formulations of the present invention were used for relative bioavailability study in a fed state, compared with an intramuscular dose of 6.4 mg/kg (composition similar to commercially available Intramuscular Injection, Makena®) as positive control.
  • the post-dose blood levels of 17-hydroxyprogesterone caproate were monitored for 24 hours after oral dosing and for 192 hours after intramuscular injection dosing.
  • About 2 mL of blood was drawn from the jugular, cephalic, or saphenous veins immediately before the dose was administered and at pre-determined intervals post-dose.
  • the blood sample was collected in a vacutainer 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.
  • Table-XIV The results of the 17-hydroxyprogesterone caproate concentration in the samples are shown in Table-XIV below:
  • oral compositions of the present invention provided significant blood levels (C avg ) of 17-hydroxyprogesterone caproate upon oral administration.
  • Formulations were used in a Phase 1b open-label study that enrolled eight healthy, pregnant women at 16 to 18 weeks gestation. All subjects received three treatments in sequence. In period one, subjects received two doses of 400 mg with oral dosage forms like those described herein. administered 12 hours apart. In period two, subjects received two doses of 800 mg oral with dosage forms like those described herein, administered 12 hours apart. In period three, subjects were given 250 mg of HPC via intramuscular injection (marketed product Makena®). Blood samples were collected periodically over 24 hours following oral dosing and over 28 days following the IM dose.
  • Cmax maximum concentration
  • AUC area under the curve
  • the PXRD (Powder X-Ray Diffraction (or XRD)) measurement of 17-HPC products was conducted using a Philips X'Pert X-Ray Diffractometer.
  • the geometry for the measurement was the standard Bragg-Brentano ⁇ -2 ⁇ geometry using a Seifert MZ IV goniometer at room temperature.
  • Standard sample holders 22 mm diameter were carefully filled with the powder samples.
  • Tube tension 45 kV
  • Tube current 40 mA
  • FIG. 5 shows the PXRD spectrograms measured for 17-HPC in Tablet (top), micronized 17-HPC API (middle), and 17-HPC reference peaks (bottom).
  • FIG. 5 shows XRD Spectrograph measured for 17-HPC products.
  • the top spectrogram was obtained from 17-HPC in tablet, the middle was from micronized 17-HPC API, and the bottom was from 17-HPC reference XRD Peaks.
  • the top spectrogram (17-HPC in tablet) in FIG. 5 was calibrated by subtracting data obtained from the placebo tablet from data obtained from the 17-HPC GMP tablet.
  • the 17-HPC reference XRD spectrogram was obtained from publically available data or databases.
  • Non-ionic surfactant e.g. 6 Tween, Span, etc
  • Anionic surfactant 5 e.g. Sodium Lauryl [50] Sulfate, etc
  • Solvent e.g. Benzyl Benzoate, 6 Benzyl alcohol, water, etc
  • the study was an open-label, four-period, four-treatment, randomized, single and multiple dose, PK study in pregnant women of three dose levels of an oral pharmaceutical composition as described herein (containing 17 HPC e.g., as described in the Examples or elsewhere herein) and injectable HPC (Makenag®).
  • the study enrolled 12 healthy pregnant women (average age of 27 years) with a gestational age of approximately 16 to 19 weeks.
  • Subjects received three dose levels of the oral pharmaceutical composition having 17 HPC (400 mg BID, 600 mg BID, or 800 mg BID) in a randomized, crossover manner during the first three treatment periods and then received five weekly injections of HPC during the fourth treatment period.
  • HPC levels were comparable or higher for all three oral doses than for injectable HPC.
  • HPC levels as a function of daily dose were linear for the three doses with the oral pharmaceutical composition having 17 HPC.
  • steady state exposure was achieved for all three doses with the oral pharmaceutical composition having 17 HPC, within seven days.
  • the approved HPC injectable product is a single fixed dose product that does not allow for dose adjustments.
  • the oral pharmaceutical composition having 17 HPC was well tolerated across the three dose levels. No adverse drug reactions, serious adverse events, or deaths were reported during the study. There was dose linearity and short duration to steady state demonstrated in this study which unexpectedly allows dose adjustments with the oral pharmaceutical composition having 17 HPC, during the course of therapy (e.g., on a sufficient time scale) to improve or modulate outcome.
  • Cmax to Cavg and Cavg to pre-dose C value which enables single point titration (e.g., based on serum or plasma 17 HPC levels at a single time point with 0-12 hours after single dose administration at steady state (e.g., at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, or 11.5 hours after single dose administration (or within a range defined by any two of these values, or within a range of within 0.5 h or 1 h of any one of these values))).
  • single point titration e.g., based on serum or plasma 17 HPC levels at a single time point with 0-12 hours after single dose administration at steady state (e.g., at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, or 11.5 hours after single dose administration (or within a
  • a pregnant female at risk for preterm birth is administered orally, a pharmaceutical composition (e.g., as described herein), in an initial dosing regimen, until steady state is achieved (e.g., 5 or more days, 6 or more days, 7 or more days).
  • a pharmaceutical composition e.g., as described herein
  • steady state e.g., 5 or more days, 6 or more days, 7 or more days.
  • the initial dosing regimen can be e.g., 400 mg per day, 450 mg per day, 500 mg per day, 550 mg per day, 600 mg per day, 650 mg per day, 700 mg per day, 750 mg per day, 800 mg per day, 850 mg per day, 900 mg per day, 950 mg per day, 1000 mg per day, 1150 mg per day, 1200 mg per day, 1250 mg per day, 1300 mg per day, 1350 mg per day, 1400 mg per day, 1450 mg per day, 1500 mg per day, 1550 mg per day, 1600 mg per day, 1650 mg per day, 1700 mg per day, 1750 mg per day, 1800 mg per day, 1850 mg per day, 1900 mg per day, 1950 mg per day or 2000 mg per day (or within a range defined by any two of these values, or within a range of within 50 mg or 100 mg of any one of these values) e.g., on a once, twice, thrice, or four times a day dosing regime.
  • the plasma or serum 17 HPC in the subject is determined and if the levels are too low, the daily dose is increased, if the levels are too high, the daily dose is increased or if they levels are appropriate, the daily dose is maintained.
  • the pharmaceutical composition can delivery the daily dose in e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 unit dosage forms per day.
  • the oral pharmaceutical composition comprises 17-hydroxyprogesterone caproate and a pharmaceutically acceptable carrier, 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., at least 20% of the 17-hydroxyprogesterone caproate is released from the oral composition at 60 minutes.
  • the oral pharmaceutical composition comprises: 17-hydroxyprogesterone caproate, and a pharmaceutically acceptable carrier including at least a hydrophilic surfactant.
  • the oral pharmaceutical composition comprises: 17-hydroxyprogesterone caproate having a mean particulate diameter of about 50 micron or less, and a pharmaceutically acceptable carrier including at least a hydrophilic surfactant.
  • the oral pharmaceutical composition comprises: 17-hydroxyprogesterone caproate having a mean particulate diameter of about 50 micron or less, and a pharmaceutically acceptable carrier including at least a hydrophilic surfactant 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., at least 20% of the 17-hydroxyprogesterone caproate is released from the oral composition at 60 minutes.
  • the oral pharmaceutical composition comprises: 17-hydroxyprogesterone caproate having a mean particulate diameter of about 50 micron or less, and a pharmaceutically acceptable carrier including at least a hydrophilic surfactant; wherein the amount of the 17-hydroxyprogesterone caproate is from about 5% to about 80% w/w of the total composition; and 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., at least 20% of the 17-hydroxyprogesterone caproate is released from the oral composition at 60 minutes.
  • the oral pharmaceutical composition comprises a hydrophilic surfactant which is an ionic hydrophilic surfactant. In one aspect, the oral pharmaceutical composition comprises a hydrophilic surfactant which is a non-ionic hydrophilic surfactant. In one aspect, the oral pharmaceutical composition comprises a hydrophilic surfactant which is a poloxamer, a polyethylene glycol sorbitan fatty acid ester, a sorbitan fatty acid ester, a polyethylene glycol glycerol fatty acid ester or a combination thereof.
  • the oral pharmaceutical composition comprises a hydrophilic surfactant, which is sodium lauryl sulfate, sodium dioctyl sulfosuccinate, a lecithin, a bile salt or a combination thereof.
  • the oral pharmaceutical composition further comprises 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.
  • the oral pharmaceutical composition is formulated as a powder, granulate, particulate, bead, pellet, sprinkle, suspension, solution, tablet, capsule, or a combination thereof.
  • the oral pharmaceutical composition is formulated as a capsule.
  • the oral pharmaceutical composition is formulated as a tablet.
  • the oral pharmaceutical composition comprises an amount of 17-hydroxyprogesterone caproate equivalent to from about 20 mg to about 400 mg of 17-hydroxyprogesterone.
  • the oral pharmaceutical composition has from about 20 mg to about 800 mg 17-hydroxyprogesterone caproate.
  • the oral pharmaceutical composition has from about 10 mg to about 300 mg 17-hydroxyprogesterone caproate.

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AU2016284459A1 (en) 2018-02-15
EP3310359A2 (fr) 2018-04-25
US20190275060A1 (en) 2019-09-12
US20210169900A1 (en) 2021-06-10
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BR112017027688A2 (pt) 2018-09-04
WO2016210003A2 (fr) 2016-12-29
MX2017016823A (es) 2018-03-12
US11590147B2 (en) 2023-02-28
IL256493A (en) 2018-02-28
ZA201801692B (en) 2019-09-25
CN107847506A (zh) 2018-03-27

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