Composition for drug delivery and method of use thereof

Abstract

To provide compositions for drug delivery and methods of use thereof.SOLUTION: Disclosed herein are compositions for administering vaginally of an active agent or a salt to a subject comprising the active agent or salt thereof, a bioadhesive, and an emulsion. Also disclosed herein are methods treating a disease of condition by administering vaginally to a subject a pharmaceutical composition, and kits comprising the pharmaceutical composition. The present invention is a method comprising administering vaginally to a subject a pharmaceutical composition in the form of an emulsion comprising e.g., an active agent or salt thereof and a bioadhesive, the pharmaceutical composition being administered at a dose of from about 10 mg to about 400 mg of the active agent or salt thereof, and the administering vaginally of the pharmaceutical composition producing a substantially zero order release rate profile of the active agent into a peritoneal cavity of the subject at least about 8 hours after the administering of the pharmaceutical composition.SELECTED DRAWING: None

Description

[Technical Field]

[0001] overview Disclosed herein is a method comprising administering a pharmaceutical composition to a subject via vaginal injection in the form of an emulsion that may contain an activator or a salt thereof and a bioadhesive, wherein the pharmaceutical composition may be administered in doses of about 10 mg to about 400 mg of the activator or a salt thereof; and a method in which the vaginal administration of the pharmaceutical composition results in a substantially zero-order release rate profile of the activator into the subject's peritoneal cavity for at least about 8 hours after administration of the pharmaceutical composition. In some embodiments, the dose may contain about 50 mg to about 100 mg of the activator or a salt thereof. In some embodiments, the activator or a salt thereof may be present in the peritoneal cavity for about 12 hours after administration of the pharmaceutical composition. In some embodiments, the vaginal administration of the pharmaceutical composition results in a peritoneal concentration of the activator, its metabolites or salts which may be at least about four times greater than the peritoneal concentration of the activator, its metabolites or salts achieved by oral administration of an oral pharmaceutical composition which may contain substantially equivalent doses of the activator or a salt thereof. In some embodiments, the method may be a method for treating a disease or symptom. In some embodiments, the disease or symptom may be selected from the group consisting of endometrial disorders, cancer, inflammatory disorders, infections, and any combination thereof. In some embodiments, the disease or symptom may be an endometrial disorder. In some embodiments, the endometrial disorder may be endometriosis, adenomyosis, or any combination thereof. In some embodiments, the amount of endometrial deposits after vaginal administration of the pharmaceutical composition may be less than the amount before vaginal administration of the pharmaceutical composition. In some embodiments, the disease or symptom may be cancer. In some embodiments, the cancer may be selected from the group consisting of cervical cancer; ovarian cancer; mesothelial cancer; peritoneal cancer; and any combination thereof. In some embodiments, the treatment may include a reduction in tumor size or a reduction in tumor growth. In some embodiments, a reduction in tumor size or a reduction in tumor growth may be determined by a reduction in tumor volume as measured by ultrasound. In some embodiments, the disease or symptom may be an inflammatory disorder. In some embodiments, the inflammatory disorder may be selected from the group consisting of pelvic inflammatory / infectious disease; chronic pelvic pain; and any combination thereof.In some embodiments, the treatment may include reducing the amount of at least one pro-inflammatory cytokine to an amount that may be less than that before vaginal administration of the pharmaceutical composition. In some embodiments, the disease or symptom may be an infection. In some embodiments, the infection may be a bacterial infection. In some embodiments, the infection may be a viral infection. In some embodiments, the infection may be a fungal infection. In some embodiments, the activator or a salt thereof may be selected from the group consisting of hormones; antineoplastic agents; GnRH agonists; GnRH antagonists; steroids; analgesics; antibiotics; antiviral compounds; antifungal compounds; anti-inflammatory agents; salts of any of these; and any combination thereof. In some embodiments, the activator may be a hormone or a salt thereof. In some embodiments, the hormone or a salt thereof may be selected from the group consisting of estradiol; ethinylestradiol; progesterone; levonorgestrel; desogestrel; synthetic progesterone; salts of any of these; and any combination thereof. In some embodiments, the activator may be an antineoplastic agent or a salt thereof. In some embodiments, the antineoplastic agent or a salt thereof may be selected from the group consisting of cyclophosphamide; methotrexate; 5-fluorouracil; doxorubicin; procarbazine; prednisolone; bleomycin; vinblastine; dacarbazine; cisplatin; epirubicin; dichloroacetate, any salt thereof; and any combination thereof. In some embodiments, the activator may be a GnRH agonist or GnRH antagonist or a salt thereof. In some embodiments, the GnRH agonist or GnRH antagonist or a salt thereof may be selected from the group consisting of leuprolide; buserelin; histrelin; goserelin; deslorerlin; nafarelin; triptorelin; cetrorelix, abarerix; ganirelix, ozarelix, degarerix or tevererix or a salt thereof; and any combination thereof. In some embodiments, the activator may be a steroid or a salt thereof. In some embodiments, the steroid or a salt thereof may be danazol or a salt thereof.In some embodiments, the activator may be an antibiotic or a salt thereof. In some embodiments, the antibiotic or a salt thereof may be selected from the group consisting of ceftobiprole; cephthaloline; clindamycin; dalbavancin; daptomycin; linezolid; mupirosin; oritabancin; tedizolid; teravancin; tigecycline; vancomycin; aminoglycoside; carbapenem; ceftazidime; cefepime; ceftobiprole; fluoroquinolone; piperacillin; ticalcillin; linezolid; streptogramin; tigecycline; daptomycin; any salt thereof; and any combination thereof. In some embodiments, the activator may be an antiviral compound or a salt thereof. In some embodiments, the antiviral compound or a salt thereof may be selected from the group consisting of ceftobiprole; cephthaloline; clindamycin; dalbavancin; daptomycin; linezolid; mupirosin; oritabancin; tedizolid; teravancin; tigecycline; vancomycin; aminoglycoside; carbapenem; ceftazidime; cefepime; ceftobiprole; fluoroquinolone; piperacillin; ticalcillin; linezolid; streptogramin; tigecycline; daptomycin; any salt thereof; and any combination thereof. In some embodiments, the activator may be an antifungal compound or a salt thereof. In some embodiments, the antifungal compound or a salt thereof may be selected from the group consisting of cyclopirox olamine; haloprozine; tolnaphthate; undecyrenate; topical nysatin; amorolfine; butenafine; naphthifine; terbinafine; any salt thereof; and any combination thereof. In some embodiments, the activator may be an anti-inflammatory agent or a salt thereof. In some embodiments, the anti-inflammatory agent or a salt thereof may be selected from the group consisting of diclofenac; ketoprofen; ibuprofen; aspirin; any salt thereof; and any combination thereof.In some embodiments, the pharmaceutical composition may be administered in doses of at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, or at least about 400 mg of the activator or a salt thereof per kg of body weight of the subject. In some embodiments, the pharmaceutical composition may be administered in doses of at least about 0.1 mg / kg, at least about 0.5 mg / kg, at least about 1 mg / kg, at least about 1.5 mg / kg, at least about 2 mg / kg, at least about 2.5 mg / kg, at least about 3 mg / kg, at least about 3.5 mg / kg, at least about 4 mg / kg, at least about 4.5 mg / kg, at least about 5 mg / kg, at least about 5.5 mg / kg, at least about 6 mg / kg, at least about 6.5 mg / kg, at least about 7 mg / kg, or less The activator or a salt thereof may be administered in doses of at least about 7.5 mg / kg, at least about 8 mg / kg, at least about 8.5 mg / kg, at least about 9 mg / kg, at least about 9.5 mg / kg, at least about 10 mg / kg, at least about 11 mg / kg, at least about 12 mg / kg, at least about 13 mg / kg, at least about 14 mg / kg, at least about 15 mg / kg, at least about 16 mg / kg, at least about 17 mg / kg, at least about 18 mg / kg, at least about 19 mg / kg, or at least about 20 mg / kg. In some embodiments, the pharmaceutical composition may comprise a substantially homogeneous mixture of an organic phase and an aqueous phase. In some embodiments, the organic phase may comprise at least one oleogel which may comprise at least one oily agent and at least one water-insoluble cellulose polymer. In some embodiments, the water-insoluble cellulose polymer may be alkylcellulose. In some embodiments, the alkylcellulose may be selected from the group consisting of methylcellulose; ethylcellulose; hydroxypropylcellulose; and any combination thereof. In some embodiments, the water-insoluble cellulose polymer may be alkylcarboxylic acid-containing cellulose or a salt thereof. In some embodiments, the alkylcarboxylic acid-containing cellulose may be substantially sodium-free carboxymethyl cellulose.In some embodiments, substantially sodium-free carboxymethylcellulose may constitute about 1% to about 10% by weight of the total weight of the pharmaceutical composition. In some embodiments, alkylcellulose may constitute about 1% to about 10% by weight of the total weight of the pharmaceutical composition. In some embodiments, ethylcellulose may constitute about 1% to about 10% by weight of the total weight of the pharmaceutical composition. In some embodiments, alkylcarboxylic acid-containing cellulose or a salt thereof may constitute about 1% to about 10% by weight of the total weight of the pharmaceutical composition. In some embodiments, the aqueous phase may comprise at least one aqueous gel. In some embodiments, the aqueous gel may further comprise at least one gelling agent. In some embodiments, the at least one gelling agent may be selected from the group consisting of carbomer; poloxamer; sodium carboxymethylcellulose; and combinations thereof. In some embodiments, the at least one gelling agent may constitute about 0.1% to about 10% by weight of the total weight of the aqueous gel. In some embodiments, the at least one gelling agent may constitute about 0.01% to about 10% by weight of the total weight of the pharmaceutical composition. In some embodiments, the oily agent may be selected from the group consisting of monoglycerides; diglycerides; triglycerides; and any combination thereof. In some embodiments, the oily agent may be isolated and purified. In some embodiments, the oily agent may be selected from the group consisting of synthetic diglycerides; synthetic triglycerides; propylene glycol isostearate; polyoxyethylene-derived oleic acid glyceride mixtures; plant-derived oils; and any combination thereof. In some embodiments, propylene glycol isostearate may constitute about 0.2% to about 2% by weight of the total weight of the pharmaceutical composition. In some embodiments, polyoxyethylene-derived oleic acid glyceride mixtures may constitute about 0.2% to about 2% by weight of the total weight of the pharmaceutical composition. In some embodiments, the organic phase may be in a weight ratio of about 10:90 to about 90:10 relative to the aqueous phase.In some embodiments, the bioadhesive substance may be selected from the group consisting of carbomer; glyceryl monooleate; hypromellose; polycarbophil; poly(methyl vinyl ether-co-maleic anhydride); salts thereof; and combinations thereof. In some embodiments, the bioadhesive substance may be polycarbophil, a salt thereof, or a combination thereof. In some embodiments, the pharmaceutical composition may contain alcohol at a concentration of about 0% to about 4% by weight based on the total weight of the pharmaceutical composition, and the alcohol may be ethanol or isopropanol. In some embodiments, the concentration of alcohol may be about 3.5% by weight based on the total weight of the pharmaceutical composition. In some embodiments, the activator may constitute about 0.00001% to about 10% by weight of the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition may consist of about 0% to about 4% by weight of the total weight of the pharmaceutical composition. It may contain 4% by weight of a penetration enhancer. In some embodiments, the pharmaceutical composition may contain about 0% to about 2% by weight of a surfactant of the total weight of the pharmaceutical composition, and the surfactant may be selected from the group consisting of nonionic; cationic; amphoteric; amphoteric; and any combination thereof. In some embodiments, the pharmaceutical composition may be administered to a subject in unit dosage form. In some embodiments, the vaginal administration of the pharmaceutical composition may be carried out about every hour, about every 4 hours, about every 8 hours, about every 12 hours or about every 24 hours. In some embodiments, the vaginal administration of the pharmaceutical composition may be carried out about 1, about 2, about 3, about 4, about 5, about 6, about 7 or 8 times within a 24-hour period. In some embodiments, the vaginal administration of the pharmaceutical composition may be performed about once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, or twenty times per week. In some embodiments, the transvaginal administration of the pharmaceutical composition may be performed about once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, twenty times, twenty-one times, twenty-two times, twenty-two times, twenty-two times, twenty-two-two times, twenty-four times, twenty-five times, twenty-six times, twenty-seven times, twenty-eight times, twenty-nine times, thirty-three times, or thirty-one times per month. In some embodiments, the pharmaceutical composition may be applied using a finger. In some embodiments, the pharmaceutical composition may be applied using a glove. In some embodiments, the pharmaceutical composition may be applied using an applicator. In some embodiments, transvaginal administration may include intravaginal administration, topical administration, suppository administration, or any combination thereof. In some embodiments, the pharmaceutical composition maintains a substantially stable and uniform appearance for about one year when stored in a sealed container at about 25°C, about 1 atmosphere, and about 50% relative humidity. In some embodiments, vaginal administration of the pharmaceutical composition results in a higher ability to achieve pregnancy about six months after the last vaginal administration of the pharmaceutical composition compared to oral administration of an oral pharmaceutical composition which may contain substantially equivalent amounts of the activator or salt thereof. [Overview of the project] [Means for solving the problem]

[0002] Disclosed herein are methods for administering a pharmaceutical composition to a subject via vaginal administration, in the form of an emulsion that may contain an activator or a salt thereof and a bioadhesive substance, wherein the vaginal administration of the pharmaceutical composition may include administering a dose of the activator or a salt thereof; and methods for minimizing, at least partially, side effects compared to oral administration of an oral pharmaceutical composition that may contain substantially equivalent doses of the activator or a salt thereof. In some embodiments, the vaginal administration may be performed at least twice within 24 hours. In some embodiments, the side effects may be selected from the group consisting of cardiotoxicity; nephrotoxicity; hepatotoxicity; and any combination thereof, if the amount of biomarkers involved in side effects after vaginal administration of the pharmaceutical composition is less than the amount of biomarkers involved in side effects after oral administration of an oral pharmaceutical composition. In some embodiments, the vaginal administration of the pharmaceutical composition results in peritoneal concentrations of the activator, its metabolites or salts that may be at least about four times greater than those achieved by oral administration of an oral pharmaceutical composition that may contain substantially equivalent doses of the activator or a salt thereof. In some embodiments, the method may be a method for treating a disease or symptom. In some embodiments, the disease or symptom may be selected from the group consisting of endometrial disorders, cancer, inflammatory disorders, infections, and any combination thereof. In some embodiments, the disease or symptom may be an endometrial disorder. In some embodiments, the endometrial disorder may be endometriosis, adenomyosis, or a combination thereof. In some embodiments, the amount of endometrial deposits after vaginal administration of the pharmaceutical composition may be less than the amount before vaginal administration of the pharmaceutical composition. In some embodiments, the disease or symptom may be cancer. In some embodiments, the cancer may be selected from the group consisting of cervical cancer; ovarian cancer; mesothelial cancer; peritoneal cancer; and any combination thereof. In some embodiments, the treatment may include a reduction in tumor size or a reduction in tumor growth. In some embodiments, a reduction in tumor size or a reduction in tumor growth may be determined by a reduction in tumor volume as measured by ultrasound. In some embodiments, the disease or symptom may be an inflammatory disorder.In some embodiments, the inflammatory disorder may be selected from the group consisting of pelvic inflammatory disease; chronic pelvic pain; and any combination thereof. In some embodiments, the treatment may include reducing the amount of at least one pro-inflammatory cytokine to an amount that may be less than that before vaginal administration of the pharmaceutical composition. In some embodiments, the disease or symptom may be an infection. In some embodiments, the infection may be a bacterial infection. In some embodiments, the infection may be a viral infection. In some embodiments, the infection may be a fungal infection. In some embodiments, the activator or a salt thereof may be selected from the group consisting of hormones; antineoplastic agents; GnRH agonists; GnRH antagonists; steroids; analgesics; antibiotics; antiviral compounds; antifungal compounds; anti-inflammatory agents; salts of any of these; and any combination thereof. In some embodiments, the activator may be a hormone or a salt thereof. In some embodiments, the hormone or a salt thereof may be selected from the group consisting of estradiol; ethinylestradiol; progesterone; levonorgestrel; desogestrel; synthetic progesterone; salts of any of these; and any combination thereof. In some embodiments, the activator may be an antineoplastic agent or a salt thereof. In some embodiments, the antineoplastic agent or a salt thereof may be selected from the group consisting of cyclophosphamide; methotrexate; 5-fluorouracil; doxorubicin; procarbazine; prednisolone; bleomycin; vinblastine; dacarbazine; cisplatin; epirubicin; dichloroacetate, any salt thereof; and any combination thereof. In some embodiments, the activator may be a GnRH agonist, a GnRH antagonist, or a salt thereof. In some embodiments, the GnRH agonist or a salt thereof may be selected from the group consisting of leuprolide; buserelin; histrelin; goserelin; deslorerin; nafarelin; triptorelin; any salt thereof; and any combination thereof. In some embodiments, the activator may be a steroid or a salt thereof. In some embodiments, the steroid or a salt thereof may be danazol or a salt thereof.In some embodiments, subjects may be monitored for at least 12 months after the end of administration. In some embodiments, the activator may be an antibiotic or a salt thereof. In some embodiments, the antibiotic or a salt thereof may be selected from the group consisting of ceftobiprole; cephthaloline; clindamycin; dalbavancin; daptomycin; linezolid; mupirosin; oritabancin; tedizolid; teravancin; tigecycline; vancomycin; aminoglycoside; carbapenem; ceftazidime; cefepime; ceftobiprole; fluoroquinolone; piperacillin; ticalcillin; linezolid; streptogramin; tigecycline; daptomycin; salts of any of these; and any combination thereof. In some embodiments, the activator may be an antiviral compound or a salt thereof. In some embodiments, the antiviral compound or a salt thereof may be selected from the group consisting of ceftobiprole; cephthaloline; clindamycin; dalbavancin; daptomycin; linezolid; mupirosin; oritabancin; tedizolid; teravancin; tigecycline; vancomycin; aminoglycoside; carbapenem; ceftazidime; cefepime; ceftobiprole; fluoroquinolone; piperacillin; ticalcillin; linezolid; streptogramin; tigecycline; daptomycin; any salt thereof; and any combination thereof. In some embodiments, the activator may be an antifungal compound or a salt thereof. In some embodiments, the antifungal compound or a salt thereof may be selected from the group consisting of cyclopirox olamine; haloprozine; tolnaphthate; undecyrenate; topical nysatin; amorolfine; butenafine; naphthifine; terbinafine; any salt thereof; and any combination thereof. In some embodiments, the activator may be an anti-inflammatory agent or a salt thereof. In some embodiments, the anti-inflammatory agent or a salt thereof may be selected from the group consisting of diclofenac; ketoprofen; ibuprofen; aspirin; any salt thereof; and any combination thereof.In some embodiments, the pharmaceutical composition may be administered in doses of at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, or at least about 400 mg of the activator or a salt thereof per kg of body weight of the subject. In some embodiments, the pharmaceutical composition may be administered in doses of at least about 0.1 mg / kg, at least about 0.5 mg / kg, at least about 1 mg / kg, at least about 1.5 mg / kg, at least about 2 mg / kg, at least about 2.5 mg / kg, at least about 3 mg / kg, at least about 3.5 mg / kg, at least about 4 mg / kg, at least about 4.5 mg / kg, at least about 5 mg / kg, at least about 5.5 mg / kg, at least about 6 mg / kg, at least about 6.5 mg / kg, at least about 7 mg / kg, or less The activator or a salt thereof may be administered in doses of at least about 7.5 mg / kg, at least about 8 mg / kg, at least about 8.5 mg / kg, at least about 9 mg / kg, at least about 9.5 mg / kg, at least about 10 mg / kg, at least about 11 mg / kg, at least about 12 mg / kg, at least about 13 mg / kg, at least about 14 mg / kg, at least about 15 mg / kg, at least about 16 mg / kg, at least about 17 mg / kg, at least about 18 mg / kg, at least about 19 mg / kg, or at least about 20 mg / kg. In some embodiments, the pharmaceutical composition may comprise a substantially homogeneous mixture of an organic phase and an aqueous phase. In some embodiments, the organic phase may comprise at least one oleogel which may comprise at least one oily agent and at least one water-insoluble cellulose polymer. In some embodiments, the water-insoluble cellulose polymer may be alkylcellulose. In some embodiments, the alkylcellulose may be selected from the group consisting of methylcellulose; ethylcellulose; hydroxypropylcellulose; and any combination thereof. In some embodiments, the water-insoluble cellulose polymer may be alkylcarboxylic acid-containing cellulose or a salt thereof. In some embodiments, the alkylcarboxylic acid-containing cellulose may be substantially sodium-free carboxymethyl cellulose.In some embodiments, substantially sodium-free carboxymethylcellulose may constitute about 1% to about 10% by weight of the total weight of the pharmaceutical composition. In some embodiments, alkylcellulose may constitute about 1% to about 10% by weight of the total weight of the pharmaceutical composition. In some embodiments, ethylcellulose may constitute about 1% to about 10% by weight of the total weight of the pharmaceutical composition. In some embodiments, alkylcarboxylic acid-containing cellulose or a salt thereof may constitute about 1% to about 10% by weight of the total weight of the pharmaceutical composition. In some embodiments, the aqueous phase may comprise at least one aqueous gel. In some embodiments, the aqueous gel may further comprise at least one gelling agent. In some embodiments, the at least one gelling agent may be selected from the group consisting of carbomer; poloxamer; sodium carboxymethylcellulose; and combinations thereof. In some embodiments, the at least one gelling agent may constitute about 0.1% to about 10% by weight of the total weight of the aqueous gel. In some embodiments, the at least one gelling agent may constitute about 0.01% to about 10% by weight of the total weight of the pharmaceutical composition. In some embodiments, the oily agent may be selected from the group consisting of monoglycerides; diglycerides; triglycerides; and any combination thereof. In some embodiments, the oily agent may be isolated and purified. In some embodiments, the oily agent may be selected from the group consisting of synthetic diglycerides; synthetic triglycerides; propylene glycol isostearate; polyoxyethylene-derived oleic acid glyceride mixtures; plant-derived oils; and any combination thereof. In some embodiments, propylene glycol isostearate may constitute about 0.2% to about 2% by weight of the total weight of the pharmaceutical composition. In some embodiments, polyoxyethylene-derived oleic acid glyceride mixtures may constitute about 0.2% to about 2% by weight of the total weight of the pharmaceutical composition. In some embodiments, the organic phase may be in a weight ratio of about 10:90 to about 90:10 relative to the aqueous phase.In some embodiments, the bioadhesive substance may be selected from the group consisting of carbomer; glyceryl monooleate; hypromellose; polycarbophil; poly(methyl vinyl ether-co-maleic anhydride); salts thereof; and combinations thereof. In some embodiments, the bioadhesive substance may be polycarbophil, a salt thereof, or a combination thereof. In some embodiments, the pharmaceutical composition may contain an alcohol in a concentration of about 0% to about 4% by weight based on the total weight of the pharmaceutical composition, and the alcohol may be ethanol or isopropanol. In some embodiments, the concentration of alcohol may be about 3.5% by weight based on the total weight of the pharmaceutical composition. In some embodiments, the activator may be about 0.00001% to about 1% by weight of the total weight of the pharmaceutical composition. It may constitute 0% by weight. In some embodiments, the pharmaceutical composition may contain a penetration enhancer in an amount of about 0% to about 4% by weight of the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition may contain a surfactant in an amount of about 0% to about 2% by weight of the total weight of the pharmaceutical composition, the surfactant may be selected from the group consisting of nonionic; cationic; amphoteric; amphoteric; and any combination thereof. In some embodiments, the pharmaceutical composition may be administered to a subject in unit dosage form. In some embodiments, the vaginal administration of the pharmaceutical composition may be carried out about every hour, about every 4 hours, about every 8 hours, about every 12 hours or about every 24 hours. In some embodiments, the vaginal administration of the pharmaceutical composition may be carried out about 1, about 2, about 3, about 4, about 5, about 6, about 7 or 8 times within a 24-hour period. In some embodiments, the vaginal administration of the pharmaceutical composition may be performed about once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, or twenty times per week. In some embodiments, the transvaginal administration of the pharmaceutical composition may be performed about once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, twenty times, twenty-one times, twenty-two times, twenty-two times, twenty-two times, twenty-two-two times, twenty-four times, twenty-five times, twenty-six times, twenty-seven times, twenty-eight times, twenty-nine times, thirty-three times, or thirty-one times per month. In some embodiments, the pharmaceutical composition may be applied using a finger. In some embodiments, the pharmaceutical composition may be applied using a glove. In some embodiments, the pharmaceutical composition may be applied using an applicator. In some embodiments, transvaginal administration may include intravaginal administration, topical administration, suppository administration, or any combination thereof. In some embodiments, the pharmaceutical composition maintains a substantially stable and uniform appearance for about one year when stored in a sealed container at about 25°C, about 1 atmosphere, and about 50% relative humidity. In some embodiments, vaginal administration of the pharmaceutical composition results in a higher ability to achieve pregnancy about six months after the last vaginal administration of the pharmaceutical composition compared to oral administration of an oral pharmaceutical composition which may contain substantially equivalent amounts of the activator or salt thereof.

[0003] Also disclosed herein are pharmaceutical compositions comprising (a) at least one oleogel which may comprise at least one oily agent and at least one water-insoluble cellulose polymer; (b) at least one aqueous gel; (c) an activator or a salt thereof; and (d) a bioadhesive substance, wherein the activator or a salt thereof may be present in the pharmaceutical composition in an amount of about 50 mg to about 400 mg. In some embodiments, the at least one oleogel and the at least one aqueous gel may be in the form of an emulsion. In some embodiments, the activator or a salt thereof may be selected from the group consisting of hormones; antineoplastic agents; GnRH agonists; GnRH antagonists; steroids; analgesics; antibiotics; antiviral compounds; antifungal compounds; anti-inflammatory agents; salts of any of these; and any combination thereof. In some embodiments, the activator may be a hormone or a salt thereof. In some embodiments, the hormone or a salt thereof may be selected from the group consisting of testosterone; estradiol; ethinylestradiol; progesterone; levonorgestrel; desogestrel; synthetic progesterone; any salt thereof; and any combination thereof. In some embodiments, the activator may be an antineoplastic agent or a salt thereof. In some embodiments, the antineoplastic agent or a salt thereof may be selected from the group consisting of cyclophosphamide; methotrexate; 5-fluorouracil; doxorubicin; procarbazine; prednisolone; bleomycin; vinblastine; dacarbazine; cisplatin; epirubicin; dichloroacetate; any salt thereof; and any combination thereof. In some embodiments, the activator may be a GnRH agonist, a GnRH antagonist, or a salt thereof. In some embodiments, the GnRH agonist, GnRH antagonist, or salt thereof may be selected from the group consisting of leuprolide; buserelin; histrelin; goserelin; deslorerin; nafarelin; triptorelin; cetrorelix, abarelix; ganirelix, ozarelix, degarelix, or teverelix; any salt thereof; and any combination thereof. In some embodiments, the activator may be a steroid or a salt thereof.In some embodiments, the steroid or a salt thereof may be danazol or a salt thereof. In some embodiments, the activator may be an antibiotic or a salt thereof. In some embodiments, the antibiotic or a salt thereof may be selected from the group consisting of ceftobiprole; cephthaloline; clindamycin; dalbavancin; daptomycin; linezolid; mupirocin; oritabancin; tedizolid; teravancin; tigecycline; vancomycin; aminoglycoside; carbapenem; ceftazidime; cefepime; ceftobiprole; fluoroquinolone; piperacillin; ticalcillin; linezolid; streptogramin; tigecycline; daptomycin; any salt thereof; and any combination thereof. In some embodiments, the activator may be an antiviral compound or a salt thereof. In some embodiments, the antiviral compound or a salt thereof may be selected from the group consisting of ceftobiprole; cephthaloline; clindamycin; dalbavancin; daptomycin; linezolid; mupirosin; oritabancin; tedizolid; teravancin; tigecycline; vancomycin; aminoglycoside; carbapenem; ceftazidime; cefepime; ceftobiprole; fluoroquinolone; piperacillin; ticalcillin; linezolid; streptogramin; tigecycline; daptomycin; any salt thereof; and any combination thereof. In some embodiments, the activator may be an antifungal compound or a salt thereof. In some embodiments, the antifungal compound or a salt thereof may be selected from the group consisting of cyclopirox olamine; haloprozine; tolnaphthate; undecyrenate; topical nysatin; amorolfine; butenafine; naphthifine; terbinafine; any salt thereof; and any combination thereof. In some embodiments, the activator may be an anti-inflammatory agent or a salt thereof. In some embodiments, the anti-inflammatory agent or a salt thereof may be selected from the group consisting of diclofenac; ketoprofen; ibuprofen; aspirin; any salt thereof; and any combination thereof.

[0004] A kit including a container that may contain the pharmaceuticals described herein and instructions for use is also disclosed herein.

[0005] A method for preparing a kit, comprising placing the pharmaceutical compositions described herein into a container, is also disclosed herein.

[0006] Also disclosed herein is a method for detecting danazole or a salt thereof in a sample, comprising (a) contacting a portion of the sample derived from a subject with albumin; and (b) detecting danazole or a salt thereof by mass spectrometry. In some embodiments, the detection may include 338 m / z [M+H] + This may include determining the amount of ions. In some embodiments, detection may include 338 m / z [M+H] + The amount of ions is measured against the internal standard [M+H] + This may include comparing the amount of ions; the internal standard may be 19-norethindrone or a salt thereof. In some embodiments, albumin may be human serum albumin. In some embodiments, between a) and (b), the sample may be dried and reconstituted with buffer.

[0007] A kit for determining the amount of danazol in a sample is also disclosed herein, comprising (a) a sample collection container; (b) albumin; and (c) instructions for use. In some embodiments, the kit may further include an internal standard; the internal standard may be 19-norethindrone or a salt thereof. In some embodiments, the kit may further include a buffer. In some embodiments, the instructions for use instruct the user to (a) collect the sample in the sample collection container; (b) contact a portion of the sample with a predetermined amount of albumin; and (c) detect danazol or a salt thereof by mass spectrometry.

[0008] Novel features are described in detail in the attached claims. A better understanding of the features and advantages can be obtained by referring to the following detailed description and attached drawings illustrating exemplary embodiments utilizing the exemplary principle. [Brief explanation of the drawing]

[0009] [Figure 1] Figure 1 shows a diagram of the peritoneal cavity and the organs contained within it. [Modes for carrying out the invention]

[0010] Detailed explanation overview

[0011] Compositions and methods for transvaginal delivery of a drug to the pelvic region in such a manner that high concentrations in ascites and tissues can be achieved at detectable low systemic circulation levels. In some cases, concentrations of at least 2 ng / mL, at least 5 ng / mL; at least >10 ng / mL or even higher can be achieved. Compared to other delivery methods (e.g., oral administration), the drug delivery methods disclosed herein may improve therapeutic efficacy. In some cases, such delivery, when applied transvaginally to a subject, may maintain a substantially zero-order release profile of a therapeutically effective amount of the activator or a salt thereof into the ascites over a predetermined time interval.

[0012] Methods for achieving a desired pharmacokinetic profile by transvaginal delivery of a pharmaceutical composition to a subject are also disclosed herein. In some cases, the pharmaceutical composition may comprise an emulsion that can be mixed with an activator and a bioadhesive substance.

[0013] The vaginal administration of the pharmaceutical compositions described herein may be used to deliver the activator or a salt thereof locally into the peritoneal cavity. Using such delivery instead of systemic delivery may reduce the amount of the activator or salt present in circulation after vaginal administration of the pharmaceutical composition compared to systemic administration (e.g., oral administration) of the pharmaceutical composition, which may contain substantially equivalent doses of the activator or salt thereof. In some cases, the methods described herein may reduce the likelihood of systemic adverse events and undesirable side effects that may occur with systemic administration of the activator or salt thereof. Detection of the amount of the activator or salt thereof in a subject sample is also intended using an assay employing the detection of albumin conjugates by mass spectrometry.

[0014] Vaginal administration of a pharmaceutical composition may be used to treat a disease or condition in a subject. In some cases, the subject may be a subject who requires such treatment, for example, a subject who is suspected of having or has been previously diagnosed with a disease or condition treatable by vaginal administration of the pharmaceutical composition described herein. The pharmaceutical composition described herein may comprise at least one activator that can be selected based on the disease or condition to be treated.

[0015] Kits that may include the pharmaceutical compositions described herein are also disclosed herein. Such kits may include instructions for the application of the pharmaceutical composition and means for applying the pharmaceutical composition.

[0016] definition

[0017] The terminology used herein is for the purpose of describing particular instances only and is not intended to be limiting. As used herein, the singular forms "a", "an" and "the" may be intended to include the plural forms as well, unless the context clearly dictates otherwise. Further, in the detailed description and / or claims, to the extent that the terms "including", "includes", "having", "has", "with" or variations thereof are used, such terms are intended to be inclusive in a manner similar to the term "comprising".

[0018] The term "about" or "approximately" may mean within an acceptable error range of a particular value determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within about plus or minus 10% according to the practice in the art. Alternatively, "about" can mean within a range of up to 20%, up to 10%, up to 5% or up to 1% of a given value. Alternatively, especially with respect to biological systems or biological processes, the term can mean within one order of magnitude, within five-fold or within two-fold of a value. Where a particular value is recited in the present application and claims, the term "about" meaning within an acceptable error range of the particular value should be assumed, unless otherwise specified. Also, when ranges and / or sub-ranges of values are provided, the ranges and / or sub-ranges may include the endpoints of the ranges and / or sub-ranges.

[0019] As used herein, the term "substantially" can refer to a value close to 100% of a given value. For example, an agent that is "substantially localized" in an organ can indicate that about 90% by weight of the agent, salt or metabolite may be present in the organ relative to the total amount of agent, salt or metabolite. In some cases, the term can refer to an amount that can be at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% or 99.99% of the total amount. In some cases, the term can refer to an amount that can be about 100% of the total amount.

[0020] The terms "subject", "patient" or "individual" as used herein can include mammals and non-mammals. Mammals can include, but are not limited to, humans, non-human primates such as chimpanzees, apes or other monkey species; livestock such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs (or canine animals) and cats (or feline animals); experimental animals including rodents such as rats, mice and guinea pigs, and any member of the class of mammals. Non-mammals can include birds, fish, etc. In some embodiments, the subject can be a mammal. In some embodiments, the subject can be a human. In some cases, the human can be an adult. In some cases, the human can be a child. In some cases, the human can be between 0 and 18 years old. In some cases, the human can be between 18 and 130 years old. In some cases, the subject can be female. In some cases, the subject can be diagnosed with or suspected of having a symptom or disease. The subject can be a patient. The subject can be an individual. In some cases, the subject, patient or individual can be used interchangeably.

[0021] The term "preventing" can mean preventing further symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, and can include preventive methods.

[0022] In some cases, “to treat,” “to treat,” “treatment,” “improve,” or “improve,” and other grammatical equivalents may include preventive measures. “To treat,” “to treat,” “treatment,” “improve,” or “improve,” and other grammatical equivalents may further include achieving therapeutic and / or preventive benefits. Therapeutic benefits may mean the eradication of the underlying disease being treated. Also, in some embodiments, therapeutic benefits may be achieved by the eradication of one or more physiological symptoms associated with the underlying disease, such that improvement can be observed in the subject, even though the subject may still be susceptible to the underlying disease.

[0023] As used herein, the terms “effective dose,” “therapeutic dose,” or “pharmaceutical dose” may refer to a sufficient amount of the administered compound that would at least partially improve the symptoms of the disease or condition being treated.

[0024] The terms “compound,” “agent,” “activator,” or “active ingredient” may be used to refer to the drugs or therapeutic agents described herein. In some cases, the terms “further compound,” “further agent,” or “further therapeutic agent” may be used interchangeably to refer to other active compounds, drugs, or therapeutic agents that may be used in the compositions described herein.

[0025] Terms such as “administer,” “give administration,” and “dosage,” as used herein, may refer to methods that may be used to enable the delivery of a compound or composition to a desired biological site of action. These methods may include oral administration, intraduodenal administration, parenteral administration (including intravenous, subcutaneous, intrathecal, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. In some cases, a subject may be administered a gel composition in the absence of supervision. In some cases, a subject may be administered a gel composition under the supervision of a medical professional (e.g., a physician, nurse, physician’s assistant, ordley, hospice staff, etc.).

[0026] In some exemplary embodiments, administration may be transvaginal. Transvaginal administration may include administration to any surface of the vagina. In some cases, transvaginal administration may be intravaginal. Transvaginal administration may include applying the composition described herein to the vagina using a finger or applicator. Transvaginal administration may include intravaginal administration, topical administration to the vagina, and a combination of administrations. Transvaginal administration may also include administration via a carrier such as a patch, suppository, implantable depot, or tablet.

[0027] As used herein, the terms “pharmaceutically acceptable salt” or simply “salt” may refer to a salt that retains at least some of the biological efficacy of the free acid and free base of the specified compound. In some cases, the salt may not be biologically or otherwise undesirable. In some embodiments, the compounds disclosed herein may have acidic or basic groups and may react with some inorganic or organic bases as well as either inorganic or organic acids to form pharmaceutically acceptable salts. In some embodiments, the salt may be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in the form of a free base separately with a suitable organic or inorganic acid and then isolating the salt thus formed.

[0028] Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds disclosed herein with inorganic substances, organic acids, or inorganic bases, such as acetates, acrylates, adipicates, alginates, aspartates, benzoates, benzenesulfons, bisulfates, bisulfites, bisartrates, bromides, butyrates, butynate-1,4-diates, camphorates, camphorsulfons, capronates, caprylates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, diglucons, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyn-1,6-diates, hydroxybenzoates, and γ-hydroxysulfates. Examples include butyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberinate, sebacinate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0029] As used herein, the terms “pharmaceutical composition” or simply “composition” may refer to an activator, optionally mixed with at least one pharmaceutically acceptable chemical component, such as a carrier, stabilizer, diluent, dispersant, suspending agent, thickener, excipient, bioadhesive, etc. The dispersant may be an emulsion, which may comprise a substantially homogeneous mixture of an organic phase and an aqueous phase. The organic and aqueous phases may contain components dissolved or suspended therein. Exemplary embodiments may describe the localization of components having a single phase, but it is understood that any component may be present in either phase.

[0030] The terms “simultaneous administration,” “administered in combination with,” and their grammatical equivalents, as used herein, may encompass the administration of selected therapeutic agents to a single patient and may include treatment regimens in which those agents are administered via the same or different routes of administration or at the same or different times. In some embodiments, the compounds disclosed herein may be administered simultaneously with other agents. These terms may include the administration of two or more agents to an animal such that both agents and / or their metabolites may be present in the animal at the same time. These may include simultaneous administration in separate compositions, administration in separate compositions at different times, and / or administration in a composition in which both agents may be present. Thus, in some embodiments, a compound and another agent may be administered in a single composition. In some embodiments, a compound and another agent may be mixed in a composition.

[0031] As used herein, the term "bioavailability" may refer to the extent to which a drug, such as an activator, salt, metabolite, or other substance, becomes available to target tissue after administration.

[0032] The parameters frequently used in pharmacokinetic (PK) studies are Tmax, Cmax, AUC(0-∞), AUC(0-t), and T 1 / 2and may include CL / F. "Tmax" may refer to the time to reach the maximum plasma concentration ("Cmax") after administration of the therapeutic agent; "AUC(0-∞)" may refer to the area under the plasma concentration-time curve from time 0 to infinity; "AUC(0-t)" may refer to the area under the plasma concentration-time curve from time 0 to time t; "T 1 / 2 " may refer to the half-life of the therapeutic agent in plasma; "T 1 / 2,elim " may refer to the half-life of the drug's removal from circulation; and "CL / F" may refer to the apparent clearance rate of the therapeutic agent;

[0033] The term "zero-order release rate profile" or "zero-order release profile" may refer to a profile in which a given concentration of an activator can be released into the subject's vascular system at a constant rate over a given time interval. In some cases, the activator may have a substantially zero-order release profile into the subject's serum, lymphatic, or peritoneal vascular system upon administration of the pharmaceutical composition.

[0034] The term “substantially absent” may be used to indicate certain components that do not need to be present in the composition or mixture. The amount of a component may be so small that it does not cause an irritant effect or produce an odor that may be unpleasant to the subject. In some cases, the amount by weight of these components may be less than about 5%, less than about 4.5%, less than about 4%, less than about 3.5%, less than about 3%, less than about 2.5%, less than about 2%, less than about 1.5%, less than about 1%, or less than about 0.5%. In some cases, the amount by weight of these components may be less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1%. In some cases, the weight of these components may be less than approximately 0.09%, less than approximately 0.08%, less than approximately 0.07%, less than approximately 0.06%, less than approximately 0.05%, less than approximately 0.04%, less than approximately 0.03%, less than approximately 0.02%, or less than approximately 0.01%. In some cases, the weight of these components may be approximately 0.1% to 5%, approximately 0.1% to 4.5%, approximately 0.1% to 4%, approximately 0.1% to 3.5%, approximately 0.1% to 3%, approximately 0.1% to 2.5%, approximately 0.1% to 2%, approximately 0.1% to 1.5%, approximately 0.1% to 1%, or approximately 0.1% to 0.5%. In some cases, the weight of these components may be 0%.

[0035] As used herein, the term “bioadhesive material” may refer to a polymer material that can bring about close contact between an active ingredient and a biological substrate. The term “mucosal adhesion” may be used interchangeably to describe bioadhesion to mucous membranes.

[0036] As used herein, the term "w / w" may refer to the weight of the components of the composition relative to the total weight of the composition.

[0037] As used herein, the term “emulsion” may refer to a dispersion of two or more liquids. In some cases, an emulsion may include a dispersion of an organic phase in an aqueous phase. In some cases, an emulsion may include a dispersion of an aqueous phase in an organic phase. In some cases, an emulsion may include a dispersion of an organic phase in another organic phase. In some cases, an emulsion may include a dispersion of an aqueous phase in another aqueous phase. In some cases, an emulsion may be a homogeneous dispersion of two or more liquids. In some cases, an emulsion may be a heterogeneous dispersion of two or more liquids.

[0038] As used herein, the term “penetration enhancer” may refer to a compound added to a composition to accelerate the penetration rate of an activator or a salt thereof through the skin of a subject. Examples of penetration enhancers include sulfoxides (e.g., dimethyl sulfoxide, DMSO), azons (e.g., laurocaprum), pyrrolidones (e.g., 2-pyrrolidone, 2P), C1-C8 alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, t-butanol, pentanol, hexanol, cyclohexanol, heptanol, octanol, etc.), glycols (e.g., propylene glycol), surfactants, or terpenes.

[0039] The terms "dose" and "administration" may be used interchangeably to refer to the amount of an active agent or pharmaceutical composition administered to a subject.

[0040] Formulation

[0041] Pharmaceutical compositions for topical delivery of activators or salts thereof are disclosed herein. In some cases, the pharmaceutical composition may comprise an emulsion which may be a substantially homogeneous mixture of an organic phase and an aqueous phase, an activator or salt thereof, and a bioadhesion substance.

[0042] In some embodiments, the pharmaceutical composition may be formulated for transvaginal delivery. Formulation of the pharmaceutical composition may involve mixing an organic phase and an aqueous phase with a bioadhesive and an activator or a salt thereof. To improve the delivery of the activator or its salt, a bioadhesive may be used to adhere the pharmaceutical composition to the epithelial surface upon transvaginal administration.

[0043] The inventors have discovered a surprising and unexpected result: when pharmaceutical compositions described herein, comprising an emulsion, are formulated with a bioadhesive substance by emulsifying an insoluble substance, they can prevent or minimize vaginal aggregates or discharges, thereby minimizing or eliminating unsightly aggregates or discharges. Such emulsions may comprise a substantially homogeneous mixture of an organic phase containing an activator or a salt thereof and a bioadhesive substance, and an aqueous phase. It is envisioned that the aqueous and organic phases may be provided as a homogeneous mixture, or that each component may be provided separately for mixing before administration. Those skilled in the art will be able to formulate either a homogeneous mixture or separate phases, depending on the application.

[0044] Emulsions containing an organic phase and an aqueous phase may contain a variety of components or components. In some cases, the organic phase may contain at least one oleogel. The oleogel may contain at least one oily agent and at least one polymer.

[0045] The oily agents may be monoglycerides, diglycerides, triglycerides, or any combination thereof. In some cases, the oily agents may be separated and purified. In some cases, the oily agents may be synthetic diglycerides, synthetic triglycerides, propylene glycol isostearate, polyoxyethylene-derived oleic acid glyceride mixtures, plant or natural oils, or any combination thereof.

[0046] In some cases, the amount of oily agent is approximately 0.1-1%, 0.1-2%, 0.1-3%, 0.1-4%, 0.1-5%, 0.1-6%, 0.1-7%, 0.1-8%, 0.1-9%, 0.1-10%, 0.1-11%, 0.1-12%, 0.1-13%, 0.1-14%, 0.1- They may be present in proportions of approximately 15%, 0.1-16%, 0.1-17%, 0.1-18%, 0.1-19%, 0.1-20%, 0.1-21%, 0.1-22%, 0.1-23%, 0.1-24%, 0.1-25%, 0.1-26%, 0.1-27%, 0.1-28%, 0.1-29%, or 0.1-30%.

[0047] In some cases, the oily agent is added in amounts of approximately 0.01-0.1%, 0.01-0.2%, 0.01-0.3%, 0.01-0.4%, 0.01-0.5%, 0.01-0.6%, 0.01-0.7%, 0.01-0.8%, 0.01-0.9%, 0.01-1%, 0.01-2%, 0.01-3%, 0.01-4%, 0.01-5%, 0.01-6%, 0.01-7%, 0.01-8%, 0.01-9%, and 0.01- They may exist in proportions of 10%, 0.01-approximately 11%, 0.01-approximately 12%, 0.01-approximately 13%, 0.01-approximately 14%, 0.01-approximately 15%, 0.01-approximately 16%, 0.01-approximately 17%, 0.01-approximately 18%, 0.01-approximately 19%, 0.01-approximately 20%, 0.01-approximately 21%, 0.01-approximately 22%, 0.01-approximately 23%, 0.01-approximately 24%, 0.01-approximately 25%, 0.01-approximately 26%, 0.01-approximately 27%, 0.01-approximately 28%, 0.01-approximately 29%, or 0.01-approximately 30%.

[0048] In some exemplary embodiments, the oily agent may be propylene glycol isostearate. Exemplary pharmaceutical compositions may contain propylene glycol isostearate in an amount of about 5 to 90% by weight relative to the total weight of the oleogel.

[0049] Monoglycerides, diglycerides, or triglycerides are molecules of formula I: [ka] (In the formula, R1, R2, and R3 are independently H; or C1-C containing a degree of unsaturation of 0, 1, 2, 3, 4, or 5) 20 (It could be alkyl.)

[0050] In some embodiments, the synthetic monoglycerides, diglycerides, or triglycerides may be "LABRAFAC® lipophile WL1349" sold by Gatefosse, propylene glycol isostearate, for example, a product sold by Gatefosse under the name "hydrophilol isostearique," and polyglycolized glycerides "LABRRAFIL® M 1944 CS" sold by Gatefosse.

[0051] LABRRAFIL® M 1944 CS is a mixture of polyoxyethylene-derived oleic acid glycerides obtained by the alcoholic decomposition of natural vegetable oils. It may be an oily liquid whose properties are shown in Table 1 below.

[0052] [Table 1]

[0053] In some cases, monoglycerides, diglycerides, or triglycerides may be of natural or plant origin. Examples of natural or plant-derived oils include sweet almond oil, argan oil, or palm oil.

[0054] The polymer in the organic phase may be a cellulose polymer. In some cases, the cellulose polymer may be ethylcellulose, sodium-free carboxymethylcellulose, or a mixture thereof. In some cases, the polymer may be a water-insoluble polymer. In some exemplary embodiments, the water-insoluble polymer may be a water-insoluble cellulose polymer.

[0055] The cellulose polymer may be a lipid-soluble cellulose polymer. In some cases, the cellulose polymer may be alkylcellulose. In some cases, the alkylcellulose may be methylcellulose, ethylcellulose, hydroxypropylcellulose, or a combination thereof. In some cases, the cellulose polymer may be alkylcarboxylic acid-containing cellulose or a salt thereof. In some cases, the alkylcarboxylic acid-containing cellulose may be sodium-free carboxymethylcellulose.

[0056] In some cases, the water-insoluble polymer is present in amounts of approximately 0.1–1%, 0.1–2%, 0.1–3%, 0.1–4%, 0.1–5%, 0.1–6%, 0.1–7%, 0.1–8%, 0.1–9%, 0.1–10%, 0.1–11%, 0.1–12%, 0.1–13%, 0.1–14%, and 0. They may be present in proportions of 1-15%, 0.1-16%, 0.1-17%, 0.1-18%, 0.1-19%, 0.1-20%, 0.1-21%, 0.1-22%, 0.1-23%, 0.1-24%, 0.1-25%, 0.1-26%, 0.1-27%, 0.1-28%, 0.1-29%, or 0.1-30%.

[0057] In some cases, the water-insoluble polymer is present in amounts of approximately 0.01-0.1%, 0.01-0.2%, 0.01-0.3%, 0.01-0.4%, 0.01-0.5%, 0.01-0.6%, 0.01-0.7%, 0.01-0.8%, 0.01-0.9%, 0.01-1%, 0.01-2%, 0.01-3%, 0.01-4%, 0.01-5%, 0.01-6%, 0.01-7%, 0.01-8%, 0.01-9%, and 0.0% of the weight of the composition. They may exist in proportions of 1-10%, 0.01-11%, 0.01-12%, 0.01-13%, 0.01-14%, 0.01-15%, 0.01-16%, 0.01-17%, 0.01-18%, 0.01-19%, 0.01-20%, 0.01-21%, 0.01-22%, 0.01-23%, 0.01-24%, 0.01-25%, 0.01-26%, 0.01-27%, 0.01-28%, 0.01-29%, or 0.01-30%.

[0058] In some exemplary embodiments, the cellulose polymer may be present in a proportion of 1 to about 10% by weight. In some exemplary embodiments, the cellulose polymer may be ethylcellulose present in a proportion of 1 to about 10% by weight based on the total weight of the composition. In some cases, the oily agent may consist of LABRRAFIL® M1944CS. In some cases, the oily agent may be present in a proportion of about 5 to 90% by weight relative to the total weight of the oleogel. In some cases, the ratio of oleogel to aqueous gel weight may be about 10:90 to about 90:10. In some cases, the cellulose polymer may be EMULFREE® P. In some cases, the cellulose polymer may be EMULFREE® P and the oily agent may consist of LABRRAFIL® M1944CS.

[0059] The aqueous phase described herein may comprise one or more aqueous gels. The aqueous phase may comprise at least one aqueous gel. In some cases, the aqueous gel may comprise at least one gelling agent. The gelling agent may be carbomer, poloxamer, sodium carboxymethylcellulose, or any mixture thereof.

[0060] In some cases, the gelling agent is added in amounts of approximately 0.1-1%, 0.1-2%, 0.1-3%, 0.1-4%, 0.1-5%, 0.1-6%, 0.1-7%, 0.1-8%, 0.1-9%, 0.1-10%, 0.1-11%, 0.1-12%, 0.1-13%, 0.1-14%, 0.1- They may be present in proportions of approximately 15%, 0.1-16%, 0.1-17%, 0.1-18%, 0.1-19%, 0.1-20%, 0.1-21%, 0.1-22%, 0.1-23%, 0.1-24%, 0.1-25%, 0.1-26%, 0.1-27%, 0.1-28%, 0.1-29%, or 0.1-30%.

[0061] In some cases, the gelling agent is added in amounts of approximately 0.01-0.1%, 0.01-0.2%, 0.01-0.3%, 0.01-0.4%, 0.01-0.5%, 0.01-0.6%, 0.01-0.7%, 0.01-0.8%, 0.01-0.9%, 0.01-1%, 0.01-2%, 0.01-3%, 0.01-4%, 0.01-5%, 0.01-6%, 0.01-7%, 0.01-8%, 0.01-9%, 0.01- They may exist in proportions of approximately 10%, 0.01-11%, 0.01-12%, 0.01-13%, 0.01-14%, 0.01-15%, 0.01-16%, 0.01-17%, 0.01-18%, 0.01-19%, 0.01-20%, 0.01-21%, 0.01-22%, 0.01-23%, 0.01-24%, 0.01-25%, 0.01-26%, 0.01-27%, 0.01-28%, 0.01-29%, or 0.01-30%.

[0062] In some embodiments, the gelling agent for the aqueous phase may be a carbomer, Carbopol974, or Carbopol980, present in a proportion of about 0.1 to about 5% by weight relative to the total weight of the aqueous phase.

[0063] In some cases, the ratio of the weight of the organic phase to the weight of the aqueous phase may be about 1:9 to about 9:1, about 1:8 to about 8:1, about 1:7 to about 7:1, about 1:6 to about 6:1, about 1:5 to about 5:1, about 1:4 to about 4:1, about 1:3 to about 3:1, about 1:2 to about 2:1, or about 1:1.5 to about 1.5:1. In some cases, the ratio of the weight of the organic phase to the weight of the aqueous phase may be about 1:1. In some embodiments, the emulsion in the compositions herein may comprise a substantially homogeneous mixture of the organic phase and the aqueous phase. In some cases, the ratio of the weight of the organic phase to the weight of the aqueous phase in such a substantially homogeneous mixture may be about 1:1.

[0064] In some cases, a homogeneous mixture of an organic phase and an aqueous phase, when stored in a sealed container, may maintain a stable, uniform appearance for a period of time. In some cases, the mixture may be stable for at least about 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, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks. In some cases, the mixture may be stable for at least about 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, 32, 33, 34, 35, or 36 months. In some cases, the mixture may be stable for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. In some cases, the sealed container may be stored at a temperature of about 25°C and about 1 atmosphere. In some cases, the sealed container may be stored at a relative humidity of about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or 100%.

[0065] In some cases, the ratio of the volume of the organic phase to the volume of the aqueous phase can be approximately 1:9 to 9:1, 1:8 to 8:1, 1:7 to 7:1, 1:6 to 6:1, 1:5 to 5:1, 1:4 to 4:1, 1:3 to 3:1, 1:2 to 2:1, or 1:1.5 to 1.5:1. In some cases, the ratio of the volume of the organic phase to the volume of the aqueous phase can be approximately 1:1.

[0066] When a water-immiscible oil phase can be mixed with an aqueous phase, the emulsion may include dispersions or droplets, as well as other lipid structures that can be formed as a result of hydrophobic forces that separate polar residues (e.g., long hydrocarbon chains) from water and orient polar head groups toward water. These other lipid structures may include monolayers, multilayers, multilayer lipid vesicles, micelles, and lamellar phases.

[0067] In some cases, the penetration enhancer may be present in an amount sufficient to achieve an increased penetration rate. In some cases, the penetration enhancer does not enhance the penetration rate of the activator or its salt below a threshold concentration. The threshold concentration may be specific to a given penetration enhancer. In some cases, the penetration enhancer is present in an amount of at least about 0.1% by weight, 0.11% by weight, 0.12% by weight, 0.13% by weight, 0.14% by weight, 0.15% by weight, 0.16% by weight, 0.17% by weight, 0.18% by weight, 0.19% by weight, 0.2% by weight, 0.21% by weight, 0.22% by weight, 0.23% by weight, 0.24% by weight, 0.25% by weight, 0.26% by weight, 0.27% by weight, 0.28% by weight, 0.29% by weight, 0.3% by weight, 0.31% by weight, 0.32% by weight, 0.33% by weight, 0.34% by weight, 0.35% by weight, 0.36% by weight, 0.37% by weight, 0.38% by weight, 0.39% by weight, 0.4% by weight %, 0.41 wt%, 0.42 wt%, 0.43 wt%, 0.44 wt%, 0.45 wt%, 0.46 wt%, 0.47 wt%, 0.48 wt%, 0.49 wt%, 0.5 wt%, 0.51 wt%, 0.52 Weight%, 0.53% by weight, 0.54% by weight, 0.55% by weight, 0.56% by weight, 0.57% by weight, 0.58% by weight, 0.59% by weight, 0.6% by weight, 0.61% by weight, 0.62% by weight, 0.63% by weight, 0 .64% by weight, 0.65% by weight, 0.66% by weight, 0.67% by weight, 0.68% by weight, 0.69% by weight, 0.7% by weight, 0.71% by weight, 0.72% by weight, 0.73% by weight, 0.74% by weight, 0.75% by weight , 0.76 wt%, 0.77 wt%, 0.78 wt%, 0.79 wt%, 0.8 wt%, 0.81 wt%, 0.82 wt%, 0.83 wt%, 0.84 wt%, 0.85 wt%, 0.86 wt%, 0.87 wt%, 0.88 wt%, 0.89 wt%, 0.9 wt%, 0.91 wt%, 0.92 wt%, 0.93 wt%, 0.94 wt%, 0.95 wt%, 0.96 wt%, 0.97 wt%, 0.98 wt%, 0.99%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20 Weight%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 3 The absorption rate of the activator or its salt is promoted when present at weight concentrations of 9% by weight, 40% by weight, 41% by weight, 42% by weight, 43% by weight, 44% by weight, 45% by weight, 46% by weight, 47% by weight, 48% by weight, 49% by weight, 50% by weight, 51% by weight, 52% by weight, 53% by weight, 54% by weight, 55% by weight, 56% by weight, 57% by weight, 58% by weight, 59% by weight, 60% by weight, 61% by weight, 62% by weight, 63% by weight, 64% by weight, 65% by weight, 66% by weight, 67% by weight, 68% by weight, 69% by weight, or 70% by weight.

[0068] In some cases, the compositions described herein do not contain penetration enhancers. In some cases, the compositions described herein contain about 0.1% by weight, 0.11% by weight, 0.12% by weight, 0.13% by weight, 0.14% by weight, 0.15% by weight, 0.16% by weight, 0.17% by weight, 0.18% by weight, 0.19% by weight, 0.2% by weight, 0.21% by weight, 0.22% by weight, 0.23% by weight, 0.24% by weight, 0.25% by weight, 0.26% by weight, 0.27% by weight, and 0.28% by weight, relative to the total weight of the composition. %, 0.29% by weight, 0.3% by weight, 0.31% by weight, 0.32% by weight, 0.33% by weight, 0.34% by weight, 0.35% by weight, 0.36% by weight, 0.37% by weight, 0.38% by weight, 0.39% by weight, 0.4% by weight Amount %, 0.41 wt%, 0.42 wt%, 0.43 wt%, 0.44 wt%, 0.45 wt%, 0.46 wt%, 0.47 wt%, 0.48 wt%, 0.49 wt%, 0.5 wt%, 0.51 wt%, 0.5 2% by weight, 0.53% by weight, 0.54% by weight, 0.55% by weight, 0.56% by weight, 0.57% by weight, 0.58% by weight, 0.59% by weight, 0.6% by weight, 0.61% by weight, 0.62% by weight, 0.63% by weight, 0.64% by weight, 0.65% by weight, 0.66% by weight, 0.67% by weight, 0.68% by weight, 0.69% by weight, 0.7% by weight, 0.71% by weight, 0.72% by weight, 0.73% by weight, 0.74% by weight, 0.75% by weight %, 0.76 wt%, 0.77 wt%, 0.78 wt%, 0.79 wt%, 0.8 wt%, 0.81 wt%, 0.82 wt%, 0.83 wt%, 0.84 wt%, 0.85 wt%, 0.86 wt%, 0.87 wt%, 0.88 wt%, 0.89 wt%, 0.9 wt%, 0.91 wt%, 0.92 wt%, 0.93 wt%, 0.94 wt%, 0.95 wt%, 0.96 wt%, 0.97 wt%, 0.98 wt%, 0.99%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% Amount%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37% It contains a penetration enhancer in an amount not exceeding %, 38% by weight, 39% by weight, 40% by weight, 41% by weight, 42% by weight, 43% by weight, 44% by weight, 45% by weight, 46% by weight, 47% by weight, 48% by weight, 49% by weight, 50% by weight, 51% by weight, 52% by weight, 53% by weight, 54% by weight, 55% by weight, 56% by weight, 57% by weight, 58% by weight, 59% by weight, 60% by weight, 61% by weight, 62% by weight, 63% by weight, 64% by weight, 65% by weight, 66% by weight, 67% by weight, 68% by weight, 69% by weight, or 70% by weight.

[0069] The oleogel and aqueous phase may each further contain, in conventional amounts known not to cause skin irritation, standard components for various types of gels, such as texturers, antioxidants, preservatives, dyes, or fragrances.

[0070] The composition may be in the form of a pharmaceutical composition. In some cases, the pharmaceutical composition may be administered in the form of a cosmetic, such as a cream or gel, which can be applied to the skin. In some cases, the composition may be in the form of a unit dosage form, which is applied in a specified amount to at least a portion of the skin. Since the pharmaceutical composition may contain a stable mixture of an oleogel and an aqueous gel, it may be free of clumps and moisture, require a smaller application area compared to conventional aqueous alcohol gels, and be fast-drying.

[0071] In some cases, the gel composition may contain bioadhesives. Examples of bioadhesives include carbomer, glyceryl monooleate, hypromellose, polycarbophil, poly(methyl vinyl ether-co-maleic anhydride), and their salts. In some cases, the pharmaceutical composition may contain one or more bioadhesives. In some cases, the pharmaceutical composition may contain at least one, two, three, four, five, six, seven, eight, nine, or ten bioadhesives.

[0072] In some exemplary embodiments, the bioadhesive material may be polycarbophil or a salt thereof. Polycarbophil is designed to mimic loaded mucin, a glycoprotein component of mucus involved in adhesion to the underlying epithelial surface. Polycarbophil is a lightly crosslinked polymer. Polycarbophil is also a weak polyacid containing multiple carboxyl radicals (COO-), which are its source of negative charge. These acid radicals enable hydrogen bonding with the cell surface. While hydrogen bonding can be weak, in the case of polycarbophil, they can be numerous. Bioadhesive materials such as polycarbophil can maintain their adhesion to vaginal epithelial cells until turnover (which can be up to 7 days in menopausal women). However, non-water-soluble polycarbophil that remains attached to vaginal epithelial cells can lead to vaginal aggregates and vaginal discharge. Therefore, it is necessary to provide formulations that can provide adhesion of a pharmaceutical composition to the epithelium of a subject while minimizing vaginal aggregates or vaginal discharge.

[0073] In some cases, bioadhesive substances make up at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.15%, at least about 0.2%, at least about 0.25%, at least about 0.3%, at least about 0.35%, at least about 0.4%, at least about 0.45%, at least about 0.5%, at least about 0.55%, at least about 0.6%, at least about 0.65%, at least about 0.7%, at least about 0.75%, at least about 0.8%, at least about 0.85%, at least about 0.9%, at least about 0.95%, at least about 1%, at least about 1.1%, and a small amount. It may be present at a weight concentration of at least approximately 1.2%, at least approximately 1.3%, at least approximately 1.4%, at least approximately 1.5%, at least approximately 1.6%, at least approximately 1.7%, at least approximately 1.8%, at least approximately 1.9%, at least approximately 2%, at least approximately 2.5%, at least approximately 3%, at least approximately 3.5%, at least approximately 4%, at least approximately 4.5%, at least approximately 5%, at least approximately 5.5%, at least approximately 6%, at least approximately 6.5%, at least approximately 7%, at least approximately 7.5%, at least approximately 8%, at least approximately 8.5%, at least approximately 9%, at least approximately 9.5%, or at least approximately 10%. In some cases, the aqueous gel may contain polycarbophil at weight concentrations of approximately 0.1% to 10%, 0.1% to 9%, 0.1% to 8%, 0.1% to 7%, 0.1% to 6%, 0.1% to 5%, 0.1% to 4%, 0.1% to 3%, 0.1% to 2%, 0.1% to 1%, 0.1% to 0.9%, 0.1% to 0.8%, 0.1% to 0.7%, 0.1% to 0.6%, 0.1% to 0.5%, 0.1% to 0.4%, 0.1% to 0.3%, or 0.1% to 0.2%.

[0074] The composition may contain alcohols. For example, the alcohol may be a C1-C8 alcohol. Examples of C1-C8 alcohols include methanol, ethanol, n-propanol, isopropanol, t-butanol, pentanol, hexanol, cyclohexanol, heptanol, and octanol.

[0075] Activating agent

[0076] The pharmaceutical compositions described herein may comprise at least one activator or a salt thereof. While exemplary activators are described herein, further activators in the compositions may be substituted to treat other indications treatable by administration of the pharmaceutical composition to a subject.

[0077] In some embodiments, the active ingredient may be a hormone, an anti-inflammatory agent, an analgesic, phenethylamine, an antineoplastic agent, a steroid, a 5-α-reductase inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a GnRH antagonist, a glycine receptor antagonist, tetrahydrocannabinol, analgesics; an antibiotic, an antiviral compound, an antifungal compound, a salt of any of these, or any combination thereof.

[0078] In some cases, the hormones may be testosterone; dihydrotestosterone (DHT); estradiol; ethinylestradiol; progesterone; levonorgestrel; desogestrel; peptide hormones, such as oxytocin; synthetic progesterone; salts of any of these or any combination thereof.

[0079] In some cases, the active ingredient may be an analgesic. Examples of analgesics include acetaminophen, bromfenac, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamete, mefenamic acid, meloxicam, nabumetone, naproxen, nepafenac, oxaprozine, phenylbutazone, piroxicam, sulindac, tolmetine, celecoxib, buprenorphine, butorphanol, codeine, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbufine, oxycodone, oxymorphone, pentazocine, propoxifene, tapentadol, tramadol, aspirin, any salt of these, or any combination thereof.

[0080] In some cases, phenethylamine may be dopamine, epinephrine, norepinephrine, phenylephrine, methylphenidate, amphetamine, any salt of these, or any combination thereof.

[0081] In some cases, antineoplastic drugs may be cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, cisplatin, epirubicin, dichloroacetate, any salt of these, or any combination thereof.

[0082] In some cases, the steroid may be danazol or a salt thereof.

[0083] In some cases, 5-α-reductase inhibitors may be dutasteride, tamsulosin, finasteride, a salt of any of these, or any combination thereof.

[0084] In some cases, the GnRH agonist, GnRH antagonist may be leuprolide, buserelin, histrelin, goserelin, deslorerin, nafarelin, triptorelin, cetrorelix, abarelix; ganirelix, ozarelix, degarelix or teverelix, any salt of these or any combination thereof.

[0085] In some cases, the GnRH antagonist can be Cetrorelics, Abarelics; Ganirellics, Ozarellics, Degarellics, Teverellics, any salt of these, or any combination thereof.

[0086] In some cases, the glycine receptor antagonist may be tranexamic acid or a salt thereof.

[0087] In some cases, the antibiotic may be ceftoviprole; cephthaloline; clindamycin; dalbavancin; daptomycin; linezolid; mupirocin; oritabancin; tedizolid; teravancin; tigecycline; vancomycin; aminoglycosides; carbapenems; ceftazidime; cefepime; ceftoviprole; fluoroquinolones; piperacillin; ticalcillin; linezolid; streptogramin; tigecycline; daptomycin; salts of any of these; or any combination thereof.

[0088] In some cases, the antiviral compound may be ceftoviprole; cephthaloline; clindamycin; dalbavancin; daptomycin; linezolid; mupirosin; oritabancin; tedizolid; teravancin; tigecycline; vancomycin; aminoglycosides; carbapenems; ceftazidime; cefepime; ceftoviprole; fluoroquinolones; piperacillin; ticalcillin; linezolid; streptogramin; tigecycline; daptomycin; salts of any of these; or any combination thereof.

[0089] In some cases, the antifungal compound may be cyclopirox olamine; haloprozine; tolnaphthate; undecylenate; topical nystatin; amorolfine; butenafine; naphthifine; terbinafine; or any combination thereof.

[0090] In some embodiments, the composition may contain an activator or a salt thereof in amounts not exceeding approximately 10 mg, not exceeding approximately 20 mg, not exceeding approximately 40 mg, not exceeding approximately 60 mg, not exceeding approximately 80 mg, not exceeding approximately 100 mg, not exceeding approximately 120 mg, not exceeding approximately 140 mg, not exceeding approximately 160 mg, not exceeding approximately 180 mg, not exceeding approximately 200 mg, not exceeding approximately 300 mg, not exceeding approximately 400 mg, or not exceeding approximately 500 mg. In some cases, the composition may contain at least approximately 10 mg, at least approximately 20 mg, at least approximately 40 mg, at least approximately 60 mg, at least approximately 80 mg, at least approximately 100 mg, at least approximately 120 mg, at least approximately 140 mg, at least approximately 160 mg, at least approximately 180 mg, at least approximately 200 mg, at least approximately 300 mg, at least approximately 400 mg, or at least approximately 500 mg of an activator or a salt thereof.

[0091] The activator may constitute a portion of the total weight of the composition. In some cases, the activator may constitute about 0.000001% to about 99% by weight, about 0.000001% to about 50% by weight, about 0.000001% to about 30% by weight, about 0.000001% to about 20% by weight, about 0.00005% to about 15% by weight, about 0.00005% to about 10% by weight, about 0.00001% to about 10% by weight, about 0.0001% to about 10% by weight, or about 0.0001% to about 5% by weight of the total weight of the composition.

[0092] In some cases, the composition may contain alcohol at a concentration that allows for the solubilization of the activator. In some cases, the composition may have an alcohol concentration of at most about 10% by weight, at most about 8% by weight, at most about 6% by weight, at most about 5% by weight, at most about 4% by weight, at most about 3% by weight, at most about 2% by weight, or at most about 1% by weight. In some cases, the alcohol concentration is about 3.5% by weight.

[0093] In some cases, the composition may contain substantially no surfactant. In some cases, the composition may contain a small amount of surfactant. The surfactant may be a nonionic surfactant, a cationic surfactant, an amphoteric surfactant, or an amphoteric surfactant.

[0094] In some cases, the composition may have a surfactant concentration of at most about 10%, at most about 8%, at most about 6%, at most about 5%, at most about 4%, at most about 3%, at most about 2%, at most about 1%, or at most about 0.1% of the total weight of the composition.

[0095] If the composition contains an activator or a salt thereof, the activator or a salt thereof may be emulsified in an emulsion. When emulsified in an emulsion, the activator may be in a form having an average particle size minimized to about the micrometer scale. In some cases, the average particle size may be minimized to about the nanometer scale.In some cases, the average particle size is approximately 0.001 nm to 500 μm, approximately 0.001 nm to 400 μm, approximately 0.001 nm to 300 μm, approximately 0.001 nm to 200 μm, approximately 0.001 nm to 100 μm, approximately 0.001 nm to 90 μm, approximately 0.001 nm to 80 μm, approximately 0.001 nm to 70 μm, approximately 0.001 nm to 60 μm, approximately 0.001 nm to 50 μm, approximately 0.001 nm to 40 μm, approximately 0.001 nm to 30 μm, approximately 0.001 nm to 20 μm, approximately 0.001nm to about 10μm, about 0.001nm to about 5μm, about 0.001nm to about 1μm, about 0.001nm to about 900nm, about 0.001nm to about 800nm, about 0.001nm to about 700nm, about 0.001nm to about 600nm, about 0. 001nm ~ approx. 500nm, approx. 0.001nm ~ approx. 400nm, approx. 0.001nm ~ approx. 300nm, approx. 0.001nm ~ approx. 200nm, approx. 0.001nm ~ approx. 100nm, approx. 0.001nm ~ approx. 90nm, approx. 0.001nm ~ approx. .001nm to about 70nm, about 0.001nm to about 60nm, about 0.001nm to about 50nm, about 0.001nm to about 40nm, about 0.001nm to about 30nm, about 0.001nm to about 20nm, about 0.001nm to about 10nm, about 0.00 1nm to about 5nm, about 0.001nm to about 1nm, about 0.001nm to about 0.9nm, about 0.001nm to about 0.8nm, about 0.001nm to about 0.7nm, about 0.001nm to about 0.6nm, about 0.001nm to about 0.5nm, about 0.001 nm to approximately 0.4nm, approximately 0.001nm to approximately 0.3nm, approximately 0.001nm to approximately 0.2nm, approximately 0.001nm to approximately 0.1nm, approximately 0.001nm to approximately 0.09nm, approximately 0.001nm to approximately 0.08nm, approximately 0.001nm to approximately 0.07nm, approximately 0.001nm to approximately 0.06nm, approximately 0.001nm to approximately 0.05nm, approximately 0.001nm to approximately 0.04nm, approximately 0.001nm to approximately 0.03nm, approximately 0.001nm to approximately 0.02nm, or approximately 0.001nm to approximately 0.01nm.In some cases, the average particle size is approximately 0.01 nm, 0.05 nm, 0.1 nm, 0.15 nm, 0.2 nm, 0.25 nm, 0.3 nm, 0.35 nm, 0.4 nm, 0.45 nm, 0.5 nm, 0.55 nm, 0.6 nm, 0.65 nm, 0.7 nm, 0.75 nm, 0.8 nm, 0.85 nm, 0.9 nm, 0.95 nm. Approximately 1nm, approximately 2nm, approximately 3nm, approximately 4nm, approximately 5nm, approximately 6nm, approximately 7nm, approximately 8nm, approximately 9nm, approximately 10nm, approximately 15nm, approximately 20nm, approximately 25nm, approximately 30nm, approximately 35nm, approximately 4 0nm, about 45nm, about 50nm, about 55nm, about 60nm, about 65nm, about 70nm, about 75nm, about 80nm, about 85nm, about 90nm, about 95nm, about 100nm, about 150nm, approx. 200nm, approx. 250nm, approx. 300nm, approx. 350nm, approx. 400nm, approx. 450nm, approx. 500nm, approx. 550nm, approx. 600nm, approx. 650nm, approx. , about 800nm, about 850nm, about 900nm, about 950nm, about 1μm, about 2μm, about 3μm, about 4μm, about 5μm, about 6μm, about 7μm, about 8μm, about 9μm, about 10μm, about 15μ m may be approximately 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 95 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, or 500 μm.

[0096] Indications

[0097] The methods and compositions described herein may be used to treat symptoms or diseases. In some cases, treatment of a disease may include improving at least one symptom of the disease or condition in part. Examples of diseases or conditions that may be treated with the pharmaceutical compositions described herein include endometrial disorders, adenomyosis, cancer, inflammatory disorders, infections, and any combination thereof. While exemplary diseases or conditions are listed herein, those skilled in the art may treat further diseases or conditions by substituting additional activators with the pharmaceutical compositions described herein.

[0098] In some cases, the disease or symptoms may be endometrial disorders. For example, an endometrial disorder may be endometriosis. Endometriosis can be a frequently painful disorder in which tissue that is normally located inside the uterus (e.g., endometrium) grows outside the uterus (endometrial implants). The methods and compositions described above may be used to treat endometriosis involving the ovaries, intestines, or pelvic endometrial tissue, or endometriosis in which endometrial tissue has spread outside the pelvic region. In endometriosis, the displaced deposits break down and bleed with each menstrual cycle. Since this displaced tissue has no way to leave the body, it can become trapped. The surrounding tissue becomes inflamed and can eventually lead to scar tissue and adhesions (abnormal tissue that binds organs together). In some cases, treatment of symptoms may involve reducing the amount of endometrial deposits to a level that may be less than before treatment.

[0099] In some cases, endometrial disorders can be adenomyosis. Adenomyosis is a disorder in which the inner wall of the uterine lining penetrates the muscular wall of the uterus (myometrium). Adenomyosis can cause menstrual cramps, decreased intra-abdominal pressure, and bloating before menstruation, which can be very difficult. Symptoms can affect the entire uterine region or be limited to one area. The cause of adenomyosis is unknown, but research suggests that various hormones, including estrogen, progesterone, prolactin, and follicle-stimulating hormone, may trigger symptoms. Current treatments include administering anti-inflammatory drugs to reduce inflammation; and administering therapeutic interventions such as aromatase inhibitors, GnRH agonists, or GnRH antagonists to suppress the expression of hormones that may trigger symptoms. In some cases, adenomyosis and endometriosis can occur simultaneously.

[0100] Treatment of endometrial disorders using the vaginal compositions described herein can be determined using many metrics known in the art. Treatment endpoints for endometrial disorders may include fertility. In some cases, fertility can be determined using in vitro assays such as human chorionic gonadotropin (hCG) assays. hCG assays may be performed on subject-derived samples, such as blood samples. Such assays can determine blood hCG levels over time using hCG-specific antibodies that can be used to determine the incidence of pregnancy. Fertility can also be determined by determining the presence of mature oocytes in the subject or the success of zygote implantation at fertilization using in vivo imaging means such as ultrasound.

[0101] In some cases, the disease or symptom may be cancer. For example, the cancer may be cancer of the reproductive tract, cervical cancer, ovarian cancer, mesothelial cancer, peritoneal cancer, or any combination thereof.

[0102] In exemplary embodiments, the vaginal administration of the pharmaceutical compositions described herein may be used to locally treat cancer in the peritoneal cavity. The vaginal administration of the pharmaceutical compositions described herein may be used to minimize adverse side effects that may occur with systemic administration. For example, the pharmaceutical composition containing the antineoplastic agent may be used to deliver the antineoplastic agent directly to the peritoneal cavity, with minimal delivery of the neoadjuvant to the circulatory system. As an exemplary example, such vaginal administration of the pharmaceutical composition may be used to mitigate known side effects of systemic antineoplastic agent administration, such as hair loss, reproductive side effects, inflammation or swelling of the skin or nails, cardiotoxicity, hepatotoxicity, etc. The reduction of side effects may be determined by methods such as monitoring the incidence of the side effect symptoms. Examples include a reduction in local irritation or inflammation, a reduction in the incidence of vomiting, a reduction in the incidence of pain, a reduction in irregular heart rate or arrhythmia, and a reduction in frequent urination or painful urination. Biomarkers may also be used to measure the reduction of side effects. In some cases, the reduction of side effects may include a reduction in toxicity-related biomarkers. In some cases, a reduction in side effects may include an increase in toxicity-related biomarkers. Examples of biomarkers include cardiac troponin I, cardiac troponin T, serum alanine aminotransferase, glutathione-S-transferase α, aspartate aminotransferase, serum creatinine, blood urea nitrogen, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), cystatin C, clatherin, fatty acid-binding protein-liver type (L-FABP), and osteopontin.

[0103] In some cases, cancer treatment may include reducing tumor size or slowing or preventing tumor growth. Imaging techniques, such as ultrasound or magnetic resonance imaging (MRI), can be used to determine the tumor volume of a subject, and this can be compared over time to determine the therapeutic effect of administering a pharmaceutical composition over time.

[0104] In some cases, the symptoms may be due to an inflammatory disorder. For example, inflammatory diseases can include pelvic inflammatory disease and chronic pelvic pain, and other examples of inflammatory diseases include sepsis and chronic inflammation resulting from chronic viral or bacterial infections. In some cases, treatment of the symptoms may involve reducing the amount of at least one pro-inflammatory cytokine to a level that may be lower than the level before treatment.

[0105] In some cases, the symptoms may be due to an infection. For example, the infection could be a bacterial infection, a viral infection, a fungal infection, or any combination thereof.

[0106] In some cases, infectious diseases may include infections caused by bacterial pathogens. Bacterial pathogens are not limited to the following groups, but include Staphylococcus species, for example, Staphylococcus aureus (for example, Staphylococcus aureus) (NCTC 10442 and Staphylococcus aureus ATCC25923), Staphylococcus epidermidis; Chlamydia species, e.g., Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydia psittaci; Enterococcus species, e.g., Enterococcus faecalis; Streptococcus pyogenes; Listeria species; Pseudomonas species; Mycobacterium species, e.g., Mycobacterium tuberculosis complex; Enterobacter species; Campylobacter species; Salmonella species; Streptococcus species, e.g., Streptococcus group A or B, Streptococcus pneumoniae; Helicobacter species, e.g., Helicobacter pylori, Helicobacter felis; Neisseria species, e.g., Neisseria gonorrhoea, Neisseria meningitidis; Borrelia burgdorferi; Shigella species, e.g., Shigella flexneri; Escherichia coli (E. coli 0157:H7 NCTC 12900); Haemophilus species, e.g., Haemophilus influenzae; Francisella tularensis; Bacillus species, e.g., Bacillus anthraces; Clostridia species, e.g., Clostridium botulinum, Clostridium difficile; Yersinia species, e.g., Yersinia pestis; Treponema species; Burkholderia species, e.g., Burkholderia cepacia complex, B. mallei, B. pseudomallei; Propionibacterium species, e.g., P.acnes, Acinetobacter species, Actinomyces species, Campylobacter species, Candida species, Corynebacterium minutissium, Corynebacterium pseudodiphtheriae, Corynebacterium stratium, Corynebacterium group G1, Corynebacterium group G2, Enterobacteriaceae, Enterococcus species, Klebsiella pneumoniae, Moraxella species, non-tuberculous mycobacteria species, Porphyromonas species, Prevotella melaninogenicus, Salmonella typhimurium, Serratia marcescens. Streptococcus agalactiae, Staphylococcus It may originate from bacterial species selected from the group consisting of Salivarius, Streptococcus mitis, Streptococcus sanguis, Streptococcus pneumoniae, Vibrio cholerae, Coccidioides species, or Cryptococcus species.

[0107] In some cases, infectious diseases may include viral infections. Viruses may originate from, but are not limited to, herpesviruses, poxviruses, hepadnaviruses, flaviviruses, togaviruses, coronaviruses, hepatitis C, hepatitis D, orthomyxoviruses, papillomaviruses, polyomaviruses, parvoviruses, cytomegaloviruses, Epstein-Barr viruses, smallpox viruses, bovinepox viruses, sheeppox viruses, Orff viruses, monkeypox viruses, vaccinia viruses, paramyxoviruses, retroviruses, adenoviruses, rhabdoviruses, bunyaviruses, filoviruses, alphaviruses, arenaviruses, lentiviruses, and any combination thereof. In some cases, viruses may be enveloped viruses. Examples of enveloped viruses include poxviruses, hepadnaviruses, flaviviruses, togaviruses, coronaviruses, hepatitis C, hepatitis D, orthomyxoviruses, cytomegaloviruses, Epstein-Barr virus, smallpox virus, bovine pox virus, sheeppox virus, Orff virus, monkeypox virus, vaccinia virus, rhabdovirus, bunyavirus, filovirus, alphavirus, arenavirus, and lentivirus.

[0108] In some cases, the infection may be caused by parasites selected from the group consisting of, but not limited to, Trypanosoma species (Trypanosoma cruzi, Trypansosoma brucei), Leishmania species, Giardia species, Trichomonas species, Entamoeba species, Naegleria species, Acanthanioeba species, Schistosoma species, Plasmodium species, Crytosporidium species, Isospora species, Balantidium species, Loa Loa, Ascaris lumbricoides, Dirofilaria immitis, and Toxoplasma species, such as Toxoplasma gondii.

[0109] Fungal pathogens, limited species, including: *C. albicans* (genera Candida), *Epidermophyton*, *Exophiala*, *Microsporum*, *Trichophyton* (*T. rubrum*, *T. interdigitale*), *Tinea*, *Aspergillus*, *Blastomyces*, *Blastoschizomyces*, *Coccidioides*, and *Cryptococcus* (*Cryptococcus*). *Neoformans*, *Histoplasma*, *Paracoccidiomyces*, *Sporotrix*, *Absidia*, *Cladophialophora*, *Fonsecaea*, *Phialophora*, *Lacazia*, *Arthrographis*, *Acremoniwn*, *Actinomadura*, *Apophysomyces*, *Emmonsia*, *Basidiobolus*, *Beauveria*, *Chrysosporium*, *Conidiobolus*, *Cunninghamella*, *Fusarium*, *Geotrichum*, *Graphiwn*, *Leptosphaeria*, *Malassezia* (example: *Malassezia*) Furfur), Mucor species, Neotestudina species, Nocardia species, Nocardiopsis species, Paecilomyces species, Phona species, Piedraia species, Pneunwcystis species, Pseudallescheria species, Pyrenochaeta species, Rhizoinucor species, Rhizopus species, Rhodotorula species, Saccharomyces species, Scedosporium species, Scoplulariopsis species, Sporobolomyces species, S:yncephalastrum species, Trichoderma species, Trichosporon species, Ulocladium species, Ustilago species, Verticillium species.

[0110] The pharmaceutical compositions described herein may also be administered prophylactically to prevent the onset of the diseases or symptoms described herein. For example, a pharmaceutical composition containing an antibiotic may be administered vaginally to a subject before surgery to prevent peritoneal infection. Medication / Pharmacokinetics

[0111] In some cases, pharmaceutical formulations may be formulated to optimize the pharmacokinetics / pharmacokinetics of the active ingredient or a salt thereof contained therein upon intravaginal administration of the pharmaceutical composition to a subject.

[0112] In some cases, a pharmaceutical composition comprising the activator or a salt thereof as described herein is available in doses of approximately 1 mg to approximately 1000 mg, approximately 5 mg to approximately 1000 mg, approximately 10 mg to approximately 1000 mg, approximately 15 mg to approximately 1000 mg, approximately 20 mg to approximately 1000 mg, approximately 25 mg to approximately 1000 mg, approximately 30 mg to approximately 1000 mg, approximately 35 mg to approximately 1000 mg, approximately 40 mg to approximately 1000 mg, approximately 45 mg to approximately 1000 mg, approximately 50 mg to approximately 1000 mg, approximately 55 mg to approximately 1000 mg, approximately 60 mg to approximately 1000 mg, approximately 65 mg to approximately 1000 mg, approximately 70 mg to approximately 1000 mg, approximately 75 mg to approximately 1000 mg, approximately 80 mg to approximately 1000 mg, approximately 85 mg to approximately 1000 mg, and approximately 90 mg to approximately 100 mg. 0mg, about 95mg to about 1000mg, about 100mg to about 1000mg, about 150mg to about 1000mg, about 200mg to about 1000mg, about 250mg to about 1000 mg, about 300mg to about 1000mg, about 350mg to about 1000mg, about 400mg to about 1000mg, about 450mg to about 1000mg, about 500mg to about 1000 It may be administered in doses of mg, approximately 550 mg to 1000 mg, approximately 600 mg to 1000 mg, approximately 650 mg to 1000 mg, approximately 700 mg to 1000 mg, approximately 750 mg to 1000 mg, approximately 800 mg to 1000 mg, approximately 850 mg to 1000 mg, approximately 900 mg to 1000 mg, or approximately 950 mg to 1000 mg.

[0113] In some cases, pharmaceutical compositions comprising the activators or salts thereof described herein are about 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, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 4 4, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 9 8, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 1 39, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179180, 181, 182, 183, 184, 184, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 5 It may be administered in doses of 20, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 mg.

[0114] In some cases, a pharmaceutical composition comprising the activator or a salt thereof described herein will have a concentration of approximately 0.5 ng / mL to approximately 10 μg / mL, approximately 1 ng / mL to approximately 10 μg / mL, approximately 5 ng / mL to approximately 10 μg / mL, approximately 10 ng / mL to approximately 10 μg / mL, approximately 15 ng / mL to approximately 10 μg / mL, and approximately 20 μg / mL after about 1 minute to about 1, 2, 3, 4, 5, 6, 7 or 10 hours or more. ng / mL~about 10μg / mL, about 25ng / mL~about 10μg / mL, about 30ng / mL~about 10μg / mL, about 35ng / mL~about 10μg / mL, about 40ng / mL~about 10μg / m L, about 45ng / mL to about 10μg / mL, about 50ng / mL to about 10μg / mL, about 55ng / mL to about 10μg / mL, about 60ng / mL to about 10μg / mL, about 65ng / mL to about 1 0μg / mL, about 70ng / mL to about 10μg / mL, about 75ng / mL to about 10μg / mL, about 80ng / mL to about 10μg / mL, about 85ng / mL to about 10μg / mL, about 90ng / mL mL ~ approx. 10 μg / mL, approx. 95 ng / mL ~ approx. 10 μg / mL, approx. 100 ng / mL ~ approx. 10 μg / mL, approx. 200 ng / mL ~ approx. 10 μg / mL, approx. 300 ng / mL ~ approx. 10 μg / m It may be administered to provide plasma concentrations of the activator, its metabolites or salts thereof at approximately 400 ng / mL to 10 μg / mL, approximately 500 ng / mL to 10 μg / mL, approximately 600 ng / mL to 10 μg / mL, approximately 700 ng / mL to 10 μg / mL, approximately 800 ng / mL to 10 μg / mL, approximately 900 ng / mL to 10 μg / mL, or approximately 1 μg / mL to 10 μg / mL.

[0115] In some cases, a pharmaceutical composition comprising the activator or a salt thereof described herein will, after administration to a subject, reach at least about 200 ng / mL, 195 ng / mL, 190 ng / mL, 185 ng / mL, 180 ng / mL, 175 ng / mL, 170 ng / mL, 165 ng / mL, 160 ng / mL, 155 ng / mL, 150 ng / mL, 145 ng / mL, 140 ng / mL, 135 ng / mL, 130 ng / mL, 125 ng / mL, An activator, its metabolite, or a salt thereof may be administered to provide plasma concentrations of 120 ng / mL, 115 ng / mL, 110 ng / mL, 105 ng / mL, 100 ng / mL, 95 ng / mL, 90 ng / mL, 85 ng / mL, 80 ng / mL, 75 ng / mL, 70 ng / mL, 65 ng / mL, 60 ng / mL, 55 ng / mL, 50 ng / mL, 45 ng / mL, 40 ng / mL, 35 ng / mL, 30 ng / mL, 25 ng / mL, 20 ng / mL, 15 ng / mL, 10 ng / mL, or 5 ng / mL.

[0116] In some cases, a pharmaceutical composition comprising the activator or a salt thereof described herein may result in at least approximately 200 ng / mL, 195 ng / mL, 190 ng / mL, 185 ng / mL, 180 ng / mL, 175 ng / mL, 170 ng / mL, 165 ng / mL, 160 ng / mL, 155 ng / mL, 150 ng / mL, 145 ng / mL, 140 ng / mL, 135 ng / mL, 130 ng / mL, 125 ng / mL, 120 ng / mL, 115 ng / mL, 110 ng / mL, 105 ng / mL, 100 ng / mL, 95 ng / mL, 90 ng / mL, 85 ng / mL in the ascites fluid after administration to a subject, approximately 1 minute to approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours later. Activators, their metabolites, or salts thereof may be administered to provide concentrations of mL, 80 ng / mL, 75 ng / mL, 70 ng / mL, 65 ng / mL, 60 ng / mL, 55 ng / mL, 50 ng / mL, 45 ng / mL, 40 ng / mL, 35 ng / mL, 30 ng / mL, 25 ng / mL, 20 ng / mL, 15 ng / mL, 10 ng / mL, 9 ng / mL, 8 ng / mL, 7 ng / mL, 6 ng / mL, 5 ng / mL, 4 ng / mL, 3 ng / mL, 2 ng / mL, 1 ng / mL, 0.9 ng / mL, 0.8 ng / mL, 0.7 ng / mL, 0.6 ng / mL, 0.5 ng / mL, 0.4 ng / mL, 0.3 ng / mL, 0.2 ng / mL, or 0.1 ng / mL.

[0117] In some cases, a pharmaceutical composition comprising the activator or a salt thereof described herein, in the ascites fluid after administration to a subject, shows concentrations of approximately 0.5 ng / mL to approximately 100 ng / mL, approximately 0.5 ng / mL to approximately 90 ng / mL, approximately 0.5 ng / mL to approximately 80 ng / mL, approximately 0.5 ng / mL to approximately 70 ng / mL, approximately 0.5 ng / mL to approximately 60 ng / mL, approximately 0.5 ng / mL to approximately 50 ng / mL, approximately 0.5 ng / mL to approximately 40 ng / mL, and approximately 0.5 ng / mL to approximately 30 ng / mL after approximately 1 minute to approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours. An activator, its metabolite or a salt thereof may be administered to provide concentrations of approximately 0.5 ng / mL to approximately 20 ng / mL, approximately 0.5 ng / mL to approximately 10 ng / mL, approximately 0.5 ng / mL to approximately 9 ng / mL, approximately 0.5 ng / mL to approximately 8 ng / mL, approximately 0.5 ng / mL to approximately 7 ng / mL, approximately 0.5 ng / mL to approximately 6 ng / mL, approximately 0.5 ng / mL to approximately 5 ng / mL, approximately 0.5 ng / mL to approximately 4 ng / mL, approximately 0.5 ng / mL to approximately 3 ng / mL, approximately 0.5 ng / mL to approximately 2 ng / mL, or approximately 0.5 ng / mL to approximately 1 ng / mL.

[0118] In some cases, a pharmaceutical composition containing the activator or a salt thereof described herein will produce at least approximately 200 ng / mg, 195 ng / mg, 190 ng / mg, 185 ng / mg, 180 ng / mg, 175 ng / mg, 170 ng / mg, 165 ng / mg, 160 ng / mg, 155 ng / mg, 150 ng / mg, 145 ng / mg, 140 ng / mg, 135 ng / mg, 130 ng / mg, 125 ng / mg, 120 ng / mg, 115 ng / mg, 110 ng / mg, 105 ng / mg, 100 ng / mg, 95 ng / mg, 90 ng / mg, and 85 ng in the peritoneal tissue after administration to a subject, approximately 1 minute to approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours later. The activator, its metabolites or salts thereof may be administered to provide concentrations of 0.1 ng / mg, 80 ng / mg, 75 ng / mg, 70 ng / mg, 65 ng / mg, 60 ng / mg, 55 ng / mg, 50 ng / mg, 45 ng / mg, 40 ng / mg, 35 ng / mg, 30 ng / mg, 25 ng / mg, 20 ng / mg, 15 ng / mg, 10 ng / mg, 9 ng / mg, 8 ng / mg, 7 ng / mg, 6 ng / mg, 5 ng / mg, 4 ng / mg, 3 ng / mg, 2 ng / mg, 1 ng / mg, 0.9 ng / mg, 0.8 ng / mg, 0.7 ng / mg, 0.6 ng / mg, 0.5 ng / mg, 0.4 ng / mg, 0.3 ng / mg, 0.2 ng / mg, or 0.1 ng / mg.

[0119] In some cases, a pharmaceutical composition comprising the activator or a salt thereof described herein in the peritoneal tissue after administration to a subject yields approximately 0.5 ng / mg to approximately 100 ng / mg, approximately 0.5 ng / mg to approximately 90 ng / mg, approximately 0.5 ng / mg to approximately 80 ng / mg, approximately 0.5 ng / mg to approximately 70 ng / mg, approximately 0.5 ng / mg to approximately 60 ng / mg, approximately 0.5 ng / mg to approximately 50 ng / mg, approximately 0.5 ng / mg to approximately 40 ng / mg, and approximately 0.5 ng / mg to approximately 30 ng / mg at approximately 1 minute to approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours later. The activator, its metabolites or salts thereof may be administered to provide concentrations of mg, approximately 0.5 ng / mg to approximately 20 ng / mg, approximately 0.5 ng / mg to approximately 10 ng / mg, approximately 0.5 ng / mg to approximately 9 ng / mg, approximately 0.5 ng / mg to approximately 8 ng / mg, approximately 0.5 ng / mg to approximately 7 ng / mg, approximately 0.5 ng / mg to approximately 6 ng / mg, approximately 0.5 ng / mg to approximately 5 ng / mg, approximately 0.5 ng / mg to approximately 4 ng / mg, approximately 0.5 ng / mg to approximately 3 ng / mg, approximately 0.5 ng / mg to approximately 2 ng / mg, or approximately 0.5 ng / mg to approximately 1 ng / mg.

[0120] In some cases, a pharmaceutical composition comprising the activator or a salt thereof described herein, after administration to a subject, lasts for approximately 1 minute to 600 minutes, approximately 1 minute to 590 minutes, approximately 1 minute to 580 minutes, approximately 1 minute to 570 minutes, approximately 1 minute to 560 minutes, approximately 1 minute to 550 minutes, approximately 1 minute to 540 minutes, approximately 1 minute to 530 minutes, approximately 1 minute to 520 minutes, approximately 1 minute to 510 minutes, approximately 1 minute to 500 minutes, approximately 1 minute to 490 minutes, approximately 1 minute to 480 minutes, and approximately 1 minute to 470 minutes. Between approximately 1 minute and 460 minutes, approximately 1 minute and 450 minutes, approximately 1 minute and 440 minutes, approximately 1 minute and 430 minutes, approximately 1 minute and 420 minutes, approximately 1 minute and 410 minutes, approximately 1 minute and 400 minutes, approximately 1 minute and 390 minutes, approximately 1 minute and 380 minutes, approximately 1 minute and 370 minutes, approximately 1 minute and 360 minutes, approximately 1 minute and 350 minutes, approximately 1 minute and 340 minutes, approximately 1 minute and 330 minutes, approximately 1 minute and 320 minutes, approximately 1 minute and 310 minutes, approximately 1 minute and 300 minutes, approximately 1 minute and 290 minutes, approximately 1 minute to approximately 280 minutes, approximately 1 minute to approximately 270 minutes, approximately 1 minute to approximately 260 minutes, approximately 1 minute to approximately 250 minutes, approximately 1 minute to approximately 240 minutes, approximately 1 minute to approximately 230 minutes, approximately 1 minute to approximately 220 minutes, approximately 1 minute to approximately 210 minutes, approximately 1 minute to approximately 200 minutes, approximately 1 minute to approximately 190 minutes, approximately 1 minute to approximately 180 minutes, approximately 1 minute to approximately 170 minutes, approximately 1 minute to approximately 160 minutes, approximately 1 minute to approximately 150 minutes, approximately 1 minute to approximately 140 minutes, approximately 1 minute to approximately 130 minutes, approximately 1 minute to approximately 120 minutes, approximately 1 minute to approximately 110 minutes, approximately 1 minute It may be administered to provide an activator or a salt thereof with a Tmax of approximately 1 to 100 minutes, approximately 1 minute to approximately 90 minutes, approximately 1 minute to approximately 80 minutes, approximately 1 minute to approximately 70 minutes, approximately 1 minute to approximately 60 minutes, approximately 1 minute to approximately 50 minutes, approximately 1 minute to approximately 40 minutes, approximately 1 minute to approximately 30 minutes, approximately 1 minute to approximately 20 minutes, approximately 1 minute to approximately 10 minutes, approximately 1 minute to approximately 9 minutes, approximately 1 minute to approximately 8 minutes, approximately 1 minute to approximately 7 minutes, approximately 1 minute to approximately 6 minutes, approximately 1 minute to approximately 5 minutes, approximately 1 minute to approximately 4 minutes, approximately 1 minute to approximately 3 minutes, or approximately 1 minute to approximately 2 minutes.

[0121] In some cases, a pharmaceutical composition comprising the activator or a salt thereof described herein, after administration to a subject, contains at least about 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, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 9 5, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179 A pharmacokinetic composition comprising the activator or a salt thereof may be administered to provide an activator, its metabolite or salt thereof for a Tmax of 180, 181, 182, 183, 184, 184, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, or 200 minutes. In some cases, a pharmacokinetic composition comprising the activator or a salt thereof described herein may provide at least about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7 after administration to a subject. An activator, its metabolite, or a salt thereof may be administered to provide a Tmax of 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0 hours.

[0122] In some cases, a pharmaceutical composition comprising the activators or salts thereof described herein may be administered to a subject to provide, after administration, at least about 1,000 μg / mL, 950 μg / mL, 900 μg / mL, 850 μg / mL, 800 μg / mL, 750 μg / mL, 700 μg / mL, 650 μg / mL, 600 μg / mL, 550 μg / mL, 500 μg / mL, 450 μg / mL, 400 μg / mL, 350 μg / mL, 300 μg / mL, 250 μg / mL, 200 μg / mL, 150 μg / mL, 100 μg / mL, or 50 μg / mL of the activator, its metabolites or salts thereof. In some cases, a pharmaceutical composition comprising the activators or salts thereof described herein may be administered to a subject to provide, after administration, at least about 100 μg / mL, 95 μg / mL, 90 μg / mL, 85 μg / mL, 80 μg / mL, 75 μg / mL, 70 μg / mL, 65 μg / mL, 60 μg / mL, 55 μg / mL, 50 μg / mL, 45 μg / mL, 40 μg / mL, 35 μg / mL, 30 μg / mL, 25 μg / mL, 20 μg / mL, 15 μg / mL, 10 μg / mL, 5 μg / mL, 4 μg / mL, 3 μg / mL, 2 μg / mL, or 1 μg / mL of the activator, its metabolites or salts thereof. In some cases, the activators described herein, their salts, or pharmaceutical compositions containing the activators or their salts may be administered to a subject to provide, after administration, at least about 1,000 ng / mL, 950 ng / mL, 900 ng / mL, 850 ng / mL, 800 ng / mL, 750 ng / mL, 700 ng / mL, 650 ng / mL, 600 ng / mL, 550 ng / mL, 500 ng / mL, 450 ng / mL, 400 ng / mL, 350 ng / mL, 300 ng / mL, 250 ng / mL, 200 ng / mL, 150 ng / mL, 100 ng / mL, or 50 ng / mL of the activator, its metabolites, or salts thereof with a Cmax.In some cases, a pharmaceutical composition comprising the activators or salts thereof described herein may be administered to a subject to provide, after administration, at least about 100 ng / mL, 95 ng / mL, 90 ng / mL, 85 ng / mL, 80 ng / mL, 75 ng / mL, 70 ng / mL, 65 ng / mL, 60 ng / mL, 55 ng / mL, 50 ng / mL, 45 ng / mL, 40 ng / mL, 35 ng / mL, 30 ng / mL, 25 ng / mL, 20 ng / mL, 15 ng / mL, 10 ng / mL, or 5 ng / mL of the activator, its metabolites or salts thereof. In some cases, a pharmaceutical composition containing the activator or a salt thereof described herein contains at least about 50 ng / mL, 49 ng / mL, 48 ng / mL, 47 ng / mL, 46 ng / mL, 45 ng / mL, 44 ng / mL, 43 ng / mL, 42 ng / mL, 41 ng / mL, 40 ng / mL, 39 ng / mL, 38 ng / mL, 37 ng / mL, 36 ng / mL, 35 ng / mL, 34 ng / mL, 33 ng / mL, 32 ng / mL, 31 ng / mL, 30 ng / mL, 29 ng / mL, 28 ng / mL, 27 ng / mL, and 26 ng An activator with a Cmax of 0.5 ng / mL, 25 ng / mL, 24 ng / mL, 23 ng / mL, 22 ng / mL, 21 ng / mL, 20 ng / mL, 19 ng / mL, 18 ng / mL, 17 ng / mL, 16 ng / mL, 15 ng / mL, 14 ng / mL, 13 ng / mL, 12 ng / mL, 11 ng / mL, 10 ng / mL, 9 ng / mL, 8 ng / mL, 7 ng / mL, 6 ng / mL, 5 ng / mL, 4 ng / mL, 3 ng / mL, 2 ng / mL, 1 ng / mL, or 0.5 ng / mL may be administered to provide the activator, its metabolites, or salts thereof.

[0123] In some cases, a pharmaceutical composition comprising the activator or a salt thereof described herein will, after administration to a subject, yield at least about 10,000 ng*h / mL, 9,900 ng*h / mL, 9,800 ng*h / mL, 9,700 ng*h / mL, 9,600 ng*h / mL, 9,500 ng*h / mL, 9,400 ng*h / mL, 9,300 ng*h / mL, 9,200 ng*h / mL, 9,100 ng*h / mL, 9,000 ng*h / mL, 8, 900ng*h / mL, 8,800ng*h / mL, 8,700ng*h / mL, 8,600ng*h / mL, 8,500ng*h / mL, 8,400ng*h / mL, 8,300ng*h / mL, 8,200ng*h / mL, 8,100ng*h / mL, 8,000ng*h / mL, 7,900ng*h / mL, 7,800ng*h / mL, 7,700ng*h / mL, 7,600ng*h / mL, 7,500ng*h / mL, 7,400ng*h / m L, 7,300ng*h / mL, 7,200ng*h / mL, 7,100ng*h / mL, 7,000ng*h / mL, 6,900ng*h / mL, 6,800ng*h / mL, 6,700ng*h / mL, 6,600ng*h / mL, 6,500ng*h / mL, 6,400ng*h / mL, 6,300ng*h / mL, 6,200ng*h / mL, 6,100ng*h / mL, 6,000ng*h / mL, 5,900ng*h / mL, 5,800ng *h / mL, 5,700ng*h / mL, 5,600ng*h / mL, 5,500ng*h / mL, 5,400ng*h / mL, 5,300ng*h / mL, 5,200ng*h / mL, 5,100ng*h / mL, 5,000 ng*h / mL, 4,500ng*h / mL, 4,000ng*h / mL, 3,500ng*h / mL, 3,000ng*h / mL, 2,500ng*h / mL, 2,000ng*h / mL, 1,500ng*h / mL or 1,An activator, its metabolite, or a salt thereof may be administered to provide an AUC(0-t) of 900 ng*h / mL, where t is at least about 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, 32, 33, 34, 35 after administration of the pharmaceutical composition containing the activator or a salt thereof. , could be 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90 hours.

[0124] In some cases, a pharmaceutical composition comprising the activator or a salt thereof described herein will, after administration to a subject, yield at least about 10,000 ng*h / mL, 9,900 ng*h / mL, 9,800 ng*h / mL, 9,700 ng*h / mL, 9,600 ng*h / mL, 9,500 ng*h / mL, 9,400 ng*h / mL, 9,300 ng*h / mL, 9,200 ng*h / mL, 9,100 ng*h / mL, 9,000 ng*h / mL, 8, 900ng*h / mL, 8,800ng*h / mL, 8,700ng*h / mL, 8,600ng*h / mL, 8,500ng*h / mL, 8,400ng*h / mL, 8,300ng*h / mL, 8,200ng*h / mL, 8,100ng*h / mL, 8,000ng*h / mL, 7,900ng*h / mL, 7,800ng*h / mL, 7,700ng*h / mL, 7,600ng*h / mL, 7,500ng*h / mL, 7,400ng*h / m L, 7,300ng*h / mL, 7,200ng*h / mL, 7,100ng*h / mL, 7,000ng*h / mL, 6,900ng*h / mL, 6,800ng*h / mL, 6,700ng*h / mL, 6,600ng*h / mL, 6,500ng*h / mL, 6,400ng*h / mL, 6,300ng*h / mL, 6,200ng*h / mL, 6,100ng*h / mL, 6,000ng*h / mL, 5,900ng*h / mL, 5,800ng *h / mL, 5,700ng*h / mL, 5,600ng*h / mL, 5,500ng*h / mL, 5,400ng*h / mL, 5,300ng*h / mL, 5,200ng*h / mL, 5,100ng*h / mL, 5,000 ng*h / mL, 4,500ng*h / mL, 4,000ng*h / mL, 3,500ng*h / mL, 3,000ng*h / mL, 2,500ng*h / mL, 2,000ng*h / mL, 1,500ng*h / mL or 1,An activator, its metabolite, or a salt thereof may be administered to provide an AUC(0-t) of 900 ng*h / mL, where t is at least about 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, 32, 33, 34, 35 after administration of the pharmaceutical composition containing the activator or a salt thereof. , could be 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90 days.

[0125] In some exemplary embodiments, a pharmaceutical composition comprising an active agent or a salt thereof described herein is administered to provide an active agent, its metabolite or a salt thereof with an AUC(0-t) of about 1,000 ng*h / mL to about 10,000 ng*h / mL, about 1,000 ng*h / mL to about 9,000 ng*h / mL, about 1,000 ng*h / mL to about 8,000 ng*h / mL, about 1,000 ng*h / mL to about 7,000 ng*h / mL, about 1,000 ng*h / mL to about 6,000 ng*h / mL, about 1,000 ng*h / mL to about 5,000 ng*h / mL, about 1,000 ng*h / mL to about 4,000 ng*h / mL, about 1,000 ng*h / mL to about 3,000 ng*h / mL or about 1,000 ng*h / mL to about 2,000 ng*h / mL after administration to a subject, where t is at least about 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, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90 days after administration of the pharmaceutical composition comprising the active agent or a salt thereof.

[0126] In some exemplary embodiments, a pharmaceutical formulation is produced such that when the pharmaceutical formulation is administered to a primate, the active agent or a salt thereof has a T of about 1 minute to about 1 hour max , a C of about 1 minute to about 8 hours max , an AUC of about 0.1 μg.hr / L to about 1,000 μg.hr / L 0>24 hour , a half-life of about 2 hours to about 24 hours or a combination thereof.

[0127] In some cases, pharmaceutical formulations may be produced such that, when administered to a subject, the activator or a salt thereof can be substantially localized to the peritoneal organs or tissues of the subject. Examples of organs or tissues of the peritoneal cavity may be those depicted in Figure 1. The peritoneal cavity may contain ascites. Peritoneal organs or tissues may include, but are not limited to, the bladder, gallbladder, intestines, uterus, endometrium, myometrium, epithelium, stomach, ovaries, ovarian cortex, ovarian epithelium, liver, spleen, or kidneys.

[0128] In some cases, when a pharmaceutical formulation is administered to a subject, the active agent is approximately 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, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 4 6, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 ,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139 ,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179 It may have a half-life of 180, 181, 182, 183, 184, 184, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, or 200 minutes.In some cases, when a pharmaceutical preparation is administered to a subject, the active agent or its salts are approximately 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7 It may have a half-life of 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0 hours.In some cases, when a pharmaceutical preparation is administered to a subject, the activator or its salt is released for approximately 1 minute to 600 minutes, approximately 1 minute to 590 minutes, approximately 1 minute to 580 minutes, approximately 1 minute to 570 minutes, approximately 1 minute to 560 minutes, approximately 1 minute to 550 minutes, approximately 1 minute to 540 minutes, approximately 1 minute to 530 minutes, approximately 1 minute to 520 minutes, approximately 1 minute to 510 minutes, approximately 1 minute to 500 minutes, approximately 1 minute to 490 minutes, approximately 1 minute to 480 minutes, approximately 1 minute to 470 minutes, and approximately 1 minute. ~460 minutes, approximately 1 minute ~ approximately 450 minutes, approximately 1 minute ~ approximately 440 minutes, approximately 1 minute ~ approximately 430 minutes, approximately 1 minute ~ approximately 420 minutes, approximately 1 minute ~ approximately 410 minutes, approximately 1 minute ~ approximately 400 minutes, approximately 1 minute ~ approximately 390 minutes, approximately 1 minute ~ approximately 380 minutes, approximately 1 minute ~ approximately 370 minutes, approximately 1 minute ~ approximately 360 minutes, approximately 1 minute ~ approximately 350 minutes, approximately 1 minute ~ approximately 340 minutes, approximately 1 minute ~ approximately 330 minutes, approximately 1 minute ~ approximately 320 minutes, approximately 1 minute ~ approximately 310 minutes, approximately 1 minute ~ approximately 300 minutes, approximately 1 minute ~ approximately 290 minutes Interval, approximately 1 minute to approximately 280 minutes, approximately 1 minute to approximately 270 minutes, approximately 1 minute to approximately 260 minutes, approximately 1 minute to approximately 250 minutes, approximately 1 minute to approximately 240 minutes, approximately 1 minute to approximately 230 minutes, approximately 1 minute to approximately 220 minutes, approximately 1 minute to approximately 210 minutes, approximately 1 minute to approximately 200 minutes, approximately 1 minute to approximately 190 minutes, approximately 1 minute to approximately 180 minutes, approximately 1 minute to approximately 170 minutes, approximately 1 minute to approximately 160 minutes, approximately 1 minute to approximately 150 minutes, approximately 1 minute to approximately 140 minutes, approximately 1 minute to approximately 130 minutes, approximately 1 minute to approximately 120 minutes, approximately 1 minute It may have a half-life of approximately 110 minutes, 1 minute to 100 minutes, 1 minute to 90 minutes, 1 minute to 80 minutes, 1 minute to 70 minutes, 1 minute to 60 minutes, 1 minute to 50 minutes, 1 minute to 40 minutes, 1 minute to 30 minutes, 1 minute to 20 minutes, 1 minute to 10 minutes, 1 minute to 9 minutes, 1 minute to 8 minutes, 1 minute to 7 minutes, 1 minute to 6 minutes, 1 minute to 5 minutes, 1 minute to 4 minutes, 1 minute to 3 minutes, or 1 minute to 2 minutes.

[0129] Detection method

[0130] A method for detecting an active agent, its metabolites, or salts thereof in a sample derived from a subject after administration of a pharmaceutical composition to the subject is also disclosed herein. The sample derived from the subject may be blood or any excretory fluid. Non-limiting examples include saliva, blood, serum, cerebrospinal fluid, semen, feces, plasma, or urine.

[0131] In some exemplary embodiments, the method may be a method for detecting danazol or a salt thereof in a sample derived from a subject. The method may include contacting a portion of the sample derived from the subject with albumin; and detecting danazol or a salt thereof by mass spectrometry. The albumin may include human or bovine albumin. In some cases, the albumin may be serum albumin.

[0132] The detection of activators such as danazol may be performed by contacting the activator with albumin to form an albumin adduct, and then determining the presence of the adduct using mass spectrometry. The method may further include comparison with an internal standard. An example internal standard may be 19-norethindrone.

[0133] Mass spectrometers may include single or tandem mass spectrometers. Mass spectrometers may include electrospray ionizers, matrix-assisted laser desorption / ionization ionizers, electron ionizers, fast atomic impact ionizers, or chemical ionizers.

[0134] An example method is [M+H] + This may include detecting danazol by determining the amount of ions. In some cases, [M+H] + Ions can contain frequencies of approximately 338 m / z.

[0135] In some cases, the sample may be dried after contact with albumin. In some cases, the sample may be reconstituted, resuspended, or diluted in a resuspension buffer after contact with albumin. The resuspension buffer may contain buffers such as saline, citrate, phosphate, phosphate-buffered saline, acetate, glycine, tris(hydroxymethyl)aminomethane (Tris) hydrochloride, Tris-buffered saline (TBS), 3-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]propan-1-sulfonic acid (TAPS), bicine, tricine, 3-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]-2-hydroxypropan-1-sulfonic acid It may be ethanesulfonic acid (TAPSO), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES), 3-(N-morpholino)propanesulfonic acid (MOPS), 2-(N-morpholino)ethanesulfonic acid (MES), 2-[[1,3-dihydroxy-2-(hydroxymethyl)propane-2-yl]amino]ethanesulfonic acid (TES), cacodylate, glycine, carbonate, or any combination thereof.

[0136] kit

[0137] A kit is disclosed herein. In some embodiments, the composition may be packaged in a container. In some embodiments, the kit may further include instructions for administering a unit dose of the composition to a subject.

[0138] The method for preparing the kit may include placing the pharmaceutical composition into a container. The method may further include including instructions for use. In some cases, the instructions for use may instruct the administration of a unit dose of the composition to a subject.

[0139] A kit for determining the amount of danazol in a sample is also disclosed herein. The kit may include a sample collection container; albumin; and instructions for use. In some cases, the internal standard may be 19-norethindrone or a salt thereof. The instructions for use may instruct the user to collect the sample in the sample collection container; to contact a portion of the sample with a predetermined amount of albumin; and to detect danazol or a salt thereof by mass spectrometry. In some cases, the kit may further include an internal standard. The internal standard may be 19-norethindrone or a salt thereof. [Examples]

[0140] Example 1: Formulation of a hormone-containing composition for transvaginal delivery:

[0141] Exemplary pharmaceutical compositions containing bioadhesives for hormone delivery can be prepared for vaginal administration to subjects using the following formulations:

[0142] Progesterone preparations (%w / w): Micronized progesterone (USP / EP) 8.0%, Carbomer (Carbopol 974P NF) 1.0%, Polycarbophil Noveon AA1 (USP) 1.5%, Sorbic acid (USP / EP) 0.1%, Labrafac Lipophile WL 1349 (USP / EP) 17.07%, EmulFree P Pharmaceutical Grade 2.0%, Purified water (USP / EP) 68.4%, Sodium hydroxide (USP / EP) QS AD pH 2.8-3.2 Purified water (USP / EP) QS 100%

[0143] A progesterone preparation can be prepared by dissolving micronized progesterone in an oil phase consisting of LABRAFAC® lipophille WL 1349 and EMULFREE® P. Alcohol may be added to this suspension at a concentration that does not function as a penetration enhancer. The carbomer is hydrated in the aqueous phase. After hydration, sorbic acid, polycarbophil, and sodium hydroxide are added to the aqueous phase. The two phases are mixed in a suitable container. The resulting composition is stored in a sealed container before vaginal administration. In addition to progesterone P(4), any synthetic progestin can be formulated using the described formulation.

[0144] Estradiol preparations: (%w / w) Micronized estradiol (USP / EP) 0.1%, Carbomer (Carbopol 974P NF) 1.0%, Polycarbophil Noveon AA1 (USP) 1.5%, Sorbic acid (USP / EP) 0.1%, Labrafac Lipophile WL 1349 (USP / EP) 17.07%, EmulFree P Pharmaceutical Grade 2.0%, Purified water (USP / EP) 76.4%, Sodium hydroxide (USP / EP) QS AD pH 2.8-3.2 Purified water (USP / EP) QS 100%

[0145] For example, estradiol can be substituted with any estrogen, such as dienestrol, estriol, or estrone.

[0146] Compositions containing bioadhesion substances and other active ingredients can be prepared in the same manner as the above-described formulations. Other active ingredients may include other hormones; antineoplastic agents; receptor agonists or antagonists; steroids; antibiotics; antiviral compounds; antifungal compounds; and anti-inflammatory agents. Example 2: Formulation of a vaginal administration composition containing danazol:

[0147] Exemplary pharmaceutical compositions containing bioadhesives for delivering danazol can be prepared for vaginal administration to subjects using the following formulations:

[0148] Danazol formulations: (%w / w) Danazol 6.67% Carbomer (Carbopol 974P NF) 1.0% Polycarbophil Noveon AA1 (USP) 1.5% Methylparaben 0.25% Labrafac Lipophile WL 1349(USP / EP)15% EmulFree P Pharmaceutical Grade 2.0% Purified water (USP / EP) 73.58%

[0149] Danazol formulations can be prepared by dissolving danazol in an oil phase consisting of LABRAFAC® lipophille WL 1349 and EMULFREE® P. Carbomer is hydrated in the aqueous phase. After hydration, methylparaben and polycarbophil are added to the aqueous phase. The two phases are mixed in a suitable container. The resulting composition is stored in a sealed container before vaginal administration. Example 3: Pharmacokinetic study in mice

[0150] The following examples illustrate the vaginal administration of the danazol preparation described in Example 2 above. Research design [Table A] Sample collection [Table B] Research details

[0151] Female CD-1 mice are acclimatized for at least two days.

[0152] A unit dose of the danazol composition is administered vaginally to group 1 mice, and the oral formulation is delivered to group 2 and 3 mice by oral force-feeding. All animals are observed at the time of administration and at each scheduled collection. All abnormalities are recorded.

[0153] A final blood sample is collected by cardiac puncture after inhalation anesthesia. A final peritoneal sample is collected by puncture.

[0154] Sample processing and storage: Blood samples are collected in tubes containing dipotassium ethylenediaminetetraacetate (K2EDTA) and stored on wet ice. Within 30 minutes of collection, whole blood is converted to plasma by centrifugation (3500 rpm at 5°C). The plasma samples are divided into two equal aliquots, each transferred to a 96-well plate (matrix tube), and stored at -80°C until analysis. The dosage is determined by gravimetric analysis. Ascites is collected at various time points using puncture.

[0155] Prior to MS / MS analysis, the sample is further subjected to high-performance liquid chromatography (HPLC) using a C18 column. The HPLC-purified sample is contacted with human serum albumin to form an albumin adduct, which is then analyzed using MS to determine the [M+H] content of the adduct. + It can be detected by monitoring approximately 338 m / z, which corresponds to the ions. result

[0156] Calculate pharmacokinetic parameters using a non-compartmental method with TK / PK analysis software program. Perform PK analysis. Include all plasma and ascites concentration data from all animals in the analysis. Example 4: Pharmacokinetic studies in humans

[0157] The following examples illustrate the vaginal administration of the danazol formulation described in Example 2 to human subjects. [Table C-1] [Table C-2] [Table C-3]

[0158] Regarding Example 2, the exemplary danazol formulation described above is administered for 3 months. Then, after 30 days, pregnancy is allowed to occur. (Since danazol can have a half-life of 9.7 hours, it can be expected that 3 days may be required to have zero drug concentration in the body.)

[0159] Similar to Example 3, blood samples are collected in a time-dependent manner to determine the PK parameters of circulating danazol. Ascites samples are collected at various time points by puncture.

[0160] With respect to Example 3, the subject samples are processed in the manner described above. The amount of danazol in the blood and ascites samples can be determined using the mass spectrometry method described above. Example 5: Treatment of endometriosis

[0161] Subjects previously diagnosed with endometriosis are administered the danazol-containing pharmaceutical composition described above in relation to Example 2 via vaginal administration. Safety parameters, including hemodynamic stability, acute immune response, cardiotoxicity, respiratory function, hepatotoxicity, and nephrotoxicity, are closely monitored. Blood samples are collected for toxicity analysis.

[0162] The pharmaceutical composition will be administered to the subject daily for 30 days. The amount of endometrial deposits will be monitored to determine the effectiveness of the treatment when symptoms improve. Example 6: Fertility after treatment In Example 5, subjects who previously received a pharmaceutical composition containing danazol via vaginal administration may be further monitored after the completion of the 30-day treatment. Fertility will be confirmed by evaluating improvements in the number of mature oocytes, implantation rate, and pregnancy rate after treatment with vaginal administration of danazol. Example 7: Treatment of ovarian cancer

[0163] A composition containing doxorubicin is prepared, similar to the hormone or danazol preparations described in Examples 1 and 2. The composition is formulated such that the application of a unit dose of the composition results in the application of approximately 100 mg of doxorubicin to the vagina.

[0164] Subjects receive intravaginal application of a unit dose of the doxorubicin composition. Each treatment is administered to each subject for 30 days. After each administration, each subject is monitored for reduction in ovarian tumor size using ultrasound to determine the effectiveness of transvaginal and oral administration. Example 8: Monitoring of cardiotoxicity

[0165] In Example 7, subjects who received doxorubicin either vaginally or orally were monitored for signs of cardiotoxicity during and after the treatment course. Blood samples were collected daily from each subject during the 30-day treatment course. Levels of cardiac troponin I and cardiac troponin T (these are biomarkers indicating cardiac damage) were assessed in each subject using blood immunoassays specific to each biomarker. Samples from subjects who had not previously received doxorubicin were included as a control. The level of cardiotoxicity in subjects who received doxorubicin vaginally or orally was assessed by monitoring for increases in either cardiac troponin I or cardiac troponin T during the treatment course and compared to samples from subjects who had not received doxorubicin. Example 9: Treatment of pelvic inflammatory disease

[0166] Similar to the hormone or danazol formulations described in Examples 1 and 2, compositions containing appropriate antibiotics against disease-causing microorganisms can be formulated.

[0167] Using an applicator, a unit dose composition containing levofloxacin can be applied vaginally to subjects previously diagnosed with an intraperitoneal infection. The composition may be formulated so that the application of a unit dose results in the application of approximately 400 mg of antibiotic to the vagina. After application, subjects are monitored for improvement of the infection. Example 10: Delivery of active ingredient to the peritoneal cavity

[0168] The following examples illustrate the administration of either a vaginal or oral danazol formulation to female human subjects. The vaginal formulation was prepared as described in Example 2 above. The oral formulation contained a total dose of 200 mg of danazol, contained in a titanium dioxide and gelatin capsule shell and formulated with starch, lactose, talcum, and magnesium stearate.

[0169] Danazol was administered to subjects daily for 5 days. A total dose of 600 mg of oral danazol (3 × 200 mg) was administered once daily to 6 subjects for 5 days. A vaginal preparation containing a total of 100 mg of danazol was administered to 7 subjects. Subsequently, samples were taken from each subject to determine the concentrations of danazol present in the body, ascites, and peritoneal tissue. Serum samples were collected from each subject to quantify the amount of danazol present in the body and analyzed as described in Example 3 above. To determine the amount of danazol present in ascites and peritoneal tissue, endometrial lesions or suspected lesions were collected and the amount of danazol present in the samples was quantified as described in Example 3. The results are shown in Table 2.

[0170] Table 2 [Table 2]

[0171] Although embodiments have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided as merely examples. Those skilled in the art can conceive of numerous variations, modifications, and substitutions. In certain embodiments, for example, the following items are provided: (Item 1) A method comprising administering a pharmaceutical composition to a subject via vaginal injection in the form of an emulsion containing an activator or a salt thereof and a bioadhesive substance, wherein the pharmaceutical composition is administered in a dose of about 10 mg to about 400 mg of the activator or a salt thereof; and the vaginal injection of the pharmaceutical composition results in a substantially zero-order release rate profile of the activator into the subject's peritoneal cavity for at least about 8 hours after the administration of the pharmaceutical composition. (Item 2) The method according to item 1, comprising the aforementioned activator or a salt thereof in a dose of approximately 50 mg to approximately 100 mg. (Item 3) The method according to item 1 or 2, wherein the activator or a salt thereof is present in the peritoneal cavity for about 12 hours after the administration of the pharmaceutical composition. (Item 4) A method comprising administering a pharmaceutical composition to a subject via vaginal injection in the form of an emulsion containing an activator or a salt thereof and a bioadhesive substance, wherein the vaginal injection of the pharmaceutical composition comprises administering a dose of the activator or a salt thereof; and the vaginal injection minimizes, at least partially, side effects compared to an oral injection of an oral pharmaceutical composition containing a substantially equivalent dose of the activator or a salt thereof. (Item 5) The method according to item 4, wherein the aforementioned vaginal administration is performed at least 1, 2, 4, or 6 times within 24 hours. (Item 6) The method according to item 5, wherein the adverse effect is selected from the group consisting of cardiotoxicity; nephrotoxicity; hepatotoxicity; and any combination thereof, when the amount of the biomarker involved in the adverse effect after vaginal administration of the pharmaceutical composition is less than the amount of the biomarker involved in the adverse effect after oral administration of the oral pharmaceutical composition. (Item 7) The method according to any one of items 1 to 6, wherein the vaginal administration of the pharmaceutical composition results in a peritoneal concentration of the activator, its metabolites or salts that is at least about four times greater than that achieved by oral administration of an oral pharmaceutical composition containing substantially equivalent doses of the activator or a salt thereof. (Item 8) A method of treating a disease or symptom, as described in any one of items 1 through 7. (Item 9) The method according to item 8, wherein the disease or symptom is selected from the group consisting of endometrial disorders, cancer, inflammatory disorders, infections, and any combination thereof. (Item 10) The method according to item 9, wherein the disease or symptoms are endometrial disorders. (Item 11) The method according to item 10, wherein the endometrial disorder is endometriosis, adenomyosis, or a combination thereof. (Item 12) The method according to item 10 or 11, wherein the amount of endometrial deposits after the vaginal administration of the pharmaceutical composition is less than the amount of the pharmaceutical composition before the vaginal administration. (Item 13) The method according to item 9, wherein the disease or symptom is cancer. (Item 14) The method according to item 13, wherein the cancer is selected from the group consisting of cervical cancer; ovarian cancer; mesothelial cancer; peritoneal cancer; and any combination thereof. (Item 15) The method according to item 13 or 14, wherein the treatment includes a reduction in tumor size or a reduction in tumor growth. (Item 16) The method according to item 15, wherein the reduction in tumor size or the reduction in tumor growth is determined by a reduction in tumor volume as measured by ultrasound. (Item 17) The method according to item 9, wherein the disease or symptoms are an inflammatory disorder. (Item 18) The method according to item 17, wherein the inflammatory disorder is selected from the group consisting of pelvic inflammatory disease; chronic pelvic pain; and any combination thereof. (Item 19) The method according to item 17 or 18, wherein the treatment comprises reducing the amount of at least one pro-inflammatory cytokine to a level lower than that before the vaginal administration of the pharmaceutical composition. (Item 20) The method according to item 9, wherein the disease or symptoms are an infectious disease. (Item 21) The method described in item 20, wherein the aforementioned infection is a bacterial infection. (Item 22) The method described in item 20, wherein the aforementioned infectious disease is a viral infection. (Item 23) The method described in item 20, wherein the aforementioned infection is a fungal infection. (Item 24) The method according to any one of items 1 to 23, wherein the activator or a salt thereof is selected from the group consisting of hormones; antineoplastic agents; GnRH agonists; GnRH antagonists; steroids; antibiotics; antiviral compounds; antifungal compounds; anti-inflammatory agents; salts of any of these; and any combination thereof. (Item 25) The method according to item 24, wherein the activator is the hormone or a salt thereof, and the hormone or salt thereof is selected from the group consisting of testosterone; estradiol; ethinylestradiol; progesterone; levonorgestrel; oxytocin; desogestrel; synthetic progesterone; any salt thereof; and any combination thereof. (Item 26) The method according to item 24, wherein the activator is the antineoplastic agent or a salt thereof, and the antineoplastic agent or a salt thereof is selected from the group consisting of cyclophosphamide; methotrexate; 5-fluorouracil; doxorubicin; procarbazine; prednisolone; bleomycin; vinblastine; dacarbazine; cisplatin; epirubicin; dichloroacetate, any salt thereof; and any combination thereof. (Item 27) The method according to item 24, wherein the activator is the GnRH agonist, GnRH antagonist, or a salt thereof, and the GnRH agonist, GnRH antagonist, or a salt thereof is selected from the group consisting of leuprolide; buserelin; histrelin; goserelin; deslorerin; nafarelin; triptorelin; cetrorelix; abarelix; ganirelix; ozarelix; degarelix; teverelix; any salt thereof; and any combination thereof. (Item 28) The method according to item 24, wherein the activator is the steroid or a salt thereof, and the steroid or salt thereof is danazol or a salt thereof. (Item 29) The method according to item 24, wherein the activator is the antibiotic or a salt thereof, and the antibiotic or a salt thereof is selected from the group consisting of ceftobiprole; cephthaloline; clindamycin; dalbavancin; daptomycin; linezolid; mupirocin; oritabancin; tedizolid; teravancin; tigecycline; vancomycin; aminoglycoside; carbapenem; ceftazidime; cefepime; ceftobiprole; fluoroquinolone; piperacillin; ticalcillin; linezolid; streptogramin; tigecycline; daptomycin; any salt thereof; and any combination thereof. (Item 30) The method according to item 24, wherein the activator is the antiviral compound or a salt thereof, and the antiviral compound or salt thereof is selected from the group consisting of ceftobiprole; cephthaloline; clindamycin; dalbavancin; daptomycin; linezolid; mupirosin; oritabancin; tedizolid; teravancin; tigecycline; vancomycin; aminoglycoside; carbapenem; ceftazidime; cefepime; ceftobiprole; fluoroquinolone; piperacillin; ticalcillin; linezolid; streptogramin; tigecycline; daptomycin; any salt thereof; and any combination thereof. (Item 31) The method according to item 24, wherein the activator is the antifungal compound or a salt thereof, and the antifungal compound or salt thereof is selected from the group consisting of cyclopirox olamine; haloprozine; tolnaphthate; undecylenate; topical nystatin; amorolfine; butenafine; naphthifine; terbinafine; any salt thereof; and any combination thereof. (Item 32) The method according to item 24, wherein the activator is the anti-inflammatory drug or a salt thereof, and the anti-inflammatory drug or salt thereof is selected from the group consisting of diclofenac; ketoprofen; ibuprofen; aspirin; salts of any of these; and any combination thereof. (Item 33) The method according to any one of items 1 to 32, wherein the pharmaceutical composition is administered in a dose of the activator or a salt thereof of at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, or at least about 400 mg. (Item 34) The pharmaceutical composition is administered in amounts of at least approximately 0.1 mg / kg, at least approximately 0.5 mg / kg, at least approximately 1 mg / kg, at least approximately 1.5 mg / kg, at least approximately 2 mg / kg, at least approximately 2.5 mg / kg, at least approximately 3 mg / kg, at least approximately 3.5 mg / kg, at least approximately 4 mg / kg, at least approximately 4.5 mg / kg, at least approximately 5 mg / kg, at least approximately 5.5 mg / kg, at least approximately 6 mg / kg, at least approximately 6.5 mg / kg, at least approximately 7 mg / kg, at least approximately 7.5 mg / kg, and less than 0.1 mg / kg, per 1 kg of body weight of the subject. The method according to any one of items 1 to 32, wherein the activator or a salt thereof is administered in a dose of at least approximately 8 mg / kg, at least approximately 8.5 mg / kg, at least approximately 9 mg / kg, at least approximately 9.5 mg / kg, at least approximately 10 mg / kg, at least approximately 11 mg / kg, at least approximately 12 mg / kg, at least approximately 13 mg / kg, at least approximately 14 mg / kg, at least approximately 15 mg / kg, at least approximately 16 mg / kg, at least approximately 17 mg / kg, at least approximately 18 mg / kg, at least approximately 19 mg / kg, or at least approximately 20 mg / kg. (Item 35) The method according to any one of items 1 to 32, wherein the pharmaceutical composition comprises a substantially homogeneous mixture of an organic phase and an aqueous phase. (Item 36) The method according to item 35, wherein the organic phase comprises at least one oleogel containing at least one oily agent and at least one water-insoluble cellulose polymer. (Item 37) The method according to item 36, wherein the water-insoluble cellulose polymer is alkylcellulose. (Item 38) The method according to item 37, wherein the alkylcellulose is selected from the group consisting of methylcellulose; ethylcellulose; hydroxypropylcellulose; and any combination thereof. (Item 39) The method according to item 36, wherein the water-insoluble cellulose polymer is alkylcarboxylic acid-containing cellulose or a salt thereof. (Item 40) The method according to item 39, wherein the alkylcarboxylic acid-containing cellulose is substantially sodium-free carboxymethylcellulose. (Item 41) The method according to item 40, wherein the substantially sodium-free carboxymethylcellulose constitutes about 1% to about 10% by weight of the total weight of the pharmaceutical composition. (Item 42) The method according to item 37, wherein the alkylcellulose constitutes about 1% to about 10% by weight of the total weight of the pharmaceutical composition. (Item 43) The method according to item 38, wherein the ethylcellulose constitutes about 1% to about 10% by weight of the total weight of the pharmaceutical composition. (Item 44) The method according to item 39, wherein the alkylcarboxylic acid-containing cellulose or a salt thereof constitutes about 1% to about 10% by weight of the total weight of the pharmaceutical composition, and further comprises the alkylcarboxylic acid-containing cellulose or a salt thereof. (Item 45) The method according to item 35, wherein the aqueous phase comprises at least one aqueous gel. (Item 46) The method according to item 45, wherein the aqueous gel further comprises at least one gelling agent. (Item 47) The method according to item 46, wherein the at least one gelling agent is selected from the group consisting of carbomer; poloxamer; sodium carboxymethylcellulose; and combinations thereof. (Item 48) The method according to item 46 or 47, wherein the at least one gelling agent constitutes about 0.1% to about 10% by weight of the total weight of the aqueous gel. (Item 49) The method according to any one of items 46 to 48, wherein the at least one gelling agent constitutes about 0.01% to about 10% by weight of the total weight of the pharmaceutical composition. (Item 50) The method according to item 36, wherein the oily agent is selected from the group consisting of monoglycerides; diglycerides; triglycerides; and any combination thereof. (Item 51) The method according to item 36, wherein the oily agent is isolated and purified. (Item 52) The method according to item 36, wherein the oily agent is selected from the group consisting of synthetic diglycerides; synthetic triglycerides; propylene glycol isostearate; polyoxyethylene-derived oleic acid glyceride mixtures; plant-derived oils; and any combination thereof. (Item 53) The method according to item 52, comprising the propylene glycol isostearate, wherein the propylene glycol isostearate constitutes about 0.2% to about 2% by weight of the total weight of the pharmaceutical composition. (Item 54) The method according to item 52, comprising the polyoxyethylene oleic acid glyceride mixture, wherein the polyoxyethylene oleic acid glyceride mixture constitutes about 0.2% to about 2% by weight of the total weight of the pharmaceutical composition. (Item 55) The method according to any one of items 35 to 54, wherein the organic phase is in a weight ratio of about 10:90 to about 90:10 with respect to the aqueous phase. (Item 56) The method according to any one of items 1 to 55, wherein the bioadhesive substance is selected from the group consisting of carbomer; glyceryl monooleate; hypromellose; polycarbophil; poly(methyl vinyl ether-co-maleic anhydride); salts thereof; and combinations thereof. (Item 57) The method according to item 56, wherein the bioadhesive substance is polycarbophil, a salt thereof, or a combination thereof. (Item 58) The method according to any one of items 1 to 57, wherein the pharmaceutical composition contains an alcohol in a concentration of about 0% to about 4% by weight based on the total weight of the pharmaceutical composition, and the alcohol is ethanol or isopropanol. (Item 59) The method according to item 58, wherein the concentration of alcohol is about 3.5% by weight based on the total weight of the pharmaceutical composition. (Item 60) The method according to any one of items 1 to 57, wherein the activator constitutes about 0.00001% to about 10% by weight of the total weight of the pharmaceutical composition. (Item 61) The method according to any one of items 1 to 57, wherein the pharmaceutical composition comprises a penetration enhancer in an amount of about 0% to about 4% by weight of the total weight of the pharmaceutical composition. (Item 62) The method according to any one of items 1 to 57, wherein the pharmaceutical composition comprises a surfactant in an amount of about 0% to about 2% by weight of the total weight of the pharmaceutical composition, and the surfactant is selected from the group consisting of nonionic; cationic; amphoteric; amphoteric; and any combination thereof. (Item 63) The method according to any one of items 1 to 62, wherein the pharmaceutical composition is administered to the subject in unit dosage form. (Item 64) The method according to any one of items 1 to 62, wherein the transvaginal administration of the pharmaceutical composition is performed approximately every hour, every four hours, every eight hours, every twelve hours, or every twenty-four hours. (Item 65) The method according to any one of items 1 to 62, wherein the transvaginal administration of the pharmaceutical composition is performed approximately once, twice, three times, four times, five times, six times, seven times, or eight times within a 24-hour period. (Item 66) The method according to any one of items 1 to 62, wherein the transvaginal administration of the pharmaceutical composition is performed approximately once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, or twenty times per week. (Item 67) The method according to any one of items 1 to 62, wherein the transvaginal administration of the pharmaceutical composition is performed approximately once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, twenty times, twenty-one times, twenty-two times, twenty-two times, twenty-two times, twenty-three times, twenty-four times, twenty-five times, twenty-six times, twenty-seven times, twenty-eight times, twenty-nine times, thirty-three times, or thirty-one times per month. (Item 68) The method according to any one of items 1 to 67, wherein the pharmaceutical composition is applied using a finger. (Item 69) The method according to any one of items 1 to 67, wherein the pharmaceutical composition is applied using gloves. (Item 70) The method according to any one of items 1 to 67, wherein the pharmaceutical composition is applied using an applicator. (Item 71) The method according to any one of items 1 to 67, wherein the transvaginal administration includes vaginal administration, topical administration, administration by suppository, or any combination thereof. (Item 72) The method according to any one of items 1 to 71, wherein the pharmaceutical composition maintains a substantially stable and uniform appearance for about one year when stored in a sealed container at about 25°C, about 1 atmosphere, and about 50% relative humidity. (Item 73) (a) at least one oleogel comprising at least one oily agent and at least one water-insoluble cellulose polymer; (b) at least one aqueous gel; (c) Activators or their salts; and (d) Bioadhesive substances A pharmaceutical composition containing, A pharmaceutical composition in which the activator or a salt thereof is present in the pharmaceutical composition in an amount of about 50 mg to about 400 mg. (Item 74) The pharmaceutical composition according to item 73, wherein the at least one oleogel and the at least one aqueous gel are in the form of an emulsion. (Item 75) The pharmaceutical composition according to item 73 or 74, wherein the activator or a salt thereof is selected from the group consisting of hormones; antineoplastic agents; GnRH agonists; steroids; antibiotics; antiviral compounds; antifungal compounds; anti-inflammatory agents; salts of any of these; and any combination thereof. (Item 76) The pharmaceutical composition according to item 75, wherein the activator is the hormone or a salt thereof, and the hormone or salt thereof is selected from the group consisting of estradiol; ethinylestradiol; progesterone; levonorgestrel; desogestrel; synthetic progesterone; any salt thereof; and any combination thereof. (Item 77) The pharmaceutical composition according to item 75, wherein the activator is the antineoplastic agent or a salt thereof, and the antineoplastic agent or a salt thereof is selected from the group consisting of cyclophosphamide; methotrexate; 5-fluorouracil; doxorubicin; procarbazine; prednisolone; bleomycin; vinblastine; dacarbazine; cisplatin; epirubicin; dichloroacetate, any salt thereof; and any combination thereof. (Item 78) The pharmaceutical composition according to item 75, wherein the activator is the GnRH agonist, the GnRH antagonist, or a salt thereof, and the GnRH agonist, the GnRH antagonist, or a salt thereof is selected from the group consisting of leuprolide; buserelin; histrelin; goserelin; deslorerin; nafarelin; triptorelin; cetrorelix, abarelix; ganirelix; ozarelix; degarelix; teverelix; any salt thereof; and any combination thereof. (Item 79) The pharmaceutical composition according to item 75, wherein the activator is the steroid or a salt thereof, and the steroid or a salt thereof is danazol or a salt thereof. (Item 80) The pharmaceutical composition according to item 75, wherein the activator is the antibiotic or a salt thereof, and the antibiotic or salt thereof is selected from the group consisting of ceftobiprole; cephthaloline; clindamycin; dalbavancin; daptomycin; linezolid; mupirocin; oritabancin; tedizolid; teravancin; tigecycline; vancomycin; aminoglycoside; carbapenem; ceftazidime; cefepime; ceftobiprole; fluoroquinolone; piperacillin; ticalcillin; linezolid; streptogramin; tigecycline; daptomycin; any salt thereof; and any combination thereof. (Item 81) The pharmaceutical composition according to item 75, wherein the activator is the antiviral compound or a salt thereof, and the antiviral compound or a salt thereof is selected from the group consisting of ceftobiprole; cephthaloline; clindamycin; dalbavancin; daptomycin; linezolid; mupirosin; oritabancin; tedizolid; teravancin; tigecycline; vancomycin; aminoglycoside; carbapenem; ceftazidime; cefepime; ceftobiprole; fluoroquinolone; piperacillin; ticalcillin; linezolid; streptogramin; tigecycline; daptomycin; any salt thereof; and any combination thereof. (Item 82) The pharmaceutical composition according to item 75, wherein the activator is the antifungal compound or a salt thereof, and the antifungal compound or salt thereof is selected from the group consisting of cyclopirox olamine; haloprozine; tolnaphthate; undecyrenate; topical nysatin; amorolfine; butenafine; naphthifine; terbinafine; any salt thereof; and any combination thereof. (Item 83) The pharmaceutical composition according to item 75, wherein the activator is the anti-inflammatory drug or a salt thereof, and the anti-inflammatory drug or a salt thereof is selected from the group consisting of diclofenac; ketoprofen; ibuprofen; aspirin; salts of any of these; and any combination thereof. (Item 84) A kit comprising a container containing a pharmaceutical composition described in any one of items 73 to 83, and instructions for use. (Item 85) A method for preparing a kit, comprising placing a pharmaceutical composition described in any one of items 73 to 83 into a container. (Item 86) A method for detecting danazol or a salt thereof in a sample, (a) Contacting a portion of the sample derived from the subject with albumin; and (b) Detection of danazol or a salt thereof by mass spectrometry. Methods that include... (Item 87) The aforementioned detection includes [M+H] 338 m / z + The method described in item 86, which includes determining the amount of ions. (Item 88) The detection includes the [M+H] m / z of 338 + The above amount of ions is measured against the internal standard [M+H] + The method according to item 87, comprising comparing with the amount of ions; wherein the internal standard is 19-norethindrone or a salt thereof. (Item 89) The method according to item 86, wherein the albumin is human serum albumin. (Item 90) The method according to item 86, wherein between (a) and (b), the sample is dried and reconstituted with a buffer. (Item 91) A kit for determining the amount of danazol in a sample, (a) Sample collection container; (b) Albumin; and (c) Instructions for use A kit that includes this. (Item 92) The kit according to item 91, further comprising an internal standard, wherein the internal standard is 19-norethindrone or a salt thereof. (Item 93) The kit described in item 91, further containing a buffer solution. (Item 94) The aforementioned instruction manual is intended for the user (a) Collect the sample in the sample collection container; (b) Contacting a portion of the sample with a predetermined amount of albumin; and (c) The kit described in item 91, which is instructed to detect danazol or a salt thereof by mass spectrometry.

Claims

1. (a) 10 mg to about 400 mg of danazol or a salt thereof; (b) Aqueous gel; (c) organic phase A composition comprising a two-phase liquid emulsion containing, The aqueous gel contains a bioadhesive substance, The organic phase comprises at least one oily agent and at least one water-insoluble cellulose polymer, and the danazole or its salt is dissolved in the organic phase. A composition wherein the two-phase liquid emulsion constitutes a substantially homogeneous mixture of the organic phase and the aqueous gel, and the composition is administered transvaginally.

2. The composition according to claim 1, wherein the two-phase liquid emulsion comprises 50 mg to about 100 mg of danazol or a salt thereof.

3. The composition according to claim 1, wherein the water-insoluble cellulose polymer is alkylcellulose.

4. The composition according to claim 3, wherein the alkylcellulose is selected from the group consisting of methylcellulose; ethylcellulose; hydroxypropylcellulose; and any combination thereof.

5. The composition according to claim 1, wherein the water-insoluble cellulose polymer is alkylcarboxylic acid-containing cellulose or a salt thereof.

6. The composition according to claim 5, wherein the alkylcarboxylic acid-containing cellulose is substantially sodium-free carboxymethylcellulose.

7. The composition according to claim 6, wherein the substantially sodium-free carboxymethylcellulose constitutes about 1% to about 10% by weight of the total weight of the two-phase liquid emulsion.

8. The composition according to claim 3, wherein the alkylcellulose constitutes about 1% to about 10% by weight of the total weight of the two-phase liquid emulsion.

9. A composition according to claim 4, comprising the ethylcellulose, wherein the ethylcellulose constitutes about 1% to about 10% by weight of the total weight of the two-phase liquid emulsion.

10. The composition according to claim 5, comprising the alkylcarboxylic acid-containing cellulose or a salt thereof, wherein the alkylcarboxylic acid-containing cellulose or a salt thereof constitutes about 1% to about 10% by weight of the total weight of the two-phase liquid emulsion.

11. The composition according to claim 1, wherein the aqueous gel further comprises at least one gelling agent.

12. The composition according to claim 11, wherein the at least one gelling agent is selected from the group consisting of poloxamer; sodium carboxymethylcellulose; and combinations thereof.

13. The composition according to claim 11, wherein the at least one gelling agent constitutes about 0.01% to about 10% by weight of the total weight of the two-phase liquid emulsion.

14. The composition according to claim 11, wherein the oily agent is selected from the group consisting of monoglycerides; diglycerides; triglycerides; and any combination thereof.

15. The composition according to claim 11, wherein the oily agent is selected from the group consisting of synthetic diglycerides; synthetic triglycerides; propylene glycol isostearate; polyoxyethylene-derived oleic acid glyceride mixtures; plant-derived oils; and any combination thereof.

16. The composition according to claim 15, comprising the propylene glycol isostearate, wherein the propylene glycol isostearate constitutes about 0.2% to about 2% by weight of the total weight of the two-phase liquid emulsion.

17. The composition according to claim 15, wherein the polyoxyethylene-derived oleic acid glyceride mixture constitutes about 0.2% to about 2% by weight of the total weight of the two-phase liquid emulsion.

18. The composition according to claim 1, wherein the bioadhesive substance is selected from the group consisting of carbomer; hypromellose; polycarbophil; poly(methyl vinyl ether-co-maleic anhydride); salts thereof; and combinations thereof.

19. The composition according to claim 1, wherein the two-phase liquid emulsion further contains an alcohol in a concentration of about 0% to about 4% by weight based on the total weight of the two-phase liquid emulsion, and the alcohol is ethanol or isopropanol.

20. The composition according to claim 19, wherein the concentration of the alcohol is about 3.5% by weight based on the total weight of the two-phase liquid emulsion.

21. The composition according to claim 1, further comprising a penetration enhancer.

22. The composition according to claim 1, further comprising a surfactant, wherein the surfactant is selected from the group consisting of nonionic; cationic; amphoteric; amphoteric; and any combination thereof.

Images