HK1232125B - Formulations and methods for vaginal delivery of antiprogestins - Google Patents

Description

Formulations and methods for vaginal delivery of antiprogestins

Cross-reference to related applications

This patent application claims the benefit of U.S. Provisional Application No. 61/988,766, filed May 5, 2014, the contents of which are incorporated herein by reference.

Technical Field

In several embodiments, the present invention relates to mucoadhesive pharmaceutical compositions and their use for topical administration of active agents, such as antiprogestins, to the vaginal mucosa. In related embodiments, the mucoadhesive compositions are administered for the treatment of various progesterone-related conditions.

Background Art

The effects of the steroid hormone progesterone on the reproductive system are well documented. For example, progesterone is crucial for establishing and maintaining pregnancy and exerts effects on various tissues of the reproductive system. The effects of progesterone on tissues outside the reproductive system have been reported but are less well characterized.

Antiprogestins are compounds that inhibit the effects of progesterone and have considerable potential for use in the pharmacological regulation of fertility and various conditions and diseases such as breast cancer and endometriosis. The first reported antiprogestin, mifepristone (RU486), is one of a variety of 19-nortestosterone derivatives with strong affinity for both progesterone and glucocorticoid receptors and has antiprogestin and antiglucocorticoid activity. Various antiprogestins based on the 19-nortestosterone backbone have also been synthesized.

Several disadvantages are associated with the use of known antiprogestins, rendering them less than ideal for long-term administration, particularly when delivered orally. If these and other limitations associated with antiprogestin therapy could be improved, it would result in significant progress in the treatment of hormone-dependent disorders.

Summary of the Invention

In one embodiment, the present invention provides pullulan-containing mucoadhesive capsules and capsule fill formulations for delivering active agents to the vaginal mucosa, the capsule fill formulations comprising an active agent, preferably an antiprogestin, and one or more excipients.

In other embodiments, the present invention provides methods for treating various progesterone-related conditions in a patient in need of such treatment by administering to the vaginal mucosa of the patient a mucoadhesive capsule comprising pullulan and a capsule-filled formulation comprising an antiprogestin and one or more excipients.

In other embodiments, the present invention provides a kit comprising a mucoadhesive capsule comprising pullulan and a capsule fill formulation comprising an active agent, preferably an antiprogestin, and one or more excipients for delivery of the agent to the vaginal mucosa in combination with a vaginal applicator.

Progesterone-related conditions that may be treated with the mucoadhesive capsules of the present invention include, but are not limited to, endometriosis and its associated pain, adenomyosis, ovarian endometriomas, dysmenorrhea, endocrine hormone-dependent tumors, uterine fibroids, endometrial hyperplasia, ovarian cancer, cervical cancer, and breast cancer. The compositions of the present invention may also be used to induce menstruation, induce labor, and for contraception.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the area under the curve (AUC) for CDB-4124 and its demethylated metabolite CDB-4453 following oral administration of 1 mg, 3 mg, 6 mg, 9 mg, and 12 mg of CDB-4124 to human women with uterine fibroids, compared to a 12 mg dose administered vaginally.

Figure 2 shows a comparison of the Cmax (peak serum concentration) of CDB-4124 and CDB-4453 following oral doses of 1 mg, 3 mg, 6 mg, 9 mg, and 12 mg in human females with uterine fibroids, compared to vaginal administration of a 12 mg dose.

Figure 3 shows pharmacokinetic data observed at steady state over a 24 hour period following administration of 1 mg, 3 mg, 6 mg, 9 mg, and 12 mg oral doses of CDB-4124 relative to a 12 mg vaginal dose.

Figures 4A-B show pharmacokinetic data observed in rabbits over a 24-hour period following the last of 10 daily doses of 12 mg CDB-4124 delivered vaginally. Panel A shows CDB-4124; Panel B shows CDB-4453.

FIG5 shows an applicator for vaginally delivering a pullulan capsule containing 12 mg of CDB-4124 to a human female.

Figures 6-13 show the overall pharmacokinetic data (CDB-4124 + CDB-4453) observed in healthy human females over a 32-hour period following a single vaginal dose of pullulan capsules containing 12 mg CDB-4124 + 99.98% PEG 1000 + 0.02% BHT (A), or after a single vaginal dose of pullulan capsules containing 12 mg CDB-4124 + 95.98% PEG 1000 + 4% isopropyl myristate + 0.02% BHT (B1), or after 7 daily vaginal doses of pullulan capsules containing 12 mg CDB-4124 + 95.98% PEG 1000 + 4% isopropyl myristate + 0.02% BHT (B2).

DETAILED DESCRIPTION

Although the present invention can be embodied in various forms, the following description of several embodiments is provided, which, along with the present disclosure, is to be considered illustrative of the present invention and is not intended to limit the present invention to the specific embodiments shown. Headings are provided for convenience only and should not be construed as limiting the present invention in any way. Embodiments shown under any heading may be combined with embodiments shown under any other heading.

It should be understood that any range, ratio, and ratio range formed by any of the numbers or data presented herein represent further embodiments of the present invention. This includes a formable range that includes or does not include a limited upper boundary and/or lower boundary. Accordingly, the skilled person will appreciate that many such ratios, ranges, and ratio ranges can be clearly derived from the data and numbers presented herein, and all represent embodiments of the present invention.

Before disclosing and describing the compounds, compositions and methods of the present invention, it should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise.

definition

The term "capsule" refers to a hard shell pharmaceutical capsule. A capsule consists of a body and a lid and may contain a fill formulation containing a pharmacologically active agent.

The term "oral" administration means that the active agent is in a formulation designed to be ingested, ie, designed to be delivered to the gastrointestinal system for absorption.

The term "effective dose" means the amount of active ingredient in a composition sufficient to treat a particular condition.

The term "selective progesterone receptor modulator" means a compound that affects the function of the progesterone receptor in a tissue-specific manner. The compound acts as a progesterone receptor antagonist in some tissues (e.g., in breast tissue) and as a progesterone receptor agonist in other tissues (e.g., in the uterus).

As used herein, the term "treat" or "treatment" refers to any treatment of any progesterone-dependent condition or disease, and includes, but is not limited to, inhibiting the condition or disease, arresting the development of the condition or disease; alleviating the condition or disease, e.g., causing regression of the condition or disease; or relieving the condition caused by the disease or disease, alleviating the symptoms of the disease or disease.

The terms "prevent" or "prevention" with respect to a progesterone-dependent condition or disease means preventing the onset of the condition or disease development when the condition or disease is not already present, or preventing further condition or disease development when the condition or disease is already present. For example, the compositions of the present invention can be used to prevent tumor recurrence. Tumor recurrence can occur due to residual microscopic tumor cell clusters or nests that subsequently expand into clinically detectable tumors.

The term "progesterone agonist" means a compound that binds to the progesterone receptor and mimics the action of the natural hormone.

The term "progesterone antagonist" refers to a compound that binds to the progesterone receptor and inhibits the effects of progesterone.

In several embodiments, the present invention is directed to methods of administering an active agent to the vaginal mucosa using a capsule comprising pullulan and a capsule fill formulation comprising the active agent and one or more excipients.

In a preferred embodiment, the present invention is directed to a method of treating a progesterone-related condition by vaginally administering to the vaginal mucosa of a patient a mucoadhesive capsule comprising pullulan and a capsule fill formulation comprising an antiprogestin and one or more excipients.

Pullulan is a linear, water-soluble polysaccharide polymer composed of maltotriose units linked to each other by α-1,6 glycosidic bonds. The three glucose units in each maltotriose unit are linked by α-1,4 glycosidic bonds. The linkage pattern of pullulan is responsible for the adhesive properties of the polysaccharide and its ability to form fibers and oxygen-impermeable films. Pullulan is produced from starch by the fungus Aureobasidium pullulans and can be commercially produced by batch fermentation as described in Leathers, Appl. Microbiol. Biotechol., 62:468-473 (2003).

capsule

Capsules suitable for use in accordance with the present invention include, but are not limited to, those available from Capsugel, which contain pullulan, carrageenan, and potassium chloride, and the capsules described in U.S. Patent No. 8,105,625 and U.S. Patent Application Publication No. 2005/0249676, the contents of each of which are incorporated herein by reference.

In one aspect, capsules for use according to the present invention comprise pullulan having a molecular weight between about 50 and 500 kDa, between 100 and 400 kDa, between about 150 and 300 kDa and preferably between about 180 and 250 kDa.

In another aspect, the capsules for use according to the present invention comprise from about 50% to about 100% pullulan by weight (unfilled capsule). In other aspects, the capsules comprise from about 60 to 90, or from 70 to 90, or from 80 to 90% by weight pullulan. Preferably, the capsules comprise from about 85 to 90% by weight pullulan.

Capsules for use according to the present invention may also contain (in addition to pullulan) but are not limited to one or more gelling agents (e.g., hydrocolloids or polysaccharides such as alginates, agar gum, guar gum, locust bean gum, carrageenan, tara gum, gum arabic, pectin, xanthan gum, etc.); salts containing cations such as K ⁺ , Li ⁺ , Na ⁺ , NH4 ⁺ , Ca ²⁺ , Mg ²⁺ ; and/or surfactants such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, benzalkonium chloride, benzethonium chloride, cetrimonium bromide, fatty acid sugar esters, glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol, dimethylpolysiloxane, sorbitan esters, or lecithin, as described in U.S. Patent Application Publication No. 2005/0249676.

Capsules for use according to the present invention may also contain one or more plasticizers (e.g., glycerol, propylene glycol, polyvinyl alcohol, sorbitol, maltitol, etc.); solubility enhancers (e.g., maltose, lactose, sorbitol, mannitol, xylitol, maltitol, etc.); enhancers (e.g., polydextrose, cellulose, maltodextrin, gelatin, gums, etc.); colorants and/or opacifiers, as described in U.S. Pat. No. 8,105,625.

In a preferred embodiment, the capsules contain pullulan in an amount of 85% to 90% by weight, potassium chloride in an amount of 1.0% to 1.5% by weight, carrageenan in an amount of 0.1% to 0.4% by weight, one or more surfactants in an amount of 0.1% to 0.2% by weight, and water in an amount of 10% to 15% by weight.

In a particularly preferred embodiment, the capsule comprises pullulan in an amount of 86.3% by weight, potassium chloride in an amount of 1.32% by weight, carrageenan in an amount of 0.27% by weight, a surfactant selected from sugar esters, sorbitan monolaurate, and combinations thereof in an amount of 0.15% by weight, and water in an amount of 12% by weight.

In another aspect, pullulan capsules provide sustained release (i.e., stable release of active agent) to subjects at a substantially constant rate over a period of time. The present inventors have found that capsules comprising pullulan are surprisingly advantageous for vaginal delivery of active agents. In particular, capsules based on pullulan are safe, effective, and convenient vehicles for delivering active agents to the vaginal mucosa. The present inventors have found that pullulan capsules adhere to the vaginal mucosa, thereby ensuring that the capsule remains in the desired position in the vagina during the duration of drug delivery. In addition, partly due to the solubility of pullulan, after drug release, no residual capsule is left in the vagina, which is different from conventional gelatin capsules. The present inventors have surprisingly found that: when used as a vaginal delivery device, pullulan capsules achieve sustained release of active agents at a substantially constant rate, thereby maintaining the low Cmax (peak concentration) of the active agent and ensuring the high local concentration of the drug. Therefore, a sustained level of active agent is delivered to the vaginal mucosa while minimizing systemic concentration.

The capsule fill formulation may comprise any active agent. Preferably, the capsule fill formulation comprises an antiprogestin, which may be a pure antiprogestin or a selective progesterone receptor modulator.

Capsule filling preparations can also contain one or more excipients. Suitable excipients can be selected based on considerations including but not limited to the active agent to be administered and dosage. Excipient can serve as filler (bulking agent), release modifier, wetting agent, tension agent or its combination. For example, excipient can include hydrophilic excipients, such as water-soluble synthetic and natural polymers, including but not limited to polyethylene glycol (PEG), polyvinyl pyrrolidone, polymethacrylate, polylysine, polyvinyl alcohol, albumin, alginate, gelatin, chitosan, cellulose, sucrose, starch, hydroxyethyl cellulose, hydroxypropyl cellulose, hyaluronic acid, carboxyethyl cellulose, carboxymethyl cellulose, dextran sulfate and derivatives thereof. The specific hydrophilic polymer for capsule filling preparations can be based on factors such as molecular weight, hydrophilicity and viscosity. Hydrophilic polymers can be used as filler or wetting agent.

Excipients may also include lipids, such as, but not limited to, one or a mixture of different grades of Gelucire, Labrafil(R), Labrasol(R), and the like. Gelcuire compositions are amphiphilic, inert polyglycolide glycerides that form micelles in aqueous media. They are identified by their melting point (degrees Celsius)/HLB (hydrophile-lipophile balance). Particularly preferred Gelucire compositions for use in capsules are Gelucire 44/14 (lauroyl macrogol-32 glyceride) and Gelucire 50/13 (stearoyl macrogol-32 glyceride).

In a preferred embodiment, the fill formulation comprises a pharmaceutically active compound, preferably CDB-4124, and the excipients Gelucire 44/14 and PEG. In a related aspect, Gelucire 44/14 is present as between 50% and 90%, preferably about 75%, of the excipient w/w, and PEG is present as between 50% and 10%, preferably about 25%, of the excipient w/w. In a particularly preferred embodiment, the fill formulation comprises CDB-4124 and an excipient consisting of 74.13% (w/w) Gelucire and 25.87% PEG 400.

In particularly preferred embodiments, the capsule fill formulation consists of, or consists essentially of, the pharmaceutically active agent, preferably CDB-4124, and as an excipient about 100% w/w PEG 1000. Optionally, 0.02% butylated hydroxytoluene is also present as 0.02% excipient w/w (as an antioxidant).

In other preferred embodiments, the capsule fill formulation comprises a pharmaceutically active agent, preferably CDB-4124, and an excipient comprising 30% to 60% w/w Wecobee M (fatty acid ester), 30% to 60% w/w PEG 1000, and 0.1% to 5% w/w lecithin. In a related embodiment, the capsule fill formulation comprises CDB-4124 as the active agent and an excipient consisting of about 50% (e.g., 50.1%) w/w Wecobee M, about 50% (e.g., 49.4%) w/w PEG 1000, and about 0.5% w/w lecithin.

It has been surprisingly found that dispersing an active ingredient, such as CDB-4124, in a mixture of isopropyl myristate or isopropyl palmitate with polyethylene glycol increases the AUC of the active ingredient without significantly changing _Cmax . Thus, capsules with such a fill formulation allow for an increase in bioavailability compared to a fill formulation lacking isopropyl myristate or isopropyl palmitate without a corresponding increase in the peak concentration of the active agent.

In a preferred embodiment, the capsule fill formulation comprises a pharmaceutically active agent, preferably CDB-4124, dispersed in a mixture of isopropyl myristate and polyethylene glycol or a mixture of isopropyl palmitate and polyethylene glycol. The isopropyl myristate or isopropyl palmitate comprises from about 15% to about 1% excipient (w/w), and the PEG comprises from about 85% to about 99% excipient (w/w). For example, the isopropyl myristate or isopropyl palmitate may comprise from about 10% to about 2% excipient (w/w), from about 6% to about 3% excipient (w/w), from about 5% to about 4% excipient (w/w), or any other range within about 15% to about 1%. In other embodiments, the w/w ratio between the polyethylene glycol and isopropyl myristate or isopropyl palmitate in the fill formulation ranges from 99:1 to 5.7:1.

In a particularly preferred embodiment, the capsule fill formulation comprises CDB-4124 dispersed in a mixture of isopropyl myristate and PEG 1000, wherein isopropyl myristate is present at about 4% excipient w/w and PEG 1000 is present at about 96% w/w. Optionally, 0.02% butylated hydroxytoluene is also present at 0.02% excipient w/w (as an antioxidant).

In a related embodiment, a capsule fill formulation comprises a pharmaceutically active agent, preferably CDB-4124, a transdermal permeation enhancer selected from dimethyl sulfoxide (DMSO), monounsaturated fatty acids (e.g., oleic acid), polyunsaturated fatty acids (e.g., linoleic acid), ethanol, 1-dodecylazacycloheptan-2-one, and mineral oil, and optionally polyethylene glycol. Preferably, the permeation enhancer comprises about 99% to about 1% excipient. More preferably, the capsule fill formulation comprises a transdermal permeation enhancer and PEG, wherein the permeation enhancer comprises about 15% to about 1% excipient w/w and the PEG comprises about 85% to about 99% excipient w/w. For example, the permeation enhancer may comprise about 10% to about 2% excipient w/w, about 6% to about 3% excipient w/w, about 5% to about 4% excipient w/w, or any other range within about 15% to about 1%. In other embodiments, the w/w ratio between the polyethylene glycol and the permeation enhancer in the fill formulation is in the range of 99:1 to 5.7:1.

Excipients may also include sugars such as mannitol, sorbitol, xylitol, glucitol, dulcitol, inositol, arabitol, arabitol, galactitol, iditol, allitol, fructose, sorbitol, glucose, xylose, trehalose, dextrose, galactose, talose, ribose, arabinose, sucrose, maltose, lactose, fucose, maltotriose, etc. The amount of sugar may be adjusted to provide osmotic pressure or wetting.

Wetting agents can be used in capsule-filled pharmaceutical preparations to facilitate the entry of water into the capsule and wet the active agent, and include gelatin, casein, lecithin, gum arabic, cholesterol, calcium stearate, stearic acid, and the like.

Capsule fill formulations may also contain one or more disintegrants such as corn starch, potato starch, modified starch, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, sodium alginate, cellulose polyacrilin potassium, gum, agar, guar gum, locust bean gum, pectin, xanthan gum, agar, and the like.

The capsule filling formulation may contain one or more flow agents or glidants to promote flowability, including colloidal silicon dioxide, corn starch, talc, calcium silicate, magnesium silicate, tricalcium phosphate, silica hydrogel, and the like.

Capsule filling formulations may also contain foaming agents such as polyethylene glycol, saponin, sorbitan trioleate, sorbitan monostearate, sorbitan monopalmitate, glyceryl monostearate, and the like.

Active agent

The capsule fill formulation may contain any pharmacologically active agent that has therapeutic efficacy when delivered vaginally.

In some embodiments, the capsule fill formulation comprises an estrogen (i.e., a natural estrogen or a synthetic compound that mimics the physiological effects of natural estrogen), including but not limited to estradiol (17β-estradiol), estradiol acetate, estradiol benzoate, estradiol cypionate, estradiol decanoate, estradiol diacetate, estradiol enanthate, estradiol valerate, 17α-estradiol, estriol, estriol succinate, estrone, estrone acetate, estrone sulfate, estrone sulfate piperazine (estrone sulfate piperazine), ethinyl estradiol (17α-ethinyl estradiol, ethinyl estradiol, ethinyl estradiol, ethinyl estradiol), 3-ethinyl estradiol acetate, 3-ethinyl estradiol benzoate, mestranol, ethinyl estradiol, nitrosated estrogen derivatives, or combinations thereof.

In other embodiments, the capsule filling formulation comprises a progestogen (i.e., a natural or synthetic compound with progestational activity, including but not limited to 17α-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one, 17α-ethynyl-19-nortestosterone, 17α-ethynyltestosterone, 17-desacetylnorgestimate, 19-nor-17-hydroxyprogesterone, 19-norprogesterone, 3β-hydroxydesogestrel, 3-ketodesogestrel (e.g., estradiol, acetoxypregnenolone, ethylbenzalgestrel, allylestradiol, amgestone, anagestrel acetate, chlormadinone acetate, chlormadinone acetate, cyproterone acetate, cyproterone acetate, d-17β-acetyloxy-13β-ethyl-17α-ethynyl adenos-4-en-3-one oxime, demegestone, desogestrel, dienogest, dihydroprogesterone, demegestone, drospirenone, dydrogesterone, ethinylgestrel (pregnenolone, 17α-ethynyltestosterone), dimethicone, doxyprogesterone, doxyprogesterone acetate ... Ethinyl alcohol, flugestrel acetate, gastrienone, gestadene, gestodene, gestorone, gestrinone, hydroxymethylprogesterone, hydroxymethylprogesterone acetate, hydroxyprogesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, levonorgestrel (1-norethinol), linegestrel (ethinyl estradiol), mecirogestone, merogestrel, medroxyprogesterone, medroxyprogesterone acetate, medroxyprogesterone acetate, medroxyprogesterone acetate Testosterone acetate, megestrol acetate, melengestrol acetate, melengestrol acetate, nestorone, noregestrol, noregestrol, norethindrone (norethindrone) (19-nor-17α-ethynyltestosterone), norethindrone acetate (norethindrone acetate), norethindrone, norgestimate, norgestrel (d-norgestrel and dl-norgestrel), norgestrel, methylnandrolone, progesterone, promegestone, quingestrol, tibolone, trimegestone, or a combination thereof.

In other embodiments, the capsule fill formulation comprises a progestogen and an estrogen.

In a preferred embodiment, the active agent is a progesterone antagonist.

In one embodiment, the capsule filling formulation comprises a steroid compound disclosed in U.S. Patent Nos. 6,861,415 and 6,900,193, the contents of which are incorporated herein by reference. In a preferred embodiment, the steroid compound is CDB-4124 (21-methoxy-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) or CDB-4453 (21-methoxy-17α-acetoxy-11β-(4-N-methylaminophenyl)-19-norpregna-4,9-diene-3,20-dione).

Other preferred progesterone antagonists that may be present in the capsule fill formulation include, but are not limited to, mifepristone (RU-486; 11β-[4N,N-dimethylaminophenyl]-17β-hydroxy-17-(1-propynyl)-estra-4,9-dien-3-one), lilopristone (11β-(4N,N-dimethylaminophenyl)-17β-hydroxy-17-((Z)-3-hydroxypropenyl)estra-4,9-dien-3-one), onapristone (11β-(4N,N-dimethylaminophenyl)-17α-hydroxy-17-(3-hydroxypropyl)-13α-estra-4,9-dien-3-one). , asoprisnil (benzaldehyde, 4-[(11β,17β)-17-methoxy-17-(methoxymethyl)-3-oxoestra-4,9-dien-11-yl]-1-(E)-oxime; J867), its metabolite J912 (4-[17β-hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-d-(1E)-oxime) and CDB-2914 (17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione).

Other antiprogestins that may be present in the capsule fill formulation include compounds described in U.S. Patent Nos. 4,386,085, 4,447,424, 4,536,401, 4,519,946, 4,609,651, 4,634,695, 4,780,461, 4,814,327, 4,829,060, 4,871,72 4, 4,921,845, 4,921,845, 5,095,129, 5,446,178, 5,478,956, 5,232,915, 5,089,488, 5,093,507, 5,244,886, 5,292,878, 5,439,913, 5,446,036, 5,576,310; 5, 684,151、5,688,808、5,693,646、5,693,647、5,696,127、5,696,130、5,696,133、5,739,125、5,407,928、5,273,971、5,728,689、5,753,655、5,843,933、5,843, 931, 6,509,334, 6,566,358, 6,713,478, 6,391,907, 6,417,214, 6,380,235, 6,339,098, 6,306,851, 6,441,019, 6,369,056, and 6,358,948, the contents of each of which are incorporated herein by reference.

Other antiprogestins that may be useful in the present invention include, but are not limited to, JNJ-1250132, (6α, 11β, 17β)-11-(4-dimethylaminophenyl)-6-methyl-4′, 5′-dihydrospiro[estra-4,9-diene-17,2′(3′H)-furan]-3-one (ORG-31710); (11β, 17α)-11-(4-acetylphenyl)- -17,23-Epoxy-19,24-dicholest-4,9,20-trien-3-one (ORG-33628); (7β,11β,17β)-11-(4-dimethylaminophenyl-7-methyl]-4',5'-dihydrospiro[estra-4,9-diene-17,2'(3'H)-furan]-3-one (ORG-31806); ZK-112993 ;ORG-31376;ORG-33245;ORG-31167;ORG-31343;RU-2992;RU-1479;RU-25056;RU- 49295; RU-46556; RU-26819; LG1127; LG120753; LG120830; LG1447; LG121046; CGP-1 9984A; RTI-3021-012; RTI-3021-022; RTI-3021-020; RWJ-25333; ZK-136796; ZK-114043; ZK-230211; ZK-136798; ZK-98229; ZK-98734; ZK-137316; 4-[17β-methoxy-17α-( 4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1-(E)-oxime; 4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1-(E)-[O-(ethylamino)carbonyl]oxime; 4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1-(E)-[O-(ethylamino)carbonyl]oxime -11β-yl]benzaldehyde-1-(E)-[O-(ethylthio)carbonyl]oxime; (Z)-6'-(4-cyanophenyl)-9,11α-dihydro-17β-hydroxy-17α-[4-(1-oxo-3-methylbutyloxy)-1-butenyl]4'H-naphtho[3',2',1';10,9,11]estr-4-en-3-one; 11β-(4-acetylphenyl)- 17β-Hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)estr-4,9-dien-3-one; 11β-(4-acetylphenyl)-19,24-dionor-17,23-epoxy-17α-cholest-4,9,20-trien-3-one; (Z)-11β,19-[4-(3-pyridyl)-o-phenylene]-17β-hydroxy-17α-[3- [hydroxy-1-propenyl]-4-androsten-3-one; 11β-[4-(1-methylvinyl)phenyl]-17α-hydroxy-17β-(3-hydroxypropyl)-13α-estra-4,9-dien-3-one; 4',5'-dihydro-11β-[4-(dimethylamino)phenyl]-6β-methylspiro[estra-4,9-dien-17β,2'(3'H)-furan]-3-one.

In a related aspect, the capsule filling formulation comprises a pharmaceutically acceptable salt of a pharmaceutically active compound such as an antiprogestogen. Depending on the process conditions, the salt compound obtained may be in neutral or salt form. Salt forms include hydrates and other solvates as well as crystalline polymorphs. Both the free base and salts of these final products may be used according to the present invention. Acid addition salts may be converted to free bases using alkaline agents such as alkali metals or by ion exchange in a manner known per se. The free base obtained may also form salts with organic or inorganic acids.

In the preparation of acid addition salts, preferably, such acids that form pharmaceutically acceptable salts are suitably used. Examples of such acids are hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic acid, alicyclic carboxylic acid or sulfonic acid, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, fumaric acid, maleic acid, hydroxymaleic acid, pyruvic acid, aspartic acid, glutamic acid, p-hydroxybenzoic acid, pamoic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, phenylacetic acid, mandelic acid, halogenated benzenesulfonic acid (alogenbensenesulfonic acid), toluenesulfonic acid, galactaric acid, galacturonic acid or naphthalenesulfonic acid. All crystalline form polymorphs can be used according to the present invention.

Base addition salts can also be used according to the present invention and can be prepared by contacting the free acid form with a sufficient amount of the desired base to produce a salt in a conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and separating the free acid in a conventional manner. Pharmaceutically acceptable base addition salts are formed by metals or amines, such as alkali metals and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, calcium, magnesium, etc. Examples of suitable amines are amino acids (e.g., lysine), choline, diethanolamine, ethylenediamine, N-methylglucamine, etc.

Conditions treatable by vaginal delivery of pullulan capsules

Pullulan capsules comprising a fill formulation comprising a pharmaceutically active agent can be administered to the vagina of a subject to treat various conditions or achieve various desired therapeutic outcomes in the subject.Preferably, the subject is a female mammal, most preferably a human female.

In some embodiments of the present invention, pullulan capsules containing a pharmaceutically active compound are administered to female patients in need thereof to treat a condition selected from the group consisting of: endometrial hyperplasia, endometriosis (or pain associated therewith), dysmenorrhea, uterine fibroids, adenomyosis, endometrioma, ovarian cancer, and cervical cancer. In a preferred embodiment, endometriosis, dysmenorrhea, uterine fibroids, adenomyosis, ovarian cancer, or cervical cancer are treated by administering an intravaginal formulation containing a compound of Formula I to the vagina of a patient in need of such treatment.

In another embodiment of the present invention, the pullulan capsules of the present invention are administered to a female in need thereof to induce menstruation in the female, in which case the capsule filling formulation preferably comprises a progestogen, such as medroxyprogesterone acetate.

In another embodiment of the present invention, the pullulan capsules of the present invention are administered to a woman in need thereof to induce labor.

In another embodiment of the present invention, the pullulan capsules of the present invention are administered to a female in need thereof as a contraceptive, in which case the capsule filling formulation preferably comprises a progestogen and optionally an estrogen.

Dosage and administration schedule

The therapeutically effective amount of the desired active agent for use in treatment varies with the length of time required for activity, the age and condition of the patient to be treated, and other factors, and is ultimately determined by the attending physician. However, in general, dosages for human treatment are typically in the range of about 0.001 mg/kg to about 500 mg/kg per day, for example, about 1 μg/kg to about 1 mg/kg per day, or about 1 μg/kg to about 100 μg/kg per day. For most large mammals, the total daily dose is about 1 to 100 mg, preferably about 2 to 80 mg. The dosage regimen can be adjusted to provide the optimal therapeutic response. The desired dose can be conveniently administered as a single dose, or as multiple doses administered at appropriate intervals, for example, as two, three, four, or more sub-doses per day.

Illustratively, the pullulan capsules of the present invention can be vaginally administered to a subject to provide the subject with an active agent, such as an antiprogestin, in an amount of about 1 μg/kg to about 1 mg/kg body weight, for example, about 1 μg/kg, about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg, about 125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, about 325 μg/kg, about 350 μg/kg, about 375 μg/kg, about 400 μg/kg, about 425 μg/kg, about 440 μg/kg, about 460 μg/kg, about 480 μg/kg, about 490 μg/kg, about 500 μg/kg, about 510 μg/kg, about 520 μg/kg, about 530 μg/kg, about 540 μg/kg, about 550 μg/kg, about 560 μg/kg, about 570 μg/kg, about 580 μg/kg, about 590 μg/kg, about 600 μg/kg, about 610 μg/kg, about 620 μg/kg, about 630 μg/kg, about 640 μg/kg, about 650 μg/kg, about 660 μg/kg, about 670 μg/kg, about 680 μg/kg, about 690 μg/kg, about 700 μg/kg, about 710 μg/kg, about 720 μg/kg, about [0014] In some embodiments, the dosage form of the present invention may be about 1 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 525 μg/kg, about 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725 μg/kg, about 750 μg/kg, about 775 μg/kg, about 800 μg/kg, about 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925 μg/kg, about 950 μg/kg, about 975 μg/kg, or about 1 mg/kg body weight.

The pharmaceutically active compound is present in the capsule-filled formulation at a therapeutically effective dose, preferably lower, than the therapeutically effective dose of the compound when administered orally. For example, the therapeutically effective dose may be less than 50 mg/day, less than 40 mg/day, less than 30 mg/day, less than 20 mg/day, less than 10 mg/day, less than 5 mg/day, less than 3 mg/day, between 1 mg/day and 50 mg/day, between 3 mg/day and 40 mg/day, between 3 mg/day and 30 mg/day, between 3 mg/day and 20 mg/day, between 3 mg/day and 10 mg/day, between 5 mg/day and 20 mg/day, or between 5 mg and 10 mg/day. In other embodiments, the effective dose may be 3 mg/day to 12 mg/day, 5 mg/day to 12 mg/day, or 12 mg/day to 25 mg/day. In other embodiments, the effective dose is 1 or 1.5 mg/day, 2 or 2.5 mg/day, 3 or 3.5 mg/day, 4 or 4.5 mg/day, 5 or 5.5 mg/day, 6 or 6.5 mg/day, 7 or 7.5 mg/day, 8 or 8.5 mg/day, 9 or 9.5 mg/day, 10 or 10.5 mg/day, 11 or 11.5 mg/day, 12 or 12.5 mg/day, 13 or 13.5 mg/day. In another related embodiment, the effective amount of the compound in the capsule fill formulation is 2, 3, 4, 5, 6, 7, 8, 9, or even 10 times less than the effective amount when administered systemically to treat endometriosis, uterine fibroids, and other diseases located in the area.

As described above, the pullulan capsule comprising the filled formulation comprising an activating agent is suitable for extending/long-term vaginal administration because it is expected that these compounds demonstrate low systemic concentrations and therefore demonstrate little hepatotoxicity or do not demonstrate hepatotoxicity. In one embodiment, the pullulan capsule is used for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 days or more days of administration period. Capsule can also be used for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more of administration period. During the administration period, capsule can be used every day or regularly, as used every other day, every other month or the like, but is preferably used once a day. The capsules may also be administered intermittently. For example, the capsules may be administered for an administration period of 1, 2, 3, 4, 5 or more months, followed by a rest period, followed by an administration period of 1, 2, 3, 4, 5 or more months, and so on.

In one embodiment, the capsules are administered intermittently so that the subject experiences menstruation during at least one of the pause periods. This approach is expected to avoid side effects associated with endometrial thickening or stasis that may accompany long-term treatment with progesterone antagonists, such as spotting, breakthrough bleeding, endometrial hyperplasia, or endometrial cancer. At least one of the pause periods, and preferably each of the pause periods, is of sufficient length to allow the subject to experience menstruation. More preferably, the subject experiences menstruation during each of the pause periods. In a particularly preferred embodiment, the capsules are administered daily for a four-month administration period, followed by a pause period during which the subject experiences menstruation, followed by another four-month administration period, and so on.

Serum estrogen and glucocorticoid levels should be routinely monitored in patients treated with the compositions of the invention.

The following non-limiting examples are provided to aid in understanding the teachings of the present invention.

Example 1. Preparation of pullulan capsules containing the selective progesterone receptor modulator CDB-4124

The following capsule fill formulations (without active agent) are liquefied at 50-70°C for liquid filling into capsules or molding into vaginal "tablets" as described below:

The fill formulations were used to fill several types of capsules, including regular gelatin capsules, softgel capsules, and pullulan capsules (Capsugel), or molded into uncoated vaginal "tablets" in order to test the suitability of different types of capsules or "tablets" as vaginal delivery vehicles.

First, standard gelatin capsules were filled with the above-mentioned fill formulations, wrapped with wet tissues, and incubated in an oven at 38°C to simulate vaginal conditions. Standard gelatin capsules were determined to be unacceptable vaginal delivery vehicles, in part due to the length of time required for the capsules to soften and release the drug. In addition, the residual capsule shell will remain in the vagina and need to be washed out after drug administration. In addition to these shortcomings, the pellets were generally not adhered to the vaginal mucosa. Accordingly, standard gelatin capsules were determined to be unacceptable vaginal delivery vehicles.

Next, the fill is compressed using a bullet-shaped plastic mold, the filled formulation is molded into an uncoated "tablet," and an applicator is used to deliver the drug. The uncoated bullet-shaped tablets are vaginally administered to human women with uterine fibroids. This vaginal administration method was determined to be impractical due to handling issues (the material typically melts during handling prior to administration) and the unavailability of a commercial-scale process for filling the bullet-shaped mold.

Standard soft gel capsules were also tried but were found to have the same problems as the gelatin capsules.

Finally, Capsugel was tested as a potential vaginal delivery vehicle and was determined to be potentially advantageous because the capsules dissolve in the uterus after a period of time and adhere to the vaginal mucosa.

Example 2. Pharmacokinetic Animal Study of Vaginal Delivery of Selective Progesterone Receptor Modulator CDB-4124

Ten healthy virgin female New Zealand white rabbits were administered a pullulan capsule (Capsugel, size 0) containing CDB-4124 intravaginally once daily for 10 consecutive days to determine the cumulative vaginal mucosal irritation potential and to obtain plasma samples for pharmacokinetic analysis. Five rabbits were assigned to each of two groups, the first group being administered with a vehicle control (pullulan capsule with .5 ml PEG 1000 filler) introduced into the upper vaginal fornix of each rabbit using a syringe applicator (Group 1), and the second group being administered with CDB-4124 (pullulan capsule with 12 mg CDB-4124 in .5 ml PEG 1000) (Group 2). Prior to the initial dose, immediately prior to each treatment, and prior to sacrifice, the external vaginal mucosa of each animal was examined for erythema, edema, and discharge. Gross pathology of all animals was examined.

All animals survived to the end of the study. The external vaginal mucosa of all Group 1 animals appeared normal during the study, and no abnormal signs were noted in any animal during the study. The external vaginal mucosa of 2/5 rabbits showed very mild erythema and/or edema 4 times and appeared normal in other respects. No macroscopic findings were noted in the ovaries, uterus, or three parts of the vagina in any group, nor were any histopathological findings observed in any group. The irritation index was considered "none". The data confirm that pullulan capsules are a safe delivery vehicle for the administration of active agents and can be safely used for local vaginal delivery of CDB-4124 with minimal vaginal irritation.

Samples (0.4 ml of blood) were collected from each rabbit in Group 2 before the last day of dosing (dose 10) and 1, 2, 3, 4, 6, 7, 10, 16, and 24 hours after the last dose administration for pharmacokinetic evaluation. The mean pharmacokinetic data are shown in Table 1 below. Graphs depicting the data from individual rabbits are shown in Figures 4A to 4B.

Table 1 - Pharmacokinetic data (Group II - 5 rabbits)

Example 3. Vaginal administration of pullulan capsules containing CDB-4124.

Capsugel was filled with the above-mentioned excipient-filled formulation with 12 mg CDB-4124 (telapriston acetate) and administered vaginally to human women with uterine fibroids once daily for a total of 2 weeks to measure the time required for the parent compound (CDB-4124) and primary metabolite (CDB-4453) to reach steady state and overall systemic exposure. The capsule was administered using a commercially available vaginal applicator modified by reversing the insert (see FIG5 ). The unmodified applicator included a syringe and a plunger, wherein the syringe had a relatively wide opening at one end and a relatively narrow opening at the other end. The applicator was designed so that the drug was placed in one end (entrance end) with a larger diameter opening, the applicator was inserted into the vagina, and the plunger was used to push the drug out of the syringe and into the vagina. In order to insert the filled NPcaps, the shell end of the capsule (having a slightly larger diameter) was placed in the narrow opening in the syringe to expose the lid. NPcaps were found to adhere to the vaginal mucosa immediately after insertion, so patients were advised of the importance of ensuring proper placement of the capsule prior to capsule release. Pharmacokinetic data were subsequently obtained from the patients.

Steady-state concentrations of the drug appear to be reached within a week of administration, after which there is no apparent drug peak as observed in other delivery methods, and in contrast to the same formulations in dogs and rabbits, where a drug peak is observed several hours after delivery. As shown in FIG1 , vaginal administration of pullulan capsules containing CDB-4124 results in approximately 1/6 of the systemic exposure of an equivalent oral dose based on the area under the curve (AUC). On the other hand, as shown in FIG2 , Cmax is lower than any of the oral doses. As shown in FIG3 , pullulan capsules containing CDB-4124 achieve sustained release of the active agent at a substantially constant rate without the high Cmax observed after oral administration of the drug.

In a previous oral study, CDB-4124 was administered at doses of 1, 3, 6, 9, and 12 mg for a total of 10 weeks. In the oral study, all doses were well tolerated and induced reliable menstrual cessation at doses as low as 3 mg. Menstrual cessation is directly related to the efficacy of the oral dose in both uterine fibroids and endometriosis. Remarkably, although the 12 mg vaginal dose achieved only a fraction of the ineffective 1 mg oral dose exposure, it resulted in menstrual cessation in 3 women. Statistical significance (p < 0.05) was seen in a pairwise comparison of 6 women in terms of both menstrual bleeding reduction using the Pictorial Blood Loss Assessment Chart (PBAC) and overall uterine fibroid symptom relief as measured by the Uterine Fibroid Symptom Quality of Life Survey (UFSQOL). Given the overall low exposure of the 12 mg dose in those women who continued to menstruate, further improvements in symptom relief were expected with longer-term exposure to the drug. In an efficacy study in which CDB-4124 was administered orally, women experienced a nearly 50% reduction in average uterine fibroid size at a 25 mg dose. When these women were subsequently upgraded to a 50 mg oral dose for another four months, uterine fibroid size was reduced to approximately 25% of its initial volume. Based on uterine fibroid symptom assessment as measured by the UFSQOL score, women taking CDB-4124 orally were generally asymptomatic. It is expected that although the maximum exposure is 1/100 of the 50 mg oral dose, CDB-4124 delivered vaginally at a 12 mg dose has greater activity than the oral 50 mg dose. Even at this low exposure, significant improvements in uterine fibroid-related conditions have been observed after only 4 weeks of treatment.

Thus, administration of pullulan capsules provides a means for delivering sustained levels of active agent to the vaginal mucosa while minimizing systemic exposure of the drug.

Example 4. Vaginal Administration of Pullulan Capsules Containing CDB-4124 Dispersed in PEG 1000 and Isopropyl Myristate

A mixture of PEG 1000 (~96% excipient w/w), isopropyl myristate (~4% excipient w/w), and BHT (~0.02% excipient w/w) was heated to 50°C under stirring until a clear liquid was obtained. CDB-4124 was added and the mixture was stirred until CDB-4124 was completely dissolved. After cooling to room temperature under continuous stirring, the formulation was filled into pullulan capsules (Capsugel).

The study was initiated in healthy women to compare the pharmacokinetics (Cmax and AUC) and safety of two different formulations of CDB-4124 for vaginal administration for 1 or 6 days. Briefly, volunteers who met the eligibility criteria were randomized to receive the formulation described in Example 3 (12 mg CDB-4124 + 99.98% PEG 1000 + 0.02% BHT) (Formulation A); or a formulation containing isopropyl myristate (12 mg CDB-4124 + 95.98% PEG 1000 + 4% isopropyl myristate + 0.02% BHT) (Formulation B) as their first assigned treatment.

Subjects received either a single dose of Formulation A or daily dosing of Formulation B for 6 days. After a 7-day washout period, subjects received the alternative treatment. On the day of treatment with Formulation A, and on the first and last day of treatment with Formulation B, subjects stayed in the clinic overnight and underwent 32-hour pharmacokinetic assessments at the following time points: 0, 0.5, 1, 2, 4, 8, 12, 16, 24, 28, and 32 hours after drug administration. Formulation B was administered daily in the clinic after a trough blood sample was drawn.

Tables 2-5 below present a comparison of the AUC and _Cmax of formulations containing isopropyl myristate (Formulation B) and formulations without isopropyl myristate (Formulation A). Tables 2-4 present the total AUC and Cmax in subjects after receiving one day of dosing with Formulation A (A), one day of dosing with Formulation B (B1), or seven days of dosing with Formulation B (B1). Table 6 presents the mean AUC and _Cmax for subjects who received a single dose of Formulation A (A) or Formulation B (B1) or seven days of dosing with Formulation B (B2). Compared to the formulation of Example 3, the formulation containing isopropyl myristate surprisingly resulted in a higher area under the curve (AUC) but _an equivalent _Cmax . The addition of isopropyl myristate to the capsule fill formulation resulted in a significant improvement in absorption and a significant reduction in inter-subject variability.

Table 2: 24-hour total AUC (ng-hour/ml)

Table 3: 32-hour total AUC (ng-hour/ml)

Table 4: 32-hour _Cmax

For Table 2-4:

A = Formulation A (12 mg CDB-4124 + 99.98% PEG 1000 + 0.02% BHT)

B1 = Formulation B (12 mg CDB-4124 + 95.98% PEG 1000 + 4% isopropyl myristate + 0.02% BHT) (1st PK)

B2 = Formulation B (12 mg CDB-4124 + 95.98% PEG 1000 + 4% isopropyl myristate + 0.02% BHT) (2nd PK; after 12 mg daily for 7 days)

Table 5: AUC (overall; 24 hours)

A**Single dose (Formulation A)

B1***Day 1 PK (Formulation B)

B2****Daily dose Day 7 PK (Formulation B).

Claims (17)

1. A pharmaceutical preparation for vaginal use, the pharmaceutical preparation comprising a mucosal adhesion capsule and a capsule filling preparation, the mucosal adhesion capsule comprising 85 to 90% pullulan by weight and excluding a solubilizing agent, the capsule filling preparation comprising an antiprogestin dispersed in a mixture of excipients (a) isopropyl myristate or isopropyl palmitate and (b) polyethylene glycol, wherein the amount of isopropyl myristate or isopropyl palmitate is 1% to 15% (w/w) of the excipient mixture, the amount of polyethylene glycol is 99% to 85% (w/w) of the excipient mixture, wherein the antiprogestin is CDB-4124. 2. The pharmaceutical formulation of claim 1, wherein the isopropyl myristate or isopropyl palmitate is present in an amount ranging from 2% to 8% (w/w) of the excipient mixture, and the polyethylene glycol is present in an amount ranging from 98% to 92% (w/w) of the excipient mixture. 3. The pharmaceutical formulation of claim 1, wherein the isopropyl myristate or isopropyl palmitate is present in an amount ranging from 3% to 5% (w/w) of the excipient mixture, and the polyethylene glycol is present in an amount ranging from 97% to 95% (w/w) of the excipient mixture. 4. The pharmaceutical formulation of claim 3, wherein the isopropyl myristate or isopropyl palmitate is present in an amount of 4% (w/w) of the excipient mixture. 5. The pharmaceutical formulation of claim 3, wherein the polyethylene glycol is present in an amount of 96% (w/w) of the excipient mixture. 6. The pharmaceutical formulation according to any one of claims 1-5, wherein the capsule-filling formulation comprises an antiprogestin dispersed in a mixture of excipients (a) isopropyl myristate and (b) PEG 1000. 7. The pharmaceutical formulation according to claim 1, wherein CDB-4124 is present in an amount ranging from 2 to 80 mg. 8. The pharmaceutical formulation according to claim 1, wherein CDB-4124 is present in an amount selected from 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg and 20 mg. 9. The pharmaceutical formulation of claim 8, wherein the formulation comprises 12 mg CDB-4124. 10. The pharmaceutical formulation according to any one of claims 1-9, wherein the excipient mixture further comprises an antioxidant. 11. The pharmaceutical formulation according to claim 10, wherein the antioxidant is butylated hydroxytoluene. 12. The pharmaceutical formulation of claim 11, wherein butylated hydroxytoluene is present at 0.02% w/w of the excipient mixture. 13. The pharmaceutical formulation of claim 11, comprising a mucosal adhesion capsule containing pullulan and a capsule-filling formulation, the capsule-filling formulation comprising 12 mg of CDB-4124 dispersed in a mixture of (a) 4% (w/w) isopropyl myristate; (b) 95.98% (w/) PEG 1000 and (c) 0.02% butylated hydroxytoluene. 14. The pharmaceutical formulation of any one of claims 1-13, wherein the mucosal adhesion capsule comprises 86.3% pullulan. 15. The pharmaceutical formulation of claim 14, wherein the mucosal adhesion capsule comprises pullulan in an amount of 86.3% by weight, potassium chloride in an amount of 1.32% by weight, carrageenan in an amount of 0.27% by weight, a surfactant selected from sugar esters, sorbitan monolaurate and combinations thereof in an amount of 0.15% by weight, and water. 16. Use of the pharmaceutical preparation according to any one of claims 1-15 in the preparation of a medicament for transvaginal administration to the vaginal mucosa of a woman, the medicament being used to treat progesterone-dependent conditions selected from: endometriosis and related pain, adenomyosis, ovarian endometrioma, dysmenorrhea, uterine fibroids, endometrial hyperplasia, ovarian cancer, and cervical cancer, wherein the antiprogestin is CDB-4124. 17. The use according to claim 16, wherein the drug is administered once daily.