Oral composition comprising 17-hydroxyprogesterone ester and related method

0001The present invention relates to 17-hydroxyprogesterone ester-containing compositions, oral dosage forms thereof and related methods. The present invention therefore includes the fields of chemistry, pharmaceutical science, medicine and other health sciences.

000217-Alpha hydroxyprogesterone (alternatively referred to herein as 17-hydroxyprogesterone or "17HP") is a C-21 endogenous produced during the synthesis of glucocorticoids and sex steroids. It is a sex steroid hormone. A similar progesterone, 17HP, is a natural progesterone. It has been isolated from both the adrenal gland and the corpus luteum. Esters of 17HP have been reported to have progestogenic effects and can therefore be used for pregnancy support related indications and for non-pregnancy support in both pre- and post-menopausal women. It has been reported that 17HP has no pre-pregnancy activity in the absence of esterification. However, 17 HP synthetic esters such as 17-hydroxyprogesterone acetate or 17-hydroxyprogesterone caproate (also referred to herein as 17-hydroxyprogesterone caproate or 17HPC) are intramuscular in animal studies. When administered, it has been shown to exhibit significant pre-pregnancy activity. 17-Hydroxyprogesterone caproate is a commonly used progestin available for intramuscular injection to prevent preterm birth (alternatively referred to herein as "PTB"). This synthetic caproic acid ester is inactive when administered orally, but has been reported to act as a long-acting progestin when administered intramuscularly. The metabolism of 17HP and the metabolism of 17-hydroxyprogesterone caproate in human females have not yet been established in ten sentences. Data from humans and animals indicate that intramuscularly administered 17-hydroxyprogesterone caproate has a progesterone pre-pregnancy effect on the endometrium (alternatively referred to herein as "P" hereafter. ) More powerful and lasts longer. This is referred to as 17-hydroxyprogesterone caproate and progesterone receptor (alternatively referred to herein as "PR" hereafter. And placental glucocorticoid receptors (alternatively referred to herein as "GR") (which may prevent the increase in placental glucotropin-releasing hormone associated with the onset of labor). May be due to the stronger binding of. 17-Hydroxyprogesterone caproate has been reported to be effective in providing luteal support in patients undergoing the IVF-embryo transfer cycle.

0003PTB is medically defined as delivery at 20-36 weeks gestation. According to the 2009 Centers for Disease Control and Prevention report, PTB occurs in about 12.3% of births in the United States alone, or 500,000 PTBs per year. Natural PTB accounts for about 70-80% of PTB. Of all pregnancies in the United States, one in eight preterm births is born prematurely, showing an increase of> 18% since 1990. Late preterm birth at 35-36 weeks gestation accounts for more than half of all PTBs. PTB is a major contributor to neonatal morbidity and mortality. The risk of mortality is three times higher at 35-36 weeks, and morbidity, such as oxygen-requiring respiratory distress, temperature instability, hypoglycemia, jaundice, attention deficit disorder, cerebral palsy, and stunted growth, are fairly common. is there. PTB-related time and cost in intensive care is a major health, social and economic problem, and the average cost of PTB delivery is up to 10 times that of normal delivery.

0004The major risk factors involved in PTB are: previous natural PTB history (past obstetric history), cervical length (<2.5 cm in mid-pregnancy), presence of fetal fibronectin in vaginal fluid; Multiple pregnancies, low maternal body mass index (BMI), maternal race; maternal age (<17 and> 35 years) and smoking. A pre-existing condition of at least one PTB is a good indicator of the likelihood of future outbreaks, with a recurrence probability of 17-50% and 28-70% for the two previous PTBs. The benefits of extending pregnancy to full month using therapeutic interventions include improving child survival and reducing neonatal stay as a function of gestational age.

0005Intramuscular injections of 17-hydroxyprogesterone caproate are available to reduce the risk of PTB in single-born pregnancies and women with a single history of spontaneous PTB. The injection solution (17-Hydroxyprogesterone caproate 250 mg in 1 mL) marketed as Makena® consists of 16-20 week injections with a typical weekly repeating treatment cycle and therefore to the doctor's office. I have ordered regular consultations. In addition to increasing the risk of repeated movements of the patient and foetation, this therapeutic regimen can also increase patient distress and / or anxiety. It is also a major drawback that injection therapy interferes with personal and family activities and disrupts professional activity history.

0006In addition, adverse events associated with weekly (every 7 days) injection of 17-hydroxyprogesterone caproate (eg, Makena®), ie injection site reactions (~ 45%), such as urticaria at the injection site. , Psychogenic pruritus, swelling, nodule formation and pain have also been reported to be significant.

0007Esters of hydroxyprogesterone, such as acetate, caproate, and undecanoate, are more lipophilic than hydroxyprogesterone. The active substance (17-hydroxyprogesterone caproate) in Makena® is highly insoluble in water (<20 ng / mL), highly lipophilic and has a ClogP of approximately 5.7. In addition, 17-hydroxyprogesterone caproate has the ability to be metabolized in the presence of fetal and adult hepatocytes and is overexpressed (~ 40% upregulation) in pregnant women with cytochrome inactivity such as CYP3A4. It is a substrate for metabolism. Oral delivery of 17 HP long-chain esters remains a challenge due to its very low water solubility and its potential for first-pass liver inactivation. It has been reported that no oral activity with the 17HP ester 17-hydroxyprogesterone caproate was observed (Saxton DJ et al. Reproductive Biology and Endocrinology 2004, 2: 80; Greene MF, NJEM 348: 2453-2455). This may be due to the very poor or no oral bioavailability of 17 HPC. Although highly desirable, to date, however, the development of orally active compositions of long-chain esters of hydroxylprogesterone remains a significant unmet requirement. In addition, the development of dosage forms that allow administration of low dose units per dose and / or infrequent daily administration is most desired.

<p num="0008"> Here, it was surprisingly found that the 17 HP ester can be effectively orally delivered to mammals. The pharmaceutical oral compositions and dosage forms of the present invention may provide effective bioavailability of 17 HP esters. In addition, the compositions and / or dosage forms disclosed herein provide effective release enhancements for 17HP esters. It was also surprisingly found that 17 HP esters can be formulated in oral compositions and their oral dosage forms at high percent w / w loads of esters. For example, if one or more solubilizers such as benzyl alcohol, benzyl benzoate, etc. are incorporated into the composition, a significant amount (ie, greater than 12% w / w) of 17 HP ester is in the composition or dosage form. It turns out that it can be solubilized in. Increased drug loading in the compositions and dosage forms of the invention has strong advantages, such as reduced unit dose size or volume (eg, tablets, capsules, syrups, elixirs, swallows, etc.), single dose. It may provide, but is not limited to, a reduction in the number of dose units to be ingested per unit, improved patient compliance, etc., but it is typical for patients to obtain a dose sufficient to provide the desired efficacy. This is because it is possible to take a smaller number of dose units per day. In a separate embodiment, the effective bioavailability of the 17 HP ester, when dispersed in an aqueous medium, is clear or colloidal in a turbid or opaque dispersion with a partially or fully solubilized agent in the dispersion. It turned out surprisingly that it would provide.</p><p num="0009"> The compositions of the present invention allow the production of solid dosage forms such as tablets, capsules, granules, beads, microparticles, etc. that can solve the drawback of having 17 HP esters in liquid solution form in a dosage unit. Also turned out. This causes a number of undesired inconveniences, such as inadequate chemical and / or physical stability of esters typical of liquid solutions due to the nature of special manufacturing processes and / or equipment, esters or solvents used. Exclude.</p><p num="0010"> All oral dosage forms of the invention have the drug in the form of solutions, suspensions, microparticles, etc. and can be produced by conventional processing and manufacturing methods known in the art.</p><p num="0011"> The present invention provides compositions and oral dosage forms containing 17 HP esters, as well as related methods. The composition and oral dosage form may be formulated to contain a therapeutically effective amount of 17 HP ester and a pharmaceutically acceptable carrier. In one embodiment, a pharmaceutically acceptable oral dosage form for pregnancy support and non-pregnancy support is provided. The oral dosage form is 17-HP after 60 minutes when measured at 37 ° C at 50 RPM in 900 mL of deionized water with 0.5 (w / v) sodium lauryl sulfate using a USP type II lysing device. Can release at least 20% by weight of the ester dose.</p><p num="0012"> In a further embodiment, a pharmaceutically acceptable oral dosage form for pregnancy support and non-pregnancy support is provided. Oral dosage forms, pharmaceutically acceptable oral dosage forms, may include 17 HP esters of therapeutically effective labor and pharmaceutically acceptable carriers. The oral dosage form is a carrier-free equivalent dose measured in 900 mL of deionized water with 0.5 (w / v) sodium lauryl sulfate at 50 RPM at 37 ° C using a USP type II solubilizer. Release at least 20% by weight or more of 17 HP ester 60 minutes after the oral dosage form administered.</p><p num="0013"> In a further embodiment, a pharmaceutically acceptable oral dosage form for pregnancy or non-pregnancy support is provided. A pharmaceutically acceptable oral dosage form may include a therapeutically effective amount of 17 HP of ester and a pharmaceutically acceptable carrier. The oral dosage form is a carrier-free equivalent dose measured in 900 mL of deionized water with 0.5 (w / v) sodium lauryl sulfate at 50 RPM at 37 ° C using a USP type II lysing device. Release at least 20% by weight or more of 17 HP ester 60 minutes after the oral dosage form administered.</p><p num="0014"> In some embodiments, the oral dosage forms of the invention can be used to treat pregnant female subjects at risk of preterm birth. Such treatment methods include the step of orally administering the oral pharmaceutical composition to a female subject. In some embodiments, the dose is sufficient to provide the intended therapeutic effect. In another embodiment, the oral dosage form can be administered to a subject in need thereof. Administration of the oral dosage form may treat at least one symptom selected from preterm birth, preterm birth, infertility and miscarriage. The symptoms and related treatments may be based on their first and second result measurements associated with the administration of 17 HP ester.</p>

0015<figref num="1">It is a plot of the in vitro release profile of the oral dosage form containing 17-hydroxyprogesterone caproate according to an embodiment of the present invention when compared to a carrier-free dose of 17-hydroxyprogesterone caproate.</figref><figref num="2">FIG. 6 is a plot of the in vitro release profile of a 17-hydroxyprogesterone-containing oral dosage form according to an embodiment of the present invention.</figref><figref num="3">FIG. 6 is a plot of the in vitro release profile of a 17-hydroxyprogesterone-containing oral dosage form according to an embodiment of the present invention.</figref>

0016Illustrative exemplary embodiments are referenced herein, and a specific language is used herein to illustrate it. However, it is understood that the limitation of the scope of the invention is not thereby intended.<u style="single">Detailed description of exemplary embodiments</u>

0017Prior to disclosing and describing the oral dosage forms and methods of the invention for the delivery and use of 17-hydroxyprogesterone esters, the invention is described herein as will be appreciated by those skilled in the art. It should be understood that it is not limited to the particular process steps and materials disclosed in, but extends to its equivalents. It should also be understood that the terms used herein are used only to describe certain embodiments and are not intended to be limiting.

0018The singular forms "one (a)", "one (an)" and "the" include multiple referents unless the situation clearly indicates otherwise. Thus, for example, a reference to "one excipient" includes a reference to one or more such excipients, and a reference to "the carrier" includes a reference to one or more such carriers. Include.<u style="single">Definition</u>

0019As used herein, "drug", "active agent", "physiologically active substance", "pharmaceutical active agent", "therapeutic active agent" and "prepared drug" are significant or effective. When administered to a subject in an amount, they can be used interchangeably to refer to an agent or substance with measurable identified or selected physiological activity. It should be understood that the term "drug" is expressly and comprehensively included in the definition of the present invention, as many agents and prodrugs are known to have specific physiological activities. These technical terms are well known in pharmaceutical and medical clots. In addition, when these terms are used, or when a particular active agent is specifically identified by name or category, such an enumeration is pharmaceutically acceptable for the active agent itself, as well as for its significant association. It should be understood that it is intended to include various salts, esters or compounds such as prodrugs, active metabolites, isomers, etc. (but not limited to these).

0020As used herein, the term "recurrent" refers to "miscarriage," "premature birth," or "premature birth," with or without a previous live birth, with or without the same partner. Or used to refer to the repetition or reoccurrence of at least one developmental event such as "multiple pregnancy".

0021As used herein, the term "treatment" refers to the administration of 17-hydroxyprogesterone ester to a subject who is asymptomatic or symptomatic when used in conjunction with administration of 17-hydroxyprogesterone ester. .. In other words, "treatment" refers to the act of reducing or eliminating symptoms (ie, symptoms manifested), or it refers to prophylactic treatment (ie, symptoms to prevent their occurrence). It can be administered to a subject who does not develop symptoms). Such preventive measures may also be referred to as symptom prevention, preventive actions, preventive measures, and the like.

0022As used herein, "ester" refers to a compound produced by a reaction between an acid and an alcohol with the elimination of water. As used herein, the term "ester" also refers to the class of organic compounds corresponding to inorganic salts produced from organic acids and alcohols. In one aspect, the "ester of 17-hydroxyprogesterone" can be a caproic acid ester, but typically a long chain fatty acid that is absorbed by the lymph vessels and first passes through hepatic metabolism for improved efficacy or safety, such as Esters of undecanoic acid and longer acids can also be represented.

0023As used herein, the terms "formulation" and "composition" are used interchangeably and refer to a mixture of two or more compounds, elements or molecules. In some embodiments, the terms "formulation" and "composition" can be used to refer to a mixture of one or more active agents and a carrier or other excipient. In addition, the term "dosage form" may include one or more formulations (s) or compositions (s) or compositions (s) provided in a format for administration to a subject. When any of the above terms are modified by the term "oral", such terms refer to a composition, formulation or dosage form formulated and intended for oral administration to a subject.

0024The terms "pharmaceutically acceptable carrier" or "carrier" are used interchangeably to refer to a pharmaceutically acceptable substance that allows a pharmaceutical composition and / or dosage form of an ester of 17-hydroxyprogesterone. Moreover, in some embodiments, the carrier is an element or element that can be altered due to changes in the rate and / or degree of release of the ester of the active agent, eg, 17-hydroxyprogesterone, from the composition and / or dosage form. It is an ingredient. In one aspect of the invention, the pharmaceutically acceptable carrier is in 900 mL of artificial intestinal juice with 0.5% w / w sodium lauryl sulfate (by USP, SIF; no enzyme) at about 37 ° C. at 50 rpm. At least in part determines, controls, or is involved in the release of esters of 17-hydroxyprogesterone from pharmaceutical oral compositions and / or dosage forms when tested using a USP type II solubilizer. A compound or a mixture of compounds.

0025In another embodiment, a pharmaceutically acceptable carrier when tested with a USP type II solubilizer in 900 mL of artificial intestinal fluid with 0.5% w / w sodium lauryl sulfate at about 37 ° C. and 50 rpm. Composition or dosage form such that after the first 60 minutes, at least 20% more of the ester of 17-hydroxyprogesterone is released compared to the oral dosage form of the ester of 17-hydroxyprogesterone administered in an equivalent dose that does not contain. Provides an ester release of 17-hydroxyprogesterone. In another particular embodiment, after the first 60 minutes, the composition or dosage form is compared to the oral dosage form of the ester of 17-hydroxyprogesterone administered in equivalent doses without a pharmaceutically acceptable carrier. Releases at least 40% more ester of 17-hydroxyprogesterone.

0026Ester release of 17-hydroxyprogesterone from the composition or dosage form can be tested at about 37 ° C using a USP type II solubilizer at 50 rpm in a suitable solubilized or unsolubilized aqueous medium. It should be noted that. For example, aqueous media include water, artificial gastric juice (SGF) (containing or not containing enzymes), artificial intestinal juice (SIF) (containing or not containing enzymes), hydro-alcoholic solutions, surfactant solutions, etc. Can be. Aqueous media can be used for the purpose of determining the rate and / or degree of ester release of 17-hydroxyprogesterone from the composition or dosage form. The aqueous medium can be a non-solubilized aqueous medium (eg, with or without a low surfactant in the medium) with respect to the total amount of esters present in the composition or dosage form. In one embodiment, the non-solubilized aqueous medium can solubilize up to about 90% of the amount of ester present in the composition or dosage form. In another embodiment, the non-solubilized aqueous medium is about 80% or less, about 70% or less, about 60% or less, about 50% or less, about 30% or less of the total amount of esters present in the composition or dosage form. Or about 20% or less can be solubilized.

0027Conversely, in another embodiment, the aqueous medium can solubilize substantially all of the esters of 17-hydroxyprogesterone present in the composition or dosage form. In one embodiment, the aqueous medium can solubilize at least about 90% of the amount of ester of 17-hydroxyprogesterone present in the composition or dosage form. In certain embodiments, the aqueous medium can solubilize about 1.5 times or more, about 3 times or more, 5 times or more the amount of ester of 17-hydroxyprogesterone present in the composition or dosage form.

0028As used herein, "subject" refers to a mammal that benefits from the administration or method of administration of the drug composition of the invention. Examples of subjects include humans and may also include other animals such as horses, pigs, cows, dogs, cats, rabbits and aquatic animals. In one particular aspect, the subject is a human. In another aspect, the subject is a woman. In yet another aspect, the oral dosage form of the present invention is for women in need of pregnancy support.

0029The term "oral administration" refers to any method of administration in which the active agent can be administered by swallowing, chewing, or inhaling the 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 past the oral cavity and / or buccal cavity. Examples of solid dosage forms include conventional tablets, multi-layer tablet capsules, caplets and the like that do not substantially release the drug in the mouth or oral cavity.

0030As used herein, the terms "releasing" and "releasing rate" are used in vitro or in vivo from a dosage form to an ambient environment, such as an aqueous medium, such as a substance, eg, a drug. ) Is used interchangeably to refer to release or release.

0031As used herein, the term "lipophilic" is used in combination with both solid and liquid lipophilic additives (alternatively referred to herein as "LA"). , "Prefer oil", generally refers to additives that have poor solubility in water or are completely insoluble in water. "Lipophilic surfactant" (alternatively referred to herein as "LS") refers to a lipophilic additive having an HLB value of 10 or less, preferably 2-10. Conversely, the term "hydrophilic" when used in combination with both solid and liquid hydrophilic additives (alternatively referred to herein as "HA"), "water". "Preference", generally refers to an additive with average or good solubility in water. A "hydrophilic surfactant" (alternatively referred to herein as "HS") is a hydrophilic additive having significant surface-active properties and an HLB value greater than 10. is there.

0032As used herein, the term "lipid or lipid substance", when used in connection with various compounds, is a fatty acid (unless otherwise stated, C).₆Refers to fatty acid esters or glycerides of fatty acid esters, mixtures thereof and derivatives thereof, but does not include salts thereof.

0033In some embodiments of the invention, the release of the agent can be a controlled release. As used herein, "controlled release" refers to the release of a drug from a dosage form according to a scheduled profile. In some embodiments, the controlled release selected can be intermediate, delayed, prolonged, sustained, pulsatile, gastric, intestinal or colonic. In another aspect, the combination of release profiles can be used to achieve specific delivery results such as immediate release of active agent followed by delayed and / or sustained release.

0034As used herein, in USP artificial gastric juice (SGF) (with or without enzymes), more than about 90% of the drug is released after the first 30 minutes. "Immediate release" is provided.

0035As used herein, the term "pregnancy support" refers to preterm birth, preterm delivery and miscarriage, but not limited to, as used to describe the functionality of the oral compositions or dosage forms of the invention. It can refer to providing extrinsic early pregnancy status support from the beginning through childbirth, including. Pregnancy support can provide improved quality of pregnancy for pregnant women, the fetus, or both. In addition, pregnancy support may include increased fertility for women attempting to become pregnant.

0036As used herein, the term "non-pregnant" support, when used to describe the functionality of the oral compositions or dosage forms of the invention, is progested to non-pregnant subjects, such as non-pregnant women. Conditions that require exogenous supplementation of gen agents, such as delaying or preventing the development of unwanted pregnancies, symptoms for progesterone deficiency, such as amenorrhea, preventing or treating fibromas, contraception, Postpartum lactation suppression, dysfunctional uterine bleeding, endometriosis, endometriosis, treatment of cervical hyperplasia, hormone replacement therapy, hypoventilation treatment, prevention and treatment of osteoporosis, breast, hypothyroidism, It can refer to the management of migraine, jaw joint syndrome, menstrual concomitant epilepsy, endometriosis and / or kidney cancer. In one embodiment, the term "non-pregnant" support requires extrinsic supplementation of the progesterone agent of the invention to a human male when used to describe the functionality of the oral composition or dosage form of the invention. It can refer to a condition, such as performing contraception, blocking estrogen activity, and the like. It should be noted that the compositions and dosage forms of the esters of 17-hydroxyprogesterone of the present invention can be administered alone or in combination with other therapies. In another embodiment, the compositions and dosage forms of the esters of 17-hydroxyprogesterone for supplementing, augmenting, alleviating, treating, healing or preventing in subjects in need thereof. Or can be used to provide prevention.

0037As used herein, a "effective amount" or "therapeutically effective amount" of an agent achieves therapeutic outcome in treating symptoms that are non-toxic, but for which the agent is known to be effective. Refers to a sufficient amount of drug to do. It is understood that various biological factors can influence the ability of a substance to perform its intended work. Therefore, the "effective amount" or "therapeutically effective amount" can in some cases be determined by such biological factors. In addition, the achievement of a therapeutic effect can be measured by a physician or other qualified healthcare professional using assessments known in the art, but individual changes and responses to the procedure are how much the therapeutic effect is achieved. It is recognized that it can be a subjective decision. Determining the effective amount is well done within the art of pharmaceutical science and medical technology (eg, Meiner and Tonascia, "Clinical Trials: Design, Conduct, and Analysis,"<u style="single">Monographs in Epidemiology and Biostatistics</u>, Vol. 8 (1986) (this description is incorporated herein by reference)).

0038As used herein, the term "about" is used to provide flexibility for the numerical range end point by providing that a given value can be "a little above" or "a little below" the end point. Used for. As used herein, multiple items, structural elements, compositional elements and / or materials may be shown in a common list for convenience. However, these lists should be interpreted so that each member of the list is independently identified as a separate and unique member. Therefore, individual members of such a list should not be construed as de facto equivalents of any other member of the same list on the basis of their presentation in a common group, unless otherwise stated.

0039Concentrations, quantities, levels and other numerical data may be represented or presented herein in range format. Such a range format is used solely for convenience and brevity, such as when each number and subrange is explicitly listed, not just the numbers explicitly listed as the limits of the range. Should be flexibly interpreted to include all individual numbers or subranges contained within that range. As an example, the numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly listed values of about 1 to about 5, but also the individual values and subranges within the indicated range. is there. Therefore, this numerical range includes individual values such as 2, 3 and 4, and subranges such as 1 to 3, 2 to 4 and 3 to 5, and 1, 2, individually. 3, 4 and 5. This same principle applies to the range of enumerating only one number as the minimum or maximum value. Moreover, such interpretations should be applied regardless of the scope or range of properties described.<u style="single">invention</u>

0040Here, preferred embodiments of the present invention will be referred to in detail. Although the present invention is described in conjunction with the preferred embodiments, it should be understood that the invention is not limited to the preferred embodiments. Instead, the invention is intended to include alternatives, variants, modifications and equivalents that may be contained within the spirit and scope of the invention as defined by the appended claims. ..

0041Shown that serum progesterone levels, such as progesterone and 17-hydroxyprogesterone, are reduced in pregnant women during pregnancy, intrauterine death, preterm birth, imminent preterm birth, premature water rupture, chorioamnionitis and placental abruption. Has been done. As mentioned above, it has been discovered that esters of 17-hydroxyprogesterone have the ability to be used during pregnancy to treat or prevent the following symptoms or outbreaks: previous spontaneous abortion, recurrence. Spontaneous abortion, previous stillbirth, previous preterm birth (&lt;37 weeks), previous premature (&lt;37 weeks) water rupture or PROM, previous pregnancy-related hypertension or pregnancy toxemia, previous uterine ablation, imminent preterm delivery or Spontaneous abortion in women who have had concluding, multiple pregnancies, primary or secondary infertility, congenital uterine malformations, or any other symptoms of endogenous progestogen (eg, progesterone) levels lower than in normal pregnancies ..

0042The need and / or efficacy of supplemental therapy with 17-hydroxyprogesterone esters for pregnancy-related support to specific subjects using the primary and secondary endpoint metrics, as well as their direct or direct effect on the newborn. Indirect effects can be determined. Examples of typical primary and secondary endpoint metrics for preterm and preterm delivery include, but are not limited to:<u style="single">Primary endpoint Metric (maternal):</u> 1. Perinatal mortality 2. Preterm birth (pregnancy less than 32 weeks) 3. Preterm birth (pregnancy less than 34 weeks) 4. Preterm birth (pregnancy less than 37 weeks) 5. Major neurogenic disability in childhood follow-up<u style="single">Secondary evaluation item Metrics (maternal):</u> 1. Imminent preterm delivery 2. Predelivery spontaneous water rupture 3. Adverse drug reaction 4. Pregnancy extension (interval between randomization and childbirth) 5. How to give birth 6. Number of hospitalizations before childbirth 7. Satisfaction with treatment 8. Use of uterine contraction suppression<u style="single">Secondary endpoint Metrics (infants):</u> 1. Birth before 37 weeks completion 2. Birth before completion of 34 weeks 3. Birth before completion of 32 weeks 4. Birth before 28 weeks completion 5. Birth weight less than the third percentile for gestation 6. Birth weight less than 2500 grams 7. Apgar score less than 7 in 5 minutes 8. Respiratory distress syndrome 9. Use of mechanical ventilation 10. Duration of mechanical ventilation 11. Intraventricular hemorrhage-grade III or IV 12. Periventricular leukomalacia 13. Retinopathy of prematurity 14. Retinopathy of prematurity-grade III or IV 15. Chronic lung disease 16. Necrotizing total enteritis 17. Neonatal sepsis 18. Fetal death 19. Newborn death 20. Admitted to neonatal intensive care unit 21. Newborn hospital stay 22. Teratogenic effects (including virilization in female babies)<u style="single">Secondary endpoint Metrics (pediatric):</u> 1. Major sensorineural disability (defined as either legal blindness, hearing aid-requiring sensorineural hearing loss, moderate or severe cerebral palsy, or developmental delay or intellectual disability) 2. Developmental delay 3. Intellectual disability 4. Movement disorders 5. Visually impaired 6. Blindness 7. Hearing loss 8. Hearing loss 9. Cerebral palsy 10. Pediatric behavior 11. Pediatric temperament 12. Learning disabilities 13. Growth assessment in childhood follow-up (weight, head circumference, height, subcutaneous fat thickness)<u style="single">In vitro fertilization</u>

00431. <u style="single">Primary endpoint Metrics:</u> 1.1. Pregnancy rate 1.2. Production 1.3. Continuous pregnancy rate 1.4. Clinical pregnancy defined as ultrasonic evidence of fetal heart activity at 6-8 weeks gestation 1.5. Fetal vitality measured by heart rate 1.6. Complete miscarriage rate 24-48 hours after receiving medical treatment for early pregnancy failure

00442. <u style="single">Secondary endpoint Metrics:</u>

00452.1. Clinical pregnancy 2.2. Periodic cancellation rate 2.3. Number of egg cells produced 2.4. Number of embryos produced 2.5. Serum hormone evaluation 2.6. Follicular fluid evaluation 2.7. Peak estradiol levels 2.8. Gonadotropin ampoules required during ovarian stimulation 2.9. Days of ovarian stimulation 2.10. Number of recovered egg cells 2.11. Number of transferred embryos 2.12. Number of frozen embryos 2.13. Embryo grade 2.14. Implantation rate 2.15. Miscarriage rate 2.16. Pregnancy results 2.17. Complete miscarriage rate per week, time to delivery of conception product, correlation between miscarriage rate and serum 17-hydroxyprogesterone levels, and type of pregnancy failure, bleeding days and patient satisfaction 2.18. Ovarian response [assessed at completion of controlled ovarian stimulation and egg collection procedures].<u style="single">abortion</u>

00461. <u style="single">Primary endpoint</u> 1.1. Miscarriage 1.2. Early miscarriage up to 12 weeks 1.3. Miscarriage after 12 weeks and less than 23 weeks 1.4. Cytokine ratio IFN / IL-10 1.5. Clinical pregnancy rate at 8 and 12 weeks gestation

00472. <u style="single">Secondary evaluation item</u> 2.1. Mother Pain relief (imminent miscarriage) b. Severity of morning sickness-increased headache c. Nausea, chest tenderness d. Report of thromboembolic events e. Thrombolytic event f. Depression g. Admission to a special treatment room h. Subsequent conception i. PIBF level j. Uterine contraction frequency. 2.2. Children Preterm birth; b. Stillbirth; c. Newborn death; d. Low birth weight less than 2500 g e. Fetal genital abnormalities; f. Teratogenic effects (impairing normal fetal development); g. Admission to a special treatment room. 2.3. General Intrauterine fetal death b. Stillbirth c. Fetal d. Monitoring of biochemical and clinical pregnancy parameters, diagnostic analysis of pregnancy results by weekly evaluation of serum progesterone e. Production rate, cycle cancellation rate, spontaneous abortion rate, biochemical pregnancy rate, ectopic pregnancy rate.

0048Several biomarkers are involved in predicting preterm birth (PTB). Among symptomatic women, the likelihood ratio (LR +) for predicting PTB is amniotic fluid (AF) interleukin-6 (IL-6), AF ureaplasma urearichum, and cervical IL-6, cervical IL- It is known to be greater than 10 using a multi-marker consisting of 8 and cervical length (CL). LR + is also known to be 5-10 with respect to serum C-reactive protein (CRP). 2.5-5 LR + were recorded for serum corticotropin-releasing hormone (CRH), cervical IL-6, and serum relaxin.

0049In non-symptomatic women, it consists of AF ureaplasma urealyticum, as well as five individual markers [fFN, CL, serum alpha-fetoprotein (AFP), serum alkaline phosphatase and serum granulocyte colony stimulating factor (G-CSF)]. Multimarkers predict PTB with LR + greater than 10. For serum relaxin and CL, LR plus was 5-10. All recorded LR + for serum alkaline phosphatase, salivary estriol, serum CRH, serum G-CSF, cervical IL-6, AF IL-6, cervical fFN, AFP and chlamydia were in the range 2.5-5. .. Finally, LR plus below 2.5 has been demonstrated for serum ferritin, serum CRP, BV and cervical ferritin.

0050Miscarriage and possible miscarriage can be classified in several ways: A) Imminent and possible miscarriage-any bleeding from the uterus occurs 20 weeks ago, but the cervix is closed and the fetus survives. B) Inevitable miscarriage or miscarriage (inevitable-especially if there is bleeding from the uterus and the cervix is open 20 weeks ago, but neither the fetal nor the placenta is out of the woman's body (Mean unstoppable)-The membrane around the fetal may or may not be ruptured; C) Incomplete abortion or miscarriage-Part of the fetal or placenta is 20 weeks before pregnancy If it has left the uterus, but some of the placenta or fetal remains in the uterus; D) Complete miscarriage-complete delivery of the fetus and all membranes around the placenta, as well as the cervix 20 weeks ago Closed; E) Miscarriage or miscarriage-Fetal death 20 weeks before pregnancy (neither the fetal nor the placenta is excreted from the uterus); F) Recurrent miscarriage-Experienced more than one consecutive miscarriage If so, it is called a recurrent miscarriage; G) Dead egg or embryoless pregnancy-occurs when a pregnancy sac develops inside the uterus but the fetus is absent after 6 weeks.

0051Imminent miscarriage (demonstrated by low endogenous progesterone or 17-hydroxyprogesterone, or vaginal bleeding with or without abnormal convulsions within 26 weeks of conception) is a common complication of pregnancy. It occurs in about 20% of confirmed pregnancies. The risk of miscarriage is increased in older women as well as women with a history of miscarriage.

0052Low serum levels of progesterone (progesterone or 17 HP) or human chorionic gonadotropin (hCG) have been shown to be risk factors for miscarriage. Imminent miscarriage causes considerable stress and anxiety in pregnant women. Since the ester of 17-hydroxyprogesterone interacts with the progesterone receptor, it is believed that treatment with the ester of 17-hydroxyprogesterone can be planned on the basis of progesterone levels. One diagnostic criterion is low serum progesterone, but levels vary widely during early pregnancy and any late decline can cause dysfunctional placenta. Nevertheless, luteal support is widely used for the management of imminent miscarriage. Pregnancy in the first trimester presents a risk of miscarriage with decreased serum progesterone levels. Levels of &lt;5 ng / ml were associated with spontaneous abortion in 86% of cases, compared to only 8% at levels of 20-25 ng / ml. A threshold of 14 ng / ml has been reported to distinguish between viable and non-persistent pregnancies. Other maternal serum biomarkers, such as the major markers CA-125, activin A, anandamide and progesterone-induced blocker (PIBF), are also good indicators of miscarriage risk.

0053In one embodiment, the compositions of the invention are intended to provide an increase in baseline endogenous progesterone and / or 17-hydroxyprogesterone. In one particular embodiment, the increase in baseline endogenous progesterone can be greater than 10%. Progesterone also has a direct pharmacological effect by reducing the synthesis of prostaglandins, thereby relaxing the uterine smooth muscle system and preventing inappropriate contractions that can cause miscarriage.

0054The oral dosage forms and methods of the invention can be used for most female subjects, but the most suitable patients to take the oral 17-hydroxyprogesterone ester of the invention have the following symptoms, symptoms and / or need: Those who have one or more of the sexes: 1) Need anti-inflammatory drugs; 2) Progesterone deficiency: C_averageBaseline progesterone in &lt;14 ng / ml early (first trimester) pregnancies or less than 50 ng / ml C in late (second and third trimester) pregnancies_averageBaseline progesterone level; 3) has a gene mutation in the SERPINH1 gene that possesses a reduction in the amount of protein; 4) has a gene variant in the prolylcarboxypeptidase gene associated with pregnancies; 5) ureaplasma urearichum, mycoplasma Has certain bacterial infections (bacterial vaginal disease), including Hominis, Gardonerella baginaris and Peptstreptococcus and Bacteroides; 6) Abnormal amniotic fluid metabolome (all metabolic processes occurring in amniotic fluid) that indicate the risk of premature babies 7) Have had above-average total phthalate exposure; 8) Abnormal pre-pregnancy physique index; 9) Have vaginal inflammatory environment in early pregnancy; 10) Increased maternal plasma urocortin levels 12) Increased cervical activity as observed by home cervical activity monitoring; 12) Tests positive for salivary estriol levels predict early delivery; 13) Fetal fibronectin screening (fFS) Shows possible results; 14) Abnormal cervical shortening compared to pregnancy as measured by cervical ultrasonography, or transvaginal ultrasound or digital with or without Cervilenz Shows formal tests; 15) Shows abnormal maternal serum biomarkers such as tumor marker CA-125 or inhibin A, or anandamide or progesterone-induced blocker (PIBF); 16) Th-1 cytokine vs. Th-2 cytokine, eg It has a non-equilibrium ratio of IFN to IL-10.

0055In addition to maintaining pregnancy, other possible uses of the oral dosage form of the invention containing an ester of 17-hydroxyprogesterone include: a) preventing estrogen dominance; b) new bone formation. To stimulate and prevent / reverse osteoporosis; c) to provide a precursor for corticosteroids (corticosteroids); d) various skin problems such as acne, seborrhea, alcohol in adult women, Treating psoriasis and keratosis; e) promoting myerin sheath production to protect nerve fibers and accelerate nerve signals; f) managing depression associated with PMS, menopause, postpartum depression, etc.; g) Protection from, but not limited to, brain / spinal cord injury, stroke and / or bleeding.

0056In one embodiment, the invention provides an oral dosage form containing an ester of 17-hydroxyprogesterone as well as related methods. Oral dosage forms are formulated to support pregnancy and may contain therapeutically effective amounts of esters of 17-hydroxyprogesterone and pharmaceutically acceptable carriers. The oral dosage form is 17-hydroxy after 60 minutes when measured at 37 ° C at 50 RPM in 900 mL of deionized water with 0.5 (w / v) sodium lauryl sulfate using a USP type II solubilizer. At least 20% by weight of the ester dose of progesterone can be released. In a further embodiment, the oral dosage form is a carrier as measured using a USP type II solubilizer at 37 ° C. at 50 RPM in 900 mL of deionized water with 0.5 (w / v) sodium lauryl sulfate. Esters of 17-hydroxyprogesterone, which is at least 20% by weight, can be released 60 minutes after the oral dosage form containing no equivalent dose.

0057A large number of 17-hydroxyprogesterone esters can be used in the compositions and oral dosage forms of the present invention. Specific acceptable esters of 17-hydroxyprogesterone include acetates of 17-hydroxyprogesterone, caproic acid esters of 17-hydroxyprogesterone, undecanoic acid esters of 17-hydroxyprogesterone, and combinations thereof. Not limited. Other pharmaceutically active and pharmaceutically acceptable esters of 17-hydroxyprogesterone may also be prepared and used in accordance with embodiments of the invention, as long as they provide the desired support in pregnant and / or non-pregnant conditions.

0058Esters of 17-hydroxyprogesterone can be present in various forms in the compositions and oral dosage forms of the present disclosure. In one embodiment, the ester of 17-hydroxyprogesterone can be present in fine particle form. The fine particle form can have an average diameter of about 50 μm or less. The fine particle form can have an average diameter of about 25 μm or less. In another embodiment, the microparticle form can have an average diameter of about 1 μm or less. In another embodiment, the ester of 17-hydroxyprogesterone may be present in a fully solubilized form. In another embodiment, the ester of 17-hydroxyprogesterone may be present in a partially solubilized form. In another embodiment, a portion of the ester of 17-hydroxyprogesterone present in the composition and / or dosage form may be present in particulate or non-solubilized form. In some embodiments, the ester of 17-hydroxyprogesterone can be present in both solubilized and particulate forms.

0059In some embodiments, the carrier in the composition or oral dosage form of the invention may act to facilitate delivery, release and / or bioavailability of the ester of 17-hydroxyprogesterone. In some embodiments, the carrier can be one compound or a mixture of two or more compounds. The carrier may include at least one of a lipophilic and / or hydrophilic component additive. The lipophilic and hydrophilic additives that can be used in the compositions of the present invention are selected from various classes of pharmaceutical auxiliaries, such as absorbents, acids, adjuvants, anti-solidification agents, anti-tack agents, etc. Antifoaming agents, anticoagulants, antibacterial agents, antioxidants, anti-inflammatory agents, astringents, disinfectants, bases, binders, buffers, chelating agents, metal ion sequestering agents, celluloses, coagulants, coating agents, Colorants, dyes, pigments, complexing agents, crystal growth regulators, modifiers, desiccants, desiccants, dehydrating agents, diluents, disintegrants, dispersants, skin softeners, emulsifiers, encapsulants, enzymes, bulking agents , Fillers, flavor shields, flavors, fragrances, gelling agents, flow promoters, hardeners, stiffeners, wetting agents, solvents, moisturizers, pH control agents, plasticizing agents, smoothing agents, easing agents, Delaying agents, spreading agents, stabilizers, antisettling agents, sweeteners, thickeners, viscosity modifiers, surfactants, opaque agents, polymers, preservatives, antigelling agents, flow control agents, Softeners, solubilizers; solvent pressure regulators, viscosity modifiers, UV absorbers or combinations thereof, but not limited to these. In some embodiments, additives from multiple classes or molds may be used.

0060Non-limiting examples of compounds that may constitute all or part of a carrier are described in the following list organized in the general category. It should be understood that the category is not limited to a particular carrier compound, but is shown solely for ease of system and presentation. With this in mind, the exemplary carrier compound may include one or more of the following:

0061Triglycerides such as olive oil; almond oil; peanut oil; babas oil; kurofusaguri seed oil; rurichisha oil; canola oil (repex 108 (Abitec)); castor oil; cocoa butter; palm oil (pleco 76 (Abitec)); coffee seed oil Corn oil; Cotton seed oil; Hamana oil; Kufair oil; Moonflower oil; Grape seed oil; Pepper oil; Hemp oil; Ilipe butter; Capoc seed oil; Flaxseed oil; Menhaden oil; Maura butter; Karashi seed oil; Oichi deer oil; Olive oil; Palm oil Palm kernel oil; peanut oil; poppy seed oil; rapeseed oil; rice bran oil; benibana oil; sardine fat; sesame oil; shark liver oil; shea nut oil; soybean oil; crow oil; sunflower oil; tall oil; tea seed oil; Tobacco seed oil; Tung oil (Chinawood oil): Bernonia oil; Wheat germ oil; Hardened castor oil (Caster wax); Hardened palm oil (Pleco 100 (Abitec)); Hardened cotton seed oil (Doritex C (Abitec)); Hardened palm Oil (Doritex PST (Abitec); Softisan 154 (Huls)); Hardened soybean oil (Sterotex HM) Glyceryl 1,2-laurate-3-millistate (Larodan); glyceryl 1,2-millistate-3-laurate (Larodan); glyceryl 1,3-palmitate-2-butyrate (Larodan); glyceryl 1,3-stear Rate-2-caplate (Larodan); glyceryl 1,2-linoliate-3-caprilate (Larodan), mixtures and derivatives thereof. Mixtures of fractionated triglycerides, modified triglycerides, synthetic triglycerides and triglycerides are also within the scope of the present invention.

0062PEG-Fatigue Monoester Surfactant (Compound Name (Listed as General Trade Name (Supplier) (HLB)): PEG 4-100 Monolaurate (Crodette L Series (Croda) (&gt; 9)); PEG 4-100 Monooleate (Crodette O Series (Croda) (&gt; 8)); PEG 4-100 Monostearate (Crodette S Series (Croda), Myrj Series (Atlas / ICI) (&gt; 6)); PEG 400 Distearate (Citrol 4DS Series (Citrol 4DS Series)) Croda) (&gt; 10)); PEG 100, 200, 300 monolaurate (Citrol ML series (Croda) (&gt; 10)); PEG 100, 200, 300 monooleate (Citrol MO series (Croda) (&gt; 10)); PEG 400 Geolate (Citrol 4DO Series (Croda) (&gt; 10)); PEG 400-1000 Monostearate (Citrol MS Series (Croda) (&gt; 10)); PEG-1 Steerate (Nikkol MYS-1EX (Nikko), Coster K1 (Condea) (2)); PEG-2 steerate (Nikkor) MYS-2 (Nikko) (4)); PEG-2 oleate (Nikko MYO-2 (Nikko) (4.5)); PEG-4 laurate (Mapeg® 200 ML (PPG), Kesco® PEG 200 ML (Stepan), Lipopeg 2L (LIPO Chem.) (9.3)); PEG-4 Oleate (Mapeg® 200 MO (PPG), Kesco® PEG 200 MO (Stepan) (8.3)); PEG-4 steerate (Kesco® PEG 200MS (Stepan), Hodag 20S (Calgene), Nikko MYS-4 (Nikko) (6.5)); PEG-5 steerate (Nikko TMGS-5 (Nikko) (9.5)) )); PEG-5 Oleate (Nikko TMGO-5 (Nikko) (9.5)); PEG-6 Oleate (Algon OL 60 (Auschem SpA), Kesco® PEG 300 MO (Stepan), Nikkor MYO-6 ( Nikko), Emulgante A6 (Condea) (8.5)); PEG-7 Oleate (Algon OL 70 (Auschem SpA) (10.4)); PEG-6 laurate (Kesco® PEG300 ML (Stepan) (11.4)); PEG-7 laurate (Lauridak 7 (Condea) (13)); PEG-6 steerate (Kesco® PEG300 MS (Stepan) (9.7)); PEG-8 laurate (Mapeg® 400 ML (PPG), lipopeg 4DL (Lipo Chem.) (13)); PEG-8 Oleate (Mapeg® 400 MO (PPG), Emulgante A8 (Condea) (12)); PEG-8 Steerate (Mapeg® 400 MS ( PPG), Myrj 45 (12)); PEG-9 oleate (Emulgante A9 (Condea) (&gt; 10)); PEG-9 steerate (cremophore S9 (BASF) (&gt; 10)); PEG-10 laurate (Nikkor MYL) -10 (Nikko), Lauridak 10 (Croda) (13)); PEG-10 Oleate (Nikkol MYO-10 (Nikko) (11)); PEG-12 Steerate (Nikkol MYS-10 (Nikko), Coster K100 (Condea) (11)); PEG-12 laurate (Kesco® PEG600 ML (Stepan) (15)); PEG-12 oleate (Kesco® PEG600 MO (Stepan) (14)); PEG-12 ricinolate (CAS # 9004-97) -1) (&gt; 10)); PEG-12 steerate (Mapeg® 600 MS (PPG), Kesco® PEG600 MS (Stepan) (14)); PEG-15 steerate (Nikkor TMGS-) 15 (Nikko), Koster K15 (Condea) (14)); PEG-15 Oleate (Nikkol TMGO-15 (Nikko) (15)); PEG-20 laurate (Kesco® PEG1000 ML (Stepan) (17) ); PEG-20 Oleate (Kesco® PEG1000 MO (Stepan) (15)); PEG-20 steerate (Mapeg® 1000 MS (PPG), Kesco® PEG1000 MS (Stepan), Myrj 49 (16)); PEG-25 steerate ( Nikkol MYS-25 (Nikko) (15)); PEG-32 laurate (Kesco® PEG1540 ML (Stepan) (16)); PEG-32 Oleate (Kesco® PEG1540 MO (Stepan) (17)) ); PEG-32 steerate (Kesco® PEG1540 MS (Stepan) (17)); PEG-30 steerate (Myrj 51 (&gt; 10)); PEG-40 laurate (Crodette L40 (Croda) (17.9)) ); PEG-40 oleate (Crodette O40 (Croda) (17.4)); PEG-40 steerate (Myrj 52, Emerest® 2715 (Henkel), Nikko MYS-40 (Nikko) (&gt; 10)); PEG -45 Stairate (Nikkor MYS-45 (Nikko) (18)); PEG-50 stearate (Myrj 53 (&gt; 10)); PEG-55 stearate (Nikko MYS-55 (Nikko) (18)); PEG-100 oleate (Crodette O) -100 (Croda) (18.8)); PEG-100 stearate (Myrj 59, Ariacell 165 (ICI) (19)); PEG-200 oleate (Albunol 200 MO (Taiwan Surf.) (&gt; 10)); PEG- 400 oleate (Henkel, Albanol 400 MO (Taiwan Surf.) (&gt; 10)); PEG-600 oleate (Albunol 600 MO (Taiwan Surf.) (&gt; 10)); and combinations thereof.

0063PEG-Fatty Acid Diester (Compound Name (Listed as General Trade Name (Supplier) (HLB)): PEG-4 Dilaurate (Mapeg® 200DL (PPG), Kesco® PEG200 DL (Stepan), Lipopeg 2 -DL (Lipo Chem.) (7)); PEG-4 Geolate (Mapeg® 200DO (PPG), (6)); PEG-4 Distearate (Kesco® 200 DS (Stepan) (5)) ); PEG-6 Gylaurate (Kesco® PEG 300DL (Stepan) (9.8)); PEG-6 Diorate (Kesco® PEG 300DO (Stepan) (7.2)); PEG-6 Distearate (Kesco®) PEG 300DS (Stepan) (6.5)); PEG-8 dilaurate (Mapeg® 400DL (PPG), Kesco® PEG 400DL (Stepan), Lipopeg 4DL (Lipo Chem.) (11)); PEG- 8 Geolate (Mapeg® 400DO (PPG), Kesco® PEG 400DO (Stepan), Lipopeg 4DO (Lipo Chem.) (8.8)); PEG-8 Distearate (Mapeg® 400DS (PPG)) , CDS 400 (Nikkor) (11)); PEG-10 dipalmitate (Polyald 2PKFG (&gt; 10)); PEG-12 dilaurate (Kesco® PEG600DL (Stepan) (11.7)); Registered trademark) PEG 600DS (Stepan) (10.7)); PEG-12 Geolate (Mapeg® 600DO (PPG), Kesco® 600DO (Stepan) (10)); PEG-20 Gylaurate (Kesco® PEG 1000DL) (Stepan) (15)); PEG-20 Dioleate (Kesco® PEG 1000DO (Stepan) (13)); PEG-20 Distearate (Kesco® PEG 1000DS (Stepan) (12)); PEG- 32 dilaurate (Kesco® PEG 1540DL (Stepan) (16)); PEG-32 dioleate (Kesco® PEG 1540DO (Stepan) (15)); PEG-32 distearate (Kesco® PEG 1540DS) (Stepan) (15)); PEG-400 Geolate (Citrol 4DO Series (Croda) (&gt; 10)); PEG-400 Distearate (Citrol 4DS Series (Croda) (&gt; 10)); and combinations thereof.

0064PEG-fatty acid mono- and di-ester mixture (compound name (listed as generic trade name (source) (HLB)): PEG 4-150 mono, dilaurate (Kesco® PEG 200-6000 mono, dilaurate (Stepan) ))); PEG4-150 Mono, Geolate (Kesco® PEG200-6000 Mono, Geolate (Stepan)); PEG 4-150 Mono, Distearate (Kesco® 200-6000 Mono, Distearate (Stepan)) , And their combinations.

0065Polyethylene glycol glycerol fatty acid ester (Compound name (listed as generic trade name (source) (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 (Glycerol laurate (Croda) (15)) )); PEG-20 glyceryl stearate (Capmul® EMG (ABITEC), (13)); (Aldo® MS-20 KFG (Lonza)); PEG-20 glyceryl oleate (Tagat (registered) Trademark) O (Goldschmidt) (&gt; 10)); PEG-30 glyceryl oleate (Tagat® O2 (Goldschmidt) (&gt; 10)); and combinations thereof.

0066Alcohol-oil transesterification product: (Compound name (listed as generic trade name (source) (HLB)): PEG-3 castor oil (Nikko 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-20TX (Nikko) (11)); PEG-23 castor oil (Emalex C-30 (Nihon Emulsion), Alkamuls® EL 620 (Rhone- Poulenc), Incrocas 30 (Croda) (11)); PEG-35 Castor oil (Cremofor EL and EL-P (BASF), Emulphor EL, Incrocas-35 (Croda), Emulsion RO 35 (Henkel)); PEG-38 Castor oil (Emulgante EL 65 (Condea)); PEG-40 Castor oil (Emalex C-40 (Nihon) Emulsion), Alkamuls® EL 719 (Rhone- Poulenc) (13)); PEG-50 castor oil (Emalex C-50 (Nihon Emulsion) (14)); PEG-56 castor oil (Eumulgin®) PRT 56 (Pulcra SA) (&gt; 10)); PEG-60 castor oil (Nikkol CO-60TX (Nikko) (14)); PEG-100 castor oil (Thornley (&gt; 10)); PEG-200 castor oil (Eumulgin) (Registered Trademark) PRT 200 (Pulcra SA) (&gt; 10)); PEG-5 Hardened Castor Oil (Nikkol HCO-5 (Nikko) (6)); PEG-7 Hardened Castor Oil (Simusol® 989 (Seppic) ), Cremofor WO7 (BASF) (6)); PEG-10 hardened castor oil (Nikkol HCO-10 (Nikko) (6.5)); PEG-20 hardened castor oil (Nikkol HCO-20 (Nikko) (11)); PEG-25 Hardened Castor Oil (Simulsol® 1292 (Seppic), SELEX ELS 250 (Auschem SpA) (11)); PEG-30 Hardened Castor Oil (Nikko HCO-30 (Nikko) (11)); PEG-40 Hardened Castor Oil (Cremophore RH 40 (BASF), Croduret (Croda), Emulsion HRE 40 (Henkel) (13)); PEG-45 Hardened Castor Oil (SELEX ELS 450 (Auschem Spa) (14)); PEG-50 Hardened Castor Oil (Emalex HC-50 (Nihon Emulsion) (14)); PEG- 60 Hardened Castor Oil (Nikkol HCO-60 (Nikko); Cremofor RH 60 (BASF) (15)); PEG-80 Hardened Castor Oil (Nikkol HCO-80 (Nikko) (15)); PEG-100 Hardened Castor Oil ( Nikkol HCO-100 (Nikko) (17)); PEG-6 corn oil (Labrafil® M 2125 CS (Gattefosse) (4)); PEG-6 almond oil (Labrafil® M 1966) CS (Gattefosse) (4)); PEG-6 apricot oil (Labrafil® M 1944 CS (Gattefosse) (4)); PEG-6 olive oil (Labrafil® M1980 CS (Gattefosse) (4)) PEG-6 peanut oil (Labrafil® M 1969 CS (Gattefosse) (4)); PEG-6 hardened palm kernel oil (Labrafil® M 2130 BS (Gattefosse) (4)); PEG-6 Palm kernel oil (Labrafil® M 2130 CS (Gattefosse) (4)); PEG-6 triolein (Labrafil® M 2735 CS (Gattefosse) (4)); PEG-8 corn oil (Labrafil (Registered Trademark)) Registered trademark) WL 2609 BS (Gattefosse) (6-7)); PEG-20 corn glycol (Crobol M40 (Croda) (10)); PEG-20 almond glyceride (Croball A40 (Croda) (10)); PEG- 25 Trioleate (TAGAT® TO (Goldschmidt) (11)); PEG-40 palm kernel oil (Crobol PK-70 (&gt; 10)); PEG-60 corn glycol (Croball M70 (Croda) (15)); PEG-60 almond glyceride (Croball A70) (Croda) (15)); PEG-4 caprylic acid / capric acid triglyceride (Labrafac® hydro (Gattefosse), (4-5)); PEG-8 caprylic acid / capric acid glyceride (Gattefosse), Labrafac CM 10 (Gattefosse) (&gt; 10)); PEG-6 caprylic acid / capric acid glyceride (Softigen® 767 (Huls), Glycerox 767 (Croda) (19)); Lauroyl macrogol-32 glyceride ( GELUCIRE 44/14 (Gattefosse) (14)); Stearoyl macrogol glyceride (GELUCIRE) 50/13 (Gattefosse) (13)); Vegetable oil mono, di, tri, tetraester and sorbitol (sorbitoglyceride (Gattefosse) (&lt;10)); pentaerythrityl tetraisostearate (crodamol PTIS (Croda)) (&lt;10)); Pentaerytrityl distearate (Albunol DS (Taiwan Surf.) (&lt;10)); Pentaerytrityl tetraoleate (Liponate PO-4 (Lipo Chem.) (&lt;10)); Pentaeri Trityl tetrastearate (Liponate PS-4 (Lipo Chem.) (&lt;10)); Pentaerytrityl tetracaprilate / Tetraca plate (Liponate PE-810 (Lipo Chem.), Crodamol PTC (Croda) (&lt;10) )); Pentaerytrityl tetraoctanoate (Nikko Pentarate 408 (Nikko)); and combinations thereof.

0067Polyglycolated fatty acids: (Compound name (listed as generic trade name (source) (HLB)): Polyglyceryl-2 stearate (Nikko DGMS (Nikko) (5-7)); Polyglyceryl-2 oleate (Nikko DGMO (Nikko)) ) (5-7)); Polyglyceryl-2 isostearate (Nikko DGMIS (Nikko) (5-7)); Polyglyceryl-3 oleate (Caprol® 3GO (ABITEC), Drewpol 3-1-O (Stepan) ) (6.5)); Polyglyceryl-4 oleate (Nikko tetragulin 1-O (Nikko) (5-7)); Polyglyceryl-4 stearate (Nikkor tetragulin 1-S (Nikko) (5-6)); Polyglyceryl -6 oleate (Drewpol 6-1-O (Stepan), Nikko hexagulin 1-O (Nikko) (9)); polyglyceryl-10 laurate (Nikkor decagulin 1-L (Nikko) (15)); polyglyceryl-10 oleate ( Nikkor Decagulin 1-O (Nikko) (14)); Polyglyceryl-10 stearate (Nikko Decagulin 1-S (Nikko) (12)); Polyglyceryl-6 ricinolate (Nikkor Hexagulin PR-15 (Nikko) (&gt; 8)); Polyglyceryl -10 Linoliate (Nikkor Decagulin 1-LN (Nikko) (12)); Polyglyceryl-6 pentaoleate (Nikkor Hexagulin 5-O (Nikko) (&lt;10)); Polyglyceryl-3 Geolate (Cremophore GO32 (BASF) (&lt; 10)); Polyglyceryl-3 distearate (Cremophore GS32 (BASF) (&lt;10)); Polyglyceryl-4 pentaoleate (Nikkor tetragulin 5-O (Nikko) (&lt;10)); Polyglyceryl-6 dioleate (Caprol (registered) Trademarks) 6G20 (ABITEC); Hodag PGO-62 (Calgene), PLUROL OLEIQUE CC 497 (Gattefosse) (8.5)); Polyglyceryl-2 Geolate (Nikkor DGDO) (Nikko) (7)); Polyglyceryl-10 trioleate (Nikko Decagulin 3-O (Nikko) (7)); Polyglyceryl-10 pentaoleate (Nikko Decagulin 5-O (Nikko) (3.5)); Polyglyceryl-10 Septa Oleate (Nikkor Decagulin 7-O (Nikko) (3)); Polyglyceryl-10 tetraoleate (Caprol® 10G4O (ABITEC); Hodag PGO-62 (CALGENE), Drewpol 10-4-O (Stepan)) (6.2)); Polyglyceryl-10 decaisostearate (Nikko Decagulin 10-IS (Nikko) (&lt;10)); Polyglyceryl-101 Decaoleate (Drewpol 10-10-O (Stepan), Caprol 10G10O (ABITEC), Nikkor Decagulin) 10-O (3.5)); Polyglyceryl-10 mono, Geolate (Caprol® PGE) 860 (ABITEC) (11)); Polymuls (Henkel) (3-20); and combinations thereof.

0068Propylene Glycol Fatty Ester: (Compound Name (Listed as General Trade Name (Supplier) (HLB)): Propylene Glycol Monocaprylate (Capriol 90 (Gattefosse), Nikkol Cefsol 218 (Nikko) (&lt;10)); Propylene Glycol Monolaurate (Lauroglycol 90 (Gattefosse), Lauroglycol FCC (Gattefosse) (&lt;10)); Propylene glycol oleate (Lutrol OP2000 (BASF) (&lt;10)); Propylene glycol millistate (Mirpyl (&lt;10)) Propylene glycol monostearate (ADM PGME-03 (ADM), LIPO PGMS (Lipo Chem.), Aldo® PGHMS (Lonza) (3-4)); Propylene glycol hydroxystearate (&lt;10)); Propylene Glycol Lysinolate (PROPYMULS (Henkel) (&lt;10)); Propylene Glycol Isostearate (&lt;10)); Propylene Glycol Monooleate (Miberol) P-O6 (Eastman) (&lt;10)); Propylene Glycol Dicaprylate / Dica Plate (Captex® 200 (ABITEC), Migliol® 840 (Huls), Neobee® M-20 (Stepan) (&gt; 6)); Propylene Glycol Dioctanoate (Captex® 800 (ABITEC) (&gt; 6)); Propylene Glycol Caprilate / Caplate (Labrafak PG (Gattefosse) (&gt; 6)); Propylene Glycol Dilaurate (&gt; 6)); Propylene Glycol Distearate (Kesco® PGDS (Stepan) (&gt; 6)); Propylene Glycol Dicaprylate (Nikkol Cefzol 228 (Nikko) (&gt; 6)); Propylene Glycol Jika plate (Nikko PDD (Nikko) (&gt; 6)); and combinations thereof.

0069Mixtures of propylene glycol esters and glycerol-esters: (Compound name (listed as generic trade name (source) (HLB)): Oleic acid (Atmos 300, Arrasel 186 (ICI) (3-4)); Stearic acid (Atmos) 150 (3-4)); and combinations thereof.

0070Mono- and diglycerides: (Compound name (listed as General Trade Name (Supplier) (HLB)): Monopalmitrain (C16: 1) (Larodan) (&lt;10)); Monoellaidin (C18: 1) (Larodan) ( &lt;10)); Monocaproin (C6) (Larodan) (&lt;10)); Monocapriline (Larodan) (&lt;10)); Monocaprin (Larodan) (&lt;10)); Monocaprin (Larodan) (&lt;10)); Glyceryl Monomillistate (C14) (Nikko MGM (Nikko) (3-4)); Glyceryl monooleate (C18: 1) (Peseol (Gattefosse), Hodag GMO-D, Nikko MGO (Nikko) (3-4)) Glyceryl monooleate (RYLO series (Danisco), DIMODAN series (Danisco), EMULDAN (Danisco), ALDO (registered trademark) MO FG (Lonza), Kesco GMO (Stepan), MONOMULS (registered trademark) series (Henkel), TEGIN O, DREWMULSE GMO (Stepan), Atlas G-695 (ICI), GMOrphic 80 (Eastman), ADM DMG-40, 70 and 100 (ADM), Myberol (Eastman) (3-4)); Glycerol monooleate / linoliate (OLICINE (Gattefosse) (3- 4)); Glyceryl ricinoleate (Maisine (Gattefosse), Maiberol 18-92, Maiverol 18-06 (Eastman) (3-4)); Glyceryl ricinoleate (Softigen® 701 (Huls), HODAG GMR -D (Calgene), ALDO® MR (Lonza) (6)); Glyceryl monolaurate (ALDO® MLD (Lonza), Hodag GML (Calgene) (6.8)); Glycerol monopalmitate ( Emalex GMS-P (Nihon) (4)); Glycerol monostearate (Capmul® GMS (ABITEC), Myvaplex (Eastman), IMWITOR® 191 (Huls), CUTINA GMS, Aldo® MS (Lonza), Nikkol MGS Series (Nikko) (5-9)); Glycerylmono-, Geolate (Capmul® GMO-K (ABITEC) (&lt;10)); Glyceryl palmitin Acid / stearic acid (CUTINA MD-A, ESTAGEL-G18 (&lt;10)); Glyceryl acetate (Lamegin® EE (Grunau GmbH) (&lt;10)); Glyceryl laurate (Imwitor® 312 (Huls)) ), MONOmuls® 90-45 (Grunau) GmbH, Aldo® MLD (Lonza) (4)); Glycerylcitrate / Lactate / Oleate / Linoliate (Imwitor® 375 (Huls) (&lt;10)); Glycerylcaprilate (Imwitor®) ) 308 (Huls), Capmul® MCMC8 (ABITEC) (5-6)); Glyceryl caprilate / caplate (Capmul® MCM (ABITEC) (5-6)); Caprylic acid mono, diglyceride ( Imwitor® 988 (Huls) (5-6)); Caprylic acid / capric acid glyceride (Imwitor® 742 (Huls) (&lt;10)); Mono- and diacetylated monoglyceride (Myvacet®) 9-45, Myvacet® 9-40, Myvacet® 9-08 (Eastman), Lamegin® (Grunau) (3.8-4)); Glyceryl monostearate (Aldo®) MS, Arrasel 129 (ICI), LIPO GMS (Lipo) Chem.), Imwitor® 191 (Huls), Myvaplex (Eastman) (4.4)); Mono, diglyceride lactic acid ester (LAMEGIN GLP (Henkel) (&lt;10)); Dicaproin (C6) (Larodan) (&lt; 10); Dicaprin (C10) (Larodan) (&lt;10); Dioctanoin (C8) (Larodan) (&lt;10); Dimyristin (C14) (Larodan) (&lt;10); Dipalmitin (C16) (Larodan) (&lt; 10); Larodan (&lt;10); Glyceryl dilaurate (C12) (Capmul® GDL (ABITEC) (3-4)); Glyceryl dioleate (Capmul® GDO (ABITEC) (3) -4)); Fatty acid glycerol ester (GELUCIRE 39/01 (Gattefosse), GELUCIRE 43/01 (Gattefosse) GELUCIRE 37/06 (Gattefosse) (1) 6)); Dipalmitoleic acid (C16: 1) (Larodan) (&lt;10); 1,2 and 1,3-Giorain (C18: 1) (Larodan) (&lt;10); (&lt;10); Girinorain (C18: 2) (Larodan) (&lt;10); and combinations thereof.

0071Sterols and Sterol Derivatives: (Compound Names (Listed as General Trade Names (Suppliers) (HLB)): Cholesterol, Cytosterols, Lanosterols (&lt;10)); PEG-24 Cholesterol Ethers (Solulan C-24 (Amerchol) (&gt; 10) )); PEG-30 Cholesterol (Nikko DHC (Nikko) (&gt; 10)); Phytosterol (GENEROL series (Henkel) (&lt;10)); PEG-25 Phytosterol (Nikko BPSH-25 (Nikko) (&gt; 10)) PEG-5 soy sterols (Nikkol BPS-5 (Nikko) (&lt;10)); PEG-10 soy sterols (Nikkol BPS-10 (Nikko) (&lt;10)); PEG-20 soy sterols (Nikkol BPS-20 (&lt;10)) Nikko) (&lt;10)); PEG-30 soy sterols (Nikkol BPS-30 (Nikko) (&gt; 10)); and combinations thereof.

0072Polyethylene glycol sorbitan fatty acid ester: (Compound name (listed as general trade name (source) (HLB)): PEG-10 sorbitan laurate (Liposolve L-10 (Lipo Chem.) (&gt; 10)); PEG-20 sorbitan Monolaurate (Tween-20 (Atlas / ICI), Crylet 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 (&gt; 10)); PEG-6 sorbitan monolaurate (Nikkol GL-1 (Nikko) (16) )); PEG-20 Sorbitan Monopalmitate (Tween-40 (Atlas / ICI), Crylet 2 (Croda) (16)); PEG-20 Sorbitan Monostearate (Tween-60 (Atlas / ICI), Crillet) 3 (Croda) (15)); PEG-4 Sorbitan Monostearate (Tween-61 (Atlas / ICI), Crillet 31 (Croda) (9.6)); PEG-8 Sorbitan Monostearate (DACOL MSS (Condea) ( &gt; 10)); PEG-6 Sorbitan Monostearate (Nikkol TS106 (Nikko) (11)); PEG-20 Sorbitan Tristearate (Tween-65 (Atlas / ICI), Crillet 35 (Croda) (11)); PEG-6 Sorbitan Tetrastearate (Nikko GS-6 (Nikko) (3)); PEG-60 Sorbitan Tetrastearate (Nikko GS-460 (Nikko) (13)); PEG-5 Sorbitan Monooleate (Tween-) 81 (Atlas / ICI), Crillet 41 (Croda) (10)); PEG-6 Sorbitan Monooleate (Nikkol TO-106 (Nikko) (10)); PEG-20 Sorbitan Monooleate (Tween-80 (Atlas)) / ICI), Crillet 4 (Croda) (15)); PEG-40 Sorbitan Oleate (Emalex ET 8040 (Nihon Emulsion) (18)); PBG-20 Sorbitan Trioleate (Tween-85 (Atlas / ICI), Crillet 45 (Croda) ( 11)); PEG-6 Sorbitan Tetraoleate (Nikkol GO-4 (Nikko) (8.5)); PEG-30 Sorbitan Tetraoleate (Nikkol GO-430 (Nikko) (12)); PEG-40 Sorbitan Tetraoleate Ate (Nikkol GO-440 (Nikko) (13)); PEG-20 sorbitol monoisostearate (Tween-120 (Atlas / ICI), Crillet 6 (Croda) (&gt; 10)); PEG sorbitol hexaoleate (Atlas) G-1086 (ICI) (10)); PEG-6 sorbitol hexastearate (Nikkol GS-6 (Nikko) (3)); and combinations thereof.

0073Polyethylene Glycol Alkyl Ether: (Compound Name (Listed as General Trade Name (Supplier) (HLB)): PEG-2 Oleyl Ether, Oles-2 (Brij 92/93 (Atlas / ICI) (4.9)); PEG-3 Oleyl Ether, Oles-3 (Volpo 3 (Croda) (&lt;10)); PEG-5 Oleyl Ether, Oles-5 (Volpo 5 (Croda) (&lt;10)); PEG-10 Oleyl Ether, Oles-10 (Volpo) 10 (Croda), Brij 96/97 (Atlas / ICI) (12)); PEG-20 oleyl ether, Ores-20 (Volpo 20 (Croda), Brij 98/99 (Atlas / ICI) (15)); PEG -4 Lauryl Ether, Laures-4 (Brij 30 (Atlas / ICI) (9.7)); PEG-9 Lauryl Ether (&gt; 10)); PEG-23 Lauryl Ether, Laures-23 (Brij 35 (Atlas / ICI)) ( 17)); PEG-2 cetyl ether (Brij 52 (ICI) (5.3)); PEG-10 cetyl ether (Brij) 56 (ICI) (13)); PEG-20 cetyl ether (BriJ 58 (ICI) (16)); PEG-2 stearyl ether (Brij 72 (ICI) (4.9)); PEG-10 stearyl ether (Brij 76 (Brij 76) ICI) (12)); PEG-20 stearyl ether (Brij 78 (ICI) (15)); PEG-100 stearyl ether (Brij 700 (ICI) (&gt; 10)); and combinations thereof.

0074Sugar ester: (Compound name (listed as general trade name (supplier) (HLB)): Sucrose distearate (SUCRO ESTER 7 (Gattefosse), Clodesta F-10 (Croda) (3)); Sucrose distearate / Monostearate (SUCRO ESTER 11 (Gattefosse), Clodesta F-110 (Croda) (12)); Sucrose dipalmitate (7.4)); Sucrose Monostearate (Crodesta F-160 (Croda) (15)); Sucrose Monopalmitate (SUCRO ESTER 15 (Gattefosse) (&gt; 10)); Sucrose monolaurate (Sucrose monolaurate 1695 (Mitsubisbi-Kasei) (15)); and combinations thereof.

0075Polyethylene Glycol Alkylphenol: (Compound Name (Listed as General Trade Name (Supplier) (HLB)): PEG-10-100 Nonylphenol (Triton X Series (Rohm &amp; Haas), Igepal CA Series (GAF, USA), Antarox CA Series) (&gt; 10)); (GAF, UK); PEG-15-100 Octylphenol Ether (Triton N-Series (Rohm &amp; Haas), Igepal CO Series (GAF, USA), Antarox CO Series (GAF, UK) (&gt; 10) )); And combinations thereof.

0076Polyethylene-Polyoxypropylene Block Copolymer (AKA- "Poloxamer"): These polymers have the following formula: HO (C &lt;2&gt; H &lt;4&gt; O) &lt;a&gt; (C &lt;3&gt; H &lt;6&gt; O ) &lt;b&gt; (C &lt;2&gt; H &lt;4&gt; O) &lt;a&gt; H (In the formula, "a" and "b" mean the number of polyoxyethylene and polyoxypropylene units, respectively. Compounds are common. Listed by name and having corresponding "a" and "b" values. POE-POP block copolymer)); (a, b values in that case)); (HO (C &lt;2&gt; H &lt;4&gt; O) &lt;a&gt;)); (Compound (C &lt;3&gt; H &lt;6&gt; O) &lt;b&gt; (C &lt;2&gt; H &lt;4&gt; O) &lt;a&gt; H (HLB)); (Poloxamer 105 (a = 11 (b = 16 (8))); (Poloxamer 108 (a = 46 (b = 16 (&gt; 10))); (Poloxamer 122 (a = 5 (b = 21) ( 3)); (Poloxamer 123 (a = 7 (b = 21 (7))); (Poloxamer 124 (a = 11 (b = 21 (&gt; 7))); (Poloxamer 181 (a = 3 (b = 30))) (Poloxamer 182 (a = 8 (b = 30 (2))); (Poloxamer 183 (a = 10 (b = 30))); (Poloxamer 184 (a = 13 (b = 30))); (Poloxamer 185 (a) = 19 (b = 30)); (Poloxamer 188 (a = 75 (b = 30 (29)); (Poloxamer 212 (a = 8 (b = 35))); (Poloxamer 215 (a = 24 (b = 35)) )); (Poloxamer 217 (a = 52 (b = 35)); (Poloxamer 231 (a = 16 (b = 39))); (Poloxamer 234 (a = 22 (b = 39))); = 27 (b = 39)); (Poloxamer 237 (a = 62 (b = 39 (24)); (Poloxamer 238 (a = 97 (b = 39))); (Poloxamer 282 (a = 10 (b = 47))) )); (Poloxamer 284 (a = 21 (b = 47)); (Poloxamer 288 (a = 122 (b = 47 (&gt; 10))); (Poloxamer 331 (a = 7 (b = 54 (0.5))); (Poloxamer 333 (a = 20 (b = 54)); (Poloxamer 334 (a = 31 (b = 54)); (Poloxamer 335 (a = 38 (b = 54))); (Poloxamer 338 (a = 128 (a = 128)) b = 54)); (Poloxamer 401 (a = 6 (b = 67)); (Poloxamer 402 (a = 13 (b = 67))); (Poloxamer 403 (a = 21 (b = 67))); (Poloxamer 407 (a = 98 (b = 67)); and combinations thereof.

0077Sorbitan fatty acid ester: (Compound name (listed as general trade name (source) (HLB)): Sorbitan monolaurate (Span-20 (Atlas / ICI), Crill 1 (Croda), Arrasel 20 (ICI) (8.6)) ); Sorbitan Monopalmitate (Span-40 (Atlas / ICI), Crill 2 (Croda), Nikko 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), Nikko SO-30 (Nikko) (4.3)); Sorbitan sesquioleate (Arrasel-C (ICI), Crill 43 (Croda), Nikkol SO-15 (Nikko) (3.7)); Sorbitan Tristearate (Span-65 (Atlas / ICI) Crill 35 (Croda), Nikkor SS-30 (Nikko) (2.1)); Sorbitan Monoisostearate (Crill 6) (Croda), Nikkor SI-10 (Nikko) (4.7)); Sorbitan sesquistearate (Nikkor SS-15 (Nikko) (4.2)); and combinations thereof.

0078Lower Alcohol Fatty Acid Esters: (Compound Name (Listed as General Trade Name (Supplier) (HLB)): Ethyl Oleate ((Croda, Nikko) (&lt;10)); Isopropyl Millistate (Crodamol IPM (Croda) (&lt;10)); Isopropyl palmitate (Crodamol IPP (Croda) (&lt;10)); Ethyl linoliate (Nikkol VF-E (Nikko) (&lt;10)); Isopropyl linoliate ( Nikko VF-IP (Nikko) (&lt;10)); and combinations thereof.

0079Ionic surfactants: (listed as compound name (HLB) fatty acid salt (&gt; 10)); sodium caproate; sodium caprilate; sodium caprate; sodium laurate; sodium myristate)); sodium myristolate; palmitin Sodium Acidate; Sodium Palmitrenate; Sodium Oleate (18); Sodium Lysinolate)); Sodium Linolate; Sodium Linolenate; Sodium Stearate; Sodium Lauryl Sulfate (40); Sodium Tetradecyl Sulfate; Sodium Lauryl Sarcosinate; Dioctylsulfosuccinate Sodium acid; bile salt (&gt; 10); sodium colate; sodium taurocholate; sodium glycocholate; sodium deoxycholate; sodium taurodeoxycholate; sodium glycodeoxycholate; sodium ursodeoxycholate; sodium kenodeoxycholate; Sodium taurokenodeoxycholate; sodium glucokenodeoxycholate; sodium corylsarcosinate; sodium N-methyltaurocorate; and combinations thereof.

0080Phospholipids: For example, egg / soy lecithin (Epikuron ; Ovothin ); lithotamago / soy lecithin; hydroxylated lecithin; lysophosphatidylcholine; cardiolipin; sphingomyelin; phosphatidylcholine; phosphatidylethanolamine; phosphatidylglycerol; Phosphatidylserine and combinations thereof.

0081Phosphoric acid ester: Diethanolammonium polyoxyethylene-10 oleyl ether phosphate; esterification product of fatty alcohol or fatty alcohol ethoxylate (with phosphoric acid or anhydride).

0082Carboxylates, eg: ether carboxylates (by oxidation of the terminal OH groups of fatty alcohol ethoxylates) succinylated monoglycerides; stearyl sodium fumarate; stearoylpropylene glycol hydrogen succinates; mono-, mono-diglycerides mono / diacetylated tartrates; mono- , Diglyceride citrate ester; fatty acid glyceryl-lactoester; and combinations thereof.

0083Acyllactilates, eg: fatty acid lactylates; calcium / sodium stearoyl-2-lacate; calcium / sodium stearoyl lactate; alginates such as sodium alginate, calcium alginate, etc.; and combinations thereof.

0084Hydrophilic polymers such as: carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, methacrylic acid copolymers, macrogol, starch, gelatin, dextrin, purululan, agar, gum arabic, 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 (vinylpyrrolidone), poly (ethylene-co-vinylpyrrolidone) , Poly (maleic acid), poly (ethylene-co-maleic acid), poly (acrylamide) or poly (ethylene oxide) -co-poly (propylene oxide); block polymer, lactic acid, glycolic acid graft copolymer, epsilon-caprolactone, Lactic acid-co-glycolic acid oligomer, trimethylene carbonate, anhydride and amino acid acrylate, benzoquinone, naphthoquinone, etc .; N-vinylpyrrolidone-co-vinyl alcohol, poly (ethylene-co-vinyl alcohol); acrylic acid or methacrylate polymer Carbomer, chitosan, methacrylate (eluidylene) and combinations thereof.

0085Acids such as: acetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitrate, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, Carboxy 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-toluene Sulphonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, salts thereof and combinations thereof.

0086Bases, 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 , Aluminum magnesium hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine and mixtures thereof.

0087Chelating agents such as: sodium EDTA, sodium diedetate and mixtures or combinations thereof. Complexing agents such as: hydroxypropyl cyclodextrin, hydroxypropyl beta cyclodextrin, sulfabutyl ether cyclodextrin and mixtures and combinations thereof. Salts, such as: acid salts, bases, fatty acid salts, fatty acid glycerides, bile acid salts, and mixtures and combinations thereof.

0088Amides such as: 2-pyrrolidone, 2-piperidone, epsilon-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, polyvinylpyrrolidone and the like.

0089Alcohols such as: ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, glycerol, sorbitol, mannitol, dimethylisosorbide, polyethylene glycol, fatty acid alcohol, vinyl alcohol polypropylene glycol, polyvinyl alcohol, tocopherol, cellulose cyclodextrin, and others. Derivatives, forms, mixtures, etc.

0090Glycerol and propylene glycol, such as: glycerin, propylene glycol, polypropylene glycol, polypropylene oxide and mixtures thereof. Polyethylene glycol (PEG), eg: PEG300, PEG400, PEG4000, PEG6000, PEG8000, PEG20000 and combinations thereof.

0091Esters such as: ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprilate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate. , Epsilon-caprolactone and its isomers. Delta-valerolactone and its isomers, beta-butyrolactone and its isomers; dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether and the like.

0092Bile acids, for example: colate, taurocolate, glycocolate, deoxycholate, polyurodeoxycholate, kenodeoxycholate, glycodeoxycolate, glycokenodeoxycholate, taurokenodeoxycholate, ursodeoxycholate, lysocolate, tauroursodeoxycholate, glyco Ursodeoxycholate, corylsarcosin).

0093Cellulose, for example: microcrystalline cellulose, ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethyl cellulose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA) ), Cellulose propionate (CPr), cellulose butyrate (CB), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl Methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose acetate trimellitate (HPMCAT) and ethylhydroxyethylcellulose (EHEC), various grades of low viscosity (MW 50,000 daltons or less) and high viscosity HPMC (above MW 50,000 Dalton) and combinations thereof.

0094Cellulose esters such as: Cellulose Acetate, Cellulose Acetate Butyrate, Cellulose Acetate Phthalate, Hydroxypropyl Methyl Cellulose Acetate and combinations thereof.

0095Mucosal adhesive polymers such as tocopherols such as tocopherols, tocopherol acetates, tocopherol succinates and combinations thereof.

0096Amino acids and modified amino acids, such as: aminoboronic acid derivatives, n-acetylcysteine and mixtures thereof.

0097Sugars such as: maltose, sucrose, dextrose, lactose, fructose, mannitol, sucralose, fructose, trehalose, dextrose, malt dextrose and combinations thereof.

0098Sugar alcohols, such as: mannitol, xylitol, sorbitol, combinations thereof, etc.

0099Penetrants 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) Acids, poly (methacryl) acids, polyvinylpyrrolidone (PVP) and crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers and PVA / PVP copolymers (with hydrophobic monomers such as methyl methacrylate, vinyl acetate, etc.), large PEO Hydrophilic polyurethane containing blocks, sodium croscarmellose, calazinan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carbox cellulose (CEC), sodium alginate , Polycarbonophile, gelatin, xanthan rubber, and sodium starch glycolate, etc.

0100Other carriers such as: dibasic calcium phosphate, croscarmellose sodium, sodium starch glycolate, sodium alginate, phospholipids, lecithin, proteins (eg collagen, gelatin, zein, gluten, mussel protein, lipoprotein); For example, alginate, calazinan, cellulose derivatives, pectin, starch); rubber (eg, xanthan gum, arabic gum, tragacant rubber, acacia gum); whale wax; natural or synthetic wax; carnauba wax; fatty acids (eg, stearic acid, hydroxystearic) Acids); magnesium stearate, calcium stearate, titanium oxide, polyacrylic acid, silicate, magnesium aluminum silicate, siloxane, dimethicone, paraffin, fatty alcohols; dibutylphthalate; dibutylsevacate; diethylphthalate; dimethylphthalate; triethylsito Rate; butyl and glycol esters of fatty acids; mineral oil; cetyl alcohol; stearyl alcohol; cypress oil; triethylcitrate, shelac, benzalkonium chloride, methylparaben, propylparaben, sodium benzoate, etc.

0101In one embodiment, the pharmaceutical composition or oral dosage form may be formulated to include at least one of the following preferred carriers:Citric acid, maleic acid, tartaric acid, ascorbic acid, lactic acid and its salts, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, silicon dioxide, aluminum magnesium silicate, triethylamine, fatty acid glyceride, pyrrolidone, polyvinylpyrrolidone, ethyl Alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, triethylcitrate, triacetin, benzylbenzoate, bile acid, bile acid salt, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose ester, carbomer, methacrylate, polyvinyl alcohol, gelatin, distea, Monopalmitrain tocopherol, tocopherol succinate, corn oil, olive oil, peanut oil, Benibana oil, sesame oil, soybean oil, hardened castor oil, glyceryl tricaplate, glyceryl trilinoliate, glyceryl tricaprylate / caplate, glyceryl tricaprylate / Caplate / linoliate, saturated polyglycolylated glyceride, linoleic acid glyceride, capric acid / capric acid glyceride, capric acid, capric acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaene Acid, glyceryl monooleate, glyceryl monolinoliate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl laurate, glyceryl caprilate, PEG-6 corn oil, PEG-6 Apricot oil, stearoyl macrogol glyceride, PEG-20 sorbitan monostearate, PEG-40 cured castor oil, PEG-35 castor oil, sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, polyglyceryl-3 Oleate, Polyglycerol Seryl-10 Oleate, Polyglyceryl-6 Dioleate, Polyglycerol Seryl-10 Mono, Dioleate, Poroxamer 188, Poroxamer 108, Poroxamer 182, Propylene Glycol Monocaprelate, Propylene Glycol Monolaurate, Propylene Glycol Dicaprilate / Dica Plate, Propylene Glycol Caprilate / Caplate, Sorbitan Monolaurate, Sorbitan Monopalmi Tate, sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate, maltose, sucrose, fructose, mannitol, xylitol and combinations thereof.

0102In one embodiment, the pharmaceutical compositions or oral dosage forms of the invention may be formulated to include hydrophilic additives. In another embodiment, the hydrophilic additive can be a hydrophilic surfactant. In one embodiment, if the hydrophilic additive comprises a hydrophilic surfactant, the hydrophilic surfactant does not adequately solubilize the ester of 17-hydroxyprogesterone. Non-limiting examples of hydrophilic additives include citric acid, maleic acid, tartrate acid, acetic acid, ascorbic acid, benzoic acid and lactic acid salts, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, silicon dioxide, kei. Aluminum magnesium acid, hydroxypropylcyclodextrin, fatty acid glyceride, salt of bile acid, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, cellulose ester, carbomer, chitosan, methacrylate , Polyvinyl alcohol, gelatin, PEG-8 capricyl / capric acid glyceride, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 cured castor oil, PEG-35 castor oil, sodium oleate, sodium lauryl sulfate, lauryl Sodium sarcosinate, sodium dioctyl sulfosuccinate, PEG-10 laurate, PEG-20 oleate, PEG-30 stearate, PEG-40 laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl stearate, PEG-40 glyceryl laurate , PEG-20 glyceryl oleate, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate, poroxamer 188, poroxamer 108, maltose , Scroose, fructose, mannitol, xylitol and combinations thereof.

0103In another particular embodiment, the carrier is a hydrophilic surfactant and can be an ionic or nonionic surfactant. Non-limiting examples of hydrophilic surfactants include proteins, gelatin, salts of bile acid, PEG-8 capricyl / capric acid glyceride, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 cured 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 lau Rate, PEG-20 glyceryl stearate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, polyglyceryl-10 oleate , Polyglyceryl-10 mono, diolate, poroxamer 188, poroxamer 108 and combinations thereof.

0104In one embodiment, the hydrophilic additive may not contain a hydrophilic surfactant and may contain citric acid, maleic acid, tartrate acid, acetic acid, ascorbic acid, benzoic acid, lactic acid, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, Calcium carbonate, silicon dioxide, magnesium aluminum silicate, hydroxypropylcyclodextrin, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methylcellulose, hydroxypropylmethylcellulose, cellulose ester, carbomer, chitosan, methacrylate, It can be polyvinyl alcohol, gelatin, maltose, sucrose, fructose, mannitol, xylitol or a combination thereof.

0105In another embodiment, the carrier in pharmaceutical composition or oral dosage form may comprise a lipophilic additive. Non-limiting examples of lipophilic additives include tributylcitrate, triethylcitrate, triacetin, ethylcellulose, cellulose ester, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, tocopherol, tocopherol acetate, tocopherols. Cucinate, corn oil, olive oil, peanut oil, Benibana oil, sesame oil, soybean oil, hardened castor oil, glyceryl trica plate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoliate, glyceryl tricaprylate / caplate, glyceryl tri Caprilate / caplate / laurate, glyceryl tricaprilate / caplate / linoliate, glyceryl tricaprilate / caplate / stearate, saturated polyglycolylated glyceride, linoleic acid glyceride, capric acid / capric acid glyceride, capric acid, capric acid, palmitin Acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoliate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl Palmitostearate, glyceryl laurate, glyceryl caprilate, distearic acid, monopalmitrein, monolaurin, ethyl oleate, PEG-6 corn oil, PEG-6 apricot oil, PEG-4 capric acid / capric acid triglyceride, PEG-20 sorbitan Monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poroxamer 182, propylene glycol monocaprilate, propylene glycol monolaurate, propylene glycol dicaprylate / dicaplate, propylene glycol Capri Rate / caplate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate and combinations thereof. In one embodiment, the carrier of the invention may contain at least 50% by weight lipophilic additives.

0106In certain embodiments, the lipophilic additive is tributylcitrate, triethylcitrate, triacetin, ethylcellulose, cellulose ester, celluloseacetate, celluloseacetate butyrate, celluloseacetate phthalate, hydroxypropylmethylcellulosephthalate, tocopherol, tocopherol acetate, tocopherol. Succinate, triglyceride, corn oil, olive oil, peanut oil, Benibana oil, sesame oil, soybean oil, hardened castor oil, glyceryl tricaplate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoleate, glyceryl tricaprylate / caprate , Glyceryl tricaprelate / caplate / laurate, glyceryl tricaprylate / caplate / linoliate, glyceryl tricaprylate / caplate / stearate, saturated polyglycolated glyceride, linoleic acid glyceride, caprylic acid / capric acid glyceride, capric acid, capryl Acids, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, glyceryl distearate, glyceryl palmitostearate, distearate, tristearic acid, paraffin oil, beeswax, animal fat , Phytosterol, cholesterol, shelac and at least one agonist selected from the combination thereof.

0107In certain embodiments, the lipophilic additive is a triglyceride. Non-limiting examples of triglycerides suitable for the present invention include corn oil, olive oil, peanut oil, palm oil, palm oil, peanut oil, Benibana oil, sesame oil, soybean oil, sunflower oil, primrose oil, cottonseed oil, vegetable oil, rurichisha. Oil, flaxseed oil, flax seed oil, omega oil, partially or fully cured castor oil, fish oil, shark oil, whale oil, parrot oil, glyceryl tricaplate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoliate, glyceryl tri Caprilate / caplate, glyceryl tricaprilate / caplate / laurate, glyceryl tricaprilate / caplate / linoliate, glyceryl tricaprate / caplate / stearate, saturated polyglycolated glyceride, linoleic glyceride, capric acid / capric acid glyceride Examples thereof include tristeares and the like, and combinations thereof.

0108In one embodiment, the lipophilic additive may not contain a lipophilic surfactant. In certain embodiments, the carrier is a lipophilic surfactant. Non-limiting examples of lipophilic surfactants suitable for the present invention include tributylcitrate, triethylcitrate, triacetin, ethylcellulose, cellulose ester, cellulose acetate, cellulose acetate butyrate, benzylbenzoate, cellulose acetate phthalate, hydroxypropylmethylcellulose. Phtalate, tocopherol, tocopherol acetate, tocopherol succinate, corn oil, olive oil, peanut oil, benibana oil, sesame oil, soybean oil, hardened castor oil, glyceryl tricaplate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoliate, Glyceryl tricaprelate / caplate, glyceryl tricaprylate / caplate / laurate, glyceryl tricaprylate / caplate / linoliate, glyceryl tricaprylate / caplate / stearate, saturated polyglycolylated glyceride, linoleic acid glyceride, capric acid / capric acid Glyconide, capric acid, capric acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoliate, glyceryl monolaurate, glycerol mono Stearate, glyceryl distearate, glyceryl palmito stearate, glyceryl laurate, glyceryl caprilate, distearic acid, monopalmitrain, monolaurin, ethyloleate, PEG-6 corn oil, PEG-6 apricot oil, PEG-4 capric acid / Capric acid triglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poroxamer 182, propylene glycol monocaprilate, propylene glycol monolaurate, polyethylene

0109In another particular embodiment, the compositions or dosage forms of the invention may or may not contain triglycerides. Thus, in one embodiment, the invention does not include lipophilic or hydrophilic additives that contain triglycerides as the intended or added constituents. However, it should be understood that the present invention does not exclude lipophilic or hydrophilic additives containing small amounts of triglycerides as impurities or as non-reactive starting materials. When such lipophilic or hydrophilic additives are used in the compositions of the present invention, the total triglyceride content is expected not to exceed 5% by weight of the composition or dosage form. Thus, "substantially free of triglycerides" means that no additional triglycerides are contained, and triglyceride impurities from lipophilic or hydrophilic additives are about 5% by weight, or 5% by weight, of the composition. It should be understood to constitute less than, less than 2% by weight, or preferably 0% by weight (without triglycerides). Furthermore, the present invention does not exclude lipophilic or hydrophilic additives that are triglyceride derivatives such as polyethylene glycol or propylene glycol derivatives of triglycerides; while these derivatized triglycerides may have surfactant properties, triglycerides It is not a surfactant in itself.

0110Non-limiting examples of such lipophilic additives include tributylcitrate, triethylcitrate, triacetin, ethylcellulose, cellulose ester, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, tocopherol, tocopherol acetate. , Tocopherol succinate, saturated polyglycolated glyceride, linoleic acid glyceride, capric acid / capric acid glyceride, capric acid, capric acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid , Benzylbenzoate, docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoliate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl laurate, glyceryl caprilate, distearate, monopalmitrain , Monolaurin, ethyl oleate, PEG-6 corn oil, PEG-6 apricot oil, PEG-4 capric acid / capric acid triglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 Oleate, Polyglyceryl-6 Dioleate, Poroxamer 182, Propylene Glycol Monocaprate, Propylene Glycol Monolaurate, Propylene Glycol Dicaprilate / Dica Plate, Propylene Glycol Caprirate / Caplate, Solbitan Monolaurate, Solbitan Monopalmitate, Solbitan Mono Examples thereof include oleate, sorbitan monostearate, sorbitans sesquioleate, sorbitan sesquistearate and combinations thereof.

0111In some embodiments, the carrier of the invention can be a controlled release material. In certain embodiments, the controlled release material is selected from the group consisting of the above hydrophilic or lipophilic additives or mixtures thereof. In another particular embodiment, the compositions or dosage forms of the invention may not contain lipophilic surfactants. In another particular embodiment, the compositions or dosage forms of the invention may not contain lipophilic additives.

0112As mentioned above, in some embodiments, the pharmaceutical compositions and oral dosage forms disclosed in the present invention may comprise at least one hydrophilic additive and at least one lipophilic additive. In one embodiment, if both hydrophilic and lipophilic additives are present, they can be present in a lipophilic additive to hydrophilic additive ratio of about 99: 1 to about 1:99. In one embodiment, the lipophilic additive to hydrophilic additive ratio can be from about 95: 5 to about 5:95. In another embodiment, the lipophilic additive to hydrophilic additive ratio can be from about 90:10 to about 10:90. In one embodiment, the lipophilic additive to hydrophilic additive ratio can be from about 90:10 to about 1:99. In another particular embodiment, the lipophilic additive to hydrophilic additive ratio can be from about 80:20 to about 20:80. In another particular embodiment, the lipophilic additive to hydrophilic additive ratio can be from about 70:30 to about 30:70. In another particular embodiment, the lipophilic additive to hydrophilic additive ratio can be from about 60:40 to about 40:60. In another particular embodiment, the lipophilic additive to hydrophilic additive ratio can be about 50:50.

0113In a separate embodiment, if both the hydrophilic surfactant and the lipophilic additive are present, they are a mixture of the hydrophilic surfactant and the lipophilic additive. When 1 part by weight is mixed with 99 parts by weight of the aqueous diluent, the dispersion thus obtained may be present in such an amount that it can be colloidal, turbid or opaque. For example, the aqueous diluent used for the dispersion is water or 0.5% w / v sodium lauryl sulfate in water. In certain embodiments, the dispersion may exhibit an absorbance greater than 0.1 when determined using a spectrometer at 400 nm. In another particular embodiment, the absorbance is greater than 0.3 at 400 nm. In another embodiment, the average particle size of the dispersion is about 60 nm or greater. In another particular embodiment, the average particle size of the dispersion is about 100 nm or greater. In another particular embodiment, the average particle size of the dispersion is about 150 nm or greater. In yet another particular embodiment, the average particle size of the dispersion is about 200 nm or greater. In yet another particular embodiment, the average particle size of the dispersion is about 250 nm or greater. For example, the aqueous diluent used for the dispersion is water or 0.5% w / v sodium lauryl sulfate in water. For the purposes of the present invention, a dispersion is considered transparent if it appears transparent to the naked eye. In one embodiment, the dispersion can be transparent.

0114The carrier may be present in an amount sufficient to solubilize the ester of 17-hydroxyprogesterone. In some embodiments, the carriers of the invention help solubilize significant amounts of esters of 17-hydroxyprogesterone in the composition. In one embodiment, the carrier can solubilize 20% by weight or more of the amount of ester of 17-hydroxyprogesterone. In another embodiment, the carrier can help load more than about 10% w / w of the ester in the composition and / or dosage form. In another embodiment, the load achieved by the carrier is greater than about 12% w / w of the composition and / or dosage form.

0115In another embodiment, 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 load obtained by inclusion of the carrier can be greater than about 18% w / w of the composition and / or dosage form. In a further embodiment, the load obtained by inclusion of the carrier is greater than about 20%; greater than about 25%, about 30%, at each percentage based on the composition and / or dosage form w / w. Can be greater than, 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%.

0116In one embodiment, the carrier may include benzyl alcohol, benzyl benzoate, a mixture thereof. In another embodiment, the carrier may comprise benzyl alcohol, benzyl benzoate or a mixture thereof, and the amount of ester of 17-hydroxyprogesterone can be from about 5 to about 80% w / w of the total composition. In one embodiment, if the carrier comprises benzyl alcohol, benzyl benzoate or a mixture thereof, the amount of ester of 17-hydroxyprogesterone can be from about 5 to about 80% w / w of the total composition. In one embodiment, the amount of ester of 17-hydroxyprogesterone can be from 5% to about 60% w / w of the total composition. In another particular embodiment, if the carrier comprises benzyl alcohol, benzyl benzoate or a mixture thereof, the amount of ester of 17-hydroxyprogesterone can be from about 5 to about 40% w / w of the total composition. In another particular embodiment, if the carrier comprises benzyl alcohol, benzyl benzoate or a mixture thereof, the amount of ester of 17-hydroxyprogesterone can be from about 5 to about 30% w / w of the total composition. In another particular embodiment, if the carrier comprises benzyl alcohol, benzyl benzoate or a mixture thereof, the amount of ester of 17-hydroxyprogesterone can be from about 5 to about 25% w / w of the total composition. In one particular embodiment, if the carrier comprises a benzyl alcohol, benzyl benzoate or a mixture thereof, the ester of 17-hydroxyprogesterone can be completely solubilized in the composition and / or dosage form. In another particular embodiment, the ester of 17-hydroxyprogesterone can be partially solubilized in the dosage form. In another particular embodiment, the ester of 17-hydroxyprogesterone can be 17-hydroxyprogesterone caproate.

0117In one embodiment, the ratio of the amount of ester of 17-hydroxyprogesterone is about 1: 0.01 (W / W) to the sum of the amounts of benzyl alcohol and benzyl benzoate present in the composition or oral dosage form. It can be about 1: 5 (W / W). In another embodiment, the ratio can be from about 1: 0.01 (W / W) to about 1: 3.5 (W / W). In another embodiment, the sum of the amounts of benzyl alcohol and benzyl benzoate present in the ester pair composition or oral dosage form of 17-hydroxyprogesterone is from about 1: 0.01 (W / W) to about 1: 2.5 (W). / W) can be. In another embodiment, the sum of the amounts of benzyl alcohol and benzyl benzoate present in the ester pair composition or oral dosage form of 17-hydroxyprogesterone is from about 1: 0.01 to about 1: 2 (W / W). obtain.

0118Pharmaceutical compositions and oral dosage forms can be formulated and delivered in various solid or liquid dosage forms. Non-limiting examples of such dosage forms include powders, granules, microparticles, beads, pellets, sprinkles, suspensions, solutions, tablets, capsules and combinations thereof. In one embodiment, the pharmaceutical composition or oral dosage form can be in the form of capsules. In another embodiment, the pharmaceutical composition or oral dosage form can be in the form of tablets. In one embodiment, the dosage form is a hard or soft capsule. Capsules may be made from conventional capsule jacket materials known in the art; such substances may include, but are not limited to, gelatin, cellulose, starch, methacrylate, carrageenan, polyvinyl alcohol and the like. .. In another embodiment, the capsule is in immediate release dosage form. In yet another embodiment, the capsule is in controlled release dosage form. In another embodiment, the tablet is in immediate release dosage form. In another embodiment, the tablet is in controlled release dosage form.

0119In one embodiment, the volume of the capsule can be about 1.5 mL or less. In another embodiment, the capsule volume 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 weight-to-capsule volume ratio of the filler encapsulated in the capsule can be from about 0.3 g / mL to about 3.5 g / mL. In certain embodiments, the ratio can be between 0.6 g / mL and about 2.5 g / mL. In another particular embodiment, the ratio can be between 0.6 g / mL and about 1.2 g / mL.

0120In another embodiment, the oral pharmaceutical capsule form of the present invention has an ester volume to volume ratio of 17-hydroxyprogesterone in a composition of about 0.02 g / mL to about 0.8 g / mL. obtain. In another embodiment, the ratio can be from about 0.02 g / mL to about 0.7 g / mL. In certain embodiments, the ratio can be from about 0.02 g / mL to about 0.5 g / mL. In another particular embodiment, the ratio can be from about 0.05 g / mL to about 0.5 g / mL. In another particular embodiment, the ratio can be from about 0.05 g / mL to about 0.35 g / mL. In another particular embodiment, the ratio can be from about 0.05 g / mL to about 0.3 g / mL. In another particular embodiment, the ratio can be from about 0.1 g / mL to about 0.25 g / mL.

0121The oral dosage form of the present invention may be formulated to contain from about 10 mg to about 800 mg an ester amount of 17-hydroxyprogesterone equivalent to 17-hydroxyprogesterone. In one embodiment, the oral dosage form may be formulated to contain an amount of 17-hydroxyprogesterone ester equivalent to 20 mg to about 400 mg of 17-hydroxyprogesterone. The pharmaceutical compositions and oral dosage forms of the invention are formulated to be administered to a subject to provide a daily dose of an ester of 17-hydroxyprogesterone equivalent to about 40 mg to about 3200 mg of 17-hydroxyprogesterone. Can be done. In one embodiment, the oral dosage form can be a capsule, which comprises from about 10 mg to about 300 mg of 17-hydroxyprogesterone caproate. In another embodiment, the oral dosage form can be a tablet, which comprises from about 20 mg to about 800 mg of 17-hydroxyprogesterone caproate.

0122To provide the desired daily dose, the pharmaceutical composition and oral dosage form may be formulated to be administered at various dose intervals. In one embodiment, the composition or oral dosage form can be formulated for about one dose every 8 hours. In another embodiment, the composition or oral dosage form may be formulated for administration to a subject, eg, a human subject, once every 6 hours. In another embodiment, the composition or oral dosage form may be formulated for about one dose every 12 hours. In a further embodiment, the composition or oral dosage form may be formulated for about one dose every 24 hours.

0123In one aspect, the oral dosage forms of the invention can be used to treat pregnant female subjects at risk of preterm birth. The treatment method comprises the step of orally administering the oral pharmaceutical composition to a female subject. In another embodiment, the oral dosage form can be administered to a subject in need thereof. Administration of the oral dosage form can treat at least one condition selected from preterm birth, preterm birth, infertility and miscarriage. In one embodiment, a subject receiving the pharmaceutical composition or oral dosage form may experience or face the risk of at least two of the following: singleborn pregnancy, preterm birth. History and / or preterm birth history, preterm birth history, cervical shortening and cervical extension, at least one miscarriage history, and multiple pregnancy history. The condition and associated treatment may be based on the primary and secondary endpoint metrics associated with the administration of the ester of 17-hydroxyprogesterone.

0124In one embodiment, the pharmaceutical composition or oral dosage form of the invention comprising an ester of 17-hydroxyprogesterone upon a single dose to a human subject is 17-hydroxyprogesterone equivalent C greater than about 0.7 ng / mL._avg-24hCan be provided. In another embodiment, the oral dosage form or composition is C of a 17-hydroxyprogesterone equivalent greater than about 10 ng / mL._avg-24hCan be provided. In another embodiment, the oral dosage form or composition is C of a 17-hydroxyprogesterone equivalent greater than about 30 ng / mL._avg-24hCan be provided. In another embodiment, the oral dosage form or composition is C of a 17-hydroxyprogesterone equivalent greater than about 50 ng / mL._avg-24hCan be provided. In a further embodiment, * the oral dosage form or composition is C of a 17-hydroxyprogesterone equivalent greater than about 100 ng / mL._avg-24hCan be provided. In one embodiment, the 17-hydroxyprogesterone equivalent C described above_avg-24hIs determined by the HPLC-MS / MS method for analysis of plasma, serum or blood samples collected after oral administration.

0125In one embodiment, upon a single dose to a human subject, the pharmaceutical composition or oral dosage form of the invention comprising 17-hydroxyprogesterone caproate is equal to or greater than about 1.0 ng / mL 17-hydroxyprogesterone. Caproate C_avg-24hCan be provided. In another embodiment, the oral dosage form or composition is equal to or greater than about 20 ng / mL 17-hydroxyprogesterone caproate C._avg-24hCan be provided. In another embodiment, the oral dosage form or composition is equal to or greater than about 50 ng / mL 17-hydroxyprogesterone caproate C._avg-24hCan be provided. In another embodiment, the oral dosage form or composition equals greater than or equal to about 100 ng / mL 17-hydroxyprogesterone caproate C._avg-24hCan be provided. In one embodiment, the 17-hydroxyprogesterone caproate C above_avg-24hIs determined by the HPLC-MS / MS method for analysis of plasma, serum or blood samples collected after oral administration.

0126The compositions and / or dosage forms of the present invention provide a significant increase in the bioavailability of 17-hydroxyprogesterone caproate as a function of 17-hydroxyprogesterone caproate administered to a subject. It turned out unexpectedly. Therefore, the compositions or dosage forms of the invention have an AUC of about 10 or less upon single-dose oral administration._(0-24h)A dose-to-dose ratio is provided (in this case, the dose is the amount of 17-hydroxyprogesterone caproate administered in mg). In one embodiment, the 17-hydroxyprogesterone caproate AUC_(0-24h)The dose ratio of 17-hydroxyprogesterone caproate to be administered is approximately 0.2 ng.^*hmL^-1mg^-1~ About 10ng^*hmL^-1mg^-1Can be. In another embodiment, 17-hydroxyprogesterone caproate AUC_(0-24h)The dose ratio of 17-hydroxyprogesterone caproate to be administered is approximately 0.3 ng.^*hmL^-1mg^-1~ About 7ng^*hmL^-1mg^-1Can be. In certain embodiments, AUC_(0-24h)The dose ratio is about 0.5 to about 6 ng^*hmL^-1mg^-1Is.

0127In certain embodiments, the oral dosage form or pharmacy upon single administration of a pharmaceutical composition or oral dosage form containing the 17-hydroxyprogesterone caproate of the invention to a human subject under feeding conditions. The composition is 17-hydroxyprogesterone caproate C, which is greater than about 1.0 ng / mL._avg-24hCan be provided. In another particular embodiment, when administered to a human subject under feeding conditions, the pharmaceutical compositions or oral dosage forms containing 17-hydroxyprogesterone of the invention are constant greater than about 1.0 ng / mL. State 17-Hydroxyprogesterone caproate C_avg-24hCan be provided. In one embodiment, the above C_avg-24hIs determined by the HPLC-MS / MS method for analysis of plasma, serum or blood samples collected after administration. In another embodiment, the compositions and oral dosage forms disclosed herein can be administered orally with or without food or food content. In certain embodiments, compositions and oral dosage forms containing caproic acid esters of 17-hydroxyprogesterone as disclosed herein are administered orally with or without food or food content. Can be done.

0128In one embodiment, the oral dosage form can be administered orally with food or under feeding conditions. In another embodiment, the composition or oral dosage form may be administered with a regular or standard diet. In certain embodiments, the composition or oral dosage form may be administered with a food or meal, eg, with a meal that provides about 200 to about 1000 calories of energy. In another particular embodiment, the composition or oral dosage form can be administered with a diet that provides about 50% calories from fat. In another embodiment, the composition or oral dosage form can be administered with a high-fat, high-calorie diet. In another embodiment, the composition or oral dosage form can be administered with a standard diet that provides about 500 to about 1000 calories of energy. The compositional structure of the diet administered may vary depending on the subject's preferences and dietary needs. However, in some situations it may be beneficial to administer the composition and oral dosage forms with a diet that provides fat-free to about 50 g of fat. In one embodiment, the diet may provide about 3 g to about 50 g of fat. In a further embodiment, the diet may provide 10 g to about 50 g of fat. In yet another embodiment, the diet may provide about 15 g to about 35 g of fat. In one embodiment, when the oral dosage form is administered to a human female, it can be performed regardless of the presence of the diet or the nutritional composition of the diet. In another embodiment, when the oral dosage form is administered, the total daily dose of 17 HP ester administered to a human female subject with food or under feeding conditions is without meals for similar therapeutic benefits. It is about 20% to about 80% of the total daily dose administered to. In certain embodiments, the daily dose under feeding conditions is about 20% to about 60% of the total daily dose administered without a meal for similar therapeutic benefits. In another embodiment, the composition or oral dosage form can be administered without a meal or under fasting conditions.

0129The oral bioavailability of an ester of 17-hydroxyprogesterone can be found in the compositions and / or dosage forms of the invention, eg, in the form of fine particles that have been ground, pulverized, or nanosized. It can be enhanced by use. In addition, oral bioavailability is at least 20% by weight of the ester from the composition or dosage form when exposed to an aqueous medium compared to equivalent doses of the ester without the carrier of the invention. It can be enhanced by using the ester with a carrier that aids in release. In certain embodiments, the oral bioavailability of caproic acid esters of 17-hydroxyprogesterone is, for example, ground, pulverized, or nanosized in the compositions and / or dosage forms of the invention. It can be enhanced by using the above ester in the form of fine particles or a combination thereof.

0130Thus, in one embodiment, the oral bioavailability of the ester of 17-hydroxyprogesterone is compared to the equivalent dose of ester present in the "untreated" microparticle form, eg, in the unpulverized or non-micronized microparticle form. And at least 10% more for compositions or dosage forms of the invention that release at least 20% of the ester in an aqueous medium. In another embodiment, the oral bioavailability of an ester of 17-hydroxyprogesterone is such composition or agent when exposed to an aqueous medium as compared to an equivalent dose of ester without the carrier of the invention. At least 10% more with respect to the compositions or dosage forms of the invention that release at least 20% more ester from the form. In certain embodiments, the ester is 17-hydroxyprogesterone caproate.

0131Esters of 17-hydroxyprogesterone can be substrates for the P-glycoprotein (P-gp) efflux transport system. Therefore, in one embodiment, oral bioavailability is effective amounts of P-gp and / or CYP3A4 inhibitors such as gorensi, grapefruit juice, bergamottin, cafestol (in unfiltered coffee), ketoconazole, erythromycin, Co-administration of the 17-hydroxyprogesterone ester of the present invention with mibefrazil, loperamide, etc. can enhance at least 10%.

0132In a further aspect, the oral pharmaceutical composition or oral dosage form of the ester of 17-hydroxyprogesterone according to the invention can be used to provide luteal support for subjects in need thereof. In one embodiment, the oral composition or dosage form adjusts or titrates the dose and / or dose regimen of the ester of 17-hydroxyprogesterone to provide effective luteal support to the subject in need thereof. Can be prescribed to allow. In one particular embodiment, the dose of the ester of 17-hydroxyprogesterone in the form of the oral composition or dosage form of the invention is adjusted to provide effective luteal support as required during early pregnancy. Or can be titrated. In another particular embodiment, the dose of the ester of 17-hydroxyprogesterone in the form of the oral composition or dosage form of the invention is as effective as required on the basis of the subject's body mass index (BMI). Can be adjusted or titrated to provide good luteal support. In another particular embodiment, the dose of ester of 17-hydroxyprogesterone in the form of the oral composition or dosage form of the invention is effective as required on the basis of the race or ethnicity of the subject. It can be adjusted or titrated to provide luteal support.

0133An example of dose adjustment or titration can be based on the total daily dose and may include administration of a higher initial loading dose or bolus dose followed by administration of a lower effective standard dose. Similarly, dose adjustment or titration can be based on the total dose per week, with the administration of a higher initial loading dose or bolus dose on the first day of the week followed by a lower effective standard dose on the second day of the week. May include administration. The dose administration regimen may include increasing the daily dose as the pregnancy progresses (ie, a gradual increase). In certain embodiments, the ester is 17-hydroxyprogesterone caproate (17-hydroxyprogesterone caproate).

0134In another embodiment, the daily oral dose of 17-hydroxyprogesterone caproate administered with food 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 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. In another embodiment 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.

0135In one particular embodiment, the oral dosage form of the invention comprises a therapeutically effective amount of an ester of 17-hydroxyprogesterone, in this case in 900 mL of deionized water with 0.5 (w / v) sodium lauryl sulfate. After 60 minutes, the oral dosage form releases at least 20% by weight of the ester dose of 17-hydroxyprogesterone, measured at 37 ° C. at 50 RPM using a USP type II lysing device. In another particular embodiment, the dosage form releases at least about 40% by weight of the ester dose of 17-hydroxyprogesterone after 60 minutes. In another particular embodiment, the dosage form releases at least about 50% by weight of the ester dose of 17-hydroxyprogesterone after 60 minutes. In another particular embodiment, the dosage form releases at least about 70% by weight of the ester dose of 17-hydroxyprogesterone after 60 minutes. In certain embodiments, the ester is 17-hydroxyprogesterone caproate. In another embodiment the dosage form is administered with food.

0136After oral administration of an ester of 17-hydroxyprogesterone (eg, 17-hydroxyprogesterone caproate) in the form of the composition or dosage form of the invention, its concentration in the subject's serum, plasma or blood is determined by radioimmunoassay (radioimmunoassay). It can be determined by analytical techniques based on RIA), high performance liquid chromatography-mass spectrometry (HPLC-MS / MS), etc. Therefore, plasma or blood levels for esters can vary. It must be understood that any relative comparison of plasma levels of any compound should be made in the same assay method or should be corrected to adjust for discrepancies in assay specificity.

0137Therefore, in one embodiment, the 17-hydroxyprogesterone caproate composition or dosage form of the present invention has an average steady state 17-hydroxyprogesterone caproate average C of about 10 ng / mL to about 800 ng / mL._maxIn this case, plasma 17-hydroxyprogesterone caproate is determined by the HPLC-MS / MS method. In certain embodiments, the composition or dosage form has an average steady-state 17-hydroxyprogesterone caproate average C of about 10 ng / mL to about 400 ng / mL._maxI will provide a.

0138In a further embodiment, the 17-hydroxyprogesterone caproate composition or oral dosage form of the present invention has a 17-hydroxyprogesterone caproate average steady state C of about 1 ng / mL or higher._minI will provide a. The plasma concentration of 17-hydroxyprogesterone caproate can be determined by the HPLC-MS / MS method. In one embodiment, the composition or oral dosage form is greater than about 10 ng / mL, 17-hydroxyprogesterone caproate average steady state C._minCan be provided. In another embodiment, the composition or oral dosage form is 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 17-hydroxyprogesterone caproate. Average steady state C_minCan be provided. In one particular embodiment, the composition or oral dosage form has an average steady state of about 1 to about 60 ng / mL C._minCan be provided. In another particular embodiment, the composition or dosage form has an average steady state of about 1 ng / mL to about 20 ng / mL C._minCan be provided.

0139Therefore, the oral dosage form of 17-hydroxyprogesterone caproate of the present invention can be an immediate release dosage form. In certain embodiments, the oral dosage form of 17-hydroxyprogesterone caproate of the present invention can be a controlled release dosage form. In another particular embodiment, the dosage form may comprise 17-hydroxyprogesterone caproate in both immediate and controlled release fraction forms.

0140As a result, the controlled release 17-hydroxyprogesterone caproate compositions or dosage forms of the present invention may provide variability at 17-hydroxyprogesterone caproate levels below about 795 ng / mL, in which case the variability Mean steady state of 17-hydroxyprogesterone caproate in plasma or serum or blood after oral administration C_maxAnd mean steady state C_min It is determined by the difference with.

0141In another particular embodiment, the oral pharmaceutical composition and / or dosage form of 17-hydroxyprogesterone caproate of the invention is as follows: habitual miscarriage, recurrent miscarriage, imminent miscarriage, postpartum pain, intrauterine. One of the conditions selected from the group consisting of membrane cancer, management of primary and secondary amenorrhea, recurrent pregnancy loss due to luteal dysfunction, progestogen deficiency, cervical insufficiency, cervical dysfunction and abnormal uterine bleeding. It can be used for the above treatment. In a further embodiment, the oral pharmaceutical compositions and / or dosage forms of the 17-hydroxyprogesterone caproate of the present invention are used to test endogenous estrogen production and for the formation and exfoliation of secretory endometrium. Can be used for.

0142In another embodiment, the oral pharmaceutical composition and / or dosage form of 17-hydroxyprogesterone caproate of the present invention can be used with omega-3 fatty acid supplementation to treat symptomatological preterm labor patients. In certain embodiments, the compositions and / or dosage forms of the invention may comprise at least one omega fatty acid. In another particular embodiment, the compositions and / or dosage forms of the invention may comprise omega-3, omega-6 or omega-9 fatty acids or mixtures thereof.<u style="single">Example</u>

0143The following examples are provided to facilitate a clearer understanding of certain embodiments of the invention and are not intended to limit the invention in any way. Unless otherwise stated or otherwise stated, all compositions provided in the Examples relate to% w / w of the final composition. With the exception of the compositions listed in Examples 1, 7, 10, 17 and 36, the 17-hydroxyprogesterone caproate of all other Example compositions is treated (crushed, pulverized or nano-sized. Note that it can be sized) or unprocessed. 17-Hydroxyprogesterone caproate in compositions 1, 7, 10, 17 and 36 is untreated for size reduction (ie, non-grinded, non-pulverized or non-nanosized), and 50 micrometers. Has a larger average particle size. USP at 37 ° C at 50 rpm in 900 mL of artificial intestinal juice with 0.5% w / w sodium lauryl sulfate The dosage form of the corresponding example was tested for the release of 17-hydroxyprogesterone caproate using a type II lysing device. The percentage of 17-hydroxyprogesterone caproate released from each composition was analyzed using HPLC.<u style="single">Examples 1 to 6</u> - 17-Hydroxyprogesterone caproate composition

0144Each component shown in Table I is used to prepare a 17-hydroxyprogesterone caproate composition as listed in Examples 1-6. Example 1 is 17-hydroxyprogesterone caproate in untreated crystalline form packed in hard gelatin capsules. Example 2 is a pulverized 17-hydroxyprogesterone caproate without a carrier packed in hard gelatin capsules. Examples 3-6 are prepared as follows: Place the required amount of each component of each composition other than 17-hydroxyprogesterone caproate in a clean stainless steel container and use a stirrer. Mix at about 50 ° C to 70 ° C. A melt transparent to turbid mixture is obtained. The required amount of 17-hydroxyprogesterone caproate is added to the clear to turbid mixture and stirred to produce a homogeneous liquid mixture. The expected weight of the resulting liquid mixture is distributed into capsules of appropriate size according to the required 17-hydroxyprogesterone caproate dose. Capsules are solidified at room temperature, then bundled, packaged in HDPE bottles and sealed with a lid.

0145The 17-hydroxyprogesterone caproates released from each of the compositions using the above dissolution test parameters are shown in Table I. Examples 1 &amp; 2 (17-hydroxyprogesterone caproate without carrier) and Examples 3-6 (17-hydroxyprogesterone caproate mixed with at least one carrier) are the compositions and dosage forms of the invention. It should be noted that it can be used for comparative purposes to help illustrate the benefits.<tables num="1"><img id="000003" he="121" wi="160" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0146The aqueous dispersion of the mixture containing the lipophilic additives and hydrophilic surfactants (if present) of Examples 3-6 in Table I can be turbid to opaque 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 embodiments, the average particle size of the dispersion may be higher than 250 nm. Each of the aqueous dispersions is prepared by mixing 1 part of the additive mixture of the corresponding example with 99 parts of the aqueous diluent. The compositions of Examples 3-6 can be prepared by mixing the additives with 17-hydroxyprogesterone caproate to obtain a homogeneous solution or suspension. If necessary, the mixture can be heated (eg, to about 40 ° C to about 80 ° C) to obtain a solution or a homogeneous suspension. Place the mixture in capsules. Dosage forms of Examples 1 and 2 have 17-hydroxyprogesterone caproate in non-pulverized and pulverized particle forms, respectively. 17-Hydroxyprogesterone caproate can be completely solubilized (for Examples 3) or partially solubilized (for Examples 5 and 6). The formulations in Table I, if in liquid form, may also be formulated in solid dosage form by the presence of a solidification aid or by mixing with a solidification aid and filling the capsule. Alternatively, they can be formulated into tablets by using suitable tablet molding aids.<u style="single">Examples 7-10</u> - 17-Hydroxyprogesterone caproate composition

0147By using the components shown in Table II, the 17-hydroxyprogesterone caproate compositions of Examples 7-10 are prepared to obtain the indicated release results.<tables num="2"><img id="000004" he="132" wi="160" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0148The compositions of Examples 7-10 are to be compressed into tablets or in capsules with the inclusion of suitable pharmaceutical aids such as diluents, binders, disintegrants, lubricants, flavors and the like. It should be noted that it can be formulated to provide granules for filling.

0149Unlike Examples 1 and 7, the 17-hydroxyprogesterone caproate release profiles of Examples 8, 9 and 10 shown in Table II illustrate the benefits of 17-hydroxyprogesterone caproate with smaller particle sizes. To do. These examples further illustrate the benefits of various manufacturing methods, such as granulation, that produce solid compositions with a suitable 17-hydroxyprogesterone caproate release profile. In some embodiments, the caproic acid ester in the composition of the examples in Table II can be replaced with another ester of 17-hydroxyprogesterone, such as acetate or undecanoate.<u style="single">Example 11</u> - 17-Hydroxyprogesterone caproate coated tablets

0150The 17-hydroxyprogesterone caproate tablets of Examples 7-10 are typically described in Table III using conventional tablet coating techniques known in the art for a weight increase of about 3-6%. It can be coated with a coating solution having a specific composition.<tables num="3"><img id="000005" he="76" wi="160" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0151The coating polymer may be selected based on the need for specific functionality to be imparted to the dosage form. For example, film coating, taste shielding, enteric coating, protective coating, sustained release coating and the like can all be used. Non-limiting examples of polymers for use in such coatings include hypromellose, polyethylene glycol, povidone, sugars, ethyl cellulose, methacrylates, cellulose phthalates and the like. A number of conventional coating aids such as talc, starch, plasticizers, opacity, colorants, flavors and the like can also be used with the coating polymer or sugar. The coating solvent can be changed appropriately based on the coating polymer or sugar applied. Examples 12-17-17-Hydroxyprogesterone caproate composition

0152Table IV lists the 17-hydroxyprogesterone caproate compositions of Examples 12-17 that can be prepared by using the constituent sets described therein and methods similar to those described for Examples 3-6. Shown. The release of 17-hydroxyprogesterone caproate from the dosage form is also shown in Table IV.<tables num="4"><img id="000006" he="184" wi="160" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0153The aqueous dispersion of the mixture of lipophilic additives and hydrophilic surfactants (if present) in the examples shown in Table IV can be turbid to opaque when observed 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 embodiments, the average particle size of the dispersion may be higher than 250 nm. Each of the aqueous dispersions is prepared by mixing 1 part of the additive mixture of the corresponding example with 99 parts of the aqueous diluent.

0154When the compositions in Table IV are liquids, solidification aids (eg polyethylene glycol, glyceryl distearate, wax, etc.) are present or mixed with solidification aids and filled into capsules. It can be formulated to be in solid dosage form. These compositions are also for compressing into tablets or filling capsules with the inclusion of suitable pharmaceutical auxiliaries such as diluents, binders, disintegrants, lubricants, flavors and the like. It should be noted that it can be prescribed to obtain granules.

0155The 17-hydroxyprogesterone caproate in the composition of the examples in Table IV is, in some embodiments, to other esters of 17-hydroxyprogesterone, such as 17-hydroxyprogesterone acetate or 17-hydroxyprogesterone undecanoate. Can be replaced.<u style="single">Examples 18-23</u> - 17-Hydroxyprogesterone caproate composition

0156Table V shows various 17-hydroxyprogesterone caproate compositions as listed in Examples 18-23 that can be prepared using the constituents described therein.<tables num="5"><img id="000007" he="125" wi="160" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0157Table VI shows various specific embodiments of different dosage forms (DF-1 to DF-9) containing 17-hydroxyprogesterone caproate that can be achieved by the various combinations of compositions shown in Table V. ..<tables num="6"><img id="000008" he="117" wi="161" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0158The dosage forms DF-1 to DF-9 described above can be a single or multiple microparticle unit in a capsule, or can exist as a single or multiple microparticle unit compressed into a single tablet or multi-layer tablet.<u style="single">Examples 24-28</u> - 17-Hydroxyprogesterone caproate composition

0159Table VII shows the 17-hydroxyprogesterone caproate compositions as listed in Examples 24-28 that can be prepared using the constituents described therein, as well as their release outcomes.<tables num="7"><img id="000009" he="191" wi="160" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0160For Example 28, the dosage form is first exposed to about 250 mL of artificial gastric juice (SGF) (without enzymes) for the first 30 minutes, then at a pH of about 6.8 to 900 mL of 0.5 wt% SLS in water.<u style="single">Examples 29 ~ 35</u> - 17-Hydroxyprogesterone caproate composition

0161Table VIII shows 17-hydroxyprogesterone caproate compositions and release data for Examples 29-35 that can be prepared using the constituents described herein, as well as methods similar to those described for Examples 12-17. Is shown.<tables num="8"><img id="000010" he="157" wi="160" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0162The above compositions may be formulated to show an immediate or controlled release profile. The aqueous dispersion of the mixture of lipophilic additives and hydrophilic surfactants (if present) in the examples of Table VIII can be turbid to opaque when viewed with the naked eye. Their absorbance at 400 nm is greater than 0.1 or, in some cases, greater than 0.3, and / or the average particle size of the dispersion can be greater than 100 nm in some embodiments. In other embodiments, 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 additives and surfactants of the corresponding example with 99 parts of the aqueous diluent.

0163High drug loading with the desired release properties (eg, 20% w / w 17-hydroxyprogesterone caproate), as can be seen from Examples 29, 30 and 35 above by using benzyl benzoate and / or benzyl alcohol. ) Can be achieved. 17-Hydroxyprogesterone caproate can still be completely solubilized in the composition (Examples 29, 30, 31 and 33) or partially solubilized (Examples 32, 34 and 35). ). In addition, when viewed with the naked eye, aqueous dispersions of mixtures with lipophilic additives and hydrophilic surfactants (if present) as listed in Examples 29-31 and 33-35 are turbid to non-turbid. Can be transparent. In some cases, their absorbance at 400 nm is greater than 0.1 or even greater than 0.3. Moreover, the average particle size of the dispersion is greater than 100 nm, or even greater than 250 nm. Each of the aqueous dispersions is prepared by mixing 1 part of the mixture of additives and surfactants of the corresponding example with 99 parts of the aqueous diluent.

0164In some embodiments, the 17-hydroxyprogesterone caproate in the composition of the examples in Table VIII is replaced with another ester of 17-hydroxyprogesterone, such as 17-hydroxyprogesterone acetate or 17-hydroxyprogesterone undecanoate. Can be.

0165The compositions of Examples 3, 31, 32, 33 and 34 can also be administered as an oral liquid in some embodiments. These compositions may be further orally administered after appropriate mixing / dilution with a diluent immediately prior to administration, such as water, milk, fruit juice, beverages and the like.

0166In certain embodiments, the contents of the composition can be adsorbed on several diluents and additional excipients and compressed into tablets.<u style="single">Example 36</u> - 17-Hydroxyprogesterone caproate tablets

0167Wet granulation can be used to prepare 17-hydroxyprogesterone caproate-containing granules for tablet molding with the constituents listed in Table IX. Therefore, 17-hydroxyprogesterone caproate, microcrystalline cellulose and sodium croscarmellose are passed through an ASTM mesh # 40 mesh sieve and mixed in a low shear granulator to produce a homogeneous formulation. A dry powder formulation is granulated to a typical granulation end point using a binder solution of starch 1500 in deionized water. Wet granules dried using a box dryer or airflow dryer can be sized / screened, smoothed with Aerosil 200 and magnesium stearate and compressed into tablets.<tables num="9"><img id="000011" he="88" wi="160" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables>

016817-Hydroxyprogesterone caproate released in the first 60 minutes when tested in 900 mL of artificial intestinal juice with 0.5% w / w sodium lauryl sulfate at 50 rpm at 37 ° C using a USP type II device. Less than 20% of the tablets of Example 36 show. On the other hand, pulverized 17-hydroxyprogesterone caproate (having a particle size d100 of about 50 μm or less), with or without a surfactant, when used in the above formulation, 17-hydroxyprogesterone caproate. At least 40% release of ate can be observed after 60 minutes.<u style="single">Examples 37-42</u> - 17-Hydroxyprogesterone caproate composition

0169Examples 37-39 in Table X have hydrophilic additives as carriers. Examples 37, 38 and 39 in the table are prepared by a wet granulation method using an organic solvent such as ethanol or ethanol-water as the granulation liquid. Some or all of the hydrophilic additives in the table (eg, povidone, pluronic, surfactant, etc.) can be dissolved in the granulation solution. Optionally, an ester of 17-hydroxyprogesterone (eg, 17-hydroxyprogesterone caproate) can be solubilized or suspended in the granulation solution. The granulation solution can then be poured onto an adsorptive hydrophilic carrier (eg, cellulose, lactose, etc.) with low shear mixing. The granules can be dried at room temperature under static airflow. The dried granules are passed through an ASTM # 40 mesh and filled into capsules of appropriate size or compressed into tablets according to the required 17-hydroxyprogesterone caproate strength per unit dosage form.

0170Using the constituents listed in Table X, the 17-hydroxyprogesterone caproate compositions of Examples 40-42 can be prepared by the following methods: of the respective inert constituents and 17-hydroxyprogesterone caproate. Place the required amount in a clean stainless steel container and mix gently using a stirrer at about 50 ° C to 70 ° C to obtain a homogeneous mixture. The expected amount of the resulting mixture is distributed in hard gelatin capsules and solidified at room temperature.

0171Each agent of Examples 37-42 with respect to the release of 17-hydroxyprogesterone caproate in 900 mL of artificial intestinal juice with 0.5% w / w sodium lauryl sulfate at 50 rpm at 37 ° C using a USP type II device. Test the shape. The percentage of 17-hydroxyprogesterone caproate released from each composition is analyzed using HPLC. The results of the release test are also shown in Table X.

0172It should be noted that the compositions of Examples 37-42 may be formulated that optionally include suitable conventional tablet molding aids such as diluents, binders, disintegrants, lubricants and the like. ..<tables num="10"><img id="000012" he="97" wi="160" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0173It can be seen that the in vitro 17-hydroxyprogesterone caproate release results of Examples 37 to 42 are superior to the release results of Example 36. It should be noted that in the above compositions, appropriate amounts of typical pharmaceutical auxiliaries, such as flow promoters, lubricants, anti-adhesion agents, disintegrants, etc., may be incorporated as needed. In addition, appropriate amounts of hydrophilic release modifiers (eg, hypromellose, eudragit, etc.) can also be optionally mixed into the compositions of Examples 37-42. Furthermore, in some specific cases, where the dosage forms of Examples 37-42 are tablets, a suitable functional coating may be applied as needed. It is also noted that in some embodiments, the example compositions in Table X can be replaced with other esters of 17-hydroxyprogesterone (eg, 17-hydroxyprogesterone acetate, 17-hydroxyprogesterone undecanoate, etc.). Should. Examples 43 and 44-17-Hydroxyprogesterone caproate compositions

0174The 17-hydroxyprogesterone caproate compositions listed in Examples 43 and 44 were prepared using the constituents listed in Table XI. Each of the compositions was made by mixing 17-hydroxyprogesterone caproate into a melt mixture of the corresponding inert constituents placed in a stainless steel container at about 35 ° C to 70 ° C with gentle agitation. It was prepared to give a free-flowing liquid mixture. The expected weight of the resulting liquid mixture was distributed in hard or soft gelatin capsules and solidified at room temperature. The liquid mixture is solidified at room temperature to give a solid aggregate, which is passed through ASTM mesh # 30 to obtain granules, which are further filled into hard gelatin capsules or compressed into tablets. It should be noted that it can also be done.

0175Each of the compositions is tested for release of 17-hydroxyprogesterone caproate in 900 mL of artificial intestinal juice with 0.5% w / w sodium lauryl sulfate at 50 rpm at 37 ° C using a USP type II device. The percentage of 17-hydroxyprogesterone caproate released from each composition is analyzed using HPLC. The results of the release test are also shown in Table XI.<tables num="11"><img id="000013" he="64" wi="161" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables><u style="single">Example 45</u> - 17-Hydroxyprogesterone caproate spray-dried multifine particles

017617-Hydroxyprogesterone caproate multifine particles can be prepared as follows: 15 g of ground 17-hydroxyprogesterone caproate and lactose mixture (95: 5 w / w) is passed through an ASTM mesh # 60 sieve. And add to about 250 mL of a solution of 8% w / v povidone K17 in water with mixing. Conventional spray drying equipment set the resulting suspension to, for example, a heat inlet temperature of about 60-75 ° C and an outlet temperature of about 30-38 ° C, a suction device set to 90-100%, about. Spray drying can be done using a pump set at 8-12 mL / min and a flow rate set at about 500-600 L / h. The final solid multifine particle 17-hydroxyprogesterone caproate composition may have a composition consisting of about 53% by weight 17-hydroxyprogesterone caproate, about 2.8% by weight lactose and about 44.2% by weight povidone K17.<u style="single">Examples 46 to 50</u> - 17-Hydroxyprogesterone caproate composition

0177The mixture of 17-hydroxyprogesterone caproate and the corresponding constituents is melted together to give a thermosetting filler to be dispensed into the capsule. Alternatively, a single-screw extruder (Killion) equipped with a melt extruder for the mixture, such as a screw with a diameter of about 1 inch and a flexible edging die with a diameter of about 6 inches and a mold opening adjusted to about 0.005 inches. , KLB100 type), and set the screw rotation speed to about 50 rpm. The residence time of the material in the extruder can be set to about 2-8 minutes. By passing over a cooling roll, the extruded strands can be cooled to room temperature. The strands are then sized through ASTM mesh # 40 to distribute the powder into the capsule. An exemplary composition for melt extrusion is shown in Table XII. These dosage forms can release more than 40% of 17-hydroxyprogesterone caproate in almost the first 60 minutes. The 17-hydroxyprogesterone caproate in Table XII is further about 12% to about 88 weight of the total composition before melt extrusion or after sizing of the melt extrusion composition to prepare solid multifine particles for tablets. It should be noted that at various concentrations of%, it may be formulated to contain one or more other substances such as lactose, starch, hydroxypropylmethylcellulose, methacrylate and the like.<tables num="12"><img id="000014" he="80" wi="160" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables><u style="single">Example 51</u> --17-Hydroxyprogesterone caproate composition produced by simultaneous grinding

0178Simultaneous grinding (or simultaneous polishing) of 80 g of 17-hydroxyprogesterone caproate with 15 g of PVP K17 and 5 g of sodium lauryl sulfate for about 12 to about 24 hours using a ceramic ball mill held at about 20 ± 5 ° C. By crushing), a composition containing 17-hydroxyprogesterone caproate can be prepared. The co-grinding composition can provide an excellent in vitro drug release profile, which is a USP type II device at 37 ° C. at 50 rpm in 900 mL of artificial intestinal juice with 0.5% w / w sodium lauryl sulfate. When tested using, it is at least more than 20% compared to the in vitro release profile of Example 1.<u style="single">Example 52</u> - 17-Hydroxyprogesterone caproate loaded pellets

017917-Hydroxyprogesterone caproate coated pellets are prepared using the ingredients listed in Table XIII. A spray solution of the coating material can be prepared by dissolving 25 g of 17-hydroxyprogesterone caproate, 6 g of Pluronic F68 and 5 g of PVP K30 in about 250 mL of dehydrated alcohol. The spray solution can be intermittently sprayed onto a rotating bed of 64 g of commercially available microcrystalline cellulose spheres (eg, having an average particle size in the range of about 250 μm to about 600 μm) in a conventional coated pan. After loading all the spray solution onto the sphere, it can be dried in a still air stream for at least 1 hour to remove the solvent. Thus, by adjusting the pan rate, spray rate and inlet airflow and temperature, 17-hydroxyprogesterone caproate loaded pellets or beads can be obtained and distributed into capsules. Auxiliary pharmaceutical processing aids such as talc, starch, etc. can be sprayed during the spraying process to avoid pellet agglomeration.

0180Appropriate similar or equivalent equipment known in the art may be used for this purpose. Furthermore, it should be noted that different drug loading pellets can be obtained by varying the amount of spray solution sprayed onto the spheres or by varying the concentration of 17-hydroxyprogesterone caproate in the spray solution. Should.<tables num="13"><img id="000015" he="53" wi="161" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables><u style="single">Example 53</u> - 17-Hydroxyprogesterone caproate suspension composition

0181A homogeneous suspension of 17-hydroxyprogesterone caproate prepared in a liquid vehicle with at least one non-solvent can be made by conventional methods known in the art. The suspension can be administered in doses as a conventional oral solution, or a suspension of known volume can be encapsulated. Pharmaceutical auxiliaries known in the art, such as anti-settlement agents, thickeners or viscosity regulators, wetting agents, etc., can be used to obtain homogeneous suspensions of the drug in a liquid vehicle.<u style="single">Example 54</u> - 17-Hydroxyprogesterone caproate composition in vivo evaluation

0182A preliminary pharmacokinetic evaluation of the 17-hydroxyprogesterone caproate of the present invention after oral administration was performed in male dogs. A single oral dose of 30 mg / kg and 5 mg / kg of 17-hydroxyprogesterone caproate formulated according to the exemplary formulation of the invention was administered as a positive control at 6.4 mg / kg (commercially available intramuscular injection, Makena®). ) And similar composition) used for relative bioavailability testing in feeding conditions when compared to intramuscular doses.

0183Blood levels after dose administration of 17-hydroxyprogesterone caproate were monitored 24 hours after oral dose administration and 192 hours after intramuscular injection dose administration. Approximately 2 mL of blood was collected from the jugular vein, cephalic vein or saphenous vein immediately prior to dose administration and at scheduled intervals after dose administration. At each point in time, blood samples were collected in the blood collection vessel and centrifuged at about 5 ° C for about 10 minutes at about 3200 rpm. The resulting sera were analyzed by HPLC-MS / MS for 17-hydroxyprogesterone caproate. The results of the 17-hydroxyprogesterone caproate concentration in the sample are shown in Table XIV below:<tables num="14"><img id="000016" he="85" wi="160" file="JP2017193554A_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0184Contrary to reports in the literature, the oral compositions of the present invention have significant blood levels of 17-hydroxyprogesterone caproate upon oral administration (C)._average) Is provided, we have surprisingly found.

0185Numerous modifications and alternative modifications may be made by the art without departing from the spirit and scope of the invention, and the appended claims are intended to cover such modifications and modifications. Accordingly, the invention has been described above with specificity and details in connection with what appears to be the most practical and preferred embodiment of the invention, but modifications such as size, material, shape, form, function and operating method. It will be apparent to those skilled in the art that changes in assembly and use (but not limited to these) may be made without departing from the principles and concepts set forth herein.

0186The present application also includes the following inventions. (1) below: A therapeutically effective amount of 17-hydroxyprogesterone caproate, and Pharmaceutically acceptable carrier Oral pharmaceutical composition comprising. (2) The pharmaceutical composition according to (1), which is prescribed for pregnancy support. (3) The pharmaceutical composition according to (1), wherein the 17-hydroxyprogesterone caproate is present in the composition in the form of fine particles having an average particle diameter of about 50 μm or less. (Four) The pharmaceutical composition according to (1), wherein the carrier comprises benzyl benzoate, benzyl alcohol or a mixture thereof. (Five) The total amount of 17-hydroxyprogesterone caproate to benzylbenzoate and benzyl alcohol in the oral dosage form is from about 1: 0.01 (w / w) to about 1: 5 (w / w) (4). Pharmaceutical composition. (6) The pharmaceutical composition according to (1), wherein the amount of the 17-hydroxyprogesterone caproate is about 5% to about 80% w / w of the total composition. (7) The pharmaceutical composition according to (1), which is in the form of a capsule or tablet. (8) The pharmaceutical composition according to (7), wherein the composition is in the form of a capsule, wherein the capsule comprises from about 30 mg to about 300 mg of 17-hydroxyprogesterone caproate. (9) The pharmaceutical composition according to (7), wherein the composition is in the form of a tablet and the tablet comprises from about 20 mg to about 800 mg of 17-hydroxyprogesterone caproate. (Ten) The pharmaceutical composition according to (7), wherein the capsule or tablet is a controlled release oral dosage form. (11) The pharmaceutical composition according to (7), wherein the ratio of the amount of 17-hydroxyprogesterone caproate to the filling volume of the capsule in the composition is about 0.02 g / mL to about 0.8 g / mL. (12) The pharmaceutical composition according to (1), wherein the carrier contains a hydrophilic additive. (13) The pharmaceutical composition according to (1), wherein the carrier contains a lipophilic additive. (14) The carriers are citric acid, maleic acid, tartaric acid, acetic acid, ascorbic acid, benzoic acid and lactic acid salts, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, silicon dioxide, aluminum magnesium silicate, hydroxypropylcyclo. Dextrin, fatty acid glyceride, bile acid salt, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, carbomer, chitosan, methacrylate, polyvinyl alcohol, gelatin, PEG-8 capricyl acid / Capric acid glyceride, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 cured 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 steerate, PEG-40 laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl steerate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitan From laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate, poroxamer 188, poroxamer 108, maltose, sucrose, fructose, mannitol, xylitol and combinations thereof. (12) The pharmaceutical composition according to (12), which comprises a compound selected from the group. (15) The carriers are citric acid, mannitol, tartaric acid, acetic acid, ascorbic acid, benzoic acid and lactic acid salts, potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, calcium carbonate, silicon dioxide, aluminum magnesium silicate, hydroxypropylcyclo. Dextrin, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methylcellulose, hydroxypropylmethylcellulose, cellulose ester, carbomer, chitosan, methacrylate, polyvinyl alcohol, gelatin, maltose, sucrose, fructose, mannitol, xylitol The pharmaceutical composition according to (12), which comprises a compound selected from the group consisting of and a combination thereof. (16) The carriers are tributylcitrate, triethylcitrate, triacetin, ethylcellulose, cellulose ester, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, tocopherol, tocopherol acetate, tocopherol succinate, benzylbenzoate, corn. Oil, olive oil, peanut oil, benivana oil, sesame oil, soybean oil, hardened castor oil, glyceryl tricaplate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoliate, glyceryl tricaprylate / caprate, glyceryl tricaprylate / caprate / Laurate, glyceryl tricaprylate / caplate / linoliate, glyceryl tricaprylate / caplate / stearate, saturated polyglycolated glyceride, linoleic acid glyceride, caprylic acid / capric acid glyceride, capric acid, caprylic acid, palmitic acid, laurate , Stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoliate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl palmitostearate , Glyceryl laurate, glyceryl caprilate, distearic acid, monopalmitrein, monolaurin, ethyl oleate, PEG-6 corn oil, PEG-6 apricot oil, PEG-4 caprylic acid / capric acid triglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poroxamer 182, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol dicaprylate / dicaplate, propylene glycol caprylate / caplate , Solbitan monolaurate, sorbitan monopalmitate, solThe pharmaceutical composition according to (13), which comprises a compound selected from the group consisting of bitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate and combinations thereof. (17) The carriers are tributylcitrate, triethylcitrate, triacetin, ethylcellulose, cellulose ester, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, tocopherol, tocopherol acetate, tocopherol succinate, corn oil, olive oil. , Pepper oil, Benibana oil, Sesame oil, Soybean oil, Hardened castor oil, Glyceryl tricaplate, Glyceryl trilaurate, Glyceryl trioleate, Glyceryl trilinoleate, Glyceryl tricaprylate / caplate, Glyceryl tricaprylate / caplate / laurate, Glyceryl tricaprylate / caplate / linoleate, glyceryl tricaprylate / caplate / stearate, capric acid, caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, The pharmaceutical composition according to (13), which comprises a compound selected from the group consisting of ethyloleate and combinations thereof. (18) The pharmaceutical composition according to (13), wherein the carrier contains at least 50% by weight of a lipophilic additive. (19) The pharmaceutical according to (1), wherein the carrier comprises at least one hydrophilic additive and at least one lipophilic additive in a lipophilic additive to hydrophilic additive ratio of about 90:10 to about 1:99. Composition. (20) A method of treating a pregnant female subject at risk of preterm birth, comprising administering to the female subject the pharmaceutical composition according to (1). (twenty one) below: A therapeutically effective amount of 17-hydroxyprogesterone caproate, and Pharmaceutically acceptable carrier Oral pharmaceutical composition comprising, in 900 mL of artificial intestinal juice with 0.5% w / w sodium lauryl sulfate, containing a carrier when measured at 37 ° C. at 50 RPM using a USP type II solubilizer. No equivalent dose A composition in which the oral dosage form releases at least 20% by weight of 17-hydroxyprogesterone caproate 60 minutes after the oral dosage form administered. (twenty two) The pharmaceutically acceptable oral dosage form according to (21), wherein the oral dosage form is formulated to support pregnancy. (twenty three) The pharmaceutically acceptable oral dosage form according to (21), wherein the 17-hydroxyprogesterone caproate is present in the oral dosage form in the form of particulates having an average particle diameter of about 50 μm or less. (twenty four) The pharmaceutically acceptable oral dosage form according to (21), wherein the carrier comprises benzyl benzoate, benzyl alcohol or a mixture thereof. (twenty five) The total amount of 17-hydroxyprogesterone caproate versus benzylbenzoate and benzyl alcohol in the oral dosage form is from about 1: 0.01 (w / w) to about 1: 5 (w / w) (24). Pharmaceutically acceptable oral dosage form. (26) The pharmaceutically acceptable oral dosage form according to (21), wherein the amount of 17-hydroxyprogesterone caproate is from about 5% to about 80% w / w of the total oral dosage form. (27) The pharmaceutically acceptable oral dosage form according to (21), wherein the pharmaceutical oral dosage form is in the form of a capsule or tablet. (28) The pharmaceutically acceptable oral dosage form according to (27), wherein the oral dosage form is in the form of a capsule, wherein the capsule comprises from about 10 mg to about 300 mg of 17-hydroxyprogesterone caproate. (29) The pharmaceutically acceptable oral dosage form according to (27), wherein the oral dosage form is in the form of a tablet, wherein the tablet comprises from about 20 mg to about 800 mg of 17-hydroxyprogesterone caproate. (30) The pharmaceutical according to (27), wherein the oral dosage form is a capsule, and the ratio of the amount of 17-hydroxyprogesterone caproate in the capsule to the filling volume of the capsule is about 0.02 g / mL to about 0.8 g / mL. Top acceptable oral dosage form. (31) The pharmaceutically acceptable oral dosage form according to (21), wherein the carrier contains a hydrophilic additive. (32) The pharmaceutically acceptable oral dosage form according to (21), wherein the carrier contains a lipophilic additive. (33) The carriers are citric acid, maleic acid, tartaric acid, acetic acid, ascorbic acid, benzoic acid and lactic acid salts, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, silicon dioxide, aluminum magnesium silicate, hydroxypropylcyclo. Dextrin, fatty acid glyceride, bile acid salt, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, carbomer, chitosan, methacrylate, polyvinyl alcohol, gelatin, PEG-8 capricyl acid / Capric acid glyceride, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 cured 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 steerate, PEG-40 laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl steerate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitan From laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate, poroxamer 188, poroxamer 108, maltose, sucrose, fructose, mannitol, xylitol and combinations thereof. (31) A pharmaceutically acceptable oral dosage form comprising a compound selected from the group. (34) The carriers are citric acid, mannitol, tartaric acid, acetic acid, ascorbic acid, benzoic acid and lactic acid salts, potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, calcium carbonate, silicon dioxide, aluminum magnesium silicate, hydroxypropylcyclo. Dextrin, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, cellulose ester, carbomer, chitosan, methacrylate, polyvinyl alcohol, gelatin, maltose, sucrose, fructose, mannitol, xylitol The pharmaceutically acceptable oral dosage form according to (31), which comprises a compound selected from the group consisting of and combinations thereof. (35) The carriers are tributylcitrate, triethylcitrate, triacetin, ethylcellulose, cellulose ester, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, tocopherol, tocopherol acetate, tocopherol succinate, benzylbenzoate, corn. Oil, olive oil, peanut oil, benivana oil, sesame oil, soybean oil, hardened castor oil, glyceryl tricaplate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoliate, glyceryl tricaprylate / caprate, glyceryl tricaprylate / caprate / Laurate, glyceryl tricaprylate / caplate / linoliate, glyceryl tricaprylate / caplate / stearate, saturated polyglycolated glyceride, linoleic acid glyceride, caprylic acid / capric acid glyceride, capric acid, caprylic acid, palmitic acid, laurate , Stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoliate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl palmitostearate , Glyceryl laurate, glyceryl caprilate, distearic acid, monopalmitrein, monolaurin, ethyl oleate, PEG-6 corn oil, PEG-6 apricot oil, PEG-4 caprylic acid / capric acid triglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poroxamer 182, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol dicaprylate / dicaplate, propylene glycol caprylate / caplate , Solbitan monolaurate, sorbitan monopalmitate, solThe pharmaceutically acceptable oral dosage form according to (32), which comprises a compound selected from the group consisting of bitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate and combinations thereof. (36) The carriers are tributylcitrate, triethylcitrate, triacetin, ethylcellulose, cellulose ester, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, tocopherol, tocopherol acetate, tocopherol succinate, corn oil, olive oil. , Pepper oil, Benibana oil, Sesame oil, Soybean oil, Hardened castor oil, Glyceryl tricaplate, Glyceryl trilaurate, Glyceryl trioleate, Glyceryl trilinoleate, Glyceryl tricaprylate / caplate, Glyceryl tricaprylate / caplate / laurate, Glyceryl tricaprylate / caplate / linoleate, glyceryl tricaprylate / caplate / stearate, capric acid, caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, The pharmaceutically acceptable oral dosage form according to (32), which comprises a compound selected from the group consisting of ethyloleate and combinations thereof. (37) The pharmaceutically acceptable oral dosage form according to (32), wherein the carrier comprises at least 50% by weight of a lipophilic additive. (38) The pharmaceutical according to (21), wherein the carrier comprises at least one hydrophilic additive and at least one lipophilic additive in a lipophilic additive to hydrophilic additive ratio of about 90:10 to about 1:99. Acceptable oral dosage form. (39) The pharmaceutically acceptable oral dosage form according to (21), which is prescribed for administration to a human subject once every 8 hours. (40) The pharmaceutically acceptable oral dosage form according to (21), which is prescribed for administration to a human subject once every 6 hours. (41) The pharmaceutically acceptable oral dosage form according to (21), which is prescribed for administration to a human subject once every 12 hours. (42) The pharmaceutically acceptable oral dosage form according to (21), which is prescribed for administration to a human subject once every 24 hours. (43) A method of treating a pregnant female subject at risk of preterm birth, comprising administering to the female subject the oral dosage form according to (21). (44) below: A therapeutically effective amount of 17-hydroxyprogesterone caproate, and Pharmaceutically acceptable carrier In 900 mL of artificial intestinal juice with 0.5% w / w sodium lauryl sulfate, in a pharmaceutically acceptable oral dosage form containing, measured at 37 ° C at 50 RPM using a USP type II solubilizer. An oral dosage form that releases at least 20% by weight of the dose of 17-hydroxyprogesterone caproate after 60 minutes. (45) A method of treating a pregnant female subject at risk of preterm birth, comprising administering to the female subject a pharmaceutically acceptable oral dosage form according to (44). (46) below: A therapeutically effective amount of 17-hydroxyprogesterone caproate A pharmaceutically acceptable oral dosage form containing, and upon single oral administration to a human subject, the dosage form is approximately 0.2 vs. approximately 10 ng.^*hmL^-1mg^-117-Hydroxyprogesterone caproate AUC_(0-24h)An oral dosage form that provides a dose ratio of 17-hydroxyprogesterone caproate to 17-hydroxyprogesterone caproate, which is the amount of 17-hydroxyprogesterone caproate administered in mg. (47) The pharmaceutically acceptable oral dosage form according to (46), which comprises a carrier selected from hydrophilic additives, lipophilic additives or combinations thereof. (48) The pharmaceutically acceptable oral dosage form according to (46), wherein the 17-hydroxyprogesterone caproate is present in the oral dosage form in the form of particulates having an average particle diameter of about 50 μm or less. (49) The pharmaceutically acceptable oral dosage form according to (46), wherein the carrier comprises benzyl benzoate, benzyl alcohol or a mixture thereof. (50) The pharmaceutically acceptable oral dosage form according to (46), which is a tablet or capsule. (51) The pharmaceutically acceptable oral dosage form according to (46), which is a controlled release oral dosage form. (52) The pharmaceutically acceptable oral dosage form according to (46), which is an immediate release oral dosage form. (53) The carriers are citric acid, maleic acid, tartaric acid, acetic acid, ascorbic acid, benzoic acid and lactic acid salts, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, silicon dioxide, aluminum magnesium silicate, hydroxypropylcyclo. Dextrin, fatty acid glyceride, bile acid salt, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, carbomer, chitosan, methacrylate, polyvinyl alcohol, gelatin, PEG-8 capricyl acid / Capric acid glyceride, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 cured 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 steerate, PEG-40 laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl steerate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitan Laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate, poroxamer 188, poroxamer 108, maltose, sucrose, fructose, mannitol, xylitol, rubber and itss. The pharmaceutical composition according to (46), which comprises one or more of the additives selected from the group consisting of combinations. (54) The carriers are tributylcitrate, triethylcitrate, triacetin, ethylcellulose, cellulose ester, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, tocopherol, tocopherol acetate, tocopherol succinate, benzylbenzoate, corn. Oil, olive oil, peanut oil, benivana oil, sesame oil, soybean oil, hardened castor oil, glyceryl tricaplate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoliate, glyceryl tricaprylate / caprate, glyceryl tricaprylate / caprate / Laurate, glyceryl tricaprylate / caplate / linoliate, glyceryl tricaprylate / caplate / stearate, saturated polyglycolated glyceride, linoleic acid glyceride, caprylic acid / capric acid glyceride, capric acid, caprylic acid, palmitic acid, laurate , Stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoliate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl palmitostearate , Glyceryl laurate, glyceryl caprilate, distearic acid, monopalmitrein, monolaurin, ethyl oleate, PEG-6 corn oil, PEG-6 apricot oil, PEG-4 caprylic acid / capric acid triglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poroxamer 182, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol dicaprylate / dicaplate, propylene glycol caprylate / caplate , Solbitan monolaurate, sorbitan monopalmitate, solThe pharmaceutical composition according to (46), which comprises one or more of lipophilic additives selected from the group consisting of bitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate and combinations thereof. .. (55) The use of 17-hydroxyprogesterone caproate in the preparation of a drug for administration to a pregnant female subject at risk of preterm birth, wherein the drug is (1), (21), (44) or (46). Use containing the composition according to any of the above.