Pharmaceutical Compositions
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.
1 . A multi-layer pharmaceutical composition comprising an antagonist in a first layer and an agonist in a second layer upon said first layer such that the antagonist is substantially sequestered when administered to a human being in an intact form, such that physical disruption of the dosage form decreases the euphoric effect of the agonist when administered to a person as compared to an immediate release agonist composition.
2 . The composition of claim 1 wherein the euphoric effect is measured by E max from a test selected from the group consisting of VAS-Drug Liking, VAS-Overall Drug Liking, Cole/ARCI-Stimulation Euphoria, Subjective Drug Value, Cole/ARCI Abuse Potential, ARCI-MBG, VAS-Good Effects, VAS-Feeling High, and pupillometry.
3 . The composition of claim 1 wherein the E max of at least one of the tests is reduced by a percentage selected from the group consisting of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% and about 100%.
4 . The composition of claim 2 or claim 3 wherein the agonist is morphine.
5 . The composition of claim 4 wherein the antagonist is naltrexone.
6 . A multi-layer pharmaceutical composition comprising an antagonist in a first layer and an agonist in a second layer upon said first layer such that the antagonist is substantially sequestered when administered to a human being in an intact form, such that physical disruption of the dosage form alters the pharmacokinetic parameters of the dosage form as compared to the intact dosage form.
7 . The composition of claim 6 wherein the pharmacokinetic parameter is selected from the group consisting of C max , T max , λ z , T 1/2 , AUC 0-8h , AUC last , AUC inf , elimination rate, clearance and volume of distribution (L).
8 . The composition of claim 7 wherein the difference is calculated based on the mean or median of the pharmacokinetic parameter.
9 . The composition of claim 8 wherein the difference is statistically significant.
10 . The composition of claim 8 wherein the median C max of the intact dosage form is less than one-half the median C max of the intact dosage form.
11 . The composition of claim 8 wherein the median T max of the substantially disrupted dosage form is approximately one-seventh that of the intact dosage form.
12 . The composition of claim 8 wherein the median AUC (0-8h) of the intact dosage form is approximately one-third that of the intact dosage form.
13 . The composition of claim 8 wherein the median T 1/2 of the intact dosage form is greater than that of the intact dosage form.
14 . The composition of claim 8 wherein the pharmacokinetic parameter is the mean or median of a measurement selected from the group consisting of C max , T max , AUC (0-8h) , and T 1/2 .
15 . The pharmaceutical composition of claim 7 wherein the T max of the antagonist released from the disrupted composition following administration to a subject is approximately equivalent to the T max of an equivalent amount of antagonist orally administered to the subject.
16 . The pharmaceutical composition of claim 7 wherein the T max of the antagonist released from the disrupted composition following administration to a subject is within approximately 30% of the T max of an equivalent amount of antagonist orally administered to the subject.
17 . The pharmaceutical composition of claim 7 wherein the T max of the antagonist released from the disrupted composition following administration to a subject is within approximately 20% of the T max of an equivalent amount of antagonist orally administered to the subject.
18 . The pharmaceutical composition of claim 7 wherein the T max of the antagonist released from the disrupted composition following administration to a subject is within approximately 10% of the T max of an equivalent amount of antagonist orally administered to the subject.
19 . The pharmaceutical composition of claim 6 wherein the C max of the antagonist released from the disrupted composition following administration to a subject is approximately equivalent to the C max of an equivalent amount of antagonist orally administered to the subject.
20 . The pharmaceutical composition of claim 6 wherein the C max of the antagonist released from the disrupted composition following administration to a subject is within approximately 30% of the C max of an equivalent amount of antagonist orally administered to the subject.
21 . The pharmaceutical composition of claim 6 wherein the C max of the antagonist released from the disrupted composition following administration to a subject is within approximately 20% of the C max of an equivalent amount of antagonist orally administered to the subject.
22 . The pharmaceutical composition of claim 6 wherein the C max of the antagonist released from the disrupted composition following administration to a subject is within approximately 10% of the C max of an equivalent amount of antagonist orally administered to the subject.
23 . The composition of claim 6 wherein the agonist is morphine.
24 . The composition of claim 23 wherein the antagonist is naltrexone.