Hydroxyprogesterone caproate compositions and methods of use in preventing preterm birth - Patents.com

Abstract

SOLUTION: HPC compositions and methods of treatment for preventing PTB and improving neonatal outcomes. The invention provides dosing regimens beginning as early as 14 weeks of fetal gestation and as long as 25 weeks. The invention provides high levels of exogenous progesterone at a time when endogenous progesterone is most needed. The invention consistently achieves activity levels of HPC that achieve efficacy. An exemplary dosing regimen consists of oral administration of HPC in the range of 1200 mg to 1600 mg, with the HPC administered in a once-daily, twice-daily, or three-times-daily dose.

Description

[Technical field]

[0001] This PCT patent application claims the benefit under PCT Rule 4.10 to co-pending U.S. patent application Ser. No. 17 / 512,365, filed October 27, 2021, which claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 106,127, filed October 27, 2020, all of which are expressly incorporated herein by reference in their entireties.

[0002] The present invention relates to hydroxyprogesterone caproate (HPC) compositions (including 17-hydroxyprogesterone ester-containing compositions) (see, e.g., https: / / en.wikipedia.org / wiki / Hydroxyprogesterone_caproate), which may be provided in oral and other dosage forms. The present invention further relates to associated methods of administration of HPC, and more particularly, to methods of administration that result in the prevention of preterm birth (PTB). Thus, the present invention involves the fields of chemistry, pharmacy, medicine and other health sciences. [Background technology]

[0003] Compositions containing HPC and methods of administering them are known in the art, particularly for preventing PTB. An exemplary injectable composition is known under the trade name MAKENA and is provided by AMAG Pharmaceuticals, Inc. (see: https: / / makena.com / ?gclsrc=aw.ds). The FDA-approved label for MAKENA is incorporated herein by reference and is referenced at the following website: https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2018 / 021945s012lbl.pdf.

[0004] To date, only an injectable formulation of HPC, consisting of a composition and delivery method, has been approved in the United States for the prevention of recurrent PTB. To overcome the current limitations of injectable HPC treatment forms, an effective orally available method and composition for treatment remains an unmet need. Injectable formulations have failed to demonstrate efficacy in conclusive trials required by the US FDA. If approved, it is hoped that an effective oral method and composition will become the preferred form for patients and healthcare providers.

[0005] Further improved HPC compositions and methods of administration are also known in the art. Such improved HPC compositions and methods of administration are disclosed in the following list of U.S. patents and applications, all of which are entitled "17-Hydroxyprogesterone Ester-Containing Oral Compositions and Related Methods": 2013 / 0029957 filed July 28, 2011, published January 31, 2013, and issued February 10, 2015 as 8,951,996, 2014 / 0271882 filed April 24, 2014, published September 18, and issued June 14, 2016 as 9,364,547, 2014 / 0377317 filed September 4, 2014, published December 25, 2014, published June 7, 2016 as 9,358,298, 2015 / 0165049 Filed on February 27, 2015, published on June 18, 2015, issued on July 26, 2016, No. 9,399,069, 2015 / 0320768 Filed on July 16, 2015, published on November 12, 2015, issued on June 7, 2016, No. 9,358,299, 2016 Filed on April 5, 2016, published on July 28, 2016, issued on July 17, 2018, No. 10,022,384, Filed on March 28, 2019, published on October 10, 2019, issued on July 14, 2020, No. 10,709,716, 202 10106596 filed July 10, 2020, published April 15, 2021; 10,709,716 filed July 13, 2020, published June 10, 2021, allowed October 26, 2022; 20170035781 filed September 21, 2022, published June 10, 2021, all of which are expressly incorporated by reference herein.

[0006] Additionally, methods and markers relevant to detecting a predisposition to PTB are known in the art. Such methods and markers are disclosed in the following list of U.S. patents and applications: 8,932,993 for "Method of testing for endometriosis and method of treating same" filed on March 7, 2013 and issued on January 13, 2015; 9,434,991 for "Method of testing for endometriosis and method of treating same" filed on March 7, 2013 and issued on September 6, 2016; 9,840,738 for "Method of testing for endometriosis and method of treating same" filed on January 12, 2015 and issued on December 12, 2017; 10,392,665 for "Biomarker pair for predicting preterm birth" filed on June 17, 2016 and issued on August 27, 2019; 10,961,584 for "Biomarker pair for predicting preterm birth" filed on April 10, 2019 and issued on March 30, 2021; 150133382 "Method of testing for endometriosis and method of treating same" Filed on January 12, 2015, published on May 14, 2015, 20150368714 "Method of testing for endometriosis and method of treating same" Filed on March 7, 2013, published on December 24, 2015, 20160367568 "Method of testing for endometriosis and method of treating same" Filed on September 5, 2016, published on December 22, 2016, September No. 20180245156, filed on the 5th, published on December 22, 2016, filed on December 11, 2017, and published on August 30, 2018 for "Method of testing for endometriosis and method of treating same," and No. 20200332360, filed on April 16, 2020, and published on October 22, 2020 for "Method and kit for diagnosing premature birth," are all expressly incorporated herein by this reference in their entireties. Summary of the Invention [Means for solving the problem]

[0007] The present invention is an HPC composition and treatment method for the prevention of recurrent PTB (e.g., delivery at less than 32, 35, or 37 weeks of gestation) and improving neonatal outcomes (e.g., improving Neonatal Composite Index (NCI)). The present invention provides dosing regimens beginning as early as 14 weeks of fetal gestation and for a period of 25 weeks. The present invention provides high levels of exogenous progesterone when endogenous progesterone is most needed. The present invention provides compositions and methods that consistently achieve therapeutically effective levels of HPC. An exemplary dosing regimen consists of oral administration of HPC in the range of 1200 mg to 1600 mg, where the HPC is administered via once daily, twice daily, or three times daily administration. The method may further include administering the HPC composition to a subject known to be at altered risk for PTB for subjects with at least one PTB risk factor, which may include a genetic marker associated with altered PTB risk.

[0008] References throughout this specification to "an embodiment," "one embodiment," or similar language mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the invention. Thus, the appearances of "an embodiment," "in one embodiment," and similar phrases throughout this specification do not necessarily all refer to the same embodiment.

[0009] Before the HPC compositions and treatment methods for preventing PTB of the present invention are disclosed and described, it is to be understood that the present invention is not limited to the particular process steps and materials disclosed herein, but extends to equivalents thereof as would be recognized by one of ordinary skill in the relevant art. It is also to be understood that the terminology used herein is used only for the purpose of describing particular embodiments, and is not intended to be limiting.

[0010] It should be noted that the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to an "excipient" includes reference to one or more such excipients, and reference to a "carrier" includes reference to one or more such carriers.

[0011] definition As used herein, the term "fetus" refers to an unborn human offspring (baby), particularly an unborn human baby having an age greater than 8 weeks after conception. As used herein, the term "newborn" refers in some instances to a newborn or child less than 4 weeks of age, and in other instances to a newborn or child less than 10 weeks of age. As used herein, the term "abortion" refers to the expulsion of a fetus from the uterus, particularly naturally or as a result of an accident, before it is capable of independent survival.

[0012] As used herein, the term "eligible PTB" or "eligible delivery" refers to a singleton PTB, whether spontaneous or directed, where the fetus has a gestational age (GA) at birth of at least 20 weeks, but less than at least one of 28, 29, 30, 31, 32, 33, 34, 35, 36, and 37 weeks. The term "eligible PTB" or "eligible delivery" applies to criteria that identify patients at risk for PTB based on a history of prior PTB.

[0013] As used herein, the term "treatment", when used in conjunction with the administration of pharmaceutical compositions and oral dosage units containing HPC, refers to the administration of the oral dosage units and pharma- ceutically acceptable compositions to an asymptomatic or symptomatic subject. In other words, "treatment" refers to reducing or eliminating symptoms associated with a condition present in a subject, or prophylactic treatment, i.e., preventing the occurrence (or recurrence) of symptoms in a subject. Such prophylactic treatment can also be referred to as prevention of symptoms.

[0014] As used herein, the terms "formulation" and "composition" are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some embodiments, the terms "formulation" and "composition" can be used to refer to a mixture of one or more active agents with a carrier or other excipient. Furthermore, the term "dosage form" can include one or more formulations or compositions provided in a manner 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 for oral administration to a subject.

[0015] As used herein, the term "fatty acid" refers to combined carboxylic acids having long aliphatic tails (chains) that are either saturated or unsaturated, conjugated or non-conjugated.

[0016] Unless otherwise specified, the term C8-C22 fatty acid glycerides refers to a mixture of mono-, di-, and / or triglycerol esters of medium to long chain (C8-C22) fatty acids.

[0017] Further, as used herein, the dispersant of the present invention is at least one selected from the group of hydrophilic surfactants or lipophilic surfactants. In one embodiment, the dispersant comprises a hydrophilic surfactant.

[0018] As used herein, the terms "solidifying agent" or "solidifying excipient" are used interchangeably and refer to a pharma- ceutically acceptable excipient that is in a solid physical state at 20° C. Similarly, a "solid lipophilic excipient" refers to a lipophilic compound or component that is in a solid physical state at 20° C. and / or that renders a composition or dosage form solid or non-liquid, such as semi-solid.

[0019] As used herein, the term "lipophilic" refers to a compound that is not freely soluble in water, and the term "lipophilic surfactant" refers to a surfactant having an HLB (hydrophilic-lipophilic balance) value of about 10 or less. Conversely, the term "hydrophilic" refers to a compound that is soluble in water, and the term "hydrophilic surfactant" refers to a surfactant having an HLB value of about 10 or more.

[0020] As used herein, the term "ionizable fatty acid" refers to a fatty acid compound whose HLB changes as a function of pH. For example, oleic acid is primarily lipophilic at low pH values ​​(such as those found in the stomach) but is primarily hydrophilic at high pH values ​​(such as those found in the intestine).

[0021] As used herein, "subject" refers to a mammalian subject that may benefit from the administration of a pharmaceutical composition or method of the present invention. Examples of subjects include humans. In one embodiment, the subject may be a human female who previously gave birth prematurely.

[0022] As used herein, a "responder" refers to a subject who responds to an exogenous oral HPC therapy. A "responder analysis" is an evaluation of the efficacy of an oral HPC therapy in a group of subjects who are likely to benefit from the oral HPC therapy.

[0023] As used herein, "group" or "subject group" refers to a collection of at least 24 human female subjects who receive and respond to exogenous oral administration of the compositions disclosed herein, i.e., HPC-containing compositions. In one embodiment, the group may include at least 25, or at least 100, or at least 300 female subjects. In another embodiment, the group may include at least 1,000 female subjects.

[0024] The term "oral administration" refers to any method of administration in which an active agent may be administered by swallowing, chewing, or inhaling a dosage form. The compositions of the present invention may be mixed with food or drink before being ingested orally.

[0025] As used herein, a "regimen" refers to an administration regimen that includes at least one dosage. As used herein, a "dosage" refers to a prescribed administration of a specific amount, number, and times over a specific period of time (reference: https: / / www.verywellhealth.com / drug-dose-definition-and-examples-1123989). As used herein, a "dosage" refers to an example of an amount of a composition (e.g., a pharmaceutical or drug) that is taken or is recommended to be taken at a specific time. For example, a regimen having an initial dosage for a female subject can provide for daily repetition of a predetermined amount of HPC administered within 30 minutes after a meal (e.g., breakfast) having a fat content of about 15 to 55 g.

[0026] As used herein, a dosage refers to a specific amount of a drug taken at one time. In contrast, a dosage refers to a prescribed administration in a specific amount, number, and frequency over a specific period of time. Also, as used herein, a "daily dosage" refers to the amount of an active agent (e.g., HPC) administered to a subject during a 24-hour period. A daily dosage may be administered via one or more administrations during a 24-hour period. In one embodiment, a daily dosage provides one administration during a 24-hour period.

[0027] As used herein, "steady state" refers to a state in which serum total HPC concentrations show a stable response to exogenous HPC administration, typically achieved at least 7 days after initiation of a dosing regimen.

[0028] As used herein, an "effective amount" or "therapeutically effective amount" of a drug refers to a non-toxic but sufficient amount of the drug to obtain a therapeutic effect in treating a condition for which the drug is known to be effective. It is understood that various biological factors may affect the ability of a substance to perform its intended role. Thus, an "effective amount" or "therapeutically effective amount" may depend on such biological factors. Furthermore, while the achievement of a therapeutic effect can be measured by a physician or other qualified medical practitioner using evaluations known in the art, it is recognized that the achievement of a therapeutic effect may be a somewhat subjective determination due to individual differences and responses to treatment. Determining an effective amount is within the ordinary skill of those in the art of pharmacy and medicine. See, for example, Meiner and Tonascia, "Clinical Trials: Design, Conduct, and Analysis", Monographs in Epidemiology and Biostatistics, Please refer to Vol.8(1986).

[0029] The terms "plasma HPC concentration", "blood HPC concentration", "total HPC concentration", "HPC concentration", "HPC level", and "serum HPC concentration" are used interchangeably and refer to the "total" HPC concentration, which is the sum of bioavailable HPC, including free and protein-bound HPC concentrations. As with any bioanalytical measurement, to promote consistency, the method employed to measure the initial serum HPC concentration should be consistent with the method used to monitor and remeasure serum HPC concentrations during the subject's clinical trial and HPC treatment. Unless otherwise noted, "HPC concentration" refers to serum total HPC concentration (level).

[0030] As used herein, the average total HPC concentration can be determined using methods and practices known in the art. For example, the average baseline blood HPC concentration of a human female is the arithmetic mean of the total blood (serum or plasma) HPC concentration determined at least two consecutive time points that are appropriately spaced apart from each other, for example, about 1 hour to about 168 hours apart. In a particular embodiment, the blood HPC concentration can be determined at least two consecutive time points that are about 24 hours to about 48 hours apart. In another particular method, the blood HPC concentration of a human male can be measured at a time between about 5:00 and about 11:00 in the morning. Furthermore, the blood HPC concentration can be determined by standard analytical procedures and methods available in the art, such as, for example, automated or manual immunoassay, liquid chromatography or liquid chromatography-tandem mass spectrometry (LC MS / MS).

[0031] As used herein, AUC 0-t The term is the area under the curve of the plasma versus time graph determined for the analyte from time 0 to time "t".

[0032] As used herein, "C max The term "C" refers to the maximum serum concentration level after a single dose or the maximum serum concentration during a 24-hour period after a total daily dose. min The term "C" refers to the minimum serum concentration level after a single dose or the minimum serum concentration during a 24-hour period after a total daily dose. pre The term "C-dose" refers to the nominal steady-state serum concentration level prior to any administration. avg ", "C ave " or "C average The terms are used interchangeably and are determined as the AUC divided by the period (t). For example, C avg -8h is AUC 0-s The mean plasma concentration during the 8 hour period after dosing is determined by dividing the C value by 8. avg - 12 h is the AUC 0-12The mean plasma concentration during the 12-hour period after dosing is determined by dividing the C value by 12. avg - 24 h is the AUC 0-24 The mean plasma concentration during the 24-hour period after dosing is determined by dividing the C value by 24. avg All values ​​are C avg-24h It is considered that.

[0033] As used herein, "C t " means the serum concentration of HPC at time "t" after a single dose of the drug. Time "t" is generally in hours unless otherwise specified. For example, C t "C (-2~0)」は、 The term "C" refers to the serum HPC concentration in a sample taken from about 2 hours before administration to a subject until just before administration. (2-4) "C" t " refers to the serum HPC concentration measured in a sample taken between about 2 and 4 hours after administration to a subject. As another example, "C5" refers to the serum HPC concentration measured in a sample taken about 5 hours after administration to a subject.

[0034] As used herein, the term "about" is used to provide flexibility to the endpoints of a numerical range by providing that a given value may be "a little above" or "a little below" the endpoint. In this specification, a number of items, structural elements, components, and / or materials may be presented in a common list for convenience. However, these lists should be construed as each member of the list being individually identified as a separate and unique member. Thus, the individual members of such lists should not be construed as de facto equivalents of other members of the same list solely based on presentation in a common group, without indication to the contrary.

[0035] In this specification, a plurality of items, structural elements, components, and / or materials may be presented in common lists for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, the individual members of such lists should not be construed as being de facto equivalent to other members of the same list solely based on presentation in a common group, unless indicated to the contrary.

[0036] Concentrations, amounts, levels, and other numerical data may be expressed or presented in a range format herein. It should be understood that such range formats are used merely for convenience and brevity, and thus should be interpreted flexibly to include not only the numerical values ​​explicitly stated as the limits of the range, but also all individual numerical values ​​or subranges or fractional units subsumed within the range, as if each numerical value and subrange were explicitly stated. As an example, a numerical range of "about 1 to about 5" should be interpreted to include not only the values ​​of about 1 to about 5 explicitly stated, but also the individual values ​​and subranges within the indicated range. Thus, included in this numerical range are individual values ​​such as 2, 3, 4, etc., and subranges such as 1 to 3, 2 to 4, 3 to 5, as well as 1, 2, 3, 4, 5. This principle also applies to ranges that recite only one numerical value as the minimum or maximum value. Moreover, such interpretation should be applied regardless of the breadth of the range or the properties being described.

[0037] Reference will now be made in detail to the preferred embodiments of the invention. While the invention will be described in conjunction with the preferred embodiments, it will be understood that it is not intended to limit the invention to those preferred embodiments. On the contrary, the invention is intended to cover alternatives, variations, modifications, and equivalents which may be included within the spirit and scope of the invention as defined by the appended claims.

[0038] An embodiment of the invention is a HPC composition and method of treatment for the prevention of PTB (e.g., birth at <32, 35, or 37 weeks gestation) and improving neonatal outcomes - e.g., improving the Neonatal Composite Index (NCI) (see efficacy endpoints). See also the NCI used at the October 29, 2019 BRUDAC meeting by both Makena and the FDA (the expository material of which is incorporated herein by reference and can be found at https: / / www.fda.gov / media / 132004 / download, https: / / www.fda.gov / media / 132003 / download).

[0039] In one embodiment, the HPC method of the present invention is for treating a pregnant subject with a qualified PTB or a qualified delivery.In one aspect, the present invention comprises treating a pregnant subject with a qualified PTB of less than GA 35 weeks.In another aspect, the current HPC method of the present invention comprises treating a pregnant subject with a qualified PTB of less than GA 32 weeks.In a further embodiment, the current HPC method of the present invention comprises treating a pregnant subject with a qualified PTB of less than GA 28 weeks.

[0040] In various embodiments of the invention, 15% or more, 20% or more, 30% or more, 40% or more, and up to 50% of a group of (pregnant) subjects had a qualifying PTB with a GA of less than 32 weeks.

[0041] In various embodiments of the invention, 35% or more, 40% or more, 45% or more, 50% or more, 67% or more, 75% or more, 80% or more, 90% or more of a group of (pregnant) subjects had eligible PTB between 32 and <35 weeks GA.

[0042] In various embodiments of the invention, 35% or more, 40% or more, 45% or more, 50% or more, 67% or more, 75% or more, 80% or more, 90% or more of a group of (pregnant) subjects had a previous PTB between 32 and less than 35 weeks GA.

[0043] In various embodiments of the invention, less than 15%, less than 25%, less than 33%, less than 50% of the group of (pregnant) subjects had eligible PTB between GA 35 weeks and 36 weeks + 6 days.

[0044] In various embodiments of the invention, less than 15%, less than 25%, less than 33%, less than 50% of a group of (pregnant) subjects had a previous PTB between GA 35 weeks and 36 weeks + 6 days.

[0045] In prior art, such as injectable HPC methods (e.g., MAKENA), the recommended HPC dosing regimen begins at GA 16 to 20 weeks and continues until GA 37 th This involves administering 250 mg of HPC per week until delivery at GA 39 weeks (or 36 weeks and 6 days), or until delivery at a maximum treatment period of 21 weeks, whichever occurs first, if treatment is initiated at GA 16 weeks. In contrast, by initiating treatment earlier than GA 16 weeks, such as GA 15 weeks or even GA 14 weeks, the present invention provides a desired level of efficacy. Additionally, the dosing regimen of the present invention provides a GA of 39 weeks or even 15 weeks or even 14 weeks. th Treatment until 2 weeks postpartum for a maximum treatment period of 25 weeks if treatment is initiated at 14 weeks GA, whichever occurs first, may also provide the desired level of efficacy.

[0046] In embodiments, the invention provides for initiating treatment of a pregnant woman at a GA of any of at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, and at least 20 weeks.

[0047] In another embodiment, the invention provides for treatment of pregnant women up to one of 39 weeks GA, 38 weeks GA, 37 weeks GA, or 2 weeks postpartum.

[0048] In a further embodiment, the present invention provides for the treatment of a pregnant woman for a period of up to one of the following weeks: 25, 24, 23, 22, 21, 20, 19, 18, and 17.

[0049] In another embodiment, the present invention provides the advantages of extending pregnancy in patients at risk for PTB, resulting in improved neonatal mortality and morbidity as a function of GA and reduced neonatal length of hospital stay.

[0050] The typical time to reach steady state (or targeted effective levels) from weekly injection HPC dosing regimens is at least several weeks, which may contribute to the questionable efficacy of such regimens. In contrast, the present invention provides steady state (or targeted effective) HPC levels between 2 and 7 days after the start of the intervention. Thus, in one embodiment, the present invention allows for steady state or targeted effective levels of HPC for up to 25 weeks, or at least 4 weeks longer than injectable HPC regimens, for improved therapeutic efficacy.

[0051] In an embodiment, the present invention can achieve steady state HPC levels in less than at least one of 1 week, 6 days, 5 days, 4 days, 3 days, and 2 days after initiation of treatment. In one embodiment, the present invention can achieve steady state (e.g., day 7), group mean C max (per day) achieves HPC levels greater than one of about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL, about 70 ng / mL, about 80 ng / mL, about 90 ng / mL, about 100 ng / mL, about 150 ng / mL, and about 180 ng / mL after a single dose.

[0052] In an embodiment, the present invention provides a group mean C of greater than one of about 6 ng / mL, about 12 ng / mL, about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, and about 50 ng / mL after daily administration. avg Achieve steady-state (e.g., day 7) levels of HPCs with

[0053] In one embodiment, the present invention provides a group mean T of less than 4 hours, less than 6 hours, less than 8 hours, less than 10 hours, and less than 12 hours after a single dose.max , to achieve steady-state (e.g., day 7) levels of HPC.

[0054] In one embodiment, the present invention provides a C of at least 6, at least 8, at least 10, at least 15, at least 20, at least 25, at least 30, and at least 40 after a single dose of any of the oral HPC compositions. max Against C min The circadian pharmacokinetic profile having the ratio of levels (circadian ratio) is provided.

[0055] PTB is a major cause of neonatal morbidity and mortality. The risk of neonatal mortality is approximately three times higher with PTB at 35-36 weeks and increases significantly as PTB GA at delivery decreases. Neonatal morbidity such as respiratory distress requiring oxygen, temperature instability, hypoglycemia, jaundice, cerebral palsy, and developmental delay are extremely common. Several components of neonatal outcome, including neonatal mortality such as death before discharge, grade III or IV intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and proven sepsis, are used to evaluate the clinical effectiveness of interventions to treat pregnant women at risk for PTB recurrence.

[0056] In one embodiment, the present invention improves (reduces the incidence of) at least one or a combination of the individual components of the neonatal outcomes of death (before hospital discharge), grade III or IV intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and proven sepsis when treatment for pregnant women at risk for PTB recurrence is initiated by at least one of GA of 14, 15, 16, 17, 18, 19, and 20 weeks. This is in clear contrast to the results of prior art methods such as non-HPC and injected HPC treatments.

[0057] In another embodiment, the present invention improves (reduces the incidence of) at least one or a combination of individual components of neonatal outcomes such as death before (hospital) discharge, grade III or IV intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and documented sepsis in pregnant women at risk for PTB recurrence when treatment is extended to 39 weeks or 2 weeks postpartum, in stark contrast to the results of prior art methods such as non-HPC and injected HPC treatments.

[0058] In further embodiments, the present invention improves (reduces the incidence of) at least one or a combination of individual components of neonatal outcomes including death before discharge, grade III or IV intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and documented sepsis, when treatment is maintained for up to 18, 19, 20, 21, 22, 23, 24, and 25 weeks for pregnant women at risk for PTB recurrence. This is in clear contrast to the results of prior art methods such as non-HPC and injected HPC treatments.

[0059] In one embodiment, compared to prior art methods (i.e., non-HPC therapy or injectable HPC therapy), the present invention improves neonatal morbidity and mortality (NCI), i.e., pre-discharge death, grade III or IV intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and documented sepsis by at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% when treatment is initiated no later than 14, 15, 16, 17, 18, 19, or 20 weeks GA (for pregnant women at risk for PTB recurrence).

[0060] In another embodiment, the present invention ameliorates (reduces the incidence of) at least one or a combination of typical neonatal morbidities, such as respiratory distress syndrome, dyspnea requiring oxygen, intraventricular hemorrhage of all grades, retinal leukomalacia, temperature instability, hypoglycemia, jaundice, cerebral palsy, developmental delay, persistent pulmonary hypertension, seizures, hypoxic-ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, RDS, hyperbilirubinemia requiring treatment, hypotension requiring treatment, when therapy is initiated (for pregnant women at risk for recurrent PTB) at a GA not later than at least one of 14, 15, 16, 17, 18, 19, and 20 weeks.

[0061] The risk of PTB in pregnant women may be increased by any or a combination of factors such as: history of spontaneous PTB (past obstetric history), history of multiple PTBs, GA of past PTB less than at least one of 37, 35, 32 weeks, recent history of spontaneous PTB (past obstetric history), cervical incompetence, cervical length <2.5 cm in mid-trimester, presence of fetal fibronectin in vaginal secretions, low maternal Body Mass Index (BMI), certain maternal races (e.g., African American), maternal ages <17 and >35 years, and smoking history. The present invention is particularly suited to subjects at risk of PTB alterations with cervical incompetence.

[0062] Dosage form In one aspect, the compositions of the present invention can be provided as solid dosage forms such as tablets, caplets, granules, beads, microparticles, etc., or as liquid solution forms in dosage units. This provides multiple options for producing the compositions, allowing manufacturers to employ a variety of manufacturing techniques. All oral dosage forms of the present invention can provide the drug in the form of a solution, suspension, microparticles, etc., all of which can be manufactured by conventional processing and manufacturing methods known in the art.

[0063] In another aspect, the composition of the present invention can be formulated to include a therapeutically effective amount of HPC and a pharma- ceutically acceptable carrier. In one embodiment, the composition of the present invention can provide a therapeutically effective level of HPC for preventing recurrent PTB and / or improving neonatal outcomes.

[0064] Prior art MAKENA is approved for intramuscular (IM) and subcutaneous injection dosing regimens of 250 mg and 275 mg per week, respectively, but efficacy may be compromised in a significant proportion (20-25%) of subjects at risk for PTB relapse due to insufficient activity levels of HPC to achieve efficacy. In contrast, the present invention consistently achieves effective levels of HPC. In an embodiment of the invention, the dosing regimen consists of oral administration of HPC in the range of 1200 mg to 1600 mg, where HPC is administered via once-daily, twice-daily, or three-times-daily dosing.

[0065] In one embodiment, the present invention provides for administering a dosing regimen of HPC to a subject with one or more risk factors, including a subject with a qualifying PTB of less than 35 weeks GA, a subject with a qualifying PTB of less than 32 weeks GA, a subject who abused substances during pregnancy, a subject who is unmarried and has no partner, a subject with an education level of 12 years or less, a subject of a certain age, a subject of a certain race, a subject of a certain sex (e.g., male, etc.), and any other risk factors (Manuck Risk Factor (MRF) (see: "Racial and Ethnic Differences in Preterm Birth" which is incorporated herein by reference and can be found at https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC6381592 / ). In certain embodiments, the dosing regimen of the present invention comprises oral administration of a HPC in the range of 1200 mg to 1600 mg, where the HPC is administered via once daily, twice daily, or three times daily administration.

[0066] In an embodiment, the dosing regimen of the present invention comprises oral administration of HPC in the range of 1200 mg to 1600 mg, where the HPC is administered via once daily, twice daily, or three times daily, with dosing initiation ranging from 14 weeks (14 weeks and 0 days) GA to 20 weeks (20 weeks and 6 days) GA.

[0067] In another embodiment, the dosing regimen of the present invention consists of oral administration of HPC in the range of 1200 mg to 1600 mg, where the HPC is administered once daily, twice daily, or three times daily, wherein the regimen extends to 39 weeks (38 weeks and 6 days) GA or 2 weeks postpartum.

[0068] In another embodiment, the dosing regimen of the present invention consists of oral administration of HPC in the range of 1200 mg to 1600 mg, where the HPC is administered once daily, twice daily, or three times daily, wherein the duration of the regimen is maintained for up to 25 weeks (start of treatment: 14 weeks to 20 weeks, end of treatment: up to 39 weeks or 2 weeks after delivery).

[0069] In one embodiment, the compositions of the present invention comprise at least one of a crystalline and an amorphous form of HPC.

[0070] The therapeutically effective amount of HPC can be formulated with a pharma- ceutically acceptable carrier to deliver a sufficient (effective) level of HPC to prevent recurrence of PTB and / or improve neonatal outcomes when administered to a qualified pregnant woman with PTB. In some embodiments, such carriers can include additives. A wide variety of additives can be used to combine with HPC in the current oral HPC pharmaceutical composition to provide a therapeutically effective level of HPC to treat pregnant women to prevent recurrent PTB and / or improve neonatal outcomes.

[0071] Examples of suitable excipients for producing amorphous or partially crystalline forms of HPC in the dosage form include: (i) tocopherol (e.g., vitamin E) or derivatives thereof; (ii) fatty acids or salts thereof; (iii) glyceryl fatty acid esters; (iv) PEG glycerides of fatty acid esters; (v) polyglycerol fatty acid esters; (vi) triglycerides; (vii) hydrogenated polyoxyl vegetable oils or glycerides; (viii) propylene glycol fatty acid esters; (ix) edible oils; (x) sterols or derivatives thereof; (xi) omega fatty acids, omega oils such as fish oil, linseed oil, algae oil, or combinations thereof.

[0072] In one embodiment, (i) tocopherol or a derivative thereof may include α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocopherol acetate, tocopherol linoleate, tocopherol succinate, tocotrienol (α-, β-, γ-, or δ-), tocophersolan, or TPGS (a PEG derivative of α-tocopherol), or the like, or a combination thereof.

[0073] In another embodiment, (ii) the fatty acid or salt thereof may include the following: octanoic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linoelaidic acid, sodium caproate, sodium caprylate, sodium laurate, sodium myristate, sodium palmitate, sodium oleate, sodium stearate, SLS, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate, and the like, or combinations thereof.

[0074] In another embodiment, (iii) the glyceryl fatty acid esters can include the following: glyceryl monooleate, glyceryl monooleate / linoleate, glyceryl monolinoleate, glyceryl ricinoleate, glyceryl monolaurate, glyceryl monopalmitate, glyceryl monostearate, glyceryl mono / dioleate, glyceryl palmitate / stearate, glyceryl acetate, glyceryl laurate, glyceryl citrate / glyceryl lactate / glyceryl oleate / glyceryl linoleate, glyceryl caprylate, glyceryl caprylate / glyceryl caprate, glyceryl dicaprylate / glyceryl dicaprate, mono / diacetylated monoglycerides, glyceryl monostearate, glyceryl dilaurate, glyceryl dioleate, and the like, or combinations thereof.

[0075] In yet another embodiment, (iv) the PEG glycerides of fatty acid esters may include the following: PEG fatty acid monoesters, PEG glycerin fatty acid esters, PEG fatty acid diesters, PEG fatty acid mono / diester mixtures, PEG triglycerides of fatty acid esters, etc., or combinations thereof. The PEG glycerin fatty acid esters may include the following: PEG glyceryl laurate, PEG glyceryl laurate, PEG glyceryl caprylate, PEG glyceryl caprate, PEG glyceryl oleate, PEG glyceryl mono / di fatty acid ester mixtures, etc., or combinations thereof. The PEG fatty acid monoesters may consist of esters of caprylic acid, capric acid, lauric acid, oleic acid, and stearic acid, etc., or combinations thereof. Examples of PEG fatty acid monoesters include PEG(1-100,200,300,400) monocaprylate, PEG(1-100,200,300,400) monocaprate, PEG(1-100,200,300,400) monolaurate, PEG(1-100,monooleate, PEG(1-100,200,300,400) monopalmitate, PEG(1-100,200,300,400) monostearate, and PEG(1-100,200,300,400) monococoate, or the like, or combinations thereof. PEG fatty acid diesters include PEG(4-32 ) dicaprylate, PEG(4-32) dicaprate, PEG(4-32) dilaurate, PEG(4-32) dioleate, PEG(4-32) distearate, and PEG(4-32) dipalmitate, or the like, or combinations thereof. PEG fatty acid mono- / di-ester mixtures may include the following: PEG caprylate / caprate, PEG mono- / di-caprylate, PEG mono- / di-caprate, PEG mono- / di-laurate, PEG mono- / di-oleate, PEG mono- / di-stearate, or the like, or combinations thereof.The fatty acid ester PEG triglyceride may include lauroyl polyoxylglyceride, stearoyl polyoxylglyceride, oleoyl polyoxylglyceride, linoleyl polyoxylglyceride, lauroyl polyoxylglyceride, caprylocaproyl polyoxylglyceride, and behenoyl polyoxylglyceride, and the like, or combinations thereof.

[0076] In a further embodiment, (v) the polyglycerin fatty acid ester is selected from the group consisting of polyglyceryl oleate (2,3,4,6,10), polyglyceryl dioleate (2,3,4,6,10), polyglyceryl trioleate (2,3,4,6,10), polyglyceryl laurate (2,3,4,6,10), polyglyceryl dilaurate (2,3,4,6,10), polyglyceryl stearate (2,3,4,6,10) trilaurate, (2,3,4,6,10) polyglyceryl stearate, (2,3,4,6,10) polyglyceryl distearate, (2,3,4,6,10) polyglyceryl tristearate, (2,3,4,6,10) polyglyceryl mono / dioleate, (3,6,10) polyglyceryl caprate, (3,6 , 10) dicaprate, polyglyceryl (3,6,10) tricaprate, polyglyceryl (3,6,10) caprylate, polyglyceryl (3,6,10) dicaprylate, polyglyceryl (3,6,10) tricaprylate, polyglyceryl (3,6,10) polystearate, polyglyceryl (3,6,10) polyoleate, polyglyceryl (3,6,10) mono- / di-oleate, polyglyceryl (3,6,10) caprylate, polyglyceryl (3,6,10) polycaprylate, polyglyceryl (3,6,10) caprate, polyglyceryl (3,6,10) polycaprate, and polyglyceryl (3,6,10) caprylate / caprate, or the like, or combinations thereof.

[0077] In another embodiment, (vi) triglycerides can include glyceryl tricaprylate, glyceryl tricaprate, glyceryl tricaprate / glyceryl tricaprate, glyceryl tricaprate / glyceryl trisuccinate, glyceryl trioleate, glyceryl tristearate, glyceryl trilaurate, medium chain natural oils, and the like, or combinations thereof.

[0078] In yet another embodiment, (vii) the hydrogenated polyoxyl vegetable oil or glyceride can consist of castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, peppermint oil, coconut oil, sunflower seed oil, or almond oil, or a combination thereof. The polyoxyl group can include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, pentaerythritol, and the like, or a combination thereof.Examples of hydrogenated polyoxyl vegetable oils or glycerides include PEG-35 castor oil (Incrocas-35, KOLLIPHOR EL, CREMOPHOR EL), PEG-40 hydrogenated castor oil (KOLLIPHOR RH40, CREMOPHOR RH40), PEG-25 trioleate (tagatrto), PEG-60 corn glyceride (CROVOL M70), PEG-60 almond oil (CROVOL A70), PEG-40 palm kernel oil (CROVOL PK70), PEG-50 castor oil (Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic / capric glyceride (LABRASOL), PEG-6 caprylic / capric glyceride (SOFTIGEN 767), PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (LABRAFIL M.2125 CS), PEG-6 almond oil (LABRAFIL M 1966 CS), PEG-6 apricot kernel oil (LABRAFIL M 1944CS), PEG-6 olive oil (LABRAFIL M 1980 CS), PEG-6 peanut oil (LABRAFIL M 1969 CS), PEG-6 hydrogenated palm kernel oil (LABRAFIL M2130 BS), PEG-6 palm kernel oil (LABRAFIL M 2130 CS), PEG-6 triolein (LABRAFIL M 2735 CS), PEG-8 corn oil (LABRAFIL WL 2609 BS), PEG-20 corn glycerides (CROVOL M40), and PEG-20 almond glycerides (CROVOL A40), or combinations thereof.

[0079] In one embodiment, (viii) the propylene glycol fatty acid esters may include the following: propylene glycol monolaurate (LAUROGLYCOL FCC), propylene glycol ricinoleate (PROPYMULS), propylene glycol monooleate (MYVEROL P-O6), propylene glycol dicaprylate / dicaprate (CAPTEX 200), and propylene glycol dioctanoate (CAPTEX 800), propylene glycol monocaprylate (CAPRYOL 90, NIKKOL Sefsol 218), propylene glycol myristate, propylene glycol monostearate, propylene glycol ricinoleate, propylene glycol isostearate, propylene glycol caprylate / caprate, propylene glycol dioleate, propylene glycol distearate, propylene glycol dilaurate, propylene glycol dicaprylate, propylene glycol dicaprate, and the like, or combinations thereof.

[0080] In another embodiment, (ix) the edible oil may include corn oil, olive oil, peanut oil, coconut oil, peppermint oil, sunflower seed oil, castor oil, safflower oil, borage oil, cottonseed oil, soybean oil, palm kernel oil, apricot kernel oil, almond oil, omega-3 oil or derivatives thereof, and the like, or combinations thereof.

[0081] In one embodiment, the (x) sterol or derivative thereof may include cholesterol, sitosterol, lanosterol, phytosterol, PEG derivatives thereof, and the like, or combinations thereof.

[0082] In one embodiment, an additive may be a substance that can be added to a pharmaceutical formulation to enhance solubilization, separation, or dispersion of particles, or to enhance dissolution and further absorption of particles into the body. Examples of additives include lipophilic additives with HLB values ​​of 10 or less, and hydrophilic additives with HLB values ​​of more than 10.

[0083] In one embodiment, the pharma- ceutically acceptable carrier may comprise a hydrophilic excipient, a lipophilic excipient, or a combination thereof.

[0084] In one embodiment, the lipophilic additive may be, but is not limited to, a mono-, di-glyceride of a fatty acid, an alcohol or a polyhydric alcohol in combination with PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (e.g., LABRAFIL M 2125 CS), PEG-6 almond oil (e.g., LABRAFIL M 1966 CS), PEG-6 apricot kernel oil (e.g., LABRAFIL M 1944 CS), PEG-6 olive oil (e.g., LABRAFIL M 1980 CS), PEG-6 peanut oil (e.g., LABRAFIL M 1969 CS, etc.), PEG-6 hydrogenated palm kernel oil (e.g., LABRAFIL M 2130 BS, etc.), PEG-6 palm kernel oil (e.g., LABRAFIL M 2130 CS, etc.), PEG-6 triolein (e.g., LABRAFIL M 2735 BS, etc.), PEG-6 oleic acid ... CS), PEG-8 corn oil (such as LABRAFIL WL 2609 BS), PEG-20 corn glycerides (such as CROVOL M40), PEG-20 almond glycerides (such as CROVOL A40), lipophilic polyoxyethylene-polyoxypropylene block copolymers (such as Pluronic L92, L101, L121), propylene glycol fatty acid esters such as propylene glycol monolaurate (such as e.LAUROGLYCOL FCC), propylene glycol ricinoleate (such as PROPYMULS), propylene glycol monooleate (such as MYVEROL P-O6), propylene glycol dicaprylate / dicaprate (such as CAPTEX® 200), and the like.Propylene glycol dioctanoate (e.g. CAPTEX® 800), propylene glycol monocaprylate (e.g. CAPRYOL® 90), propylene glycol oleate (e.g. LUTROL); propylene glycol myristate; propylene glycol monostearate; propylene glycol hydroxystearate; propylene glycol ricinoleate; propylene glycol isostearate; propylene glycol monooleate; propylene glycol dicaprylate / dicaprate; propylene glycol dioctanoate; propylene glycol caprylate-caprate; propylene glycol dilaurate; propylene glycol distearate; propylene glycol dicaprylate; propylene glycol dicaprate; mixtures of propylene glycol esters and glycerol esters such as mixtures of propylene glycol and oleic acid ester of glycerol (e.g. ARLACEL®) 186); sterols and sterol derivatives such as cholesterol, sitosterol, phytosterol, phytosterol fatty acid esters, PEG-5 soy sterol, PEG-10 soy sterol, PEG-20 soy sterol; glyceryl palmitostearate, glyceryl stearate, glyceryl distearate, glyceryl monostearate, or combinations thereof; sorbitan fatty acid esters such as sorbitan monolaurate (such as ARLACEL® 20).Sorbitan monolaurate (e.g. ARLACEL 20), sorbitan monopalmitate (e.g. SPAN-40), sorbitan monooleate (e.g. SPAN-80), sorbitan monostearate, and sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, linoleyl polyoxyl-6 glyceride, 3-oleate polyglyceryl, lauroyl PEG-32 glyceride, sorbitan trioleate, sorbitan sesquioleate, sorbitan tristearate, sorbitan monoisostearate, sorbitan sesquistearate, and the like; fatty acids such as capric acid, caprylic acid, oleic acid, linoleic acid, myristic acid, menthol, menthol derivatives, lecithin, phosphatidylcholine, bile salts, and the like, and mixtures thereof. In some cases, the additive for the composition and oral dosage form can be a lipophilic surfactant.

[0085] In certain embodiments, lipophilic additives can be lipophilic surfactants.Non-limiting examples of lipophilic surfactants suitable for the present invention include tributyl citrate, triethyl citrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetate butyrate benzyl benzoate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, tocopherol, tocopherol acetate, tocopherol succinate, corn oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, hydrogenated castor oil, glyceryl tricaprate, glyceryl trilaurate, Glyceryl Trioleate, Glyceryl Trilinoleate, Glyceryl Tricaprylate / Caprate, Glyceryl Tricaprylate / Caprate / Laurate, Glyceryl Tricaprylate / Caprate / Glyceryl Linoleate, Glyceryl Tricaprylate / Caprate / Glyceryl Stearate, Saturated Polyglycolized Glyceryl Linoleate, Glyceryl Caprylate / Caprate, Caprylic Acid, Palmitic Acid, Auric Acid, Stearic Acid, Linoleic Acid, Oleic Acid, Arachidonic Acid, Eicosanoic Acid Sapentaenoic Acid, Docosahexaenoic Acid, Glyceryl Monooleate, Glyceryl Monolinoleate, Glyceryl Monolaurate, Glyceryl Monostearate, Glyceryl Distearate, Glyceryl Palmitostearate, Glyceryl Laurate, Glyceryl Caprylate, Distearin, Monopalmitolein, Monolaurin, Ethyl Oleate, PEG-6 Corn Oil, PEG-6 Apricot Kernel Oil, PEG-4 Caprylic / Capric Triglyceride, PEG-20 Sorbitan Monostearate, PEG-4 Laurate, Zilla PEG-6 oleate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poloxamer 182, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dicaprylate / dicaprate, propylene glycol caprylate / caprate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate, and combinations thereof.

[0086] In one embodiment, the pharmaceutical composition or oral dosage form of the present invention can be formulated to include a hydrophilic additive. In one aspect, the hydrophilic additive can be composed of, but is not limited to, a nonionic surfactant, an ionic surfactant, a zwitterionic surfactant, and the like, or a combination thereof. Suitable hydrophilic surfactants can include alcohol-oil transesterification products; polyoxyethylene hydrogenated vegetable oils; polyoxyethylene vegetable oils; alkyl sulfate ester salts, dioctyl sulfosuccinate ester salts; polyethylene glycol fatty acid esters; polyethylene glycol fatty acid mono- and di-ester mixtures; polysorbates, polyethylene glycol derivatives of tocopherol, and the like, or a combination thereof. Two or more hydrophilic additives from the same class or different classes can be referred to as a hydrophilic surfactant, unless expressly specified otherwise. In one embodiment, non-limiting examples of hydrophilic surfactants can include PEG-8 caprylic / capric acid glycerides, lauroyl macrogol-32 glycerides, stearoyl macrogol glycerides, PEG-40 hydrogenated castor oil, PEG-35 castor oil, SLS. sodium dioctyl sulfosuccinate, polyethylene glycol fatty acid mono- and di-ester mixtures, polysorbate 80, polysorbate 20, polyethylene glycol 1000 tocopherol succinate, phytosterols, phytosterol fatty acid esters, poloxamers (e.g., poloxamer 407, poloxamer 188, poloxamer 108), and the like, or combinations thereof.

[0087] In another embodiment, the hydrophilic additive can be a hydrophilic surfactant. In one embodiment, when the hydrophilic additive comprises a hydrophilic surfactant, the hydrophilic surfactant does not significantly solubilize the ester of 17-hydroxyprogesterone. Non-limiting examples of hydrophilic additives include salts of citric acid, maleic acid, tartaric acid, acetic acid, ascorbic acid, benzoic acid and lactic acid, potassium hydroxide, sodium hydroxide, sodium bicarbonate, calcium carbonate, silicon dioxide, magnesium aluminum silicate, hydroxypropyl cyclodextrin, fatty acid glycerides, bile salts, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol methylcellulose, hydroxypropyl methylcellulose, cellulose esters, carbomer, chitosan, methacrylic acid ester polyvinyl alcohol, gelatin, PEG-8 caprylic / capric acid glyceride, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 hydrogenated castor oil. , PEG-35 castor oil, sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, PEG-10 laurate, PEG-20 oleate, PEG-30 stearate, PEG-40 laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl lacrimalate, 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, poloxamers (e.g., poloxamer 407, poloxamer 188, poloxamer 108), maltose, sucrose, fructose, mannitol, xylitol, and combinations thereof.

[0088] Poloxamer refers to polyethylene-polyoxypropylene block copolymers (also known as "poloxamers") and can be of any of the following formulas: These polymers have the formula HO(C <2> H <4> O) (C<3>H<6>O) (C <2> H <4> O) H, where "a" and "b" indicate the number of polyoxyethylene and polyoxypropylene units, respectively. Compounds are listed by common name with the corresponding "a" and "b" values. POE-POP block copolymers));(a, b));(HO(C <2> H <4> O) );(COMPOUND(C<3>H<6>OO) (C <2> H <4> O) H(HLB));(Poloxamer 105(a=11(b=16(8));(Poloxamer 108(a=46(b=16(>(1010));(Poloxamer 122(a=5(b=21(3));(Poloxamer 123(a=7(b=21(7));(Poloxamer 124(a=ll(b=21(>7));(Poloxamer 181(a=3(b=30));(Poloxamer 182(a=8(b=30( 2));(Poloxamer 183(a=l0(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));10(Poloxamer 231( a=16(b=39));(Poloxamer 234(a=22(b=39));(Poloxamer 235(a=27(b=39));(Poloxamer 237(a=62(b=39(24));(Poloxamer 238(a=97(b=39));(Poloxamer 282(a=10(b=47));(Poloxamer 284(a=21(b=47));(Poloxamer 288(a=122(b=47(>10)) ;(Poloxamer 331 (a=7 (b=54 (0.5));(Poloxamer 333 (a=20 (b=54));(Poloxamer 334 (a=31 (b=54));(Poloxamer 335 (a=38 (b=54));(Poloxamer 338 (a=128 (b=54));(Poloxamer 401 (a=6 (b=67));(Poloxamer 402 (a=13 (b=67));(Poloxamer 403 (a=21 20 (b=67));(Poloxamer 407 (a=98 (b=67)); and combinations thereof.

[0089] In another specific embodiment, the carrier may be a hydrophilic surfactant, which may be an ionic or non-ionic surfactant.Non-limiting examples of hydrophilic surfactants include proteins, gelatin, salts of bile acids, PEG-8 caprylic / capric acid glycerides, lauroyl macrogol-32 glycerides, stearoyl macrogol glycerides, PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, PEG-10 laurate, PEG-20 oleate, PEG-30 stearate, lauric acid ...8 caprylic / capric acid glycerides, lauroyl macrogol-32 glycerides, stearoyl macrogol glycerides, PEG-8 caprylic / capric acid glycerides, PEG-8 caprylic / capric acid glycerides, PEG-8 caprylic / capric acid glycerides, PEG-8 caprylic / capric acid glycerides, PEG-8 caprylic / capric acid glycerides, PEG-8 caprylic / capric acid glycerides, PEG-8 caprylic / capric acid glycerides, PEG In some embodiments, the glyceryl stearate may include PEG-40 glyceryl laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl lacrimalate, 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- and dioleate, poloxamers (e.g., poloxamer 407, poloxamer 188, poloxamer 108), and combinations thereof.

[0090] In one embodiment, the hydrophilic additive can be free of hydrophilic surfactants and includes citric acid, maleic acid, tartaric acid, acetic acid, ascorbic acid, benzoic acid, lactic acid, potassium hydroxide, sodium hydroxide, sodium bicarbonate, calcium carbonate, silicon dioxide, magnesium aluminum silicate, hydroxypropyl cyclodextrin, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methylcellulose, hydroxypropyl methylcellulose, cellulose esters, carbomer, chitosan, methacrylates, polyvinyl alcohol, gelatin, maltose, sucrose, fructose, mannitol, xylitol, and combinations thereof.

[0091] In yet another embodiment, the additive can be composed of sterol and derivatives of sterol.In various embodiments, these additives can be hydrophilic or lipophilic.Examples of hydrophilic sterols include: lanosterol PEG-24 cholesterol ether (e.g., SOLULAN C-24, Amerchol), PEG-30 soy sterol (e.g., NIKKOL BPS-30, from Nikko), PEG-25 phytosterol (e.g., NIKKOL BPSH-25, from Nikko), PEG-30 cholestanol (e.g., NIKKOL DHC, from Nikko). Examples of lipophilic sterol surfactants include cholesterol, sitosterol, phytosterol (e.g., GENEROL series manufactured by Henkel), PEG-5 soy sterol (e.g., NIKKOL BPS-S manufactured by Nikko), PEG-10 soy sterol (e.g., NIKKOL BPS-10 manufactured by Nikko), PEG-20 soy sterol (e.g., NIKKOL BPS-20 manufactured by Nikko), and the like, or combinations thereof.

[0092] In another embodiment, the oral composition may further comprise a polymeric release modifier. The polymeric release modifier may be a cellulose, such as low molecular weight, low viscosity types of hydroxypropylcellulose (e.g., grades such as METHOCEL E5, E6, E10 E15, LV100, etc.), higher molecular weight, medium to high viscosity hydroxypropylcellulose (e.g., METHOCEL K4M, K15M, K100M, etc.), polyvinylpyrrolidone (e.g., KOLLIDON, k17, K30, etc.), polyvinyl acetate, hydroxypropyl methylcellulose (HPMC), hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic acid), poly(methacrylic acid), polyvinylpyrrolidone (PVP) and crosslinked PVP polyvinyl alcohol (PVA), PVA / PVP copolymers and PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate, vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), carboxymethyl cellulose (CMC), carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, sodium starch glycolate, etc., or combinations thereof. Example 1

[0093] Example 1. Exemplary Oral HPC Compositions The following examples of oral HCP compositions are provided to facilitate a clearer understanding of certain embodiments of the methods of the present invention and are not intended to be limiting in any way. [Table 1]

[0094] Oral HPC compositions using current oral HPC methods can use additional tableting methods known in the art (e.g., powder encapsulation, melt extrusion, wet granulation, dry granulation, direct compression, spray coating, etc.). Carriers for oral HPC compositions using current methods can include at least one lipophilic and / or hydrophilic component additive. Lipophilic and hydrophilic additives that can be used in the compositions of the present method include absorbents, acids, adjuvants, anti-caking agents, anti-tacking agents, antifoaming agents, anticoagulants, antibacterial agents, antioxidants, antiseborrheic agents, astringents, preservatives, bases, binders, buffers, chelating agents, sequestering agents, cellulose, coagulation agents, coating agents, colorants, dyes, pigments, complexing agents, crystal growth regulators, denaturants, desiccants, dehydrating agents, diluents, disintegrants, dispersants, emollients, emulsifiers, encapsulating agents, enzymes, extenders, fillers, flavors, and the like. The pharmaceutical adjuvant may be selected from various classes of pharmaceutical adjuvants including, but not limited to, masking agents, flavoring agents, fragrances, gelling agents, lubricants, hardening agents, hardening agents, wetting agents, lubricants, humectants, pH adjusters, plasticizers, soothing agents, anti-inflammatory agents, retarders, spreading agents, stabilizers, suspending agents, sweetening agents, thickening agents, consistency modifiers, surfactants, opacifying agents, polymers, preservatives, anti-gelling agents, rheology modifiers, emollients, solubilizers; solvent tonics, viscosity modifiers, ultraviolet light absorbers, or combinations thereof.

[0095] The oral composition used in this method can be composed of HPC in crystalline form and carrier.The form of the drug can be exchanged with other forms such as micronized, sieved, crushed, amorphous, nano-sized, etc.The oral HPC dosage form can also be single or multiple particulate units in capsules, or single or multiple particulate units compressed as monolith / matrix tablets or multi-layer tablets. [Table 2] Example 2

[0096] Example 2. Comparison of the pharmacokinetics of an exemplary composition following oral administration to a prior art injectable intramuscular HPC composition To evaluate the safety, tolerability, and HPC concentrations following multiple doses of oral HPC, a clinical trial was conducted in pregnant women receiving three doses of 400 mg BID, 600 mg BID, and 800 mg BID of oral HPC composition 1B#.i shown in Table 1B, followed by 250 mg of injectable HPC (i.e., MAKENA) once weekly.

[0097] The primary objective of this study was to evaluate plasma HPC concentrations after three doses of the presently invented oral HPC composition and method compared to a commercially available injectable HPC (e.g., MAKENA) dose.

[0098] The study was an open-label, four-period, four-treatment, randomized, single- and repeat-dose, PK study in pregnant women of three dose levels of an oral HPC composition and an IM injectable HPC (MAKENA). Twelve healthy pregnant women approximately 16-19 weeks gestational age were enrolled in the study. Subjects received three dose levels of the oral HPC composition (400 mg BID, 600 mg BID, 800 mg BID) with meals in a randomized crossover fashion during the first three treatment periods, followed by five weekly injections of the IM injectable HPC (MAKENA) during the fourth treatment period.

[0099] During each HPC oral dosing period, subjects received a single dose of the oral composition on day 1, followed by twice daily doses on days 2 through 8. After the three-dose treatment period, followed by a washout period, all subjects received five weekly HPC injections.

[0100] During the study period, blood samples for pharmacokinetics were collected at the following times: Oral treatment Day 1: Blood samples were taken 0 hours after administration (before administration), 2, 4, 6, 8, 10, 12, 14, and 24 hours after administration. Day 7: Blood was taken at 0 hours (before administration) before the first dose of the 8th dose. th day Day 8: Blood samples are taken at 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, and 36 hours after AM administration. ·Injection treatment (MAKENA) Week 5: Blood samples taken at 0, 6, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after administration. [Table 3]

[0101] As shown in Table 2, the mean C obtained from the dosing regimen of the oral HPC composition max and C avg The levels were clearly different from those of the injectable IM HPC. In particular, the oral HPC dosing regimen of 800 mg BID significantly increased C avg was about three times higher. max The average T max The oral HPC dosing regimen (mean T max The circadian ratio (C) was significantly different between the IM HPC administration regimen (~4 to ~8 h) and the injectable IM HPC administration regimen (~27 h). max / C min ) When oral HPC and injectable IM HPC were administered once a week, oral HPC was more specific than injectable IM HPC. The range of variation ratios for oral HPC administration was about 6 to about 44, whereas the range for injectable HPC administration was 1.6 to 3.3.

[0102] Therefore, in another embodiment, the change ratio (C max / C min The diurnal variation profile, measured by the HPC variability profile (as shown in Table 2), is approximately 7-fold higher than that of injection therapy, compared to the weekly HPC variability profile, and may be essential to confer a favorable benefit to the risk profile of the oral treatment method of the present invention. Example 3

[0103] The time to reach steady state or predicted effective serum HPC concentrations after dosing was estimated from simulations using single dose PK parameters obtained from the clinical trial described in Example 2. The time to reach steady state or predicted effective HPC concentrations after dosing was estimated to be about 2 to 7 days for the oral HPC compositions and treatment methods of the present invention, versus the estimated 5 weeks required for injectable HPC. Thus, patients receiving oral HPC therapy disclosed herein will benefit from the faster attainment of predicted effective levels, versus the several weeks typically observed with currently available injectable therapy.

[0104] It should also be noted that, based on the results and associated simulations, treatment with the oral HPC methods and compositions of the present invention achieves steady-state / predicted effective HPC concentrations in patients over a longer treatment period compared to patients with injection therapy. For example, in the present invention, in both treatments, when treatment begins at 16 weeks of fetal gestation and ends at approximately 37 weeks (normal GA at delivery), the steady-state or predicted effective concentrations are maintained for a longer period of time, at least about 5-10 weeks, compared to currently approved injection treatments. This extended treatment period makes the treatment more effective in preventing PTB.

[0105] Additionally, for treatment with early intervention of exogenous progestins such as HPC against endogenous progesterone production during pregnancy, the oral HPC inventive methods disclosed herein are predicted to provide benefits of reduced PTB recurrence rates and improved NCI (reduced incidence) as predicted differences from placebo for oral HPC methods and compositions (Table 3). [Table 4]

[0106] Thus, in one embodiment, the current method of the invention involves early intervention with oral HPC starting at GA 14 or less than 18 weeks in a current pregnancy at risk for recurrent PTB in pregnant women at altered risk for PTB.

Example 4

[0107] Moreover, in pregnant women with PTB risk, it was surprisingly found that the improvement of NCI and the reduction of the PTB incidence rate before 35 weeks of gestation were associated with the early GA of previous PTB. Table 4 shows the predicted performance of the oral HPC method of the present invention regarding the results of NCI improvement and PTB incidence rate in patients with changed risks.

Table 5

[0108] As shown in Table 4, depending on the target-modified risk patient population based on eligible previous PTB, the oral HPC therapy method can reduce the incidence rate of PTB < 35 weeks of gestation by about 5% or more and expect an improvement in NCI (reduction in incidence rate) compared to the placebo-administered pregnant subject group with a similar modified risk based on eligible previous PTB.

[0109] The present invention can be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. Therefore, the scope of the present invention is shown not by the foregoing description but by the appended claims. All changes that come within the meaning and range of equivalency of the claims are embraced within their scope.

Claims

1. 1. A method of preventing or reducing the likelihood of recurrent PTB in a subject, the method comprising orally administering to the subject an oral dosage form having an effective amount of a pharmaceutical composition comprising a HPC, the subject comprising a pregnant subject; said administering results in a C min of HPC in said subject of about 4 ng / ml to about 16 ng / ml; the administering comprises a dosing regimen comprising at least one of once-daily dosing, twice-daily dosing, and three-times-daily dosing, and the dosing regimen provides a total daily dose of about 1,200 mg to about 1,600 mg of the HPC; and The method comprises: the administration regimen begins when the subject's fetal GA is at least one of 14 weeks or less, 15 weeks or less, 16 weeks or less, 17 weeks or less, and less than 18 weeks, and continues for at least one or more of 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, and 2 weeks postpartum; The subject has a qualifying PTB of less than at least one of 35 weeks, 34 weeks, 33 weeks, and 32 weeks; compared to the administration of a placebo, the administration of the HPC results in at least one of the following minimal improvements in neonatal overall NCI outcome in the subject: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%; The method includes at least one of the following:

2. 10. The method of claim 1, wherein the administration of the HPC, compared to the administration of a placebo, a reduction in the likelihood that said subject's newborn will die before discharge from the hospital; improvement in the subject's neonatal grade III or IV intraventricular hemorrhage; improvement in neonatal respiratory distress syndrome in said subject; amelioration of neonatal bronchopulmonary dysplasia in said subject; amelioration of necrotizing enterocolitis in the neonate of said subject; amelioration of documented sepsis in the neonate of said subject; A reduction of the subject's neonatal length of stay (LOS) in a medical care facility by at least 3 days; and a minimum response rate of at least one of 5%, 7%, 9%, 10%, 12%, 13%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50% of the subjects who deliver no earlier than at least one of 32 weeks, 35 weeks, and 37 weeks when the HPC is administered to a group of subjects; A method that brings about multiple results.

3. 10. The method of claim 1, wherein the administering comprises: the subject's C in the range of about 35 ng / ml to about 180 ng / ml ｍａｘ , C of the subject in the range of about 6 ng / ml to about 50 ng / ml ａｖｇ , an effective level of HPC in the subject for about 1 day to 1 week; T in the range of about 2 hours to about 12 hours after administration ｍａｘ , C of plasma HPC concentration in the subject on at least one of days 7, 6, 5, 4, 3, and 2. ａｖｇ Post-dose efficacy minimum threshold level (EMTL), and a minimum daily volatility of at least one of 6, 8, 10, 13, 15, 18, 20, 25, 30, 35, 40, and 44; The method of claim 1, wherein the method results in at least one of the following:

4. 10. The method of claim 1, wherein the subject has an altered risk of PTB and the oral dosage form comprises a solid oral dosage form.

5. 5. The method of claim 4, wherein the altered risk is determined to be due to the subject having at least one indicator of an altered risk of PTB; the subject has at least one PTB alteration risk-associated biomarker (PARABM); the subject has a qualifying PTB of less than at least one of 35 weeks, 34 weeks, 33 weeks, and 32 weeks; the subject has cervical insufficiency; the subject has previously undergone cervical cerclage; the subject is in need of a cervical cerclage; the subject has a history of substance abuse during pregnancy; the subject is unmarried and unpartnered, the subject has an education level of 12 years or less; the subject is of a predetermined age; the subject is of a predetermined race; the subject's fetus is male; at least one of the subject's previous fetus and the subject's current fetus is a singleton; and The method includes another MRF.

6. 6. The method of claim 5, wherein the eligible PTB includes at least one of PTB with a GA of less than 35 weeks and PTB with a GA of less than 32 weeks.

7. 6. The method of claim 5, wherein the method comprises identifying in the subject's DNA at least one PARABM comprising at least one minor allele of a biomarker in Table 1 of U.S. 9,840,738 having an OR greater than 1.

0.

8. A method as described in claim 7, wherein the method comprises a step of detecting whether the biomarkers of IBP4 and SHBG are present in a biological sample of the subject, the step comprising subjecting the sample to a proteomics workflow comprising mass spectrometry quantification.

9. 1. A method of preventing or reducing the likelihood of recurrent PTB in a subject, the method comprising orally administering to the subject an oral dosage form having an effective amount of a pharmaceutical composition comprising a HPC, wherein the administration of the HPC comprises: said administering results in a C min of HPC in said subject of about 4 ng / ml to about 16 ng / ml; The administering comprises a dosing regimen, the dosing regimen comprising at least one of once-daily dosing, twice-daily dosing, and three-times-daily dosing; and the dosing regimen comprises a total daily dose of about 1,200 mg to about 1,600 mg of HPC; and The method comprises: wherein the dosing regimen begins when the subject's fetal GA is at least one of 14 weeks or less, 15 weeks or less, 16 weeks or less, 17 weeks or less, and less than 18 weeks; the subject has a qualifying PTB of less than any one of 35 weeks, 34 weeks, 33 weeks, and 32 weeks; compared to the administration of a placebo, the administration of the HPC results in a minimal improvement of at least one of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50% in overall NCI outcomes in the neonate of the subject; and a reduction in the likelihood that said subject's newborn will die before discharge from the hospital; improvement in the subject's neonatal grade III or IV intraventricular hemorrhage; improvement in neonatal respiratory distress syndrome in said subject; amelioration of neonatal bronchopulmonary dysplasia in said subject; amelioration of necrotizing enterocolitis in the neonate of said subject; amelioration of documented sepsis in the neonate of said subject; A reduction of the subject's neonatal length of stay (LOS) in a medical care facility by at least 3 days; and a minimum response rate of at least one of 5%, 7%, 9%, 10%, 12%, 13%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50% of the subjects who deliver no earlier than at least one of 32 weeks, 35 weeks, and 37 weeks when the HPC is administered to a group of subjects; A method that brings about multiple results.

10. 10. The method of claim 9, wherein the subject comprises a pregnant subject, and the administration regimen begins when the GA of the subject's fetus is less than or equal to at least one of 14 weeks, 15 weeks, and 16 weeks, and continues for at least one or more of 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, and 2 weeks postpartum.

11. 10. The method of claim 9, wherein the administering comprises: the subject's C in the range of about 35 ng / ml to about 180 ng / ml ｍａｘ , C of the subject in the range of about 6 ng / ml to about 50 ng / ml ａｖｇ , an effective level of HPC in the subject in about 1 day to 1 week; T in the range of about 2 hours to about 12 hours after administration ｍａｘ , C of plasma HPC concentration in the subject on at least one of days 7, 6, 5, 4, 3, and 2. ａｖｇ Post-dose efficacy minimum threshold level (EMTL), and a minimum daily volatility of at least one of 6, 8, 10, 13, 15, 18, 20, 25, 30, 35, 40, and 44; The method of claim 1, wherein the method results in at least one of the following:

12. 10. The method of claim 9, wherein the subject has an altered risk of PTB and the oral dosage form is a solid oral dosage form.

13. 13. The method of claim 12, wherein the altered risk comprises the subject having at least one indicator of altered risk of PTB; the subject has at least one PTB alteration risk-associated biomarker (PARABM); the subject has a qualifying PTB of less than at least one of 35 weeks, 34 weeks, 33 weeks, and 32 weeks; the subject has cervical insufficiency; The subject had previously undergone cervical cerclage; the subject is in need of a cervical cerclage; The subject had a history of substance abuse during pregnancy; The subject is unmarried and has no partner. The subject's education level is 12 years or less; the subject is of a predetermined age; the subject is of a predetermined race; the subject's fetus is male; at least one of the subject's previous fetus and the subject's current fetus is a singleton; and The method includes another MRF.

14. 14. The method of claim 13, wherein the eligible PTB includes at least one of PTB of less than GA 35 weeks and less than GA 32 weeks.

15. 15. The method of claim 14, wherein the eligible PTB comprises an immediately preceding PTB.

16. 14. The method of claim 13, wherein the method comprises identifying in the subject's DNA at least one PARABM comprising at least one minor allele of a biomarker in Table 1 of U.S. 9,840,738 having an OR greater than 1.

0.

17. 17. The method of claim 16, wherein the method comprises detecting whether the biomarkers of IBP4 and SHBG are present in a biological sample of the subject, the detecting step comprising subjecting the sample to a proteomics workflow comprising mass spectrometry quantification.

18. 1. A method of preventing or reducing the likelihood of recurrent PTB in a subject, the method comprising orally administering to the subject an oral dosage form having an effective amount of a pharmaceutical composition comprising a HPC; said administering results in a C min of HPC in said subject of about 4 ng / ml to about 16 ng / ml; the administering comprises a dosing regimen, the dosing regimen comprising at least one of once-daily dosing, twice-daily dosing, and three-times-daily dosing; and the dosing regimen comprises a total daily dose of about 1,200 mg to about 1,600 mg of HPC; and The method comprises: the dosing regimen begins when the subject's fetal GA is at least one of 14 weeks or less, 15 weeks or less, 16 weeks or less, 17 weeks or less, and less than 18 weeks; the subject has a qualifying PTB of less than any one of 35 weeks, 34 weeks, 33 weeks, and 32 weeks; compared to the administration of a placebo, the administration of the HPC results in a minimal improvement of at least one of the following in the overall NCI outcome of the neonate in the subject: at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%; and The administering comprises administering: the subject's C in the range of about 35 ng / ml to about 180 ng / ml ｍａｘ , C of the subject in the range of about 6 ng / ml to about 50 ng / ml ａｖｇ , an effective level of HPC in the subject in about 1 day to 1 week; T in the range of about 2 hours to about 12 hours after administration ｍａｘ , C of plasma HPC concentration in the subject on at least one of days 7, 6, 5, 4, 3, and 2. ａｖｇ Post-dose efficacy minimum threshold level (EMTL), and a minimum daily volatility of at least one of 6, 8, 10, 13, 15, 18, 20, 25, 30, 35, 40, and 44; The method of claim 1, wherein the method results in at least one of the following:

19. 20. The method of claim 18, wherein the subject comprises a pregnant subject, and the administration regimen begins when the GA of the subject's fetus is less than or equal to at least one of 14 weeks, 15 weeks, and 16 weeks, and continues for at least one or more of 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, and 2 weeks postpartum.

20. 19. The method of claim 18, wherein the administration of the HPC, compared to administration of a placebo, is a reduction in the likelihood that said subject's newborn will die before discharge from the hospital; improvement in the subject's neonatal grade III or IV intraventricular hemorrhage; improvement in neonatal respiratory distress syndrome in said subject; amelioration of neonatal bronchopulmonary dysplasia in said subject; amelioration of necrotizing enterocolitis in the neonate of said subject; amelioration of documented sepsis in the neonate of said subject; A reduction of the subject's neonatal length of stay (LOS) in a medical care facility by at least 3 days; and a minimum response rate of at least one of 5%, 7%, 9%, 10%, 12%, 13%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50% of the subjects who deliver no earlier than at least one of 32 weeks, 35 weeks, and 37 weeks when the HPC is administered to a group of subjects; A method that brings about multiple results.

21. 20. The method of claim 18, wherein the subject has an altered risk of recurrent PTB and the oral dosage form is a solid oral dosage form.

22. 22. The method of claim 21, wherein the altered risk comprises the subject having at least one indicator of altered risk of PTB; the subject has at least one PTB alteration risk-associated biomarker (PARABM); the subject has a qualifying PTB of less than at least one of 35 weeks, 34 weeks, 33 weeks, and 32 weeks; the subject has cervical insufficiency; The subject had previously undergone cervical cerclage; the subject is in need of a cervical cerclage; The subject had a history of substance abuse during pregnancy; The subject was unmarried and had no partner. The subject's education level is 12 years or less; the subject is of a predetermined age; the subject is of a predetermined race; the subject's fetus is male; at least one of the subject's previous fetus and the subject's current fetus is a singleton; and The method includes another MRF.

23. 23. The method of claim 22, wherein the eligible PTB includes at least one of PTB of less than GA 35 weeks and less than GA 32 weeks.

24. 24. The method of claim 23, wherein the eligible PTB comprises an immediately preceding PTB.

25. 23. The method of claim 22, wherein the method comprises identifying in the subject's DNA at least one PARABM comprising at least one minor allele of a biomarker in Table 1 of U.S. 9,840,738 having an OR greater than 1.

0.

26. A method according to claim 25, wherein the method comprises a step of detecting whether the biomarkers of IBP4 and SHBG are present in a biological sample of the subject, the detecting step comprising subjecting the sample to a proteomics workflow comprising mass spectrometry quantification.

27. 1. A method of preventing or reducing the likelihood of recurrent PTB in a subject, the method comprising orally administering to the subject an oral dosage form having an effective amount of a pharmaceutical composition comprising a HPC; said administering results in a C min of HPC in said subject of about 4 ng / ml to about 16 ng / ml; the administering comprises a dosing regimen, the dosing regimen comprising at least one of once-daily dosing, twice-daily dosing, and three-times-daily dosing; and the dosing regimen comprises a total daily dose of about 1,200 mg to about 1,600 mg of HPC; and The method comprises: the dosing regimen begins when the subject's fetal GA is at least one of 14 weeks or less, 15 weeks or less, 16 weeks or less, 17 weeks or less, and less than 18 weeks; the subject has a qualifying PTB of less than any one of 35 weeks, 34 weeks, 33 weeks, and 32 weeks; compared to the administration of a placebo, the administration of the HPC results in a minimal improvement of at least one of the following: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50% in the overall NCI outcome of the neonate of the subject; and wherein the subject has an altered risk of PTB.

28. 28. The method of claim 27, wherein the altered risk comprises the subject having at least one indicator of altered risk of PTB; the subject has at least one PTB alteration risk-associated biomarker (PARABM); the subject has a qualifying PTB of less than at least one of 35 weeks, 34 weeks, 33 weeks, and 32 weeks; the subject has cervical insufficiency; The subject had previously undergone cervical cerclage; the subject is in need of a cervical cerclage; The subject had a history of substance abuse during pregnancy; The subject was unmarried and had no partner. The subject's education level is 12 years or less; the subject is of a predetermined age; the subject is of a predetermined race; the subject's fetus is male; at least one of the subject's previous fetus and the subject's current fetus is a singleton; and The method includes another MRF.

29. 29. The method of claim 28, wherein the eligible PTB includes at least one of PTB of less than GA 35 weeks and less than GA 32 weeks.

30. 30. The method of claim 29, wherein the qualified PTB comprises an immediately preceding PTB and the oral dosage form is a solid oral dosage form.

31. 30. The method of claim 28, wherein the method comprises identifying in the subject's DNA at least one PARABM comprising at least one minor allele of a biomarker in Table 1 of U.S. 9,840,738 having an OR greater than 1.

0.

32. A method according to claim 31, wherein the method comprises a step of detecting whether the biomarkers of IBP4 and SHBG are present in a biological sample of the subject, the detecting step comprising subjecting the sample to a proteomics workflow comprising mass spectrometry quantification.

33. 33. The method of claim 32, wherein the subject comprises a pregnant subject, and wherein the dosing regimen begins when the GA of the subject's fetus is less than or equal to at least one of 14 weeks, 15 weeks, and 16 weeks, and continues for at least one or more of 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, and 2 weeks postpartum.

34. 28. The method of claim 27, wherein the administration of the HPC, compared to administration of a placebo, is a reduction in the likelihood that said subject's newborn will die before discharge from the hospital; improvement in the subject's neonatal grade III or IV intraventricular hemorrhage; improvement in neonatal respiratory distress syndrome in said subject; amelioration of neonatal bronchopulmonary dysplasia in said subject; amelioration of necrotizing enterocolitis in the neonate of said subject; amelioration of documented sepsis in the neonate of said subject; A reduction of the subject's neonatal length of stay (LOS) in a medical care facility by at least 3 days; and a minimum response rate of at least one of 5%, 7%, 9%, 10%, 12%, 13%, 15%, 20%, 25%, 30%, 35%, 40%, and 45%, and 50% of the subjects who deliver no earlier than at least one of 32 weeks, 35 weeks, and 37 weeks when the HPC is administered to a group of subjects; The method of claim 1, wherein the method results in at least one of the following:

35. 28. The method of claim 27, wherein the administering comprises: the subject's C in the range of about 35 ng / ml to about 180 ng / ml ｍａｘ , C of the subject in the range of about 6 ng / ml to about 50 ng / ml ａｖｇ , an effective level of HPC in the subject in about 1 day to 1 week; T in the range of about 2 hours to about 12 hours after administration ｍａｘ , C of plasma HPC concentration in the subject on at least one of days 7, 6, 5, 4, 3, and 2. ａｖｇ Post-dose efficacy minimum threshold level (EMTL), and a minimum daily volatility of at least one of 6, 8, 10, 13, 15, 18, 20, 25, 30, 35, 40, and 44; The method of claim 1, wherein the method results in at least one of the following:

36. The method of claim 6, wherein the eligible PTB includes the immediately preceding PTB.