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    • 专利摘要:
    FORMULATIONS AND METHODS FOR VAGINAL DISTRIBUTION OF ANTIPROGESTINES CROSS REFERENCE FOR RELATED APPLICATIONS. The object of the present invention is relevant to the field of vaginal delivery of pharmaceutically active agents. Modalities of the present invention disclose methods for treating a variety of progesterone related disorders by vaginal administration of a pullulan capsule consisting of one or more antiprogestins.
    公开号:BR112014029131B1
    申请号:R112014029131-4
    申请日:2013-05-30
    公开日:2021-03-09
    发明作者:Joseph S. Podolski；Kuang Hsu
    申请人:Allergan Pharmaceuticals International Limited；
    IPC主号:
    专利说明:

    DESCRIPTIVE REPORT REMISSIVE REFERENCE TO RELATED ORDERS
    [001] This Order claims the priority of US Provisional Patent Application No. 61 / 653,674 filed on May 31, 2012, the contents of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION
    [002] In various embodiments, the present invention relates to mucoadhesive pharmaceutical compositions and their use for the local administration of active agents, such as antiprogestogestin to the vaginal mucosa. In related embodiments, mucoadhesive compositions are administered to treat a variety of conditions related to progesterone. BACKGROUND OF THE INVENTION
    [003] The effect of the steroid hormone progesterone on the reproductive system has been well documented. For example, progesterone is vital for establishing and maintaining pregnancy and has an effect on various tissues of the reproductive system. The action of progesterone on tissues outside the reproductive system has been reported, but it is less well characterized.
    [004] Antiprogestins, compounds that inhibit the action of progesterone, have considerable potential for use in pharmacological regulation of fertility and a variety of conditions and diseases such as breast cancer and endometriosis. The first reported antiprogestin, Mifepristone (RU 486), is one of a series of derivatives -northestosterone-19 with strong affinity for progesterone and glucocorticoid receptors and with antiprogestational and antiglucocorticoid activity. A variety of antiprogestins based on the norprogesterone-19 backbone have also been synthesized.
    [005] Several disadvantages are associated with the use of known antiprogestins, making them less than ideal for chronic administration, particularly when distributed orally. If these and other limitations associated with antiprogestin treatment could be improved, it would result in a significant advance in the treatment of hormone-dependent disorders. SUMMARY OF THE INVENTION
    [006] In one embodiment, the present invention provides a mucoadhesive capsule comprising pullulan and a capsule fill formulation comprising an active agent, preferably an antiprogestin and one or more excipients to deliver the active agent to the vaginal mucosa.
    [007] In other embodiments, the present invention provides methods for treating a variety of progesterone related conditions in which a patient in need of such treatment by administering a mucoadhesive capsule comprising pullulan and a capsule fill formulation which comprises an antiprogestin and one or more excipients for the patient's vaginal mucosa.
    [008] In one embodiment, the present invention provides a kit comprising a mucoadhesive comprising pullulan and a capsule fill formulation comprising an active agent, preferably an antiprogestin and one or more excipients to deliver the active agent to the vaginal mucosa in combination with a vaginal applicator.
    [009] Progesterone-related conditions that can be treated with the mucoadhesive capsules of the invention include, but are not limited to, endometriosis and associated pain, adenomyosis, ovarian endometriomas, dysmenorrhea, hormone-dependent endocrine tumors, uterine fibroids, endometrial hyperproliferation , ovarian cancer, cervical cancer and breast cancer. Compositions of the present invention can also be used to induce menstruation, to induce labor and for contraception. BRIEF DESCRIPTION OF THE FIGURES
    [0010] FIG. 1 illustrates the area under the curve (AUC) of CDB-4124 and its monodemethylated metabolite CDB-4453, after the administration of CDB-4124 to human females with uterine fibroids at 1 mg, 3 mg, 6 mg, 9 mg and 12 mg oral doses compared to vaginal administration of a 12 mg dose.
    [0011] FIG. 2 illustrates a comparison between the Cmax (peak serum concentration) of CDB-4124 and CDB-4453 after oral doses of 1 mg, 3 mg, 6 mg, 9 mg and 12 mg for human females with uterine fibroids, compared with administration vaginal dose of 12 mg.
    [0012] FIG. 3 illustrates pharmacokinetic data observed at steady state for a period of 24 hours after oral administration of 1 mg, 3 mg, 6 mg, 9 mg and 12 mg versus 12 mg vaginal doses of CDB-4124.
    [0013] FIG. 4A-B illustrates pharmacokinetic data observed over a 24-hour period in rabbits after the last of 10 daily doses of 12 mg CDB-4124 delivered to the vagina. Panel A illustrates CDB-4124; Panel B illustrates CDB-4453.
    [0014] FIG. 5 illustrates the applicator used to vaginally deliver pullulan capsules comprising 12 mg CDB-4124 to human females. DETAILED DESCRIPTION OF THE INVENTION
    [0015] While the present invention is capable of being incorporated in several forms, the description below of several modalities is made with the understanding that the present disclosure is considered as an exemplification of the invention and is not intended to limit the invention to the modalities illustrated. Titles are provided for convenience only and should not be construed to limit the invention in any way. The modalities illustrated under any title can be combined with the modalities illustrated under any other title.
    [0016] It is to be understood that any ranges, proportions and scales of the ratios that can be formed by any of the numbers or data presented in this document represent other embodiments of the present invention. This includes intervals that can be formed that do or do not include a finite upper and / or lower limit. Therefore, those skilled in the art will observe such proportions that many, ranges and ranges of ratios can be unequivocally derived form the data and numbers presented here and all represent embodiments of the invention.
    [0017] Before the present compounds, compositions and methods are disclosed and described, it is to be understood that the terminology used in this document is for the purpose of describing particular modalities only and is not intended to be a limiting factor. It should be noted that, as used in the embodiment of the present invention and the appended Claims, the singular forms "a", "one" include plural referents, unless the context clearly expresses otherwise.
    [0018] Definitions
    [0019] The term “capsule” refers to a hard shell pharmaceutical capsule. The capsule consists of a body and the cap and can include a fill formulation containing a pharmacologically active agent.
    [0020] The term "oral" administration means that the active agent is a formulation designed to be ingested, that is, designed to be delivered to the gastrointestinal system for absorption.
    [0021] The term "effective dose" means an amount of active component of the composition sufficient to treat a given condition.
    [0022] The term "selective progesterone receptor modulators" means compounds that affect progesterone receptor functions in a specific form of tissue. The compounds act as progesterone receptor antagonists in some tissues (for example, in breast tissue) and as progesterone receptor agonists in other tissues (for example, in the uterus).
    [0023] The term "treat" or "treatment" as used here refers to any treatment of any progesterone-dependent disorder or disease and includes, but is not limited to, inhibiting the disorder or disease stopping the development of the pathology or disease ; alleviate the disorder or illness, for example causing regression of the disorder or illness; or relieve the condition caused by the disease or disorder, relieving the symptoms of the disease or disorder.
    [0024] The term "prevent" or "prevention", in relation to a disorder dependent on progesterone or disease, means to prevent the appearance of the disorder or development of the disease if nothing had happened, or to prevent further disorder or development of the disease, if the disorder or illness was already present. For example, compositions of the present invention can be used to prevent the recurrence of tumors. Tumor recurrence may occur because of residual microscopic groups or nests of tumor cells that later expand into clinically detectable tumors.
    [0025] The term "progesterone agonist" means that a compound that binds to a progesterone receptor and mimics the action of the natural hormone.
    [0026] The term "progesterone antagonist" means a compound that binds to a progesterone receptor and inhibits the effect of progesterone.
    [0027] In one embodiment, the present invention relates to methods for 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.
    [0028] In a preferred embodiment the present invention relates to methods for the treatment of a progesterone-related condition by the vaginal administration of a mucoadhesive in which a patient in need of such treatment through the administration of a mucoadhesive capsule comprising pullulan and a capsule filling formulation comprising an antiprogestin and one or more excipients for the patient's vaginal mucosa.
    [0029] Pullulan is a water-soluble polysaccharide polymer made up of maltotriose units linked to each other by a β-1,6 glycosidic bond. The three glucose units in each maltotriose unit are connected by a β-1,4 glycosidic bond. The pullulan binding pattern is responsible for the adhesive properties of the polysaccharide and its ability to form oxygen-impermeable fibers and films. Pullulan is produced from starch by the fungus Aureobasidium pullulans and can be produced commercially by batch fermentation, as described in Leathers, Appl. Microbiol. Biotechol., 62: 468-473 (2003).
    [0030] Capsules
    [0031] Capsules suitable for use according to the invention include, but are not limited to, NPcaps® available from Capsugel containing pullulan, carageenan and potassium chloride, as well as capsules described in US Patent No. 8,105,625 and in the Publications of US Patent Application no. ° 2005/0249676, the content of each of which is included in the addendum by reference.
    [0032] In one aspect, capsules for use according to the invention comprise pullulan with a molecular weight between about 50 to 500 kDa, between 100 and 400 kDa, between about 150 to 300 kDa and preferably between about 180 and 250 kDa.
    [0033] In another aspect, capsules for use according to the invention comprise pullulan from about 50% to about 100% by weight (empty capsule). In other respects, the capsules make up about 60 to 90 or 70 to 90 or 80 to 90% by weight of pullulan. Preferably, the capsules comprise about 85 to 90% by weight of pullulan.
    [0034] Capsules for use according to the invention may comprise (in addition to pullulan), without limitation, one or more clotting agents (for example, hydrocolloids or polysaccharides such as alginates, agar gum, guar gum, locust bean, carrageenan, gum tare, gum arabic, pectin, xanthan and the like); salts comprising cations such as K +, Li +, Na +, NH4 +, Ca2 +, Mg2 +; and / or surfactants such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, benzalkonium chloride, benzethonium chloride, cetrimide, fatty acid sugar esters, glycerol monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol, dimethylsteroloxane lecithin, as described in Patent Application Publication no. 2005/0249676.
    [0035] Capsules for use according to the invention may further include one or more plasticizing agents (for example, glycerol, propylene glycol, polyvinyl alcohol, sorbitol, maltitol and the like); dissolution, enhancing agents (for example, maltose, lactose, sorbitol, mannitol, xylitol, maltitol and the like); reinforcing agents (for example, polydextrose, cellulose, maltodextrin, gelatin, gums and the like); dyes, and / or opacifiers as described in US Patent No. 8,105,625.
    [0036] In a preferred embodiment, the capsule comprising 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 from 10% to 15% by weight.
    [0037] 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%, in weight, surfactants, selected from sugar esters, sorbitan monolaurate and combinations in an amount of 0.15% by weight and water in an amount of 12% by weight.
    [0038] In another aspect, the pullulan capsule provides a continuous release of the active agent at a substantially constant rate over a period of time (i.e., a stable release of the active agent) to the subject. The present inventors have found that capsules comprising pullulan are surprisingly advantageous for vaginal delivery of active agents. In particular, pullulan-based capsules are a safe, effective and convenient vehicle for delivering active agents to the vaginal mucosa. The present inventors found that the pullulan capsules adhere to the vaginal mucosa, ensuring that the capsules remain in the vagina at a desired location during the period of drug distribution. In addition, due in part to the solubility of pullulan, no residual capsule is left in the vagina after the drug is released, unlike conventional gelatin capsules. The present inventors surprisingly found that when used as a vaginal delivery device, pullulan capsules effect a continuous release of active agents, at a substantially constant rate, maintaining a low Cmax (peak concentration) of the active agent and ensuring a high concentration drug site. Thus, sustained levels of the active agent are distributed to the vaginal mucosa while systemic concentrations are minimized.
    [0039] The filling capsule formulation can include any active agent. Preferably, the capsule fill formulation is comprised of an antiprogestin which can be a pure antiprogestin or a selective progesterone receptor modulator.
    [0040] The capsule filling formulation may 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 the dosage. Excipients can function as agents, release modifiers, wetting agents, tonicity agents or combinations thereof. For example, excipients may include hydrophilic excipients, such as natural and synthetic water-soluble polymers, including, but not limited to, polyethylene glycol (PEG), polyvinyl piyrolidone, polymethacrylates, polylysine, polyvinyl alcohol, albumin, alginate, gelatin, chitosan, cellulose, FICOLL®, hydroxyethyl cellulose, starch, carboxyethylcellulose, rich in starch,, hydroxypropyl cellulose, hyaluronic acid, cellulose sesquioxide, carboxymethylcellulose, dextran sulfate and its derivatives. Particular hydrophilic polymers for use in filler capsule formulations can be based on factors such as molecular weight, hydrophilicity and viscosity. Hydrophilic polymers can be used as bulking or wetting agents.
    [0041] Excipients may also include lipids such as, without limitation, one or a mixture of different degrees of Gelucire, Labrafil (R), Labrasol (r) and the like. Gelcuire compositions are amphiphilic inert polyglycolated glycerides, which form micelles in aqueous media. They are identified by their melting point (degrees Celsius) / HLB value (hydrophilic-lipophilic balance). Gelcuire compositions particularly preferred for use in capsules are Gelucire 44/14 (polyoxyl-32 lauroyl glycerides) and Gelucire 50/13 (polyoxy-32 stearoyl glycerides).
    [0042] In a preferred embodiment, the fill formulation comprises a pharmaceutically active compound, preferably CDB-4124 and excipients Gelucire 44/14 and PEG. In related aspects, Gelucire 44/14 is present as between 50% and 90%, preferably about 75% w / w excipient and PEG is present between 50% and 10%, preferably about 25% w / w excipient. In particularly preferred embodiments, the fill formulation comprises CDB-4124 and excipients consisting of 74.13% (w / w) Gelucire and 25.87% PEG 400.
    [0043] In particularly preferred embodiments, the capsule fill formulation consists of or consists essentially of a pharmaceutically active agent, preferably CDB-4124 and about 100% w / w PEG 1000 as an excipient. Optionally, 0.02% butylhydroxytoluene is also present in the 0.02% w / w excipient (as an antioxidant).
    [0044] In other preferred embodiments, the capsule filling formulation is composed of a pharmaceutically active agent, preferably CDB-4124 and excipients consisting of 30% to 60% w / w M Wecobee (fatty acid ester), 30% at 60% w / w 1000 PEG and 0.1% to 5% w / w lecithin. In a related embodiment, the capsule fill formulation comprises CDB-4124 as an active agent and excipients consisting of about 50% (eg 50.1%) w / w, Wecobee M, approximately 50% (eg 49 , 4%) w / w 1000 PEG and approximately 0.5% w / w lecithin.
    [0045] Excipients can also include sugars such as mannitol, sorbitol, xylitol, glucitol, ducitol, inositol, arabinitol, arabitol, galactitol, iditol, allitol, fructose, sorbose, glucose, xylose, trehalose, glucose, galactose, thalose, ribose, arabinose , sucrose, maltose, lactose, fucose, matotriosis and the like. The amount of sugar can be adjusted to provide the osmotic pressure or humectant.
    [0046] Wetting agents can be used in drug capsule fill formulation formulation to facilitate water entry into the capsule and wetting of the active agent and include gelatin, casein, lecithin, acacia gum, cholesterol, calcium stearate, stearic acid , etc.
    [0047] The capsule filler formulation may include one or more disintegrants such as corn starch, potato starch, modified starches, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, sodium alginate, cellulose polyacrylic pot, gums, agar, guar, locust bean, pectin, xanthan gum, agar, etc.
    [0048] The capsule fill formulation can comprise one or more flow agents or glidants to promote fluidity including colloidal silica, corn starch, talc, calcium silicate, magnesium silicate, tribasic calcium phosphate, silicone hydrogel, etc. .
    [0049] The capsule filling formulation can also include a foaming agent such as polyethylene glycol, saponin, sorbitan trioleate, sorbitan monostearate, sorbitan monopalmitate, glyceryl monostearate and the like.
    [0050] Active agents
    [0051] The capsule filling formulation can comprise any pharmacologically active agent that has a therapeutic effect when distributed vaginally.
    [0052] In some embodiments, the capsule fill formulation comprises an estrogen (ie, a natural estrogen or a synthetic compound that mimics the physiological effect of natural estrogens) including, but not limited to, estradiol (17 β-estradiol), estridiol acetate, estradiol benzoate, estridiol cypionate, estridiol decanoate, estradiol diacetate, estradiol heptanoate, estradiol valerate, 17α-estradiol, estriol, estriol succinate, estrone, estrone acetate, estrone sulfate, stropipate (sulfate estrone piperazine), ethinyl estradiol (17α-ethinyl estradiol, ethinyl estradiol, ethinyl estradiol), ethinyl estradiol 3-acetate, ethinyl estradiol 3-benzoate, mestranol, quinestrol, estrogen nitrates derivatives or combinations thereof.
    [0053] In other embodiments, the capsule fill formulation comprises a progestin (ie, natural or synthetic compounds that have progestational activity, including, but not limited to, 17a-17-hydroxy-11-methylene-19-norpregna-4 , 15-dien-20-in-3- one, 17α-ethynyl-19-nortestosterone, where 17α, 17- deacetylnorgestimate, 19-nor-17-hydroxyprogesterone, 19-norprogesterone, 3beta-hydroxidesogestrel, 3-quetodesogestrel (etonogestrel) , acetoxypregnenolone, algestone acetophenide, allyltrenol, amgestone, anagestone acetate, chlormadinone, chlormadinone acetate, cyproterone, cyproterone acetate, oxime d-17β-acetoxy-13β-ethyl-17α-ethinylgon-4-in-3-one, demon , desogestrel, dienogest, dihydrogesterone, dimethisterone, drospirenone, didrogesterone, ethisterone (pregneninolone 17α ethinyl testosterone), ethinodiol diacetate, fluorogestone acetate, gastrinone, gestadene, gestodene, gestonorone, gestrinone, hydroxymethylprone, hydroxymethyl, hydroxymethyl, hydroxymethyl, hydroxy xiprogesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, levonorgestrel (l-norgestrol), linestrenol (linoestrenol), mecirogestone, medrogestone, medroxyprogesterone, normetroestrone, melamine, estrogen, norestrone, melamine, estrogen, melamine, norestrone (norethisterone) (19-nor- 17α-ethyltestosterone), norethisterone acetate (norethisterone acetate), norethinodrel, norgestimate, norgestrel (dl-norgestrel and d-norgestrel), norgestrienone, normetisterone, progesterone, promegestone, quingestanol, tibolone, trimestanol, tibolone or their combinations.
    [0054] In other embodiments, the capsule fill formulation comprises an estrogen and progesterone.
    [0055] In a preferred embodiment, the active agent is a progesterone antagonist.
    [0056] In one embodiment, the capsule fill formulation comprises a steroid compound disclosed in US Patent Nos. 6,861,415 and 6,900,193, the contents of which are incorporated into the addendum by reference. In a preferred embodiment, the steroidal compound is CDB-4124 (21-methoxy-17α-acetoxy-11β- (4 N, N-dimethylaminophenyl) -19- norpregna-4,9-diene-3,20-dione) or CDB -4453 (21-methoxy-17α-acetoxi- 11β- (4-N-methylaminophenyl) -19-norpregna-4,9-diene-3,20-dione).
    [0057] Other preferred progesterone antagonists that may be present in the capsule fill formulation include, but are not limited to, Mifepristone (RU-486; 11 β - [4 N, N-dimethylaminophenyl] -17 β -hydroxy-17- (1 -propynyl) -estra-4,9-dien-3-one), Lilopristone (11 β - (4 N, N-dimethylaminophenyl) -17 β -hydroxy-17 - ((Z) -3-hydroxypropenyl) estra-4 , 9-dien-3-one), Onapristone (11 β - (4 N, N-dimethylaminophenyl) -17 β -hydroxy-17- (3-hydroxypropyl) -13 β -estra-4,9- dien-3- ona), asoprisnil (benzaldehyde, 4 - [(11 β, 17 β) -17-methoxy-17- (methoxymethyl) -3-oxoestra-4,9-dien-11-yl] -1- (E) -oxy ; J867), its metabolites J912 (4- [17 β -Hydroxy-17 β - (methoxymethyl) -3-oxoestra-4,9-dien-11 β -il] benzaldehyde- (1E) -oxy) and CDB-2914 (17 β-acetoxy-11 β - (4- N, N-dimethylaminophenyl) -19-norpregna-4,9-dien-3,20-dione).
    [0058] Other antiprogestins that may be present in the capsule fill formulation include compounds described in US 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, 4,871,724, 4,921,845, 4,921, 4,421, 4,921, 4,821, 4,421, 4,921, 4,821, 4,421, 4,921, 4,421, 4,921, 4,421, 4,921, 4,441, 4,921, 4,441, and 4,921,845. 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, 6,6,3,3, 6,6, 4,3, 6,6, 3,3, 6,6 the contents of each of which are incorporated herein by reference ..
    [0059] Other antiprogestins that may be useful in the invention include, but are not limited to, JJNJ-1250132, (6 β, 11 β, 17 β) -11- (4-dimethylaminophenyl) -6-methyl-4 ', 5'- dihydrospiro [estrra-4,9-diene-17,2 '(3'H) - furan] -3-one (ORG-31710); (11 β, 17 β) -11- (4-acetylphenyl) -17,23-epoxy-19,24-dinorcola-4,9,20-trien-3-one (ORG-33628); (7 β, 11 β, 17 β) -11- (4-dimethylaminophenyl-7-methyl] -4 ', 5'-dihydrospiro [estrra-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-19984A; RTI-3021-012; RTI-3021-022; RTI-3021-020; RWJ-25333; ZK-136796; ZK-114043; ZK-114043; ZK-114043; ZK-114043; ZK-114043; ZK-114043; -230211; ZK-136798; ZK-98229; ZK-98734; ZK-137316; 4- [17 β -Methoxy-17β- (methoxymethyl) -3-oxoestra- 4,9-dien-11β-yl] benzaldehido-1 - (E) -oxy; 4- [17β-Methoxy-17β- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehido-1- (E) - [O- (ethylamino) carbonyl] oxime; 4- [17 β -Methoxy-17 β - (methoxymethyl) -3- oxoestra-4,9-dien-11β-yl] benzaldehyde-1- (E) - [O- (ethylthio) carbonyl] oxime; ( Z) -6 '- (4-cyanophenyl) -9.11 β-dihydro-17 β -hydroxy-17 β - [4- (1-oxo-3-methylbutoxy) -1-butenyl] 4'H-naftho [ 3 ', 2', 1 '; 10,9,11] estr-4-en-3-one; 11 β - (4-acetylphenyl) -17 β -hydroxy-17 β - (1,1,2,2 , 2-pentafluoroethyl) estra-4,9-dien-3-one; 11beta- (4-Acetylphenyl) -19,24-dinor- 17,23-epoxy-17alpha-chola-4,9,20-trien-3-one; (Z) -11beta, 19- [4- (3-Pyridinyl) -o-phenylene] -17beta-hydroxy-17 β- [3-hydroxy-1-propenyl] -4-androsten-3-one; 11beta- [4- (1-methylethyl) phenyl] -17β-hydroxy-17beta- (3-hydroxypropyl) -13β-estrra-4,9-dien-3-one; 4 ’, 5’-Dihydro-11beta- [4- (dimethylamino) phenyl] -6beta-methylpiro [estra-4,9-dien-17beta, 2’ (3’H) -furan] -3-one.
    [0060] In related aspects, capsule fill formulations comprise a pharmaceutically acceptable salt of a pharmaceutically active compound such as an antiprogestin. Depending on the conditions of the process, the obtained salt compound can be in neutral or salt form. Salt forms include hydrates and other solvents and also crystalline polymorphs. Both the free base and the salts of these final products can be used in accordance with the invention. Acid addition salts. they can in a way known for themselves be transformed into a free base using basic agents such as alkaloid or by ion exchange. The free base obtained can also form salts with organic or inorganic acids.
    [0061] In the preparation of acid addition salts, preferably such acids are used which form properly pharmaceutically acceptable salts. Examples of such acids are hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic acid, alicyclic carboxylic or sulfonic acids, 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, hydroximalic acid, pyruvic acid, aspartic acid, glutamic acid, p-hydroxybenzoic acid, embonic acid, ethanesulfonic acid, hydroxyethhanesulfonic acid, phenylacetic acid, mandelic acid alogenbensenesulfonic acid, toluenesulfonic acid, galactaric acid, galacturonic acid or naphthalenesulfonic acid. All polymorphs of crystalline form can be used in accordance with the invention.
    [0062] Acid addition salts can also be used in accordance with the invention and can be prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. Acid addition salts. pharmaceutically acceptable are formed with metals or amines, such as alkali and alkali metals or organic amines. Examples of metals used are sodium, potassium, calcium, magnesium and the like. Examples of suitable amines are amino acids such as lysine, choline, diethanolamine, ethylenediamine, N-methylglucamine and the like.
    [0063] Disorders that can be treated by vaginal distribution of pullulan capsules
    [0064] Pullulan capsules, which comprise a filler formulation comprising a pharmaceutically active agent, can be administered into a subject's vagina to treat a variety of disorders or achieve a variety of desired therapeutic effects on a subject. Preferably, the subject is a female mammal, more preferably a human female.
    [0065] In some embodiments of the invention, a pullulan capsule comprising a pharmaceutically active compound is administered to a female patient in need of treating a disorder selected from the group consisting of endometrial hyperproliferation, endometriosis (pain or associated), dysmenorrhea, uterine fibroids, adenomyosis, endometrioma, ovarian cancer, cervical cancer. In a preferred embodiment, endometriosis, dysmenorrhea, uterine fibroids, adenomyosis, ovarian cancer or cervical cancer are treated by administering an intravaginal preparation containing a compound of the general formula to the vagina of a patient in need of such treatment.
    [0066] In another embodiment of the invention, a pullulan capsule of the invention is administered to a female in need to induce menstruation in the female sex in which case the capsule filler formulation preferably comprises a progestin such as medroxyprogesterone acetate.
    [0067] In yet another embodiment of the invention, a pullulan capsule of the invention is administered to a female in need to induce labor.
    In yet another embodiment of the invention, a pullulan capsule of the invention is administered to a female in need of them as a contraceptive, in which case the filler capsule formulation preferably comprises a progestin and optionally an estrogen.
    [0069] Dosages and administration regimes
    [0070] The therapeutically effective amount of active agent required for use in therapy varies with the length of time that the activity is desired, and the age and condition of the patient to be treated, among other factors and is ultimately determined by the attending physician. In general, however, doses used for human treatment are usually in the range of approximately 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 from 1μg / kg to about 100 μg / kg / day. For most large mammals, the total daily dose is about 1 to 100 mg, preferably about 2 to 80 mg. The dosage can be adjusted to provide an optimal therapeutic response. The desired dose can be conveniently administered as a single dose or multiple doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
    [0071] Illustratively, a pullulan capsule of the invention can be administered vaginally 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 of 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 450 μg / kg, about 475 μg / kg, about 500 μg / 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 of body weight
    [0072] Pharmaceutically active compounds are present capsule fill formulation at the effective therapeutic dose which is preferably lower compared to the effective therapeutic dose of the compound when administered orally. For example, the effective therapeutic 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 day and 10 mg / day, between 5 mg / day and 20 mg / day or between 5 mg and 10 mg / day. In other modalities, the effective dose can be 3 mg per day at 12 mg / day, 5 mg / day at 12 mg / day, or 12 mg / day at 25 mg / day. In certain 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, 14 or 14.5 mg / day, 15 or 15.5 mg / day, 16 or 16.5 mg / day, 17 or 17.5 mg / day, 18 or 18.5 mg / day, 19 or 19.5 mg / day, 20 or 20.5 mg / day, 21 or 21.5 mg / day, 22 or 22.5 mg / day, 23 or 23.5 mg / day, 24 or 24.5 mg / day or 25 or 25.5 mg / day. In other related embodiments, the effective amount in the compound in the capsule fill formulation is 2 times, 3 times, 4 times 5 times, 6 times, 7 times, 8 times, 9 times and even 10 times less than the effective amount when systematically administered the treatment of endometriosis, uterine fibroid, and other diseases located in the region.
    [0073] Pullulan capsules, which comprise a filler formulation comprising an active agent, as described above, are suitable for prolonged / chronic vaginal administration, because these compounds are expected to exhibit low systemic concentrations and therefore little or no liver toxicity. In one embodiment, pullulan capsules are administered for an administration period of 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 or more days. The capsules can also be administered for an administration period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months. The capsules can also be administered for an administration period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years. During the administration period, the capsules can be administered daily or periodically, like every other day, every other month, and the like, but preferably they are administered once a day. Capsules can also be administered intermittently. For example, capsules can be administered for an administration period of 1, 2, 3, 4, 5 or more months, followed by an interruption period, followed by an administration period of 1, 2, 3, 4, 5 or more months and so on.
    [0074] In one embodiment, the capsule is administered intermittently, such that the subject menstruates for at least one interruption period. This approach is expected to avoid the adverse effects associated with a thickened or stagnant endometrium that may accompany prolonged treatment with progesterone antagonists, such as spotting, bleeding, endometrial hyperproliferation or endometrial cancer. At least one and preferably at each interruption period is of sufficient length for the subject to experience menstruation. More preferably, the subject experiences menstruation during each interruption period. In a particularly preferred embodiment, the capsule is administered daily for a period of administration of four months, followed by a period of interruption during which the subject experiences menstruation, followed by another period of administration of four months and so on.
    [0075] Patients undergoing treatments with the compositions of the present invention should be monitored routinely for their serum levels of estrogen and glucocorticoids.
    [0076] Non-limiting examples are provided to assist in understanding the teachings of the present invention. Example 1. Preparation of Pullulan capsules comprising the Selective Progesterone Receptor Modulator CDB-4124
    [0077] The following capsule filling formulations (without active agent) were liquefied at 50-70 ° C for liquid filling into capsules or molded as vaginal "tablets" as described below:
    [0078]

    [0079] Filling formulations were used to fill various types of capsules, including regular gelatin capsules, soft gelatin capsules and pullulan capsules (Capsugel NPcaps®) or were molded into uncoated vaginal “tablets” to test the suitability of different types of capsules or “tablets” as vaginal delivery vehicles.
    [0080] First, the standard gelatin capsules were filled with the filler formulations above, wrapped with wet paper towels and incubated in an oven at 38 ° C to simulate vaginal conditions. Standard gelatin capsules have been determined to be unacceptable vaginal delivery vehicles in part because of the length of time required for the capsules to soften and release the drug. In addition, residual capsule casings will remain in the vagina and need to be washed after administration of the drug. In addition to these deficiencies, it was determined that the pills would generally not adhere to the vaginal mucosa. Therefore, standard gelatin capsules were determined to be unacceptable vaginal delivery vehicles.
    [0081] Then, the fill formulation was molded into coated "tablets" using a bullet-shaped plastic mold to compress the fill and an applicator was used to deliver the drug. Uncoated bullet-shaped tablets were administered vaginally to human females with uterine fibroids. This method of vaginal administration was determined to be impractical due to handling concerns (the material would often melt during delivery, prior to administration and also because a commercial scale process for filling the bullet-shaped mold was not available.
    [0082] Standard soft gelatin capsules have also been tried, but have been found to have the same problems as gelatin capsules.
    [0083] Finally, Capsugel NPcaps® were tested as a potential vaginal delivery vehicle and were determined to be potentially beneficial as capsules dissolved in the uterus after a period of time and adhered to the vaginal mucosa. Example 2. Pharmacokinetic studies with Vaginal Distribution Animals of the Selective Progesterone Receptor Modulator CDB-4124
    [0084] Pullulan Capsules (Capsugel NPcaps®, size 0) comprising CDB-4124 were administered once daily for 10 consecutive days intravaginally to 10 healthy white virgin female New Zealand rabbits in order to determine the membrane irritation potential of cumulative vaginal mucosa and obtain plasma samples for pharmacokinetic analysis. Five rabbits were assigned to each of the two groups, the first dosed with vehicle control (pullulan capsules with, 5 ml 1000 PEG of filling) introduced into the upper vaginal cavity of each rabbit using a syringe applicator (Group 1), the second with CDB-4124 (pullulan capsules with 12 mg CDB-4124 in, 5 ml PEG 1000) (Group 2). The external vaginal mucosa of each animal was examined for erythema, edema and discharge before the initial dose, immediately before each treatment and before sacrifice. All animals were examined for gross pathology.
    [0085] All animals survived until the end of the study. The external vaginal mucosa of all animals in Group 1 was normal during the study and no abnormal physical signs were noted for any animal during the study. The external vaginal mucosa of 2/5 rabbits showed very mild erythema and / or edema on 4 occasions and appeared normal, otherwise. No gross results were noted in the ovaries, uteri or three sections of the vagina in both groups, nor were any histopathological results observed in both groups. The irritation rate was considered to be "none". The data confirm that pullulan capsules are a safe delivery vehicle for administering the active agents and can be used for local vaginal delivery of CDB-4124, with minimal vaginal irritation.
    [0086] Samples (0.4 m of blood) for pharmacokinetic evaluation were collected from each rabbit in Group 2, before dosing on the last day (10th doses) and in 1, 2, 3, 4, 6, 7, 10 , 16 and 24 hours after the last dose administration. Average pharmacokinetic data are shown in table 1 below. A graph showing data for individual rabbits is illustrated in figure 4A-B. Table 1 - Pharmacokinetic data (Group II - 5 rabbits)
    Example 3. Vaginal Administration of Pullulan Capsules Comprising CDB-4124.
    [0087] Capsugel NPcaps® were filled with the filler excipient formulations described above with 12 mg CDB-4124 (telapristone acetate) and administered vaginally to human females with uterine fibroids, once daily for a period of 2 weeks for determine the length of time required to reach steady state and the overall systemic exposure of the parent compound (CDB-4124) and the primary metabolite (CDB-4453). The capsules were administered using a modified commercially available vaginal applicator, reversing the insertion (see Fig. 5). The unmodified applicator comprises a barrel and the plunger with the barrel with a relatively large opening on one end and a relatively narrow opening on the other side. The applicator is designed such that the drug is placed at the end with the largest opening diameter (inlet end), the applicator is inserted into the vagina and the plunger is used to push the drug out of the barrel and into the vagina. For insertion of the filled NPcaps, the end of the capsule lining (with a slightly larger diameter) was placed in the narrow opening in the barrel, leaving the lid exposed. NPcaps were found to adhere to the vaginal mucosa immediately after insertion, so patients were advised of the importance of ensuring that the capsule is positioned correctly before the capsule is released. Then, pharmacokinetic data of the patients were obtained.
    [0088] The steady state of drug concentration appears to have been reached within one week of administration, after which there was no obvious drug spike as seen in other delivery methods and in contrast to the same formulation in dogs and rabbits, where a drug spike was observed several hours after distribution. As illustrated in Figure 1, vaginal administration of pullulan capsules comprising CDB-4124 resulted in about 1/6 of the systemic exposure of an equivalent oral dose based on the area under the curve (AUC). Cmax on the other hand, as shown in Figure 2, was lower than any of the oral doses. As illustrated in Figure 3, pullulan capsules comprising CDB-4124 effect a continuous release of active agents at a substantially constant rate without the high Cmax observed after oral administration of the drug.
    [0089] In a previous oral study, doses of 1, 3, 6, 9 and 12 mg of CDB-4124 were administered over a period of 10 weeks. In the oral study, all doses were well tolerated and reliable cessation of menstruation was induced at doses as low as 3 mg. The cessation of menstruation directly correlates with the effectiveness of an oral dose in endometriosis and uterine fibroids. Notably, a 12 mg vaginal dose, despite reaching only a fraction of the ineffective 1mg oral dose exposure, resulted in the cessation of menstruation in 3 of the women. Statistical significance (p <0.05) was seen in a peer comparison of the 6 women both from the perspective of decreasing menstrual bleeding using the Pictorial Blood Loss Assessment Chart (PBAC) and also the reduction in symptoms of global uterine fibroids. as determined by the Uterine Fibroids Symptoms Quality of Life Survey (UFSQOL). Given the low global exposure of the 12 mg dose, in those women who continued to menstruate, further improvements in symptom reduction are expected with longer exposure to the drug. In efficacy studies in which CDB-4124 was administered orally, women experienced approximately a 50% reduction in the size of the average fibroids at a dose of 25 mg. When those women were then scaled to an oral dose of 50 mg oral dose for an additional period of four months, the size of the fibroids was reduced to approximately 25% of the initial volume. Based on the assessment of fibroid symptoms as marked by UFSQOL, women on oral CBD-4124 were, in general, symptom free. It is expected that the vaginal distribution of CDB-4124 at the dose of 12 mg will have greater activity than the oral dose of 50 mg, despite a maximum exposure 1 / 100th of the oral dose of 50 mg. Even with this low exposure after just 4 weeks of treatment, significant improvements in the related condition of fibroids were observed.
    [0090] In this sense, administration of pullulan capsules provides a means to distribute sustained levels of active agent in the vaginal mucosa, minimizing the systemic exposure of medications.
    权利要求:
    Claims (11)
    [0001]
    1. Mucoadhesive capsule, characterized by comprising pullulan and containing a capsule filling formulation comprising a selective progesterone receptor modulator (SPRM) and one or more excipients for administering transmucosa to the vaginal mucosa of a human female for contraception or for the treatment of a progesterone-dependent condition selected from the group consisting of endometriosis and associated pain, adenomyosis, ovarian endometriomas, dysmenorrhea, uterine fibroids, endometrial hyperproliferation, ovarian cancer and cervical cancer.
    [0002]
    2. Mucoadhesive capsule according to Claim 1, characterized in that the dose of SPRM is less than the minimum effective dose when administered orally.
    [0003]
    Mucoadhesive capsule according to Claim 1 or 2, characterized in that SPRM is administered in a dosage of 0.5 mg / kg to 500 mg / kg, preferably, in which SPRM is administered daily in a dosage of 1 mg to 50 mg, or preferably, where SPRM is administered in a dosage of 12.5 mg or less.
    [0004]
    Mucoadhesive capsule according to Claim 1, characterized in that the capsule comprises from 85 to 90% by weight of pullulan.
    [0005]
    Mucoadhesive capsule according to Claim 4, characterized in that the capsule comprises 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.
    [0006]
    Mucoadhesive capsule according to Claim 5, characterized in that 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, surfactants 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.
    [0007]
    7. Mucoadhesive capsule according to Claim 5, characterized in that the fill formulation consists of a SPRM, lauroyl polyoxyl-32 glycerides with a melting point of 44 degrees Celsius and a hydrophilic-lipophilic balance of 14 and a polymer of polyethylene glycol, preferably, in which said lauroyl polyoxyl-32 glycerides are present between 50% and 90% of excipient w / w, preferably, in which the fill formulation comprises a SPRM and excipients consisting of 74.13% (p / p) of inert amphiphilic polyglycolated glycerides and 25.87% PEG 400.
    [0008]
    Mucoadhesive capsule according to Claim 5, characterized in that the fill formulation consists of a SPRM and PEG 1000 and, optionally, a butylated hydroxytoluene.
    [0009]
    Mucoadhesive capsule according to any one of Claims 1 to 8, characterized in that the SPRM is CDB-4124 (21-methoxy-17α-acetoxy-11β- (4-N, N-dimethylaminophenyl) -19- norpregna- 4,9-dien-3,20-dione).
    [0010]
    10. Mucoadhesive capsule according to any one of Claims 1 to 9, characterized in that the capsule is administered once a day.
    [0011]
    11. Mucoadhesive capsule according to any one of Claims 6 to 8 and 10, characterized in that the SPRM is CDB- 2914 (17α-acetoxy-11β- (4-N, N-dimethylaminophenyl) -19-norpregna- 4,9-dien-3,20-dione).
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    同族专利:
    公开号 | 公开日
    US20150111862A1|2015-04-23|
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    CN104334158A|2015-02-04|
    US10328022B2|2019-06-25|
    IL235450D0|2014-12-31|
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    MX2019003467A|2019-06-06|
    IL235450A|2020-02-27|
    ZA201408262B|2015-12-23|
    AU2013267359C1|2016-09-29|
    EA201492290A1|2015-03-31|
    EP2854763B1|2018-09-26|
    PH12014502516B1|2015-01-12|
    CN104334158B|2018-08-10|
    BR112014029131A2|2018-05-29|
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    CA2872644A1|2013-12-05|
    SG10201704858PA|2017-07-28|
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    KR20150014928A|2015-02-09|
    JP6341910B2|2018-06-13|
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    法律状态:
    2018-06-12| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2019-10-01| B07D| Technical examination (opinion) related to article 229 of industrial property law|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-02-11| B25A| Requested transfer of rights approved|Owner name: ALLERGAN PHARMACEUTICALS INTERNATIONAL LIMITED (IE) |
    2020-08-11| B07E| Notice of approval relating to section 229 industrial property law|
    2020-08-25| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|
    2020-12-29| B09A| Decision: intention to grant|
    2021-03-09| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 30/05/2013, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201261653674P| true| 2012-05-31|2012-05-31|
    US61/653,674|2012-05-31|
    PCT/US2013/043447|WO2013181449A1|2012-05-31|2013-05-30|Formulations and methods for vaginal delivery of antiprogestins|
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