Vaginal delivery of chemotherapeutic agents and inhibitors of membrane efflux systems for cancer therapy

Abstract

Devices, methods, and compositions for cancer therapy by administration of chemotherapeutic agents and/or inhibitors of membrane efflux systems to the vagina for topical and systemic tumor targets.

1 - 33 . (canceled)  
     
     
         34 . A method for a vaginal delivery of chemotherapeutic agents to a systemic circulation for treatment, control and maintenance of cancer in a human female patient, wherein said agent is delivered into the systemic circulation through a vaginal mucosa from a mucoadhesive composition or from an intravaginal device incorporated with said composition, said method comprising steps of: 
 a) providing the mucoadhesive vaginal composition consisting of from about 1 to about 1000 mg/day of the chemotherapeutic agent selected from the group consisting of daunorubicin, doxorubicin, idarubicin, amrubicin, pirarubicin, epirubicin, mitoxantrone, etoposide, teniposide, vinblastine, vincristine, mitomycin C, paclitaxel, docetaxel, actinomycin D, colchicine, topotecan, irinotecan, gemcitabine and a mixture thereof;    from about 30 to about 95% of a lipophilic or hydrophilic carrier selected from the group consisting of saturated mono-, di- or triglyceride of fatty acids from 8 to 18 carbons, a mixture thereof, polyethylene glycol of molecular weight between about 200 and 8000, a derivative thereof and a mixture thereof; from about 5 to about 25% of a mucoadhesive agent selected from the group consisting of a cellulose derivative, natural gum, alginate and pectin; and    from about 5 to about 25% of a sorption promoter selected from the group consisting of a non-ionizable glycol ester derivative, a glycol derivative with a glycerol ester, a non-ionizable glycol ether derivative and an interesterified stone oil;    wherein said composition is formulated as or incorporated into the device as a suppository, cream, gel, foam, ointment, capsule containing microparticles, microcapsules, microparticles, nanoparticles, or liposome suspension; and    b) delivering said composition to the vaginal mucosa by administering said composition or inserting said device incorporated with said composition into the vagina,    wherein said vaginal device is a vaginal tampon, vaginal ring, vaginal strip, vaginal capsule, vaginal tablet, vaginal pessary, vaginal cup or vaginal sponge.    
     
     
         35 . The method of  claim 34  wherein said chemotherapeutic agent is colchicine administered in a range from about 4 to about 8 mg/day, paclitaxel administered in a range from about 60 to about 100 mg/day, topotecan administered in a range from about 0.5 to about 1.5 mg/day, doxorubicin administered in a range from about 100 to about 1000 mg/day, vincristine administered in a range from about 1-2 mg/week, verapamil administered in a range from about 10 to about 125 mg/dose or cyclosporin administered in about 60 mg/dose.  
     
     
         36 . The method of  claim 35  wherein said mucoadhesive agent is hydroxypropyl methylcellulose, wherein said lipophilic carrier is the saturated mono-, di- or triglyceride of fatty acids of from 8 to 18 carbons, or the mixture thereof, and wherein said hydrophilic carrier is a polyethylene glycol (PEG) 8000, PEG 6000, PEG 4000, PEG 3000, PEG 2000, PEG 1500, PEG 400 or a mixture thereof and wherein said sorption promoter is ethoxydiglycol.  
     
     
         37 . A mucoadhesive vaginal composition for vaginal delivery of chemotherapeutic agents to a systemic circulation for treatment, control and maintenance of cancer in a human female patient, said composition essentially consisting of: 
 a) from about 1 to about 1000 mg of the chemotherapeutic agent selected from the group consisting of daunorubicin, doxorubicin, idarubicin, amrubicin, pirarubicin, epirubicin, mitoxantrone, etoposide, teniposide, vinblastine, vincristine, mitomycin C, paclitaxel, docetaxel, actinomycin D, colchicine, topotecan, irinotecan, gemcitabine and a mixture thereof;    from about 30 to about 95% of a lipophilic or hydrophilic carrier selected from the group consisting of saturated mono-, di- or triglyceride of fatty acids from 8 to 18 carbons, a mixture thereof, polyethylene glycol of molecular weight between about 200 and 8000, a derivative thereof and a mixture thereof;    from about 5 to about 25% of a mucoadhesive agent selected from the group consisting of a cellulose derivative, natural gum, alginate and pectin; and    from about 5 to about 25% of a sorption promoter selected form the group consisting of a non-ionizable glycol ester derivative, a glycol derivative with a glycerol ester, a non-ionizable glycol ether derivative and an interesterified stone oil;    wherein said composition is formulated as a suppository, cream, gel, foam, ointment, capsule containing microparticles, microcapsules, microparticles, nanoparticles or a liposome suspension.    
     
     
         38 . The composition of  claim 37  wherein said chemotherapeutic agent is colchicin administered in a range from about 4 to about 8 mg/day, paclitaxel administered in a range from about 60 to about 100 mg/day, topotecan administered in a range from about 0.5 to about 1.5 mg/day, doxorubicin administered in a range from about 100 to about 1000 mg/day, vincristine administered in a range from about 1-2 mg/week, verapamil administered in a range from about 10 to about 125 mg/dose or cyclosporin administered in about 60 mg/dose.  
     
     
         39 . The composition of  claim 38  wherein said sorption promoter is ethoxydiglycol present in from about 10 to about 15%, wherein said mucoadhesive agent is a cellulose derivative hydroxypropyl methylcellulose present in from about 10 to about 15%, wherein said lipophilic carrier is the saturated mono-, di- or triglyceride of fatty acids of from 8 to 18 carbons or the mixture thereof, and wherein said hydrophilic carrier is a polyethylene glycol (PEG) 8000, PEG 6000, PEG 4000, PEG 3000, PEG 2000, PEG 1500, PEG 400 or a mixture thereof.  
     
     
         40 . The composition of  claim 39  wherein said chemotherapeutic agent is released from said composition or from the device incorporated with said composition in a controlled release manner for a continuous or pulsed release.  
     
     
         41 . The composition of  claim 40  additionally comprising a penetration enhancer or a solubilizer.  
     
     
         42 . The composition of  claim 41  administered daily, bi-daily, weekly, monthly or quarterly.  
     
     
         43 . The composition of  claim 42  incorporated into a vaginal device.  
     
     
         44 . The composition of  claim 43  said device is a vaginal tampon, vaginal ring, vaginal strip, vaginal capsule, vaginal tablet, vaginal pessary, vaginal cup or vaginal sponge.  
     
     
         45 . A vaginal device for delivery of chemotherapeutic agents to the general circulation, 
 wherein said device is a vaginal tampon, vaginal ring, vaginal strip, vaginal capsule, vaginal tablet, vaginal bioadhesive tablet, vaginal pessary, vaginal cup or vaginal sponge incorporated with a mucoadhesive composition comprising from about 1 to about 1000 mg of the chemotherapeutic agent selected from the group consisting of daunorubicin, doxorubicin, idarubicin, amrubicin, pirarubicin, epirubicin, mitoxantrone, etoposide, teniposide, vinblastine, vincristine, mitomycin C, paclitaxel, docetaxel, actinomycin D, colchicine, topotecan, irinotecan, gemcitabine and a mixture thereof;    from about 30 to about 95% of a lipophilic or hydrophilic carrier selected from the group consisting of saturated mono-, di- or triglyceride of fatty acids from 8 to 18 carbons, a mixture thereof, polyethylene glycol of molecular weight between about 200 and 8000, a derivative thereof and a mixture thereof;    from about 5 to about 25% of a mucoadhesive agent selected from the group consisting of a cellulose derivative, natural gum, alginate and pectin; and    from about 5 to about 25% of a sorption promoter selected form the group consisting of a non-ionizable glycol ester derivative, a glycol derivative with a glycerol ester, a non-ionizable glycol ether derivative and an interesterified stone oil;    wherein said composition is formulated as a suppository, cream, gel, foam, ointment, capsule containing microparticles, microcapsules, microparticles, nanoparticles or a liposome suspension.    
     
     
         46 . The device of  claim 45  wherein said device is incorporated with the composition comprising from about 4 to about 8 mg/day of colchicin, from about 60 to about 100 mg/day of paclitaxel, from about 0.5 to about 1.5 mg/day of topotecan, from about 100 to about 1000 mg/day of doxorubicin, from about 1-2 mg/week of doxorubicin, from about 10 to about 125 mg/dose of verapamil or about 60 mg/dose of cyclosporin, about 10% of hydroxypropyl methylcellulose, about 75% of saturated triglyceride of fatty acids for a hydrophilic drug or PEG 6000/PEG 400 for a lipophilic drug and about 15% of ethoxydiglycol.  
     
     
         47 . The device of  claim 46  wherein said device is the vaginal tampon.  
     
     
         48 . The device of  claim 46  wherein said device is the vaginal strip.  
     
     
         49 . The device of  claim 46  wherein said device is the vaginal pessary.  
     
     
         50 . The device of  claim 46  wherein said device is the vaginal sponge.  
     
     
         51 . The device of  claim 46  wherein said device is the vaginal foam.  
     
     
         52 . The device of  claim 46  wherein said device is the vaginal ring.  
     
     
         53 . The device of  claim 46  wherein said device is the vaginal capsule, vaginal tablet, vaginal bioadhesive tablet or vaginal cup.