Non-mucoadhesive film dosage forms

Abstract

Orally disintegrating film dosage forms for delivering active pharmaceutical agents, methods of formulating the dosage forms to retard absorption through the oral mucosa, and methods of using the dosage forms for the treatment of various medical conditions are provided.

1 ) A non-mucoadhesive orally disintegrating film, able to disintegrate upon contact with saliva in the buccal cavity within about sixty seconds, comprising donepezil or a pharmaceutically acceptable salt thereof in combination with a hydrophilic binder and a water-soluble diluent, wherein:
 a) said film is characterized predominantly by gastrointestinal absorption when placed on the tongue, allowed to disintegrate, and subsequently swallowed;   b) said film comprises from about 2.5 to about 20 mg of donepezil or a pharmaceutically acceptable salt thereof;   c) said donepezil hydrochloride is present in an amount of from about 0.05% to about 50% (w/w), based on the total weight of the film,   d) said film has a T max  of from about 3 to about 4 hours, and   e) said donepezil or pharmaceutically acceptable salt thereof has an absolute bioavailability in said film of about 100%.   
     
     
         2 ) The film of  claim 1  wherein said donepezil is present as amorphous donepezil hydrochloride. 
     
     
         3 ) The film of  claim 1  characterized by greater than 95% gastrointestinal absorption. 
     
     
         4 ) The film of  claim 1  wherein said film comprises from about 40% to about 80% (w/w) of one or more ingredients that constitute a hydrophilic binder and a water soluble diluent. 
     
     
         5 ) The film of  claim 1 , further comprising from about 5 to about 25 wt. % of an aminoalkyl methacrylate copolymer, having a molecular weight of from about 120,000 to about 180,000. 
     
     
         6 ) The film of  claim 1  further comprising from about 10 to about 40 wt. % of a cyclodextrin or derivative thereof. 
     
     
         7 ) The film of  claim 1  comprising from about 0.5 to about 2.0 wt. % citric acid. 
     
     
         8 ) The film of  claim 1  comprising amorphous donepezil hydrochloride, made by a process comprising:
 a) dissolving donepezil hydrochloride in a hydrophilic binder, water soluble diluent and liquid solvent to form a liquid intermediate; 
 b) spreading said liquid intermediate on a flat surface; and 
 c) evaporating said liquid solvent from said liquid intermediate to form said final film product. 
 
     
     
         9 ) The film of  claim 7 , wherein said donepezil hydrochloride dissolved in step (a) is Form I donepezil hydrochloride. 
     
     
         10 ) A non-mucoadhesive orally disintegrating film, able to disintegrate upon contact with saliva in the buccal cavity within about sixty seconds, comprising amorphous donepezil hydrochloride in combination with a hydrophilic binder and a water-soluble diluent, wherein:
 a) said film comprises from about 2.5 to about 20 mg of amorphous donepezil hydrochloride;   b) said donepezil is present in an amount from about 0.05% to about 50% (w/w), based on the total weight of the formulation,   c) said film has a T max  of from about 3 to about 4 hours, and   d) said donepezil has an absolute bioavailability in said dosage form of about 100%.   
     
     
         11 ) Use of the non-mucoadhesive orally disintegrating film of  claim 1  in the manufacture of a medicament for the treatment of mild to moderate dementia in a human patient, for the administration of said film to the tongue of said patient, for swallowing said film within about sixty seconds of administration, and predominantly for the gastrointestinal absorption of said donepezil or pharmaceutically acceptable salt thereof. 
     
     
         12 ) The use of  claim 11  wherein greater than 95 wt. % of said donepezil or pharmaceutically acceptable salt thereof is absorbed gastrointestinally. 
     
     
         13 ) The use of  claim 11  wherein said donepezil consists essentially of amorphous donepezil hydrochloride. 
     
     
         14 ) A non-mucoadhesive orally disintegrating film, able to disintegrate upon contact with saliva in the buccal cavity within about sixty seconds, comprising ondansetron or a pharmaceutically acceptable salt thereof, in combination with a hydrophilic binder and a water-soluble diluent, wherein:
 a) said film is characterized predominantly by gastrointestinal absorption when placed on the tongue, allowed to disintegrate, and subsequently swallowed;   b) said film comprises from about 4 to about 24 mg of ondansetron or pharmaceutically acceptable salt thereof;   c) said ondansetron or pharmaceutically acceptable salt thereof is present in an amount from about 0.05% to about 50% (w/w), based on the total weight of the formulation,   d) said film has a T max  of from about 1.5 to about 2.5 hours, and   e) said ondansetron or pharmaceutically acceptable salt thereof has an absolute bioavailability in said dosage form of from about 45% to about 75%.   
     
     
         15 ) The film of  claim 14  comprising Form B ondansetron base. 
     
     
         16 ) The film of  claim 14 , further comprising from about 5 to about 25 wt. % of an aminoalkyl methacrylate copolymer, having a molecular weight of from about 120,000 to about 180,000. 
     
     
         17 ) The film of  claim 14  further comprising from about 10 to about 40 wt. % of a cyclodextrin of derivative thereof. 
     
     
         18 ) The film of  claim 14  wherein said film comprises from about 40% to about 80% (w/w) of one or more ingredients that constitute a hydrophilic binder and a water soluble diluent. 
     
     
         19 ) Use of the non-mucoadhesive orally disintegrating film of  claim 13  in the manufacture of a medicament for the treatment or prevention of emesis in a human patient, for the administration of said film to the tongue of said patient, for swallowing said film within about sixty seconds of administration, and predominantly for the gastrointestinal absorption of said ondansetron or pharmaceutically acceptable salt thereof. 
     
     
         20 ) The use of  claim 19 , wherein said emesis is from postoperative nausea and vomiting, chemotherapy induced nausea and vomiting, or radiation induced nausea and vomiting. 
     
     
         21 ) The use of  claim 19  wherein said film comprises Form B ondansetron base. 
     
     
         22 ) The use of  claim 19  wherein greater than 95 wt. % of said ondansetron or pharmaceutically acceptable salt thereof is absorbed gastrointestinally. 
     
     
         23 ) A non-mucoadhesive orally disintegrating film, able to disintegrate upon contact with saliva in the buccal cavity within about sixty seconds, comprising a defined amount of an active pharmaceutical agent, or a pharmaceutically acceptable salt thereof, a hydrophilic binder and a water-soluble diluent, wherein:
 a) said film is characterized predominantly by gastrointestinal absorption when placed on the tongue, allowed to disintegrate, and subsequently swallowed;   b) said film is bioequivalent to an immediate release tablet or capsule or orally dissolving/dispersing tablet (ODT) that comprises said active pharmaceutical agent or a pharmaceutically acceptable salt thereof in said defined amount; and   c) said film comprises from about 0.05% to about 50% (w/w) of said active pharmaceutical agent, based on the total weight of the formulation.   
     
     
         24 ) The film of  claim 23  characterized by greater than 95% gastrointestinal absorption. 
     
     
         25 ) The film of  claim 23  comprising from about 40% to about 80% (w/w) of one or more ingredients that constitute said hydrophilic binder and water soluble diluent. 
     
     
         26 ) The film of  claim 23  wherein said active pharmaceutical agent is selected from: donepezil hydrochloride; ondansetron base; desloratadine; olanzapine; risperidone; rivastigmine tartrate; sildenafil; vardenafil; galantamine; diclofenac potassium; buprenorphine HCl; naloxone HCl dehydrate; alprazolam; clonazepam; diazepam; lorazepam; sumatriptan; eletriptan; rizatriptan; zolmitriptan; naratriptan; almotriptan; frovatriptan; cetirizine hydrochloride; loratadine; ambroxol hydrochloride; apomorphine; ascorbic acid; betamethasone; caffeine; dextromethorphan; glimepiride; hydrocortisone; ketotifen; loperamide; meclozine; melatonin; neramexane; piroxicam; sodium picosulfate; and zinc histidine; or a pharmaceutically acceptable salt thereof; or a combination thereof. 
     
     
         27 ) The film of  claim 23  wherein said immediate release tablet or capsule or orally dissolving/dispersing tablet (ODT) is characterized by a time to dissolution for 75% of the active pharmaceutical agent of greater than about twenty minutes, and less than about ninety minutes, when tested in a type II dissolution apparatus at pH 2.0 and 37° C. at a paddle speed of 50 rpm. 
     
     
         28 ) The film of  claim 23 , wherein said active pharmaceutical agent is subject to first pass metabolism. 
     
     
         29 ) The film of  claim 23 , further comprising means for promoting gastrointestinal absorption of said active pharmaceutical agent. 
     
     
         30 ) The film of  claim 23 , wherein said immediate release tablet or capsule or orally dissolving/dispersing tablet (ODT) is characterized by (i) predominant gastrointestinal absorption when administered orally, (ii) a first pharmacokinetic profile, and (iii) the presence of said active agent in said defined amount; made by a process comprising:
 a) formulating said film to comprise said active agent in said defined amount and to be characterized by a second pharmacokinetic profile that is bioequivalent to said first pharmacokinetic profile when disintegrated orally and absorbed in the gastrointestinal tract; and   b) clinically testing said orally administered dosage form and said orally disintegrating film for bioequivalence.   
     
     
         31 ) The film of  claim 23  in the form of a single layer. 
     
     
         32 ) The film of  claim 23  wherein said film does not contain a surfactant. 
     
     
         33 ) A non-mucoadhesive orally disintegrating film, able to disintegrate upon contact with saliva in the buccal cavity within about sixty seconds, comprising a defined amount of an active pharmaceutical agent, or a pharmaceutically acceptable salt thereof, a hydrophilic binder and a water-soluble diluent, wherein:
 a) said film is characterized predominantly by gastrointestinal absorption when placed on the tongue, allowed to disintegrate, and subsequently swallowed;   b) said film comprises from about 0.05% to about 50% (w/w) of said active pharmaceutical agent, based on the total weight of the formulation; and   c) said film has:
 i) a T max  greater than about 4.5 hours; 
 ii) an absolute bioavailability of greater than about 65%, optionally with a T max  greater than about 1.5 hours; 
 iii) an absolute bioavailability of from about 45% to about 65%, and a T max  of less than 3.0 hours; 
 iv) a T max  of from 3.0 to 4.5 hours; or 
 v) a T max  of less than 1.0 hours. 
   
     
     
         34 ) The film of  claim 33 , wherein said active agent has a T max  greater than about 4.5 hours. 
     
     
         35 ) The film of  claim 33 , wherein said active agent has an absolute bioavailability of greater than about 65%, optionally with a T max  greater than about 1.5 hours. 
     
     
         36 ) The film of  claim 33 , wherein said active agent has an absolute bioavailability of from about 45% to about 65%, and a T max  of less than 3.0 hours. 
     
     
         37 ) The film of  claim 33 , wherein said active agent has a T max  of from 3.0 to 4.5 hours. 
     
     
         38 ) The film of  claim 33 , wherein said active agent has a T max  of less than 1.0 hours. 
     
     
         39 ) The film of  claim 33  wherein said active pharmaceutical agent is selected from: donepezil hydrochloride; ondansetron base; desloratadine; olanzapine; risperidone; rivastigmine tartrate; sildenafil; vardenafil; galantamine; diclofenac potassium; buprenorphine HCl; naloxone HCl dehydrate; alprazolam; clonazepam; diazepam; lorazepam; sumatriptan; eletriptan; rizatriptan; zolmitriptan; naratriptan; almotriptan; frovatriptan; cetirizine hydrochloride; loratadine; ambroxol hydrochloride; apomorphine; ascorbic acid; betamethasone; caffeine; dextromethorphan; glimepiride; hydrocortisone; ketotifen; loperamide; meclozine; melatonin; neramexane; piroxicam; sodium picosulfate; and zinc histidine; or a pharmaceutically acceptable salt thereof; or a combination thereof. 
     
     
         40 ) A non-mucoadhesive orally disintegrating film, able to disintegrate upon contact with saliva in the buccal cavity within about sixty seconds, comprising a defined amount of an active pharmaceutical agent, or a pharmaceutically acceptable salt thereof, a hydrophilic binder, a water-soluble diluent, wherein said film is characterized predominantly by gastrointestinal absorption when placed on the tongue, allowed to disintegrate, and subsequently swallowed; and said active pharmaceutical agent is selected from: donepezil hydrochloride; ondansetron base; desloratadine; olanzapine; risperidone; rivastigmine tartrate; sildenafil; vardenafil; galantamine; diclofenac potassium; buprenorphine HCl; naloxone HCl dehydrate; alprazolam; clonazepam; diazepam; lorazepam; sumatriptan; eletriptan; rizatriptan; zolmitriptan; naratriptan; almotriptan; frovatriptan; cetirizine hydrochloride; loratadine; ambroxol hydrochloride; apomorphine; ascorbic acid; betamethasone; caffeine; dextromethorphan; glimepiride; hydrocortisone; ketotifen; loperamide; meclozine; melatonin; neramexane; piroxicam; sodium picosulfate; and zinc histidine; or a pharmaceutically acceptable salt thereof; or a combination thereof. 
     
     
         41 ) The film of  claim 40  comprising means for promoting gastrointestinal absorption, wherein said means comprises:
 a) an ingredient that retards said active pharmaceutical ingredient from dissolving in the buccal cavity; 
 b) an ion exchange resin; 
 c) a pH adjusting agent that adjusts the ionization of the active pharmaceutical ingredient to a less mucosally absorbable state; or 
 d) said active pharmaceutical ingredient in base form. 
 
     
     
         42 ) Use of the non-mucoadhesive orally disintegrating film of  claim 23 ,  33  or  40  in the manufacture of a medicament for the administration of said film to the tongue of said patient, for swallowing said film within about sixty seconds of administration, and predominantly for the gastrointestinal absorption of said active agent or pharmaceutically acceptable salt thereof. 
     
     
         43 ) The use of  claim 42  wherein greater than 95 wt. % of said ondansetron or pharmaceutically acceptable salt thereof is absorbed gastrointestinally. 
     
     
         44 ) The use of  claim 42  wherein said active pharmaceutical agent is selected from: donepezil hydrochloride; ondansetron base; desloratadine; olanzapine; risperidone; rivastigmine tartrate; sildenafil; vardenafil; galantamine; diclofenac potassium; buprenorphine HCl; naloxone HCl dehydrate; alprazolam; clonazepam; diazepam; lorazepam; sumatriptan; eletriptan; rizatriptan; zolmitriptan; naratriptan; almotriptan; frovatriptan; cetirizine hydrochloride; loratadine; ambroxol hydrochloride; apomorphine; ascorbic acid; betamethasone; caffeine; dextromethorphan; glimepiride; hydrocortisone; ketotifen; loperamide; meclozine; melatonin; neramexane; piroxicam; sodium picosulfate; and zinc histidine; or a pharmaceutically acceptable salt thereof; or a combination thereof. 
     
     
         45 ) The use of  claim 42  wherein said film is provided on a dose card that contains a plurality of individually wrapped films protected by moisture impermeable removable laminar covers. 
     
     
         46 ) The use of  claim 42  wherein said film is wrapped individually in a moisture impermeable flat pouch comprising two walls adhered around the edges. 
     
     
         47 ) A method of making a bioequivalent non-mucoadhesive orally disintegrating film, comprising:
 a) providing an orally administered dosage form that comprises an active pharmaceutical agent in a defined amount, and that is characterized by (i) predominant gastrointestinal absorption when administered orally, and (ii) a first pharmacokinetic profile;   b) formulating a first batch of non-mucoadhesive orally disintegrating film, able to disintegrate upon contact with saliva in the buccal cavity within about sixty seconds, that comprises said active agent in said defined amount, and that is characterized by (i) a defined formulation, (ii) predominant gastrointestinal absorption when dissolved orally, and (iii) a second pharmacokinetic profile that is bioequivalent to said first pharmacokinetic profile; and   c) clinically testing said orally administered dosage form and said orally disintegrating film for bioequivalence.   
     
     
         48 ) The method of  claim 47  wherein said active pharmaceutical agent is selected from: donepezil hydrochloride; ondansetron base; desloratadine; olanzapine; risperidone; rivastigmine tartrate; sildenafil; vardenafil; galantamine; diclofenac potassium; buprenorphine HCl; naloxone HCl dehydrate; alprazolam; clonazepam; diazepam; lorazepam; sumatriptan; eletriptan; rizatriptan; zolmitriptan; naratriptan; almotriptan; frovatriptan; cetirizine hydrochloride; loratadine; ambroxol hydrochloride; apomorphine; ascorbic acid; betamethasone; caffeine; dextromethorphan; glimepiride; hydrocortisone; ketotifen; loperamide; meclozine; melatonin; neramexane; piroxicam; sodium picosulfate; and zinc histidine; or a pharmaceutically acceptable salt thereof; or a combination thereof. 
     
     
         49 ) The method of  claim 47 , further comprising:
 a) measuring a first dissolution or disintegration profile for said orally disintegrating film from said first batch;   b) preparing a second batch of non-mucoadhesive orally disintegrating film that is characterized by said defined formulation;   c) measuring a second dissolution or disintegration profile for said orally disintegrating film from said second batch; and   d) comparing said first and second dissolution or disintegration profiles for equivalence.   
     
     
         50 ) The method of  claim 47 , further comprising packaging said film from said second batch in a dose card that contains a plurality of individually wrapped films protected by moisture impermeable removable laminar covers. 
     
     
         51 ) The method of  claim 47 , further comprising packaging said film from said second batch in a moisture impermeable flat pouch comprising two walls adhered around the edges.