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.

What is claimed is: 
     
         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;   c. a buffer sufficient to maximize the absorption of the agonist; and   d. a chelator or an antioxidant.   
     
     
         2 . The composition of  claim 1 , wherein said chelator is selected from the group consisting of ethylenediamineeteraacetic acid and salts thereof, proteins, polysaccharides, polynucleic acids, glutamic acid, histidine, organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid, phosphonates, transferrin, desferrioxamine, and combinations thereof. 
     
     
         3 . The composition of  claim 1 , wherein said chelator is ethylenediaminetetraacetic acid disodium salt (EDTA). 
     
     
         4 . The composition of  claim 1 , wherein said agonist is a partial agonist. 
     
     
         5 . The composition of  claim 1 , wherein said agonist is an opioid agonist. 
     
     
         6 . The composition of  claim 1 , wherein said composition has a local pH of about 4 to about 9. 
     
     
         7 . The composition of  claim 1 , further comprising a therapeutically effective amount of an antagonist or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The composition of  claim 7 , wherein said composition comprises a first and a second region, said first region comprising said agonist and said second region comprising said antagonist. 
     
     
         9 . The composition of  claim 8 , wherein said first region has a local pH of about 4 to about 9. 
     
     
         10 . The composition of  claim 9 , wherein said local pH is about 5.5. 
     
     
         11 . The composition of  claim 8 , wherein said second region has a local pH of about 2 to about 4. 
     
     
         12 . The composition of  claim 11 , wherein said local pH is about 2. 
     
     
         13 . 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. 
     
     
         14 . 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. 
     
     
         15 . The composition of  claim 1 , wherein said composition comprises at least one self-supporting film-forming polymer. 
     
     
         16 . 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. 
     
     
         17 . The film dosage composition of  claim 1 , wherein said buffer comprises sodium citrate, citric acid, and combinations thereof. 
     
     
         18 . The film dosage composition of  claim 1 , wherein said buffer comprises acetic acid, sodium acetate, and combinations thereof. 
     
     
         19 . 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;   d. A buffering system; and   e. A chelator or an antioxidant;   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.   
     
     
         20 . The composition of  claim 17 , wherein said chelator is selected from the group consisting of ethylenediamineeteraacetic acid and salts thereof, proteins, polysaccharides, polynucleic acids, glutamic acid, histidine, organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid, phosphonates, transferrin, desferrioxamine, and combinations thereof. 
     
     
         21 . The composition of  claim 17 , wherein said chelator is ethylenediaminetetraacetic acid disodium salt (EDTA). 
     
     
         22 . The composition of  claim 19 , wherein said agonist is a partial agonist. 
     
     
         23 . The composition of  claim 19 , wherein said agonist is an opioid agonist. 
     
     
         24 . The composition of  claim 19 , wherein said composition comprises a first region and a second region, said first region comprising said agonist and said second region comprising said antagonist. 
     
     
         25 . The composition of  claim 19 , wherein said agonist has a local pH of about 4 to about 9. 
     
     
         26 . The composition of  claim 19 , wherein said antagonist has a local pH of about 2 to about 4. 
     
     
         27 . 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; 
 iv. A chelator or an antioxidant; and 
   b. Administering said film dosage composition to a patient.   
     
     
         28 . The method of  claim 27 , wherein said chelator is selected from the group consisting of ethylenediamineeteraacetic acid and salts thereof, proteins, polysaccharides, polynucleic acids, glutamic acid, histidine, organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid, phosphonates, transferrin, desferrioxamine, and combinations thereof. 
     
     
         29 . The method of  claim 27 , wherein said chelator is ethylenediaminetetraacetic acid disodium salt (EDTA). 
     
     
         30 . The method of  claim 27 , wherein said agonist is a partial agonist. 
     
     
         31 . The method of  claim 27 , wherein said agonist is an opioid agonist. 
     
     
         32 . The method of  claim 27 , wherein said agonist has a local pH of about 4 to about 9. 
     
     
         33 . The method of  claim 27 , wherein said agonist has a local pH of about 5.5. 
     
     
         34 . The method of  claim 27 , wherein said composition further comprises a therapeutically effective amount of an antagonist or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The method of  claim 32 , wherein said antagonist has a local pH of about 2 to about 4. 
     
     
         36 . The method of  claim 27 , wherein said film dosage composition is administered to the user through a mucosal membrane of said patient. 
     
     
         37 . The method of  claim 36 , wherein said film dosage composition remains in the mucosal membrane of said patient for a period of at least 1 minute. 
     
     
         38 . 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; 
 vi. A chelator or an antioxidant; and 
   b. Administering said film dosage composition to a user.   
     
     
         39 . The method of  claim 38 , wherein said chelator is selected from the group consisting of ethylenediamineeteraacetic acid and salts thereof, proteins, polysaccharides, polynucleic acids, glutamic acid, histidine, organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid, phosphonates, transferrin, desferrioxamine, and combinations thereof. 
     
     
         40 . The method of  claim 38 , wherein said chelator is ethylenediaminetetraacetic acid disodium salt (EDTA). 
     
     
         41 . The method of  claim 38 , wherein said composition comprises a first and a second region, wherein said first region comprises said agonist and said second region comprises said antagonist. 
     
     
         42 . The method of  claim 38 , wherein said agonist is a partial agonist. 
     
     
         43 . The method of  claim 38 , wherein said agonist is an opioid agonist. 
     
     
         44 . 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; 
 iii. A second buffering system in an amount sufficient to inhibit the absorption of said antagonist; and 
 iv. A chelator or an antioxidant. 
   
     
     
         45 . The composition of  claim 43 , wherein said chelator is selected from the group consisting of ethylenediamineeteraacetic acid and salts thereof, proteins, polysaccharides, polynucleic acids, glutamic acid, histidine, organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid, phosphonates, transferrin, desferrioxamine, and combinations thereof. 
     
     
         46 . The composition of  claim 44 , wherein said chelator is ethylenediaminetetraacetic acid disodium salt (EDTA). 
     
     
         47 . The composition of  claim 44 , wherein said agonist is a partial agonist. 
     
     
         48 . The composition of  claim 44 , wherein said agonist is an opioid agonist. 
     
     
         49 . The composition of  claim 44 , 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. 
     
     
         50 . The composition of  claim 44 , wherein said first buffering system is present in an amount sufficient to provide a local pH of said first region of about 5.5. 
     
     
         51 . The composition of  claim 44 , 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. 
     
     
         52 . The composition of  claim 44 , wherein said second region is coated onto at least one surface of said first region. 
     
     
         53 . The composition of  claim 44 , wherein said second region is laminated to at least one surface of said first region. 
     
     
         54 . The composition of  claim 107 , wherein said first and second region are in a side-by-side arrangement. 
     
     
         55 . 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;   d. A buffering system sufficient to obtain a local pH of said antagonist of about 2 to about 4; and   e. A chelator or an antioxidant.   
     
     
         56 . 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;   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; and   e. A chelator or an antioxidant.   
     
     
         57 . 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; 
 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; and 
 iv. A chelator or an antioxidant. 
   
     
     
         58 . The composition of  claim 57 , wherein said first and second buffering systems are the same. 
     
     
         59 . 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; 
 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 
 v. A chelator or an antioxidant; and 
   b. Drying said film-forming composition to form a self-supporting film dosage composition.   
     
     
         60 . 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 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 
 v. A chelator or an antioxidant; and 
   b. Administering said film dosage composition to a user.   
     
     
         61 . 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; 
 iii. A second buffering system in an amount sufficient to inhibit the absorption of said antagonist; and 
 iv. A chelator or an antioxidant; 
   wherein said second region dissolves at a faster rate when placed in the oral cavity of the user than said first region.   
     
     
         62 . The composition of  claim 61 , wherein said chelator is selected from the group consisting of ethylenediamineeteraacetic acid and salts thereof, proteins, polysaccharides, polynucleic acids, glutamic acid, histidine, organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid, phosphonates, transferrin, desferrioxamine, and combinations thereof. 
     
     
         63 . The composition of  claim 61 , wherein said chelator is ethylenediaminetetraacetic acid disodium salt (EDTA). 
     
     
         64 . The composition of  claim 61 , wherein said first polymeric matrix comprises a moderate-dissolving polymer. 
     
     
         65 . The composition of  claim 61 , wherein said second polymeric matrix comprises a fast-dissolving polymer. 
     
     
         66 . The composition of  claim 61 , wherein said first buffering system is sufficient to provide a local pH for said agonist of from about 4 to about 9. 
     
     
         67 . The composition of  claim 61 , wherein said second buffering system is sufficient to provide a local pH for said antagonist of from about 2 to about 4. 
     
     
         68 . 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; 
 iv. A chelator or an antioxidant; and 
   c. Combining said first film-forming composition and said second film-forming composition together to form a self-supporting film dosage composition.   
     
     
         69 . The process of  claim 68 , wherein said chelator is selected from the group consisting of ethylenediamineeteraacetic acid and salts thereof, proteins, polysaccharides, polynucleic acids, glutamic acid, histidine, organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid, phosphonates, transferrin, desferrioxamine, and combinations thereof. 
     
     
         70 . The process of  claim 68 , wherein said chelator is ethylenediaminetetraacetic acid disodium salt (EDTA). 
     
     
         71 . The process of  claim 68 , wherein said first film-forming composition is dried prior to said step of combining said first film-forming composition and said second film-forming composition together. 
     
     
         72 . The process of  claim 68 , wherein said second film-forming composition is dried prior to said step of combining said first film-forming composition and said second film-forming composition together. 
     
     
         73 . The process of  claim 68 , wherein said first film-forming composition is at least partially dried prior to said step of combining said first film-forming composition and said second film-forming composition together. 
     
     
         74 . The process of  claim 68 , wherein said second film-forming composition is at least partially dried prior to said step of combining said first film-forming composition and said second film-forming composition together. 
     
     
         75 . A film dosage composition comprising:
 a. a polymeric carrier matrix;   b. a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt thereof;   c. a buffer sufficient to maximize the absorption of the buprenorphine or a pharmaceutically acceptable salt thereof;   d. a therapeutically effective amount of naloxone or a pharmaceutically acceptable salt thereof; and   e. a chelator or an antioxidant.   
     
     
         76 . The composition of  claim 75 , wherein said chelator is selected from the group consisting of ethylenediamineeteraacetic acid and salts thereof, proteins, polysaccharides, polynucleic acids, glutamic acid, histidine, organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid, phosphonates, transferrin, desferrioxamine, and combinations thereof. 
     
     
         77 . The composition of  claim 75 , wherein said chelator is ethylenediaminetetraacetic acid disodium salt (EDTA). 
     
     
         78 . The composition of  claim 75 , wherein said composition has a local pH of about 4 to about 9. 
     
     
         79 . The composition of  claim 75 , wherein said composition comprises a first and a second region, said first region comprising said buprenorphine or a pharmaceutically acceptable salt thereof and said second region comprising said naloxone or a pharmaceutically acceptable salt thereof. 
     
     
         80 . The composition of  claim 79 , wherein said first region has a local pH of about 4 to about 9. 
     
     
         81 . The composition of  claim 80 , wherein said local pH is about 5.5. 
     
     
         82 . The composition of  claim 79 , wherein said second region has a local pH of about 2 to about 4. 
     
     
         83 . The composition of  claim 82 , wherein said local pH is about 2. 
     
     
         84 . The composition of  claim 75 , wherein said polymeric carrier matrix comprises at least one polymer in an amount of at least 25% by weight of said composition. 
     
     
         85 . The composition of  claim 75 , wherein said buffer is present in an amount of from about 2:1 to about 1:5 buffer to agonist. 
     
     
         86 . The composition of  claim 75 , wherein said composition comprises at least one self-supporting film-forming polymer. 
     
     
         87 . The film dosage composition of  claim 75 , wherein said agonist is present in an amount of from about 2 mg to about 16 mg per dosage. 
     
     
         88 . The film dosage composition of  claim 75 , wherein said buffer comprises sodium citrate, citric acid, and combinations thereof. 
     
     
         89 . The film dosage composition of  claim 75 , wherein said buffer comprises acetic acid, sodium acetate, and combinations thereof. 
     
     
         90 . The film dosage composition of  claim 75 , wherein said chelator is present in an amount sufficient to inhibit the oxidation of said naloxone or a pharmaceutically acceptable salt thereof. 
     
     
         91 . The film dosage composition of  claim 77 , wherein said EDTA is present in an amount sufficient to inhibit the oxidation of said naloxone or a pharmaceutically acceptable salt thereof. 
     
     
         92 . The film dosage composition of  claim 77 , wherein said EDTA is present in an amount of about 1 to about 7.5% by weight of the total film dosage composition. 
     
     
         93 . The film dosage composition of  claim 77 , wherein said EDTA is present in an amount of about 1 to about 2% by weight of the total film dosage composition. 
     
     
         94 . The film dosage composition of  claim 77 , wherein the weight ratio of said naloxone or a pharmaceutically acceptable salt thereof to said EDTA is about from about 0.5:2 to about 2:0.5. 
     
     
         95 . The film dosage composition of  claim 77 , wherein the weight ratio of said naloxone or a pharmaceutically acceptable salt thereof to said EDTA is about from about 1:2 to about 2:1. 
     
     
         96 . 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 buprenorphine or a pharmaceutically acceptable salt thereof; 
 iii. a buffer sufficient to maximize the absorption of the buprenorphine or a pharmaceutically acceptable salt thereof; 
 iv. a therapeutically effective amount of naloxone or a pharmaceutically acceptable salt thereof; and 
 v. a chelator or an antioxidant; and 
   b. Administering said film dosage composition to a patient.   
     
     
         97 . The composition of  claim 96 , wherein said chelator is selected from the group consisting of ethylenediamineeteraacetic acid and salts thereof, proteins, polysaccharides, polynucleic acids, glutamic acid, histidine, organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid, phosphonates, transferrin, desferrioxamine, and combinations thereof. 
     
     
         98 . The composition of  claim 96 , wherein said chelator is ethylenediaminetetraacetic acid disodium salt (EDTA). 
     
     
         99 . The method of  claim 96 , wherein said buprenorphine or a pharmaceutically acceptable salt thereof has a local pH of about 4 to about 9. 
     
     
         100 . The method of  claim 96 , wherein said naloxone or a pharmaceutically acceptable salt thereof has a local pH of about 2 to about 4. 
     
     
         101 . The method of  claim 96 , wherein said film dosage composition is administered to the user through a mucosal membrane of said patient. 
     
     
         102 . The method of  claim 96 , wherein said film dosage composition remains in the mucosal membrane of said patient for a period of at least 1 minute. 
     
     
         103 . The film dosage composition of  claim 96 , wherein said chelator is present in an amount sufficient to inhibit the oxidation of said naloxone or a pharmaceutically acceptable salt thereof. 
     
     
         104 . The film dosage composition of  claim 98 , wherein said EDTA is present in an amount sufficient to inhibit the oxidation of said naloxone or a pharmaceutically acceptable salt thereof. 
     
     
         105 . The film dosage composition of  claim 98 , wherein said EDTA is present in an amount of about 1 to about 7.5% by weight of the total film dosage composition. 
     
     
         106 . The film dosage composition of  claim 98 , wherein said EDTA is present in an amount of about 1 to about 2% by weight of the total film dosage composition. 
     
     
         107 . The film dosage composition of  claim 98 , wherein the weight ratio of said naloxone or a pharmaceutically acceptable salt thereof to said EDTA is about from about 0.5:2 to about 2:0.5. 
     
     
         108 . The film dosage composition of  claim 98 , wherein the weight ratio of said naloxone or a pharmaceutically acceptable salt thereof to said EDTA is about from about 1:2 to about 2:1. 
     
     
         109 . A film dosage composition comprising:
 a. A first region comprising:
 i. A first polymeric matrix; 
 ii. A therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt thereof; and 
 iii. A first buffering system in an amount sufficient to optimize the absorption of said buprenorphine or a pharmaceutically acceptable salt thereof; 
   b. A second region comprising:
 i. A second polymeric matrix; 
 ii. A therapeutically effective amount of naloxone or a pharmaceutically acceptable salt thereof; 
 iii. A second buffering system in an amount sufficient to inhibit the absorption of said naloxone or a pharmaceutically acceptable salt thereof; and 
 iv. A chelator or an antioxidant. 
   
     
     
         110 . The composition of  claim 109 , wherein said chelator is selected from the group consisting of ethylenediamineeteraacetic acid and salts thereof, proteins, polysaccharides, polynucleic acids, glutamic acid, histidine, organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid, phosphonates, transferrin, desferrioxamine, and combinations thereof. 
     
     
         111 . The composition of  claim 109 , wherein said chelator is ethylenediaminetetraacetic acid disodium salt (EDTA). 
     
     
         112 . The composition of  claim 109 , 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. 
     
     
         113 . The composition of  claim 109 , wherein said first buffering system is present in an amount sufficient to provide a local pH of said first region of about 5.5. 
     
     
         114 . The composition of  claim 109 , 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. 
     
     
         115 . The composition of  claim 109 , wherein said second region is coated onto at least one surface of said first region. 
     
     
         116 . The composition of  claim 109 , wherein said second region is laminated to at least one surface of said first region. 
     
     
         117 . The composition of  claim 109 , wherein said first and second region are in a side-by-side arrangement. 
     
     
         118 . The film dosage composition of  claim 109 , wherein said chelator is present in an amount sufficient to inhibit the oxidation of said naloxone or a pharmaceutically acceptable salt thereof. 
     
     
         119 . The film dosage composition of  claim 111 , wherein said EDTA is present in an amount sufficient to inhibit the oxidation of said naloxone or a pharmaceutically acceptable salt thereof. 
     
     
         120 . The film dosage composition of  claim 111 , wherein said EDTA is present in an amount of about 1 to about 7.5% by weight of the second region. 
     
     
         121 . The film dosage composition of  claim 111 , wherein said EDTA is present in an amount of about 1 to about 2% by weight of the second region. 
     
     
         122 . The film dosage composition of  claim 111 , wherein the weight ratio of said naloxone or a pharmaceutically acceptable salt thereof to said EDTA is about from about 0.5:2 to about 2:0.5. 
     
     
         123 . The film dosage composition of  claim 111 , wherein the weight ratio of said naloxone or a pharmaceutically acceptable salt thereof to said EDTA is about from about 1:2 to about 2:1. 
     
     
         124 . 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 buprenorphine or a pharmaceutically acceptable salt thereof; 
 iii. A therapeutically effective amount of an naloxone or a pharmaceutically acceptable salt thereof; 
 iv. A buffer in an amount sufficient to optimize absorption of said buprenorphine or a pharmaceutically acceptable salt thereof and sufficient to inhibit absorption of said naloxone or a pharmaceutically acceptable salt thereof when said film dosage composition is placed in the mouth of a user; and 
 v. A chelator or an antioxidant. 
   b. Drying said film-forming composition to form a self-supporting film dosage composition.   
     
     
         125 . A self-supporting film dosage composition comprising:
 a. A first region comprising:
 i. A first polymeric matrix; 
 ii. A therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt thereof; and 
 iii. A first buffering system in an amount sufficient to optimize the absorption of said buprenorphine or a pharmaceutically acceptable salt thereof; 
   b. A second region comprising:
 i. A second polymeric matrix; 
 ii. A therapeutically effective amount of naloxone or a pharmaceutically acceptable salt thereof; 
 iii. A second buffering system in an amount sufficient to inhibit the absorption of said naloxone or a pharmaceutically acceptable salt thereof; and 
 iv. A chelator or an antioxidant; 
   wherein said second region dissolves at a faster rate when placed in the oral cavity of the user than said first region.   
     
     
         126 . The composition of  claim 125 , wherein said first polymeric matrix comprises a moderate-dissolving polymer. 
     
     
         127 . The composition of  claim 125 , wherein said second polymeric matrix comprises a fast-dissolving polymer. 
     
     
         128 . The composition of  claim 125 , wherein said first buffering system is sufficient to provide a local pH for said agonist of from about 4 to about 9. 
     
     
         129 . The composition of  claim 125 , wherein said second buffering system is sufficient to provide a local pH for said antagonist of from about 2 to about 4. 
     
     
         130 . 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 buprenorphine or a pharmaceutically acceptable salt thereof; and 
 iii. A buffer in an amount sufficient to optimize absorption of said buprenorphine or a pharmaceutically acceptable salt thereof 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 naloxone or a pharmaceutically acceptable salt thereof; 
 iii. A buffer in an amount sufficient to inhibit absorption of said naloxone or a pharmaceutically acceptable salt thereof when said film dosage composition is placed in the mouth of a user; and 
 iv. A chelator or an antioxidant; and 
   c. Combining said first film-forming composition and said second film-forming composition together to form a self-supporting film dosage composition.   
     
     
         131 . The process of  claim 130 , wherein said first film-forming composition is dried prior to said step of combining said first film-forming composition and said second film-forming composition together. 
     
     
         132 . The process of  claim 130 , wherein said second film-forming composition is dried prior to said step of combining said first film-forming composition and said second film-forming composition together. 
     
     
         133 . The process of  claim 130 , wherein said first film-forming composition is at least partially dried prior to said step of combining said first film-forming composition and said second film-forming composition together. 
     
     
         134 . The process of  claim 130 , 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. 
     
     
         135 . The composition of  claim 1 , wherein the self-supporting film dosage composition contains a chelator and no antioxidant. 
     
     
         136 . The composition of  claim 1 , wherein the self-supporting film dosage composition contains both a chelator and an antioxidant. 
     
     
         137 . The composition of  claim 136 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         138 . The composition of  claim 1 , wherein the self-supporting film dosage composition contains an antioxidant and no chelator. 
     
     
         139 . The composition of  claim 138 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         140 . The composition of  claim 19 , wherein the self-supporting film dosage composition contains a chelator and no antioxidant. 
     
     
         141 . The composition of  claim 19 , wherein the self-supporting film dosage composition contains both a chelator and an antioxidant. 
     
     
         142 . The composition of  claim 141 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         143 . The composition of  claim 19 , wherein the self-supporting film dosage composition contains an antioxidant and no chelator. 
     
     
         144 . The composition of  claim 141 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         145 . The method of  claim 27 , wherein the self-supporting film dosage composition contains a chelator and no antioxidant. 
     
     
         146 . The method of  claim 27 , wherein the self-supporting film dosage composition contains both a chelator and an antioxidant. 
     
     
         147 . The method of  claim 146 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         148 . The method of  claim 27 , wherein the self-supporting film dosage composition contains an antioxidant and no chelator. 
     
     
         149 . The composition of  claim 148 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         150 . The method of  claim 38 , wherein the self-supporting film dosage composition contains a chelator and no antioxidant. 
     
     
         151 . The method of  claim 38 , wherein the self-supporting film dosage composition contains both a chelator and an antioxidant. 
     
     
         152 . The method of  claim 151 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         153 . The method of  claim 38 , wherein the self-supporting film dosage composition contains an antioxidant and no chelator. 
     
     
         154 . The composition of  claim 153 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         155 . The composition of  claim 44 , wherein the second region contains a chelator and no antioxidant. 
     
     
         156 . The composition of  claim 44 , wherein the second region contains both a chelator and an antioxidant. 
     
     
         157 . The composition of  claim 156 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         158 . The composition of  claim 44 , wherein the second region contains an antioxidant and no chelator. 
     
     
         159 . The composition of  claim 158 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         160 . The composition of  claim 55 , wherein the self-supporting film dosage composition contains a chelator and no antioxidant. 
     
     
         161 . The composition of  claim 55 , wherein the self-supporting film dosage composition contains both a chelator and an antioxidant. 
     
     
         162 . The composition of  claim 161 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         163 . The composition of  claim 55 , wherein the self-supporting film dosage composition contains an antioxidant and no chelator. 
     
     
         164 . The composition of  claim 163 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         165 . The composition of  claim 56 , wherein the self-supporting film dosage composition contains a chelator and no antioxidant. 
     
     
         166 . The composition of  claim 56 , wherein the self-supporting film dosage composition contains both a chelator and an antioxidant. 
     
     
         167 . The composition of  claim 166 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         168 . The composition of  claim 56 , wherein the self-supporting film dosage composition contains an antioxidant and no chelator. 
     
     
         169 . The composition of  claim 168 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         170 . The composition of  claim 57 , wherein the second region contains a chelator and no antioxidant. 
     
     
         171 . The composition of  claim 57 , wherein the second region contains both a chelator and an antioxidant. 
     
     
         172 . The composition of  claim 172 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         173 . The composition of  claim 57 , wherein the second region contains an antioxidant and no chelator. 
     
     
         174 . The composition of  claim 173 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         175 . The method of  claim 59 , wherein the self-supporting film dosage composition contains a chelator and no antioxidant. 
     
     
         176 . The method of  claim 59 , wherein the self-supporting film dosage composition contains both a chelator and an antioxidant. 
     
     
         177 . The method of  claim 176 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         178 . The method of  claim 59 , wherein the self-supporting film dosage composition contains an antioxidant and no chelator. 
     
     
         179 . The method of  claim 178 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         180 . The method of  claim 60 , wherein the self-supporting film dosage composition contains a chelator and no antioxidant. 
     
     
         181 . The method of  claim 60 , wherein the self-supporting film dosage composition contains both a chelator and an antioxidant. 
     
     
         182 . The method of  claim 181 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         183 . The method of  claim 60 , wherein the self-supporting film dosage composition contains an antioxidant and no chelator. 
     
     
         184 . The method of  claim 183 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         185 . The method of  claim 61 , wherein the second region contains a chelator and no antioxidant. 
     
     
         186 . The method of  claim 61 , wherein the second region contains both a chelator and an antioxidant. 
     
     
         187 . The method of  claim 186 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         188 . The method of  claim 61  wherein the second region contains an antioxidant and no chelator. 
     
     
         189 . The method of  claim 188 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         190 . The process of  claim 68 , wherein the second film-forming composition contains a chelator and no antioxidant. 
     
     
         191 . The process of  claim 68 , wherein the second film-forming composition contains both a chelator and an antioxidant. 
     
     
         192 . The process of  claim 191 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         193 . The process of  claim 68  wherein the second film-forming composition contains an antioxidant and no chelator. 
     
     
         194 . The process of  claim 193 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         195 . The composition of  claim 75 , wherein the self-supporting film dosage composition contains a chelator and no antioxidant. 
     
     
         196 . The composition of  claim 75 , wherein the self-supporting film dosage composition contains both a chelator and an antioxidant. 
     
     
         197 . The composition of  claim 196 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         198 . The composition of  claim 75 , wherein the self-supporting film dosage composition contains an antioxidant and no chelator. 
     
     
         199 . The composition of  claim 198 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         200 . The method of  claim 96 , wherein the self-supporting film dosage composition contains a chelator and no antioxidant. 
     
     
         201 . The method of  claim 96 , wherein the self-supporting film dosage composition contains both a chelator and an antioxidant. 
     
     
         202 . The method of  claim 201 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         203 . The method of  claim 96 , wherein the self-supporting film dosage composition contains an antioxidant and no chelator. 
     
     
         204 . The method of  claim 203 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         205 . The composition of  claim 109 , wherein the second region contains a chelator and no antioxidant. 
     
     
         206 . The composition of  claim 109 , wherein the second region contains both a chelator and an antioxidant. 
     
     
         207 . The composition of  claim 206 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         208 . The composition of  claim 109 , wherein the second region contains an antioxidant and no chelator. 
     
     
         209 . The composition of  claim 208 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         210 . The process of  claim 124 , wherein the self-supporting film dosage composition contains a chelator and no antioxidant. 
     
     
         211 . The process of  claim 124 , wherein the self-supporting film dosage composition contains both a chelator and an antioxidant. 
     
     
         212 . The process of  claim 212 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         213 . The process of  claim 124 , wherein the self-supporting film dosage composition contains an antioxidant and no chelator. 
     
     
         214 . The process of  claim 213 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         215 . The composition of  claim 125 , wherein the second region contains a chelator and no antioxidant. 
     
     
         216 . The composition of  claim 125 , wherein the second region contains both a chelator and an antioxidant. 
     
     
         217 . The composition of  claim 216 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         218 . The composition of  claim 125 , wherein the second region contains an antioxidant and no chelator. 
     
     
         219 . The composition of  claim 218 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         220 . The process of  claim 130 , wherein the second film-forming composition contains a chelator and no antioxidant. 
     
     
         221 . The process of  claim 130 , wherein the second film-forming composition contains both a chelator and an antioxidant. 
     
     
         222 . The process of  claim 221 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof. 
     
     
         223 . The process of  claim 130  wherein the second film-forming composition contains an antioxidant and no chelator. 
     
     
         224 . The process of  claim 223 , wherein the antioxidant is selected from the groups consisting of dibutylhydroxytoluene, dibutylated hydroxyanisole, propyl gallate, sodium sulfate, citric acid, sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole and combination thereof.