Compositions and methods for treatment of postpartum hemorrhage

Abstract

The present disclosure relates to pharmaceutical formulations comprising uterotonic prostaglandins for use in treatment of postpartum hemorrhage. In particular, the disclosure relates to one or more topically administered formulations in solid, liquid, or semi-solid dosage forms comprising nano-structured carriers and uterotonic prostaglandins and / or acceptable salts thereof, providing alternative routes of administration.

Description

Attorney Docket no.: 1880P0117PCTCOMPOSITIONS AND METHODS FOR TREATMENT OF POSTPARTUM HEMORRHAGEFIELD OF THE INVENTION

[0001] The present disclosure pertains to treatment of postpartum hemorrhage due to uterine atony.BACKGROUND

[0002] Postpartum hemorrhage (PPH), the most common form of major obstetric hemorrhage is defined as the loss of one liter (1,000 cc or more) of blood during obstetrical delivery. Postpartum hemorrhage remains a leading cause of maternal morbidity and mortality worldwide, even in high-income countries [1-2], Postpartum hemorrhage results from various causes, especially uterine atony [3], Importantly, postpartum hemorrhage can occur following a vaginal delivery or with delivery by a cesarean section. As with most medical problems, prevention is usually the first priority, followed by treatment if prevention has not been successful. In developed countries clinical practice of postpartum hemorrhage prevention involves a group of interventions known as active management of the third stage of labor [4], This approach commonly includes prophylactic injection of 5 or 10 international units of oxytocin after delivery of the anterior shoulder in vaginal births or immediately after birth in cesarean deliveries, early clamping of the umbilical cord, and controlled cord traction. Evidence indicates that routine active management of the third stage of labor is effective in reducing the risk of postpartum hemorrhage [5], This approach is largely dependent on the delivery occurring in a hospital or other healthcare facility equipped with personnel and medical resources to implement active management of the third stage of labor. The percentage of babies bom in hospitals varies by region, with some regions having nearly all births taking place in health facilities, while others have much lower rates: Eastern Europe and Central Asia: 98% of births occur in health facilities; in East Asia and the Pacific: 89% of births occur in health facilities; while the lowest rates are in Central, Eastern or Southern Africa where less than 65% of births occur in health facilities.

[0003] The management of PPH relies on physical and medicinal means. Oxytocin is the first-choice agent to stop PPH; a result of its high efficacy and low incidence of adverse effects [7], Oxytocin is a bioactive peptide that induces uterine contractions (i.e., uterotonic action) it isAttorney Docket no.: 1880P0117PCTformulated as a liquid injectable dose form. Oxytocin has a short half-life of 3-5 minutes, when used as an intravenous infusion to maintain uterine contraction. When used intramuscularly, the latent phase lasts 2-5 minutes, but the uterine activity can last 2-3 hours [8], Carbetocin is a newer long-acting synthetic analogue of oxytocin with agonist properties but is not widely available. Neither oxytocin nor Carbetocin can be used orally. They also cannot be given intravenously as a large bolus dose because they cause severe hypotension [9], In addition, because each of these is a labile peptide, it must be stored in refrigerated conditions, therefore limiting its availability in low resource areas.

[0004] Some prostaglandins also have uterotonic effects and have been used in obstetric practice for the prevention and especially the treatment of postpartum hemorrhage

[0010] , Clinically the uterotonic effects of certain natural prostaglandins and synthetic prostaglandin analogues are greater than that of oxytocin and are not susceptible to oxytocin-induced desensitization of myometrium that occurs when oxytocin and its synthetic analogue(s) are used as a uterotonic when parturition has been induced with oxytocin.

[0005] However, at the current time there exists several barriers to the effective clinical use of uterotonic prostaglandins for treatment of PPH. Firstly, in the United States, many uterotonic prostaglandins are not approved by the FDA for use in treating PPH. For example, the use of misoprostol for prevention and treatment of post-partum haemorrhage has been described

[0011] , However, misoprostol has only been approved by the FDA to decrease the risk of having stomach ulcers in patients taking nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin. Misoprostol, as it is currently dosed and formulated, is for oral intake with absorption in the gastrointestinal tract. Secondly, because it is not approved as a uterotonic agent for treatment of PPH the currently FDA approved dosage, dose form, and route of administration is inappropriate for treatment of PPH. The treatment of PPH with uterotonic agents, including uterotonic prostaglandins, requires rapid and sustained bioavailability. In emergent situations, it is preferred that the uterotonic drug has immediate bioavailability and sustained uterotonic activity. These effects cannot be reliability achieved using formulations that were designed to be absorbed in the gastro-intestinal tract.Attorney Docket no.: 1880P0117PCT

[0006] Another, barrier to use of uterotonic prostaglandins, especially in low resource and underdeveloped regions or when delivery is occurring in remote areas, is that uterotonic prostaglandins are unstable. Uterotonic prostaglandins tend to decompose at or above room temperature and / or in the presence of low or high pH conditions and / or in the presence of water. Indeed, in a recent study, significant percentages of degraded uterotonic prostaglandin preparations were detected in several commercial products

[0012] ,

[0007] Thus, there is an important need to provide better formulations of uterotonic prostaglandins and better methods for administration of uterotonic prostaglandin analogues specifically for the treatment of postpartum hemorrhage or bleeding caused by uterine atony.SUMMARY

[0008] The compositions and methods of the current disclosure provide for novel nano-carrier formulations and pharmaceutical compositions of uterotonic prostaglandins in either liquid, semisolid, or solid dose forms that can be directly administered topically onto the mucous membranes of the mouth, vagina, or rectum of a human subject in need of treatment of postpartum hemorrhage due to uterine atony.BRIEF DISCRIPTION OF THE DRAWINGS

[0009] Figure 1 shows the pharmacokinetic data of equivalent doses of sublingual dose in a nanostructured carrier formulation from Example 1 in comparison to a single intramuscular injection dose of commercial (Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]but-l-enyl]cyclopentyl]hept-5-enoic acid (carboprost). The Sublingual dose achieves a higher plasma level in a shorter time.

[0010] Figure 2 shows the pharmacokinetic data of equivalent doses of 7-[(lR,2R,3R)-3-hydroxy-2-[(E)-4-hydroxy-4-methyloct-l-enyl]-5-oxocyclopentyl]heptanoic acid (misoprostol) in the commercially available tablet form in comparison with the compound formulated as a SNEDD from Example 2 when administered sublingually to a test subject. The SNEDD dose form achieves a higher plasma level in a shorter time.Attorney Docket no.: 1880P0117PCT[Oi l] Figure 3 shows the faster drug release of a 200 mcg dose from the nano-structured carrier rapid release dose form from Example 2 in comparison to the 200 mcg dose in a standard commercial tablet of 7-[(lR,2R,3R)-3-hydroxy-2-[(E)-4-hydroxy-4-methyloct-l-enyl]-5-oxocyclopentyl]heptanoic acid (misoprostol) in 2 ml of human saliva.DETAILED DESCRIPTION

[0012] The inventors have discovered that there is improved bioavailability, faster dissolution in mucosal fluids, and faster absorption into the circulatory system by administration of uterotonic prostaglandins according to Formula 1 as formulated in specific mucosal nano-material carrier dose forms disclosed herein. The formulations can be in solid, liquid, and semi-liquid dose forms, and enable non-gastrointestinal, direct trans-mucosal absorption when topically applied to mucosa of the mouth, vagina, or rectum. Use of the formulations and dose form described herein results in more rapid absorption and higher plasma concentrations of the prostaglandins according to Formula 1 than other existing dose forms and improved biological availability of the prostaglandins according to Formula 1, than when given topically, intramuscularly or when administered as oral tablet without the specific nano-material carrier formulations disclosed herein.Formula 1wherein R1 is selected from COOH, COO-straight or branched chain alkyl, B(OH)2, B(ORio)(ORn) or N-methylsulfonylformamide;

[0013] Rio and Rn, if present, are independently selected from optionally substituted alkyl, cycloalkyl, alkylcycloalkyl, and / or when Rio and Rn are present and adjacent to each other can together form an alkyl bridged 5 or 6 membered heterocyclic ring;

[0014] R2 is hydrogen; hydroxyl, methyl, oxygen, or fluorine;Attorney Docket no.: 1880P0117PCT

[0015] R3 is hydrogen, hydroxyl, methyl, oxygen, or fluorine;

[0016] R4 is hydrogen, hydroxyl, methyl, oxygen, or fluorine;

[0017] R5 is hydrogen, hydroxyl, methyl, oxygen, or fluorine;

[0018] R6 is straight or branched chain alkyl of 1 to 8 carbon atoms, inclusive, vinyl (-CH=CH2), cycloalkyl group containing 3 to 6 carbon atoms, phenyl, phenoxy, O-optionally substituted aryl, O-optionally substituted straight or branched chain alkyl of 1-8 carbons,

[0019] wherein a dashed line parallel to a solid line between two atoms indicates an optional double bond at that position,

[0020] wherein a hydrogen, several hydrogens or all hydrogens may be replaced with deuterium or, if appropriate, the compound is a pharmaceutically acceptable salt, ester, or prodrug form thereof.

[0021] The inventors have also found that the specific formulations disclosed unexpectedly also act to stabilize uterotonic prostaglandins.

[0022] Compounds embodied by Formula 1 may have one or more asymmetric centers and therefore can exist in different stereoisomeric configurations. Consequently, the compounds of Formula 1 can occur as individual (pure) enantiomers, individual pure enantiomeric diastereomers as well as a mixture of enantiomers or diastereomers. The scope of the present disclosure includes both single enantiomers and mixtures thereof in all ratios. The scope of the present disclosure further includes all tautomeric forms ("tautomers") of the compounds of Formula 1, and all mixtures thereof in any ratio. It will be appreciated by one skilled in the art that a single compound may exhibit more than one type of isomerism.Attorney Docket no.: 1880P0117PCT

[0023] The compositions described herein can be used in a human subject for the treatment of postpartum hemorrhage due to uterine atony. Furthermore, the compositions described can be combined with any additional pharmaceutically acceptable carriers or adjuvants as may be necessary and incorporated into medicaments. Such procedures and ingredients are known to the person of skill in the art.

[0024] Preferred compounds according to formula 1 include: 7-[(lR,2R,3R)-3-hydroxy-2-[(E)-4-hydroxy-4-methyloct-l-enyl]-5-oxocyclopentyl]heptanoic acid [misoprostol acid]; (Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]but-l-enyl]cyclopentyl]hept-5-enoic acid; (Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-3-methyloct-l-enyl]cyclopentyl]hept-5-enoic acid; (Z)-7-[(lR,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-l-enyl]-5-oxocyclopentyl]hept-5-enoic acid; and (Z)-7-[(lR,2R,3R)-3-hydroxy-2-[(E,3R)-3-hydroxy-4-phenoxybut-l-enyl]-5-oxocyclopentyl]-N-methylsulfonylhept-5-enamide, each of which are in any of their various racemic, enantiomers, individual pure enantiomeric diastereomers as well as mixtures of enantiomers or diastereomers. The scope of the present disclosure includes both single enantiomers and mixtures thereof in all ratios and tautomeric forms, all of which can be in pharmacological acceptable salt forms.

[0025] In a preferred aspect of the present disclosure there is a stable liquid dose formulation for topical trans-mucosal absorption comprised of a uterotonic prostaglandin and a nanomaterial, a stabilizing compound, and a compound that enables muco-adherent or muco-penetrant properties. The liquid dose formulation can be directly applied to the mucosa of the oral cavity, rectal or vaginal canals of the human subject in need thereof. Examples of muco-adherent compounds include, but are not limited to, chitosan, xanthum gums, sodium carboxymethylcelluose, hydroxypropylmethylcelluose, Carbopol, thiolated hyaluronic acid and polylactic acid. Nonlimiting examples for muco-penetrants include, but are not limited to; polyethylene glycol, chitosan derivatives, glucuronic acid, and hexuronic acids.

[0026] In another aspect of the present disclosure there is a stable solid dose formulation for topical trans-mucosal absorption comprised of a uterotonic prostaglandin and a nanomaterial, a stabilizing compound, and compounds that enable muco-adherent or muco-penetrant properties that can beAttorney Docket no.: 1880P0117PCTdirectly applied to the mucosa of the oral cavity, rectal or vaginal canals of the human subject in need thereof.

[0027] In another preferred aspect of the present disclosure the stable solid dose formulation for topical trans-mucosal absorption is in a rapidly dissolving dose form comprised of a uterotonic prostaglandin and a nanomaterial, a stabilizing compound, compounds that enable muco-adherent or muco-penetrant properties, and pharmacologically acceptable compounds that promote rapid disintegration of the solid form that can be directly applied to the mucosa of the oral cavity, rectal or vaginal canals of the human subject in need thereof.

[0028] A preferred aspect of the present disclosure is that the uterotonic prostaglandin is complexed with a suitable nanomaterial to enhance pharmacological properties such as, but not limited to, stability, solubility, mucosal penetration, and / or mucosal adherence.

[0029] In another preferred aspect of the present disclosure the uterotonic prostaglandin is covalently bonded to another suitable chemical entity to enhance pharmacological properties such as, but not limited to, stability, solubility, mucosal penetration, and / or mucosal adherence.

[0030] In another aspect of the present disclosure there is a stable semi-liquid dose formulation for topical trans-mucosal absorption form, comprised of a uterotonic prostaglandin with a suitable nanomaterial.

[0031] In yet another aspect of the present disclosure there is a stable composition of a uterotonic agent that is complexed within the structure of a nanomaterial or nanoparticle which is muco-adherent.

[0032] In a further aspect of the present disclosure there is a stable composition of a uterotonic agent covalently linked to a cyclodextrin moiety.

[0033] In a preferred aspect of the present disclosure the uterotonic prostaglandin is present at dose of 1 pg to 2 mg per unit dose form.Attorney Docket no.: 1880P0117PCT

[0034] In a further aspect the topical trans-mucosal absorption dose form is comprised of a uterotonic prostaglandin along with another uterotonic chemical entity.

[0035] In an aspect of the present disclosure, liquids such as, but not limited to, liquid emulsions and ionic liquids, or semi-solid dosage forms such as, but not limited to, gels and foams are used for rectal drug delivery of the uterotonic drug composition and formulations. A preferred aspect is a dose form in an applicator device that is pre-fdled with the drug formulation prior to dose administration.

[0036] In an aspect of the present disclosure a specific rectal delivery device is described for the purpose of delivering a uterotonic agent to the rectum for the purposes such as, but not limited to, induction of uterine contractions and treatment of postpartum hemorrhage. The rectal delivery device can be either pre-filled with the liquid or semi-solid dose form or may be filled directly at the time of use.

[0037] In a preferred aspect of the present disclosure the semi-solid dosage forms such as, but limited to, gels and foams, and the liquid dose forms such as, but not limited to, emulsions, nanoemulsions, and ionic liquids also have muco-(adherent) (penetrant) properties.

[0038] The compositions according to the present disclosure can be packaged in a kit. The kit can be a dosage unit kit containing a single dose or a plurality of doses of a formulation disclosed herein in a suitable container. The kit may include instructions for use. The kit may enable mixing of the components at time of use of the formulations disclosed herein. The components of the formulation may be contained in separate compartments of a single container or in separate containers. The kit may also contain pre-mixed components of the formulations disclosed herein.

[0039] In certain aspects, the formulation may be placed in a sealed container such as a glass or plastic vial or a bottle or be encompassed in a unit dose delivery device such as, but not limited to, a syringe, pressurized delivery device, a single use vial, or other suitable medically acceptable container for topical application.Attorney Docket no.: 1880P0117PCT

[0040] In certain aspects, the kit may contain one or more containers for dry components and one or more containers for liquid components, which are mixed together to form a formulation disclosed herein before administration to a subject in need thereof.

[0041] In certain aspects, the kit may contain a self-emulsifying composition as described herein alone or to be used in combination with other components in other formulation states as disclosed herein.

[0042] The kits are generally designed and adapted for topical use, on a mucosal tissue such as, but not limited to, the sublingual mucosa, rectal, and / or vaginal mucosa. They may contain one or more delivery vehicles or devices specific for the approach of administration such as, but not limited to, a spray bottle or syringe for sublingual, vaginal and / or rectal administration, or a solid dose form such as a tablet, or a semi-sloid dose form such as a gel. The formulations or selfemulsifying compositions may be placed in the delivery vehicles or devices from the manufacturer or added to the delivery vehicles or devices before administration to a subject in need thereof.

[0043] A non-limiting exemplary kit includes a formulation disclosed herein, which contains one or more dosages of between about lOupg to 2000pg of the therapeutic agent, such as 7-[(lR,2R,3R)-3-hydroxy-2-[(E)-4-hydroxy-4-methyloct-l-enyl]-5-oxocyclopentyl]heptanoic acid, a derivative or analogue thereof alone or in combination with other uterotonic agents including a pharmaceutically acceptable salt of the derivative or analogue thereof. The kit may also include instructions for administering a single dose of the therapeutic agent.Definitions

[0044] Definitions of specific functional groups and chemical terms are described in more detail below. As used herein, the chemical elements are identified in accordance with thePeriodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books,Attorney Docket no.: 1880P0117PCTSausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0045] "Acyl" or "carbonyl" refers to the group -C(O)R wherein R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycly- lalkyl, any of which may be optionally substituted, e.g., with one or more substituents. For example, when R is alkyl, such a group may be referred to as an alkylcarbonyl group.

[0046] "Alkoxy" refers to the group -O-R wherein R is alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl, any of which may be optionally substituted, e.g., with one or more substituents.

[0047] "Alkyl" refers to a saturated aliphatic hydrocarbon chain, which may be straight or branched. An alkyl group may have an indicated number of carbon atoms. For example, C1-C12 alkyl refers to an alkyl group having from 1 to 12 (inclusive) carbon atoms. C1-C4 alkyl refers to an alkyl group having 1, 2, 3 or 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl. An alkyl group may be optionally substituted, e g., with one or more substituents.

[0048] "Alkylene" refers to a divalent alkyl group, e.g., -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH(CH3)CH2-.

[0049] An alkyl or alkylene may be optionally substituted, e.g., with one or more substituents.

[0050] "Alkenyl" refers to a straight or branched hydrocarbon chain having one or more double bonds. An alkenyl group may have an indicated number of carbon atoms. For example, C2-C12 alkenyl refers to an alkenyl group having from 2 to 12 (inclusive) carbon atoms. C2-C4 alkenyl refers to an alkenyl group having 2, 3 or 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the doubleAttorney Docket no.: 1880P0117PCTbond carbons may optionally be the point of attachment of the alkenyl substituent. An alkenyl may be optionally substituted, e.g., with one or more substituents.

[0051] "Alkenylene" refers to a divalent alkenyl, e.g., -CH=CH-, -CH=CH2CH2- or - CH=C=CH-. An alkenylene may be optionally substituted, e.g., with one or more substituents.

[0052] "Alkynyl" refers to a straight or branched hydrocarbon chain having one or more triple bonds. An alkynyl group may have an indicated number of carbon atoms. For example, C2-C12 alkynyl refers to an alkynyl group having from 2 to 12 (inclusive) carbon atoms. C2-C4 alkynyl refers to an alkynyl group having 2, 3 or 4 carbon atoms. Examples of alkynyl groups include, but are not limited to; ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.

[0053] "Alkynylene" refers to a divalent alkynyl, e.g., -C=C- or -C=C-CH2-. An alkynylene may be optionally substituted with one or more substituents.

[0054] "Amino" refers to the group -NR’R" wherein R’ and R" are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl, or R’ and R", together with the nitrogen to which they are attached, may form a ring. Examples of amino groups include, but are not limited to, -NH2, alkylamino groups such as -NHCH3, - NHCH2CH3 and -NH-CH(CH3)2, dialkylamino groups such asN(CH3)2 and -N(CH2CH3)2, and arylamino groups such as -NFIPh. Examples of cyclic amino groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, perhydrodiazepinyl, morpholino, and thiomorpholino. The groups R’ and R" may be optionally substituted, e.g., with one or more substituents, or when R’ and R" together with the nitrogen to which they are attached form a ring, the ring may be optionally substituted, e.g., with one or more substituents.

[0055] "Aryl" refers to an aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system, wherein any ring atom capable of substitution can be substituted (e.g., with one or more substituents). The substituents may be positioned at various locations on an aryl group. ForAttorney Docket no.: 1880P0117PCTexample, substituents on a phenyl group may be located at an ortho-position, a meta- position, the para- position, or combinations thereof. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

[0056] "Arylalkyl" refers to an alkyl group in which an alkyl hydrogen atom is replaced with an aryl group. Arylalkyl includes groups in which more than one hydrogen atom has been replaced with an aryl group. Examples of arylalkyl groups include but are not limited to benzyl, 2-phenylethyl, 3 -phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups. Arylalkyl groups can be optionally substituted, e.g., with one or more substituents on either the alkyl portion or the aryl portion of the arylalkyl group.

[0057] "Aryloxy" refers to the group -O-R wherein R is aryl or heteroaryl, either of which may be optionally substituted, e g., with one or more substituents.

[0058] "Carboxyl" refers to the group -C(=O)OR, wherein R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl any of which may be optionally substituted, e.g., with one or more substituents.

[0059] "Carbonylamino" or "amido" refers to the group -C(O)NR’R" wherein R’ and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl, or R’ and R" together with the nitrogen to which they are attached, may form a ring. The groups R’ and R" may be optionally substituted, e g., with one or more substituents, or when R’ and R" together with the nitrogen to which they are attached form a ring, the ring may be optionally substituted, e.g., with one or more substituents.

[0060] "Cycloalkyl" refers to nonaromatic, saturated or partially unsaturated monocyclic, bicyclic, tricyclic or polycyclic hydrocarbon groups. Cycloalkyl groups may include about 3 to about 12 carbon atoms. For example, monocyclic cycloalkyl groups may include 3 to 10 carbon atoms, e.g., 3, 4, 5, 6, 7 or 8 carbon atoms. Bicyclic carbocyclic groups contain 8 to 12 carbon atoms, e g., 9Attorney Docket no.: 1880P0117PCTor 10 carbon atoms. Any ring atom can be substituted (e.g., with one or more substituents). Cycloalkyl groups include fused, spiro, and bridged bicyclic ring systems. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, methylcyclohexyl, adamantyl, norbornyl and norbomenyl.

[0061] "Cycloalkylalkyl", as used herein, refers to an alkyl group substituted with a cycloalkyl group. A cycloalkylalkyl is a radical with the formula -R,Ra, where R is an alkyl radical and Ro. is a cycloalkyl radical. The term includes alkyl groups where a carbon or hydrogen bond of an alkyl group is replaced.

[0062] “Alkylcycloalkyl”, as used herein, is a term used in chemistry to describe a cycloalkyl radical that is linked to an alkyl radical. For example, C4-10 (alkylcycloalkyl) refers to a cycloalkyl radical with three to seven carbon atoms that is linked to an alkyl radical.

[0063] "Excipient" refers to physiologically compatible additives useful in preparation of a pharmaceutical composition. Examples of pharmaceutically acceptable carriers and excipients can, for example, be found in Remington Pharmaceutical Science, 16th Ed.

[0064] "Haloalkyl" as used herein refers to an alkyl group in which one or more hydrogen atoms are replaced with a halogen, and includes alkyl moieties in which all hydrogens have been replaced with halogens (e g., perfluoroalkyl such as CF3).

[0065] "Halogen" or "halo" refers to fluoro, chloro, bromo or iodo moieties.

[0066] "Heteroalkyl" refers to an alkyl group, as defined herein, wherein at least one carbon atom of the alkyl group is replaced with a heteroatom. Suitable heteroalkyl groups include, but are not limited to, methoxymethyl (-CH2-O-CH3).

[0067] "Heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic or tricyclic ring having one or more heteroatoms. For example, a heteroaryl group may be an aromatic 5-8 membered monocyclic ring having 1-4 heteroatoms, an 8-12 membered bicyclic ring having 1-6 heteroatoms, or an 11-14 membered tricyclic ring system having 1-9 heteroatoms. HeteroarylAttorney Docket no.: 1880P0117PCTgroups can contain fused rings, which are rings that share one or more common atoms. Any ring atom capable of substitution can be substituted (e g., with one or more substituents). Examples of heteroaryl groups include, but are not limited to, tetrazoylyl, triazolyl, thienyl, thiazolyl, isothiazolyl, purinyl, pyrimidyl, pyridyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, furanyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, isoindolyl, indolizinyl, indazolyl, benzimidazolyl, phthalazinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl and naphthyridinyl.

[0068] The term "heteroaryl alkyl", as used herein, refers to an alkyl group substituted with a heteroaryl group. "Heteroatom" refers to an atom other than carbon in the ring of a heterocyclic group or a heteroaromatic group or the chain of a heteroalkyl group. For example, heteroatoms may be selected from the group consisting of nitrogen, oxygen, silicon, phosphorus and sulfur. Particularly suitable heteroatoms are nitrogen, oxygen and sulfur. Groups containing more than one heteroatom may contain different heteroatoms.

[0069] "Heterocyclyl" or "heterocycloalkyl" refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring system containing at least one heteroatom. Heterocyclyl groups may include about 3 to about 12 member atoms.

[0070] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0071] "Mercapto" or "thiol" refers to an -SH radical. The term "thioalkoxy" or "thioether" refers to an -S-alkyl radical. The term "thioaryloxy" refers to an -S-aryl radical.

[0072] "Oxo" refers to an oxygen atom, which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.

[0073] "Phosphonate" refers to -P(O)(OR)2, wherein each R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroaryl alkyl and heterocyclylalkyl, each of which may be optionally substituted with one or more substituents.Attorney Docket no.: 1880P0117PCT

[0074] "Ring" means a collection of member atoms that are cyclic. Rings may be carbocyclic, aromatic, or heterocyclic or heteroaromatic, and may be substituted or unsubstituted, and may be saturated or unsaturated. Ring junctions with the main chain may be fused or spirocyclic. Rings may be monocyclic or bicyclic. Rings contain at least 3 member atoms and at most 12 member atoms. Monocyclic rings may contain 3 to 10 member atoms and bicyclic rings may contain from 8 to 12 member atoms. Bicyclic rings themselves may be fused or spirocyclic. Rings may be optionally substituted or unsubstituted, e.g., with one or more substituents.

[0075] "Substituent" refers to a group "substituted" on a group such as an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, at any substitutable atom of that group. Suitable substituents include, without limitation: acyl, alkoxy, alkyl, alkenyl, alkynyl, amino, aryl, arylalkyl, carbonylamino, carboxy, cycloalkyl, cycloalkylalkyl, cyano, halo, haloalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, nitro, oxo (e.g., C=O), phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamide, thioamido, thiol, thioalkyl, thioxo (e.g., C=S), and ureido. Substituents on a group are independently any one single, or any combination of the aforementioned substituents. A substituent may itself be substituted with any one of the above substituents. Substituents may be abbreviated herein, for example, the abbreviations Me, Et, Ph, Bn and Ac represent methyl, ethyl, phenyl, benzyl and acetyl respectively. A more comprehensive list of the abbreviations used by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.

[0076] "Sulfinyl" refers to a -S(=O)R group, wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl, any of which may be optionally substituted with one or more substituents.

[0077] "Sulfonic acid" and "sulfonate" refer to -S(O)2OH and -S(O)2O- groups respectivelyAttorney Docket no.: 1880P0117PCT

[0078] "Sulfonyl" refers to a -S(O)2R group, wherein R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl, any of which may be optionally substituted with one or more substituents.

[0079] "Sulfonamido" refers to a -S(O)2NR’R" group wherein R’ and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroaryl alkyl and heterocyclylalkyl, any of which may be optionally substituted with one or more substituents.

[0080] "Thioalkyl" refers to the group -S-alkyl.

[0081] "Thioamido" refers to -C(S)NR’R" wherein R’ and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl, or R’ and R", together with the nitrogen to which they are attached, may form a ring. The groups R’ and R" may be optionally substituted, e.g., with one or more substituents, or when R’ and R" together with the nitrogen to which they are attached form a ring, the ring may be optionally substituted with one or more substituents.

[0082] "Thioxo" refers to a sulfur atom, which forms a thiocarbonyl when attached to carbon.

[0083] "Ureido" refers to -N(R)C(0)NR’R", wherein each R, R’ and R" is independently selected from the group consisting selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl, any of which may be optionally substituted with one or more substituents.

[0084] As used herein, the terms “treating and treatment” refers to mitigating, improving, relieving, ameliorating, or alleviating at least one sign or symptom (such as bleeding from the uterus ) of a condition, disease, or disorder in a human subject, or the improvement of an ascertainable measurement associated with a condition, disease, or disorder.Attorney Docket no.: 1880P0117PCT

[0085] As used herein, the term "complex” refers to the intermolecular co-association of chemical compounds, elements, or molecular structures by non-covalent bond interactions between two or more chemical compounds, elements, or molecular structures. Similarly, as used herein, the term “complexation” is the process of formation of a complex. Non-limiting examples of a complex are; inclusion complexes, ionic complexes, resin complexes, clathrates, and pharmacosomes.

[0086] As used herein, a bond represented with a dashed line and a solid line indicates an optional double bond at that position. Meaning the molecule could exist with or without a double bond at that specific location within the structure; essentially signifying a potential point of variation within the molecule being described.

[0087] As used herein, the terms “pharmacologic composition,” “pharmacologic composition formulation,” “pharmaceutical formulation,” or synonymously “formulation” refers to a medicinal dosage form that is created using a mixture of excipients or other chemicals prepared according to a specific recipe and preparation procedure. As used herein, the term “formulating” refers to the process in which different chemical substances, including the active drug, and various excipients are combined to produce a final medicinal product suitable for use in a human subject. Nonlimiting examples of a pharmaceutical formulation are; tablet, gels, liquids, capsules, lotions, powders, suppositories, and the like. The terms of "composition" and "formulation" are used interchangeably in this application as are the terms “pharmacologic” and “pharmaceutical.”

[0088] As used herein, the term “liquid” refers to a state of matter that is not solid or gaseous at temperatures ranging from 1 degrees Centigrade to 99 degrees Centigrade and cannot hold its own shape. As used herein a “liquid” has a viscosity less than 1,000 centipoise (cps), where 1 centipoise is equivalent to the viscosity of water at normal temperature and pressure as defined by the National Institute of Standards and Technology.

[0089] As used herein, the term “rapidly dissolving dose form” refers to a solid pharmaceutically acceptable formulation of active pharmaceutical ingredients and excipients that dissolve or disintegrate in less than 10 seconds without addition of water or other liquids when applied to the surface of a mucosal tissue such as, but not limited to, the moist oral mucosa, rectal mucosa, andAttorney Docket no.: 1880P0117PCTvaginal mucosa. Non-limiting examples of a “rapidly dissolving dose form” are Orally Disintegrating Tablets (ODT), Fast Disintegrating Tablets (FDT), and Fast Dissolving Granules (FDG). As used herein a “rapidly dissolving dose form” is not meant to be swallowed and drug absorption occurs topically across the mucosal tissue to which it is applied.

[0090] Alternatively, the “rapidly dissolving dose form” can also be used when mixed with 0.5 to 3 mL of a pharmaceutically acceptable aqueous medium immediately prior to topical application to a subject in need thereof.

[0091] As used herein, the term “semi-solid” refers to a state of matter that is in between a liquid and a solid. As used herein, a semi-solid substance cannot hold its own shape at temperatures of 20 degrees Centigrade and above and has a viscosity greater than 1,000 centipoise (cps), where 1 centipoise is equivalent to the viscosity of water at normal temperature and pressure as defined by the National Institute of Standards and Technology. As used herein a “gel” is a semi-solid.

[0092] As used herein, the term "treating" or "treatment" refers to mitigating, improving, relieving, ameliorating, or alleviating at least one sign or symptom (such as bleeding from the uterus ) of a condition, disease, or disorder in a human subject, or the improvement of an ascertainable measurement associated with a condition, disease, or disorder.

[0093] As used herein, the terms “topical” or “topically applied” or “administered topically” are synonymous and refer to applying or depositing a pharmaceutically active compound or compounds on the surface of an epithelium or epithelial tissue such as, but not limited to, a mucosa membrane or tissue.

[0094] As used herein, the term “mucosa” refers to the lining of most of the body cavities and hollow internal organs such as, but not limited to, the mouth, nose, eyelids, lungs, rectum and the vagina. The term mucous membrane(s) is synonymous with the terms; mucosa, mucosal tissues, and mucosal epithelium. The mucosa tissues consist of an epithelial layer on a basement membrane and a connective tissue layer (the lamina propria) and contain goblet-shaped cells that secrete mucus which keeps the surface moist and lubricated.Attorney Docket no.: 1880P0117PCT

[0095] As used herein, the term “muco-adherent” is synonymous with the term “mucoadhesive” and refers to substances that stick to or adhere to the mucosal tissues or mucous membranes by forces that are measurable and by any number of mechanisms such as, but not limited to, the following: hydrogen-bonding, ionic interaction, covalent bonding, hydrophobic interaction, Vander Waals interaction, or combinations thereof.

[0096] As used herein, the term “muco-penetrant” is synonymous with the term “mucosal penetration” and refers to substances that enhance the transfer of a chemical compound through the mucous, mucosal tissues, or mucous membranes by mechanisms such as, but not limited to, the following; enzymatic degradation, paracellular, and transcellular transit to improve absorption into the submucosal tissues.

[0097] As used herein, the term “nano-structured carriers” and the synonymous term “nanomaterial carrier” refers to nano-sized compositions capable of being, without limitation; combined, complexed, or attached covalently with active pharmaceutical compounds to form a vehicle or device useful to deliver such pharmaceutical compositions to an animal subject. Nonlimiting examples of nano-structured carriers include: dendrimers, liposomes, micelles, polymeric nanoparticles, nano-gels, nano-emulsions, and the like that are made mostly, but not always, from carbon based organic materials such as, but not limited to: lipids, carbohydrates, phospholipids, natural and synthetic polymers that are any of various organic compounds.

[0098] As used herein, nanoscale dimension (nano-sized or nano) is defined as measuring from 1 to 999 nanometers (nm) in size.

[0099] The term “oils” as used herein are lipids that are liquids at 20 degrees centigrade and above such as, but not limited to; sunflower oil, palm oil, medium-chain mono- and diglycerides of fatty acids, medium-chain triglycerides and their esters, glycerol, fatty acid-propylene glycol, fatty acids, and the like.Attorney Docket no.: 1880P0117PCT

[0100] The term “fats” as used herein are lipid substances that are solids at 20 degrees Centigrade and become liquids at higher temperatures. Non-limiting examples are; glycerol stearate, stearic acid, cetyl palmate, dipalmitoyl phosphatidylcholine, hydrogenated lipids, and the like.

[0101] The term “carbohydrates” as used herein are organic compounds such as, but not limited to; alginate, starch, chitosan, cellulose, pectin, cyclodextrins, oligosaccharides and polysaccharides, hyaluronic acid, and the like.

[0102] The term “synthetic polymers” as used herein are organic compounds such as, but not limited to; polylactic acid, poly-(lactide-co-glycolide) (PLGA), polyanhydrides, poly- s -caprolactone, poly-alkyl- cyanoacrylates, and polyphosphazene.

[0103] As used herein, the term “oral mucosa” means the mucosal membrane that lines the inside of the mouth or oral cavity including the buccal area (i.e. cheeks), tongue, sublingual region, gums, upper and lower palette as well as the inner surface of the lips.

[0104] The term “phospholipids” as used herein are a group of polar lipids that consist of two fatty acids, a glycerol unit, and a phosphate group which is esterified to an organic molecule. Nonlimiting examples of phospholipids are; choline, ethanolamine, inositol, 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine, and the like.

[0105] As used herein, the term “pharmaceutically acceptable excipient" or more simply “excipient” or “excipients” refers to a substance that is useful in preparing a pharmaceutical composition, that is generally safe, non-toxic, neither biologically nor otherwise undesirable, and includes substances that are acceptable for veterinary use as well as human pharmaceutical use. Typically, excipients are substances other than the active pharmaceutical ingredient. Examples of excipients include, but not limited to; water, sodium chloride, dextrose, polysorbate 80, carboxymethylcellulose sodium, benzalkonium chloride or phosphate buffered saline, gelatin, dextran, alginates, glycine, mannitol, moisturizers, colorants, fragrances, stabilizers, bulking agents, wetting agents, solubilizers, penetration enhancers, wetting agents, binding agents, flavoring agents, taste masking agents, etc.Attorney Docket no.: 1880P0117PCT

[0106] The term "pharmaceutically acceptable salt" of a compound as used herein means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3 -phenyl propionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. A "pharmaceutically acceptable salt" of a compound also includes salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

[0107] As used herein, the term “pharmaceutically acceptable solution” means a liquid carrier or inert medium used as a solvent (or diluent) in which the medicinally active agent is formulated and / or administered.

[0108] As used herein, the term “rectal mucosa” means the mucosal membrane that lines the inside of the rectal canal or rectal cavity.

[0109] As used herein, the term “stereoisomer” means molecules that have the same molecular formula, molecular weight and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in space. By definition, molecules that are stereoisomers of each other represent the same structural isomer. The chemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)Attorney Docket no.: 1880P0117PCTMcGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0110] As used herein, the term “treating" or "treatment" of a disease means inhibiting the disease, i.e., arresting or reducing the pathophysiologic process or processes of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the pathophysiologic process or processes of disease or reducing the clinical manifestations of the pathophysiologic process or processes of the specific disease.

[0111] As used herein, the term “vaginal mucosa” means the mucosal membrane that lines the vaginal canal or vaginal cavity including the exterior surface of the cervix.

[0112] As used herein, the term “myometrium” means the muscular tissue layer or wall of the uterus. The relational term “myometrial” means relating to, affecting, or of the muscular middle layer of the uterus.

[0113] As used herein, the term “uterine atony” refers to partial or complete loss of the uterus to contract. Loss of such muscular tone in uterine atony is subjectively clinically recognizable to those skilled in obstetrics.

[0114] As used herein, the term “uterotonic” means; individually the contraction of uterine myometrial smooth muscle cells, and / or collectively contraction of the body of uterus or isolated uterine muscle strips.

[0115] As used herein, the term “uterotonic agents” means; any natural or synthetic chemical compound that has biological activity and induces contractions of uterine myometrial smooth muscle. Non-limiting examples are; ergometrine, oxytocin, carbetocin, prostaglandin E2, Prostaglandin F2 alpha, and the like.Attorney Docket no.: 1880P0117PCT

[0116] As used herein, the term “uterotonic prostaglandin” means; compounds according to Formula 1 that have a biological activity that induces contractions of uterine myometrial smooth muscle.Examples

[0117] The example preparations and / or formulations described herein are meant to be nonlimiting examples of nano structured carrier compositions and formulations. Variations of the reagents used, and processes used to produce the exemplar nano structured carrier compositions and formulations described herein are known by those skilled in the art and produce nano structured carrier compositions and formulations that are within the spirit of the current disclosure.Example 1 - Solid and Liquid formulation of nano-complex

[0118] Cyclodextrins (CDs) are supram olecular oligosaccharides that have ring shaped five or more a-D-glucopyranoside units linked by a-l,4-glycosidic bonds. The interiors of cyclodextrins have a hydrophobic cavity, the size of which is determined by the number of glucose units in the molecule. Inclusion complexes are formed with certain chemical compounds (“guest molecule(s)”) under specific reaction conditions in which the guest molecule is contained within the hydrophobic cavity. The nano-complex is stable and may exhibit improved chemical or biological properties compared to the guest molecule alone. The size of the guest-host cyclodextrin complex varies but is less than 25 nm.

[0119] Preparation of (Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]but-l-enyl]cyclopentyl]hept-5-enoic acid - cyclodextrin nano-complex using (2-Hydroxypropyl)-beta-cyclodextrin (HP-PCD ) is achieved by combining an aqueous solution of HP-PCD at a concentration of 0.1 mM with a 0.01 mM solution of (Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]but-l-enyl]cyclopentyl]hept-5-enoic acid in ethanol at a 1:1 v / v ratio. The solution is then stirred to facilitate complexation of compounds. Subsequently, the solution is then frozen by immersion of the flask containing the solution complex in liquid nitrogen and then lyophilized to obtain a solid form of the complex. The solid complex is then pulverized to a fine powder of the nano- structure complex which can be stored or used immediately. Optionally, the finely powdered nano-complexAttorney Docket no.: 1880P0117PCTmay be formulated into a rapidly dissolving tablet or granulated dose form into which additional pharmaceutically acceptable excipients can be optionally added. All of these dose forms of the nano-structed complex can be directly topically applied to the mucosa of the oral cavity, rectal canal, and / or vagina.

[0120] The resultant finely powdered nano-complex can also be dissolved in a clear solution comprised of; soy lecithin, sodium deoxycholate, benzyl alcohol, caprylic / capric triglyceride, and / or ethylenediaminetetraacetic acid (EDTA) to produce a stable ready to use liquid dose form. A buffered saline solution of other pharmacologically acceptable solution may also be mixed with the resultant solution. Additional pharmaceutically acceptable excipients can be optionally added to the solution. The liquid formulation is applied topically to the oral, rectal, and / or vaginal mucosa.Example 2 - Liquid formulation of Self-Nano-Emulsifying Drug Delivery System

[0121] Self-nano-emulsifying drug delivery systems (SNEDDS) are nano-emulsion preconcentrates or anhydrous forms of nano-emulsions. These are isotropic mixtures of oils, surfactants, cosurfactants, and sometimes co-solvents, which emulsify spontaneously in aqueous media to produce an oil-in-water nano-emulsion. Spontaneous nano-emulsification of these formulation occurs with contact of the physiologic fluids such as, but not limited to, those on the surface of the oral cavity, rectal canal, and / or vagina.

[0122] To prepare a Self-Nano-Emulsifying Drug Delivery System (SNEDDs) 10 mg of 7-[(lR,2R,3R)-3-hydroxy-2-[(E)-4-hydroxy-4-methyloct-l-enyl]-5-oxocyclopentyl]heptanoic acid (misoprostol acid) is dissolved in 5 ml of a mixture of oleic acid and glycerin triacetate (90:10 %v / v). The solution is then added to 45 ml of a mixture 50 / 50 (%v / v) of diethylene glycol monoethyl ether and ethoxylated castor oil (Kolliphor EL, Sigma-Aldrich). To facilitate homogenization the mixture is placed in a water bath at 40°C. The solution is mixed by vortex mixer to obtain a clear uniform mixture and cooled to room temperature. The resultant SNEDD is stable at room temperature and will spontaneously generate a nano-emulsion when applied to the moist surface of the mucosal tissue. In vitro simulation in a human saliva sample of less than 1 ml will produce a nano-emulsion in less than 10 seconds with average globule sizes of less than 200Attomey Docket no.: 1880P0117PCTnm. The liquid SNEDD formulation obtained can be directly applied topically to the mucosa of the oral cavity, rectal canal, and / or vagina. Optionally, the SNEDD formulation obtained can also be combined with other pharmaceutically acceptable excipients for direct topical application to mucosa of the oral cavity, rectal canal, and / or vagina.Example 3 - Rapidly dissolving dose form

[0123] The liquid SNEDDS obtained in Example 2 herein can also be converted to a solid rapidly dissolving dose form by combining the liquid SNEDD with pharmaceutically acceptable excipients that adsorb or absorb the liquid SNEDD. On contact with a moist mucosa surface such as, but not limited to, the oral cavity, rectal canal, and / or vagina, the fast dissolving granules disintegrate to produce a nano-emulsion of the active drug substance. Alternatively, the solid rapidly dissolving dose form can be mixed with 0.5 -3 mL of a pharmaceutically acceptable aqueous medium that will result in a nano-emulsion of the active drug substance in less than 5 seconds. To produce the fast dissolving granules dose form of the liquid SNEDD from Example 2, the liquid SNEDDS : Copolyvidone : Maltodextrin : Microcrystalline cellulose were combined in a blender at a ratio of 1.1 :1.3 : 5.6 : 2.0 parts respectively until a granular powder was obtained. The resultant powder was lyophilized and ground into finer granules comprising the solid rapidly dissolving dose form of fast dissolving granules.Example 4 - Liquid and Semi solid formulation of Lipid nanoparticle

[0124] Lipid nanoparticles (LNPs) are spherical nanocarriers made of lipid components that are used to deliver therapeutic agents. Several types of lipid nanoparticles exist such as, but not limited to, liposomes, and nanostructured lipid carriers. Pharmacologically active substances can be enclosed in the aqueous interior of liposomes or can be entrapped in the hydrocarbon chain region of the lipid bilayer. Typically, nano-liposomes may be either uni-lamellar vesicles (ULV) with diameters of 20-900 nm or multi-lamellar vesicles (MLV), with diameters of >500 nm, in which concentric bilayers form an onion-like multilayer structure.

[0125] To produce lipid nanoparticles containing (Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-3-methyloct-l-enyl]cyclopentyl]hept-5-enoic acid, that compound in a 2 mL ethanol solution and phospholipids in 4 mL of chloroform are mixed. Phospholipids; 1,2-dimyristoyl-w-Attorney Docket no.: 1880P0117PCTglycero-3-phosphocholine (DMPC), l,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPG), 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) are used in molar ratio of (85: 10: 5). After complete mixing, solvent evaporation is performed under a stream of nitrogen gas at room temperature in a round bottom flask until no liquid remains. Subsequently, a thin film is created at the bottom of the flask which is then desiccated in under vacuum at room temperature for 8-12 hours to complete the solvent evaporation. The thin film formulation is resuspended in PBS at pH 7.4 and 37° C. and is mixed by vortex for 5 minutes and rehydrated at 37° C. for 30 minutes. Liposomes that are produced are large uni-lamelar vesicles (ULVs) and multi -lamellar vesicles (MLVs). To reduce size, the ULVs are gradually extruded through 200 nm and 100 nm polycarbonate membranes using a high pressure homogenizer. The resultant nano-lipid particles are then mixed to the desired concentration in a pharmaceutically acceptable solution with or without additional pharmaceutically acceptable excipients for use as a topically applied solution. Alternatively, the resultant nano-lipid particles are formulated into a semi-solid dose form for topical application to a mucosa of the oral cavity, rectal canal, and / or vagina with or without additional pharmaceutically acceptable excipients.References1. Callaghan WM, et al. Trends in postpartum hemorrhage: United States, 1994-2006. Am J Obstet Gynecol 2010;202:353.el-6.2. Laie Say, et al. Global causes of maternal death: a WHO systematic analysis,The Lancet Global Health, 2014; 2: 6. e323-e333.3. ACOG, Practice Bulletin 183: Postpartum Hemorrhage. Am J Obstet Gynecol 2017;130:4. el68-el81.4. Dahlke JD, et al. Prevention and management of postpartum hemorrhage: a comparison of 4 national guidelines, Am J Obstet Gynecol 2015; 213, 76el-76.el0,5. Leduc D, et al. Active Management of the Third Stage of Labour: Prevention and Treatment of Postpartum Hemorrhage, J Obstet Gynecol Canada, 2009; 31: 10. 980-993.Attorney Docket no.: 1880P0117PCT6. Geller SE, et al. Factors associated with acute postpartum hemorrhage in low-risk women delivering in rural India. Int J Gynaecol Obstet 2008; 101: 94-99.7. Salati JA, et al. Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage. Cochrane Database SystRev. 2019; 4(4): Cd001808.8. Osilla EV, et al. Oxytocin. [Updated 2023 Jul 24], In: StatPearls [Internet], Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: NIH, The National Library of Medicine, National Center for Biotechnology Information website.9. Anderson CM, et al. Oxytocin and Hypotension. Hawaii J Health Soc Welf. 2022 Dec;81(12):328-332.10. Rajan PV, Wing DA. Postpartum hemorrhage: evidence-based medical interventions for prevention and treatment. Clin Obstet Gynecol. 2010; 53(1): 165-81.11. Giilmezoglu AM, et al. WHO multicentre randomised trial of misoprostol in the management of the third stage of labour. Lancet. 2001; 358(9283): 689-95.12. Hagen N, , et al. Stability of misoprostol tablets collected in Malawi and Rwanda:Importance of intact primary packaging. PLoS ONE. 2020; 15(9): e0238628.

Claims

Attorney Docket no.: 1880P0117PCTCLAIMS1. A pharmacologic composition comprising at least one uterotonic prostaglandin according to Formula 1 at a concentration of lOug to 2000ug and a nano- structured carrier for topical application to the mucosal membrane of the rectal canal, the oral cavity, and / or the vaginal canalFormula 1whereinR1 is selected from COOH, COO-straight or branched chain alkyl, B(0H)2, B(ORio)(ORu) or N-methylsulfonylformamide;Rio andRn, if present, are independently selected from optionally substituted alkyl, cycloalkyl, alkylcycloalkyl, and / or when Rw and Rn are present and adjacent to each other can together form an alkyl bridged 5 or 6 membered heterocyclic ring;R2 is hydrogen; methyl, hydroxyl, oxygen, or fluorine;R3 is hydrogen, methyl, hydroxyl, oxygen, or fluorine;R4 is hydrogen, methyl, hydroxyl, oxygen, or fluorine;R5 is hydrogen, methyl, hydroxyl, oxygen, or fluorine; andR6 is straight or branched chain alkyl of 1 to 8 carbon atoms, inclusive, vinyl (-CH=CH2), cycloalkyl group containing 3 to 6 carbon atoms, phenyl, phenoxy, O-optionally substituted aryl, O-optionally substituted straight or branched chain alkyl of 1-8 carbons;or the compound is a pharmaceutically acceptable salt, ester, or prodrug form thereof, wherein a hydrogen, several hydrogens or all hydrogens may be replaced with deuterium.

2. The pharmacologic composition according to claim 1, wherein topical application is to the mucosal membrane of the oral cavity.Attorney Docket no.: 1880P0117PCT3. The pharmacologic composition according to claim 2, wherein topical application is sublingual.

4. The pharmacologic composition according to claim 1, wherein topical application is to the mucosal membrane of the vaginal canal.

5. The pharmacologic composition according to claim 1, wherein topical application is to the rectal canal.

6. The pharmacologic composition according to claim 1, wherein the at least one uterotonic prostaglandin and the nano-structured carrier are attached by a co-valent bond.

7. The pharmacologic composition according to claim 1, wherein the at least one uterotonic prostaglandin and the nano-structured carrier are in a complex.

8. The pharmacologic composition according to claim 1, wherein the nano-structured carrier is a cyclodextrin moiety.

9. The pharmacologic composition according to claim 1, wherein the nano-structured carrier is a lipid nanoparticle.

10. The pharmacologic composition according to claim 1, wherein the at least one uterotonic prostaglandin and the nano-structured carrier are in a pharmaceutical formulation comprising a liquid dose form.

11. The pharmacologic composition according to claim 10, wherein the liquid dose is a Self-Nano- Emulsifying Drug Delivery System (SNEDDS).

12. The pharmacologic composition according to claim 1, wherein the at least one uterotonic prostaglandin and the nano-structured carrier are formulated into a semi-solid dose form.Attorney Docket no.: 1880P0117PCT13. The pharmacologic composition according to claim 1, wherein the at least one uterotonic prostaglandin and the nano- structured carrier are formulated into a rapidly dissolving solid dose form.

14. The pharmacologic composition according to claim 1, wherein Formula I is 7-[(lR,2R,3R)-3- hydroxy-2-[(E)-4-hydroxy-4-methyl oct-1 -enyl]-5-oxocy cl opentyl]heptanoic acid [misoprostol acid],15. The pharmacologic composition according to claim 1, wherein Formula I is (Z)-7- [(lR,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]but-l- enyl]cyclopentyl]hept-5-enoic acid.

16. The pharmacologic composition according to claim 1, wherein Formula I is (Z)-7- [(lR,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-3-methyloct-l-enyl]cyclopentyl]hept-5- enoic acid.

17. The pharmacologic composition according to claim 1, wherein Formula I is (Z)-7- [(lR,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-l-enyl]-5-oxocyclopentyl]hept-5-enoic acid.

18. The pharmacologic composition according to claim 1, wherein Formula I is (Z)-7- [(lR,2R,3R)-3-hydroxy-2-[(E,3R)-3-hydroxy-4-phenoxybut-l-enyl]-5-oxocyclopentyl]-N- methylsulfonylhept-5-enamide.

19. The pharmacologic composition according to any preceding claim, wherein the pharmacologic composition is lyophilized.

20. Use of the pharmacologic composition according to any preceding claim in a drug product.

21. A method of treating postpartum hemorrhage caused by uterine atony in a human subject in need thereof comprising topically administering to the mucosal epithelium of the oral, rectal, and / or vaginal cavity a pharmacologic formulation comprising a uterotonic prostaglandin at a concentration of lOug to 2000 ug and a nano-structured carrier.Attorney Docket no.: 1880P0117PCT22. A dosage unit kit of the pharmacologic composition of claim 1 , comprising separate containers for each component, or a single container for dry components and a single container for liquid components, wherein the contents of the containers are mixed together to form the pharmacologic composition before administration to a subject in need thereof.

23. The dosage unit kit according to claim 22, wherein separate containers for each component are provided.

24. The dosage unit kit according to claim 22, wherein a single container for dry components and a single container for liquid components are provided.

25. The dosage unit kit according to claim 22, further comprising a self-emulsifying composition.

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