Sublingual and buccal film compositions

Abstract

The present invention relates to products and methods for treatment of various symptoms in a patient, including treatment of pain suffered by a patient. The invention more particularly relates to self-supporting dosage forms which provide an active agent while providing sufficient buccal adhesion of the dosage form. Further, the present invention provides a dosage form which is useful in reducing the likelihood of diversion abuse of the active agent.

1 . A self-supporting film dosage composition comprising:
 a. A polymeric carrier matrix;   b. A therapeutically effective amount of an agonist or a pharmaceutically acceptable salt thereof; and   c. a buffer sufficient to maximize the absorption of the agonist.   
     
     
         2 . The composition of  claim 1 , wherein said agonist is a partial agonist. 
     
     
         3 . The composition of  claim 1 , wherein said agonist is an opioid agonist. 
     
     
         4 . The composition of  claim 1 , wherein said composition has a local pH of about 4 to about 9. 
     
     
         5 . The composition of  claim 1 , further comprising a therapeutically effective amount of an antagonist or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The composition of  claim 5 , wherein said composition comprises a first and a second region, said first region comprising said agonist and said second region comprising said antagonist. 
     
     
         7 . The composition of  claim 6 , wherein said first region has a local pH of about 4 to about 9. 
     
     
         8 . The composition of  claim 7 , wherein said local pH is about 5.5. 
     
     
         9 . The composition of  claim 6 , wherein said second region has a local pH of about 2 to about 4. 
     
     
         10 . The composition of  claim 9 , wherein said local pH is about 2. 
     
     
         11 . The composition of  claim 1 , wherein said polymeric carrier matrix comprises at least one polymer in an amount of at least 25% by weight of said composition. 
     
     
         12 . The composition of  claim 1 , wherein said buffer is present in an amount of from about 2:1 to about 1:5 buffer to agonist. 
     
     
         13 . The composition of  claim 1 , wherein said composition comprises at least one self-supporting film-forming polymer. 
     
     
         14 . The film dosage composition of  claim 1 , wherein said agonist is present in an amount of from about 2 mg to about 16 mg per dosage. 
     
     
         15 . The film dosage composition of  claim 1 , wherein said buffer comprises sodium citrate, citric acid, and combinations thereof. 
     
     
         16 . The film dosage composition of  claim 1 , wherein said buffer comprises acetic acid, sodium acetate, and combinations thereof. 
     
     
         17 . A self-supporting film dosage composition comprising:
 a. A polymeric carrier matrix;   b. A therapeutically effective amount of an agonist or a pharmaceutically acceptable salt thereof;   c. A therapeutically effective amount of an antagonist or a pharmaceutically acceptable salt thereof; and   d. A buffering system;   wherein said buffering system comprises a buffer capacity sufficient to inhibit the absorption of said antagonist during the time which said composition is in the oral cavity of a user.   
     
     
         18 . The composition of  claim 17 , wherein said agonist is a partial agonist. 
     
     
         19 . The composition of  claim 17 , wherein said agonist is an opioid agonist. 
     
     
         20 . The composition of  claim 17 , wherein said composition comprises a first region and a second region, said first region comprising said agonist and said second region comprising said antagonist. 
     
     
         21 . The composition of  claim 17 , wherein said agonist has a local pH of about 4 to about 9. 
     
     
         22 . The composition of  claim 17 , wherein said antagonist has a local pH of about 2 to about 4. 
     
     
         23 . A method of treatment, comprising the steps of:
 a. Providing a film dosage composition comprising:
 i. A polymeric carrier matrix; 
 ii. A therapeutically effective amount of an agonist or a pharmaceutically acceptable salt thereof, and 
 iii. A buffer in an amount sufficient to maximize the absorption of said agonist; and 
   b. Administering said film dosage composition to a patient.   
     
     
         24 . The method of  claim 23 , wherein said agonist is a partial agonist. 
     
     
         25 . The method of  claim 23 , wherein said agonist is an opioid agonist. 
     
     
         26 . The method of  claim 23 , wherein said agonist has a local pH of about 4 to about 9. 
     
     
         27 . The method of  claim 23 , wherein said composition further comprises a therapeutically effective amount of an antagonist or a pharmaceutically acceptable salt thereof. 
     
     
         28 . The method of  claim 27 , wherein said antagonist has a local pH of about 2 to about 4. 
     
     
         29 . The method of  claim 23 , wherein said film dosage composition is administered to the user through a mucosal membrane of said patient. 
     
     
         30 . The method of  claim 29 , wherein said film dosage composition remains in the mucosal membrane of said patient for a period of at least 1 minute. 
     
     
         31 . A method of treatment, comprising the steps of:
 a. Providing a film dosage composition comprising:
 i. A polymeric carrier matrix; 
 ii. A therapeutically effective amount of an agonist or a pharmaceutically acceptable salt thereof, 
 iii. A therapeutically effective amount of an antagonist or a pharmaceutically acceptable salt thereof, 
 iv. A first buffer in an amount sufficient to obtain a local pH of said agonist of about 4 to about 9; 
 v. A second buffer in an amount sufficient to obtain a local pH of said antagonist of about 2 to about 4; and 
   b. Administering said film dosage composition to a user.   
     
     
         32 . The method of  claim 31 , wherein said composition comprises a first and a second region, wherein said first region comprises said agonist and said second region comprises said antagonist. 
     
     
         33 . The method of  claim 31 , wherein said agonist is a partial agonist. 
     
     
         34 . The method of  claim 31 , wherein said agonist is an opioid agonist. 
     
     
         35 . A self-supporting film dosage composition comprising:
 a. A first region comprising:
 i. A first polymeric matrix; 
 ii. A therapeutically effective amount of an agonist or a pharmaceutically acceptable salt thereof, and 
 iii. A first buffering system in an amount sufficient to optimize the absorption of said agonist; 
   b. A second region comprising:
 i. A second polymeric matrix; 
 ii. A therapeutically effective amount of an antagonist; and 
 iii. A second buffering system in an amount sufficient to inhibit the absorption of said antagonist. 
   
     
     
         36 . The composition of  claim 35 , wherein said agonist is a partial agonist. 
     
     
         37 . The composition of  claim 35 , wherein said agonist is an opioid agonist. 
     
     
         38 . The composition of  claim 35 , wherein said first buffering system is present in an amount sufficient to provide a local pH of said first region of from about 4 to about 9. 
     
     
         39 . The composition of  claim 35 , wherein said first buffering system is present in an amount sufficient to provide a local pH of said first region of about 5.5. 
     
     
         40 . The composition of  claim 35 , wherein said second buffering system is present in an amount sufficient to provide a local pH of said second region of from about 2 to about 4. 
     
     
         41 . The composition of  claim 35 , wherein said second region is coated onto at least one surface of said first region. 
     
     
         42 . The composition of  claim 35 , wherein said second region is laminated to at least one surface of said first region. 
     
     
         43 . An orally dissolving film formulation comprising a first region comprising a therapeutically effective amount of an agonist and second region comprising a therapeutically effective amount of an antagonist, wherein said formulation provides an in vivo plasma profile having a Cmax of about 0.624-5.638 ng/ml for said agonist and an in vivo plasma profile having a Cmax of about 46.04-323.75 pg/ml for said antagonist. 
     
     
         44 . The formulation of  claim 43 , wherein said agonist is a partial agonist. 
     
     
         45 . The formulation of  claim 43 , wherein said agonist is an opioid agonist. 
     
     
         46 . The formulation of  claim 43 , wherein said formulation provides a mean AUC of about 5.431-56.238 hr*ng/ml for said agonist. 
     
     
         47 . The formulation of  claim 43 , wherein said formulation provides a mean AUC of about 102.88-812.00 hr*pg/ml for said antagonist. 
     
     
         48 . The formulation of  claim 43 , wherein said formulation comprises about 2 to about 16 mg of said agonist. 
     
     
         49 . The formulation of  claim 43 , wherein said formulation comprises about 0.5 to about 4 mg of said antagonist. 
     
     
         50 . A self-supporting film dosage composition comprising:
 a. A polymeric carrier matrix;   b. A therapeutically effective amount of an agonist or a pharmaceutically acceptable salt thereof;   c. A therapeutically effective amount of an antagonist or a pharmaceutically acceptable salt thereof; and   d. A buffering system sufficient to obtain a local pH of said antagonist of about 2 to about 4.   
     
     
         51 . A self-supporting film dosage composition comprising:
 a. A polymeric carrier matrix;   b. A therapeutically effective amount of an agonist or a pharmaceutically acceptable salt thereof;   c. A therapeutically effective amount of an antagonist or a pharmaceutically acceptable salt thereof; and   d. A buffering system sufficient to inhibit absorption of said antagonist and optimize absorption of said agonist when said film dosage composition is placed in the mouth of a user.   
     
     
         52 . A self-supporting film dosage composition comprising:
 a. A first region comprising:
 i. A first polymeric matrix; 
 ii. A therapeutically effective amount of an agonist or a pharmaceutically acceptable salt thereof, and 
 iii. A first buffering system in an amount sufficient to optimize absorption of said agonist when said film dosage composition is placed in the mouth of a user; and 
   b. A second region comprising:
 i. A second polymeric matrix; 
 ii. A therapeutically effective amount of an antagonist; and 
 iii. A second buffering system in an amount sufficient to inhibit absorption of said antagonist when said film dosage composition is placed in the mouth of a user. 
   
     
     
         53 . The composition of  claim 52 , wherein said first and second buffering systems are the same. 
     
     
         54 . A process of forming a film dosage composition comprising the steps of:
 a. Casting a film-forming composition, said film-forming composition comprising:
 i. A polymeric carrier matrix; 
 ii. A therapeutically effective amount of an agonist or a pharmaceutically acceptable salt thereof, 
 iii. A therapeutically effective amount of an antagonist or a pharmaceutically acceptable salt thereof, and 
 iv. A buffer in an amount sufficient to optimize absorption of said agonist and sufficient to inhibit absorption of said antagonist when said film dosage composition is placed in the mouth of a user; and 
   b. Drying said film-forming composition to form a self-supporting film dosage composition.   
     
     
         55 . A method of treatment, comprising the steps of:
 a. Providing a film dosage composition comprising:
 i. A polymeric carrier matrix; 
 ii. A therapeutically effective amount of an agonist or a pharmaceutically acceptable salt thereof; 
 iii. A therapeutically effective amount of an antagonist or a pharmaceutically acceptable salt thereof, and 
 iv. A buffering system in an amount sufficient to provide an in vivo plasma profile having a Cmax of about 0.624-5.638 ng/ml for said agonist and an in vivo plasma profile having a Cmax of about 41.04-323.75 pg/ml for said antagonist; and 
   b. Administering said film dosage composition to a user.   
     
     
         56 . A self-supporting film dosage composition comprising:
 a. A first region comprising:
 i. A first polymeric matrix; 
 ii. A therapeutically effective amount of an agonist or a pharmaceutically acceptable salt thereof; and 
 iii. A first buffering system in an amount sufficient to optimize the absorption of said agonist; 
   b. A second region comprising:
 i. A second polymeric matrix; 
 ii. A therapeutically effective amount of an antagonist; and 
 iii. A second buffering system in an amount sufficient to inhibit the absorption of said antagonist 
   wherein said second region dissolves at a faster rate when placed in the oral cavity of the user than said first region.   
     
     
         57 . The composition of  claim 56 , wherein said first polymeric matrix comprises a moderate-dissolving polymer. 
     
     
         58 . The composition of  claim 56 , wherein said second polymeric matrix comprises a fast-dissolving polymer. 
     
     
         59 . The composition of  claim 56 , wherein said first buffering system is sufficient to provide a local pH for said agonist of from about 4 to about 9. 
     
     
         60 . The composition of  claim 56 , wherein said second buffering system is sufficient to provide a local pH for said antagonist of from about 2 to about 4. 
     
     
         61 . A process of forming a film dosage composition comprising the steps of:
 a. Casting a first film-forming composition, said first film-forming composition comprising:
 i. A polymeric carrier matrix; 
 ii. A therapeutically effective amount of an agonist or a pharmaceutically acceptable salt thereof, and 
 iii. A buffer in an amount sufficient to optimize absorption of said agonist when said film dosage composition is placed in the mouth of a user; 
   b. Casting a second film-forming composition, said second film-forming composition comprising:
 i. A polymeric carrier matrix; 
 ii. A therapeutically effective amount of an antagonist or a pharmaceutically acceptable salt thereof, and 
 iii. A buffer in an amount sufficient to inhibit absorption of said antagonist when said film dosage composition is placed in the mouth of a user; and 
   c. Laminating said first film-forming composition and said second film-forming composition together to form a self-supporting film dosage composition.   
     
     
         62 . The process of  claim 61 , wherein said first film-forming composition is dried prior to said step of laminating said first film-forming composition and said second film-forming composition together. 
     
     
         63 . The process of  claim 61 , wherein said second film-forming composition is dried prior to said step of laminating said first film-forming composition and said second film-forming composition together. 
     
     
         64 . The process of  claim 61 , wherein said first film-forming composition is at least partially dried prior to said step of laminating said first film-forming composition and said second film-forming composition together. 
     
     
         65 . The process of  claim 61 , wherein said second film-forming composition is at least partially dried prior to said step of laminating said first film-forming composition and said second film-forming composition together.