Pharmaceutical Compositions for the Deterrence and/or Prevention of Abuse

Abstract

Provided herein is a pharmaceutical composition comprising an antagonist, an agonist, a seal coat, and a sequestering polymer, wherein the antagonist, agonist, seal coat and at least one sequestering polymer are all components of a single unit, and wherein the seal coat forms a layer physically separating the antagonist from the agonist from one another. Methods for manufacturing such a pharmaceutical composition are also provided.

What is claimed is: 
     
         1 . A multi-layer pharmaceutical composition comprising an agonist and an antagonist thereof, wherein the agonist and antagonist are not in contact with one another in the intact form of the composition, wherein the agonist is substantially released and the antagonist is substantially sequestered upon administration to a human being. 
     
     
         2 . A pharmaceutical composition of  claim 1  wherein the agonist and antagonist are separated from one another by a seal coat comprising a sequestering polymer. 
     
     
         3 . A pharmaceutical composition of  claim 2  wherein the seal coat comprises a sequestering polymer hydrophobicity-enhancing additive. 
     
     
         4 . A pharmaceutical composition of  claim 2  wherein the seal coat further comprises a charge-neutralizing additive. 
     
     
         5 . A pharmaceutical composition of  claim 1  wherein the agonist and antagonist are separated from one another by seal coat comprising a sequestering polymer, a sequestering polymer hydrophobicity-enhancing additive, and a charge-neutralizing additive. 
     
     
         6 . A pharmaceutical composition of any one of  claims 2 - 5  wherein the sequestering polymer is Eudragit® RS. 
     
     
         7 . A pharmaceutical composition of  claim 3 ,  5  or  6  wherein the sequestering polymer hydrophobicity-enhancing additive is talc. 
     
     
         8 . A pharmaceutical composition of  claim 4 ,  5  or  6  wherein the charge-neutralizing additive is sodium lauryl sulfate. 
     
     
         9 . A pharmaceutical composition of any one of  claims 1 - 8  wherein the composition comprises at least a first layer comprising an agonist and a second layer comprising an antagonist thereof, and wherein the first and second layers are physically separated from one another by a third layer. 
     
     
         10 . A pharmaceutical composition of  claim 9  wherein the first layer is external to the second layer. 
     
     
         11 . A pharmaceutical composition of  claim 9  or  10  wherein the third layer includes at least one sequestering polymer, and optionally includes a sequestering polymer hydrophobicity-enhancing additive, a charge-neutralizing additive, or both, and wherein the weight-by-weight ratio of sequestering polymer hydrophobicity-enhancing additive or charge-neutralizing additive to the sequestering polymer in the third layer is such that no more than 10% of the antagonist is released from the composition as determined using the USP paddle method at 37° C., 100 rpm, with incubation in a buffer containing a surfactant. 
     
     
         12 . A pharmaceutical composition of  claim 9  or  10  wherein the third layer includes at least one sequestering polymer, and optionally includes a sequestering polymer hydrophobicity-enhancing additive, a charge-neutralizing additive, or both, wherein the weight-by-weight ratio of sequestering polymer hydrophobicity-enhancing additive or charge-neutralizing additive to the sequestering polymer in the third layer is such that no more than approximately 10% of the antagonist is released from the composition in vivo following administration to a patient. 
     
     
         13 . A pharmaceutical composition of  claim 9  or  10  wherein the third layer includes at least one sequestering polymer, and optionally includes a sequestering polymer hydrophobicity-enhancing additive, a charge-neutralizing additive, or both, wherein the weight-by-weight ratio of sequestering polymer hydrophobicity-enhancing additive or charge-neutralizing additive to the sequestering polymer in the third layer is such that no more than approximately 10% of the antagonist is released from the composition in vivo following administration to a patient as determined by measuring plasma 6-beta naltrexol levels. 
     
     
         14 . A pharmaceutical composition of any one of  claim 9  or  10  wherein the third layer includes at least one sequestering polymer, and optionally includes a sequestering polymer hydrophobicity-enhancing additive, a charge-neutralizing additive, or both, wherein the weight-by-weight ratio of sequestering polymer hydrophobicity-enhancing additive or charge-neutralizing additive to the sequestering polymer in the third layer is such that no more than approximately 10% of the antagonist is released from the composition in vivo following administration to a patient in the fed state. 
     
     
         15 . A pharmaceutical composition of any one of claims  claim 9 - 14  wherein third layer comprises a sequestering polymer and a charge-neutralizing additive present at less than approximately 4% on a weight-by-weight basis with respect to the sequestering polymer. 
     
     
         16 . A pharmaceutical composition of any one of  claims 9 - 15  wherein the third layer comprises a sequestering polymer and a sequestering polymer hydrophobicity-enhancing additive present at approximately a 1:1 ratio on a weight-by-weight basis with respect to the sequestering polymer. 
     
     
         17 . A pharmaceutical composition of any one of  claims 9 - 16  wherein the third layer comprises a sequestering polymer, a charge-neutralizing additive and a sequestering polymer hydrophobicity-enhancing additive wherein the charge-neutralizing additive is present at less than approximately 4% on a weight-by-weight basis with respect to the sequestering polymer and the sequestering polymer hydrophobicity-enhancing additive is present at approximately a 1:1 ratio on a weight-by-weight basis with respect to the sequestering polymer. 
     
     
         18 . A pharmaceutical composition of any one of  claims 9 - 17  wherein the third layer comprises the charge-neutralizing additive sodium lauryl sulfate at less than approximately 4% on a weight-by-weight basis with respect to the first sequestering polymer. 
     
     
         19 . A pharmaceutical composition of any one of  claims 9 - 18  wherein the third layer comprises the sequestering polymer hydrophobicity-enhancing additive talc at approximately a 1:1 ratio on a weight-by-weight basis with respect to the sequestering polymer. 
     
     
         20 . A pharmaceutical composition of any one of  claims 9 - 19  further comprising an osmotic pressure regulating agent within the first layer. 
     
     
         21 . A pharmaceutical composition of  claim 20  wherein the osmotic pressure regulating agent is sodium chloride. 
     
     
         22 . A pharmaceutical composition of any one of  claims 1 - 21  further comprising a sustained release carrier which imparts sustained release properties to the agonist. 
     
     
         23 . A pharmaceutical composition of  claim 22  wherein the sustained release carrier is Eudragit L100-55. 
     
     
         24 . A pharmaceutical composition comprising an antagonist in direct contact with a seal coat, an agonist in direct contact with the seal coat and a sequestering polymer but not the antagonist, wherein the antagonist and agonist are present within a single multilayer pharmaceutical unit. 
     
     
         25 . A pharmaceutical composition comprising a pharmaceutical dosing unit consisting essentially of a multilayer bead comprising an antagonist and an agonist that are not in direct contact with one another. 
     
     
         26 . A pharmaceutical composition comprising a plurality of pharmaceutically active units wherein each unit comprises an antagonist, an agonist, a seal coat, and a sequestering polymer wherein the antagonist and the agonist are not in direct contact with one another. 
     
     
         27 . A pharmaceutical composition comprising a pharmaceutically inert support material, an antagonist in direct contact with the support material, a seal coat in direct contact with the antagonist and an agonist, and a sequestering polymer in direct contact with the agonist. 
     
     
         28 . A pharmaceutical composition comprising an antagonist indirectly and fixably bound to an agonist such that physical disruption of the intact dosage form causes the antagonist and agonist to be admixed together. 
     
     
         29 . A pharmaceutical composition of any one of  claims 2 - 24  and  26  wherein a charge-neutralizing additive is in admixture with the sequestering polymer in an amount sufficient to decrease the amount of antagonist released from the composition in vivo. 
     
     
         30 . A pharmaceutical composition of  claim 29  wherein the charge-neutralizing additive is sodium lauryl sulfate. 
     
     
         31 . The pharmaceutical composition of  claim 31  wherein the amount of charge-neutralizing additive relative to the amount of sequestering polymer on a weight-by-weight basis is approximately 1%, approximately 1.5%, approximately 2%, approximately 2.5%, approximately 3%, approximately 3.5%, approximately 4%, approximately 4.5%, approximately 5%, approximately 5.5%, approximately 1-2%, approximately 2-3%, approximately 3-4% or approximately 4-5%. 
     
     
         32 . The pharmaceutical composition of  claim 31  wherein the wherein the amount of charge-neutralizing additive relative to the amount of sequestering polymer is approximately 1 to approximately 3%. 
     
     
         33 . The pharmaceutical composition of  claim 31  wherein the wherein the amount of charge-neutralizing additive relative to the amount of sequestering polymer is approximately 3.2%. 
     
     
         34 . The pharmaceutical composition of  claim 31  wherein the wherein the amount of charge-neutralizing additive relative to the amount of sequestering polymer is approximately 3.4%. 
     
     
         35 . The pharmaceutical composition of any one of  claims 1 - 34  further comprising a sequestering polymer hydrophobicity-enhancing additive in an amount sufficient to decrease the amount of antagonist released from the composition in vivo. 
     
     
         36 . The pharmaceutical composition of  claim 35  wherein sequestering polymer hydrophobicity-enhancing additive is present at greater than approximately 66% and less than approximately 150% of the amount of sequestering polymer on a weight-by-weight basis. 
     
     
         37 . The pharmaceutical composition of  claim 35  wherein sequestering polymer hydrophobicity-enhancing additive is present at approximately the same amount as the sequestering polymer on a weight-by-weight basis. 
     
     
         38 . The pharmaceutical composition of any one of  claims 35 - 37  wherein the sequestering polymer hydrophobicity-enhancing additive is talc. 
     
     
         39 . The pharmaceutical composition of any one of  claims 2 - 24  and  26  wherein both a charge-neutralizing additive and a sequestering polymer hydrophobicity-enhancing additive are present in an amount sufficient to decrease the amount of antagonist released from the composition in vivo. 
     
     
         40 . The pharmaceutical composition of any one of  claims 1 - 39  wherein the sequestering polymer comprises Eudragit RS. 
     
     
         41 . The pharmaceutical composition of any one of  claims 1 - 40  wherein the agonist is in a controlled-release form. 
     
     
         42 . The pharmaceutical composition of  claim 41  wherein the agonist is in contact with a sequestering polymer. 
     
     
         43 . The pharmaceutical composition of any one of  claims 1 - 42  wherein the antagonist is not substantially released in vivo following administration to a patient. 
     
     
         44 . The pharmaceutical composition of any one of  claims 1 - 42  wherein the antagonist is not substantially released in vivo following administered to a patient in the fed state. 
     
     
         45 . The pharmaceutical composition of  claim 43  or  44  wherein less than approximately 10% of the antagonist is released. 
     
     
         46 . The pharmaceutical composition of  claim 43  or  44  wherein less than approximately 5% of the antagonist is released. 
     
     
         47 . The pharmaceutical composition of  claim 43  or  44  wherein less than approximately 3% of the antagonist is released. 
     
     
         48 . The pharmaceutical composition of  claim 43  or  44  wherein release of the antagonist is determined by measuring plasma levels of naltrexone. 
     
     
         49 . The pharmaceutical composition of  claim 43  or  44  wherein release of the antagonist is determined by measuring plasma levels of 6-beta-naltrexol. 
     
     
         50 . The pharmaceutical composition of any one of  claims 1 - 49  wherein the antagonist is an opioid antagonist. 
     
     
         51 . The pharmaceutical composition of  claim 50  wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazacine, and levallorphan. 
     
     
         52 . The pharmaceutical composition of  claim 51  wherein the opioid antagonist is naltrexone. 
     
     
         53 . The pharmaceutical composition of any one of  claims 1 - 52  wherein the agonist is an opioid agonist. 
     
     
         54 . The pharmaceutical composition of  claim 53  wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, hydrocodone and oxycodone. 
     
     
         55 . The pharmaceutical composition of  claim 54  wherein the opioid agonist is morphine. 
     
     
         56 . A method for correlating the amount of naltrexone released from a pharmaceutical composition comprising naltrexone by measuring plasma levels of 6-beta-naltrexol. 
     
     
         57 . A method for measuring the amount of antagonist or derivative thereof in a biological sample, the antagonist or derivative having been released from a pharmaceutical composition in vivo, the method comprising the USP paddle method at 37° C., 100 rpm, but further comprising incubation in a buffer containing a surfactant. 
     
     
         58 . The method of  claim 57  wherein the surfactant is Triton X-100. 
     
     
         59 . The method of  claim 58  wherein the buffer is 0.2% Triton X-100, 0.2% sodium acetate, 0.002 N HCl, pH 5.5. 
     
     
         60 . The method of any one of  claims 56 - 59  wherein the antagonist or derivative is naltrexone or 6-beta-naltrexol. 
     
     
         61 . The method of  claim 60  wherein the derivative is 6-beta-naltrexol. 
     
     
         62 . A method for preparing a pharmaceutical composition comprising adhering an antagonist to a pharmaceutically inert support material, coating the antagonist with a seal coat, coating the seal coat with an agonist, and coating the agonist with a sequestering polymer. 
     
     
         63 . The method of  claim 62  wherein the sequestering polymer provides a controlled-release function with respect to the agonist. 
     
     
         64 . A method of manufacturing a pharmaceutical composition of any one of  claims 1 - 56  wherein: an antagonist is applied to an inert core material to form an inner layer; a seal coat is then applied upon the inner layer; and, a composition comprising an agonist is then applied upon the seal coat. 
     
     
         65 . The method of  claim 64  wherein an additional layer containing a blocking agent is applied upon the active agent layer. 
     
     
         66 . The method of  claim 64  wherein the core is water-soluble. 
     
     
         67 . A multiple layer pharmaceutical composition comprising an agonist and an antagonist within distinct layers of the composition, wherein at least 90% of the antagonist is sequestered for at least 24 hours following administration to a human being. 
     
     
         68 . A multiple layer pharmaceutical composition comprising an agonist and an antagonist within distinct layers of the composition, wherein at least 95% of the antagonist is sequestered for at least 24 hours following administration to a human being. 
     
     
         69 . The composition of either of  claim 67  or  68  wherein the antagonist is an opioid antagonist. 
     
     
         70 . The composition of  claim 69  wherein the antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazacine, levallorphan, derivatives or complexes thereof, and pharmaceutically acceptable salts thereof. 
     
     
         71 . The composition of  claim 70  wherein the antagonist is naltrexone. 
     
     
         72 . The composition of either of  claim 67  or  68  wherein the agonist is an opioid. 
     
     
         73 . The composition of  claim 72  wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenazocine, phenomorphan, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, derivatives thereof, complexes thereof, and pharmaceutically acceptable salts thereof. 
     
     
         74 . The composition of  claim 73  wherein the agonist is morphine. 
     
     
         75 . The composition of either of  claim 67  or  68  wherein the antagonist is an opioid antagonist and the agonist is an opioid. 
     
     
         76 . The composition of  claim 75  wherein the antagonist is naltrexone and the agonist is morphine. 
     
     
         77 . A pharmaceutical composition comprising naltrexone within a sequestering subunit and morphine in contact with the subunit but not the naltrexone, wherein administration of the composition to a human being results in the release of substantially all of the morphine from the composition but less than 10% of the naltrexone from the composition within 24 hours of administration. 
     
     
         78 . A pharmaceutical composition comprising naltrexone within a sequestering subunit and morphine in contact with the subunit but not the naltrexone, wherein administration of the composition to a human being results in the release of substantially all of the morphine from the composition but less than 5% of the naltrexone from the composition within 24 hours of administration. 
     
     
         79 . The pharmaceutical composition of either of  claim 77  or  78  wherein naltrexone release is determined by measuring the amount of 6-beta-naltrexone in the plasma of the human being.