Compositions and methods for reducing overdose
Drug delivery formulations, uses thereof and methods of making same are provided in order to reduce the potential for abuse, misuse or improper administration of an addictive substance or any active substance and to prevent, reduce, inhibit, or delay purposeful or accidental overdose of an active substance by ingesting too many dosage forms at once, for example.
1. A unit dose formulation comprising:
at least one active substance, wherein release of said at least one active substance is inhibited when the number of unit dosage forms ingested exceeds a predetermined number;
at least one actuator; and
at least one regulator surrounding said at least one active substance and said at least one actuator,
whereby when the unit dose formulation is exposed to a fluid media having a process variable, said process variable being pH, said at least one regulator is capable of adjusting the pH to inhibit the release of said at least one active substance via said at least one actuator, when the number of unit dosage forms exceeds the predetermined number.
2. The unit dose formulation of claim 1 , wherein said at least one regulator is present in an amount sufficient to raise the variable above the threshold, such that dissolution of said at least one actuator and release of said at least one active substance via the actuator is inhibited when the number of unit dosage forms ingested exceeds the predetermined number.
3. The unit dose formulation of claim 1 , wherein said at least one regulator is present in an amount sufficient to decrease the variable below the threshold, such that dissolution of said at least one actuator and release of said at least one active substance via the actuator is inhibited when the number of unit dosage forms ingested exceeds the predetermined number.
4. The unit dosage formulation of claim 1 , wherein the fluid media is an acidic media.
5. The unit dosage formulation of claim 1 , wherein the fluid media is a basic media.
6. The unit dosage formulation of claim 1 , wherein the regulator and/or actuator is a physical/chemical barrier.
7. The unit dosage formulation of claim 1 , wherein the regulator is a pH independent barrier and the actuator is a pH dependent barrier.
8. The unit dose formulation of claim 1 , wherein said at least one regulator comprises at least one alkalinizing agent.
9. The unit dose formulation of claim 8 , wherein said at least one alkalinizing agent is selected from the group consisting of alkaline earth metal salts, alkali metal salts, aluminum salts, amino acids, and amino acid derivatives.
10. The unit dose formulation of claim 9 , wherein said at least one alkalinizing agent is selected from the group consisting of magnesium hydroxide, magnesium trisilicate, aluminum hydroxide, magnesium oxide, calcium carbonate, sodium bicarbonate, sodium citrate, sodium carbonate, sodium acetate, magnesium carbonate, L-arginine, meglumine, and combinations thereof.
11. The unit dose formulation of claim 10 , wherein said at least one alkalinizing agent is magnesium hydroxide.
12. The unit dose formulation of claim 1 , wherein said at least one regulator comprises at least one acidifying agent.
13. The unit dose formulation of claim 12 , wherein said at least one regulator is selected from the group consisting of an inorganic acid, an organic acid, and combinations thereof.
14. The unit dose formulation of claim 13 , wherein said at least one acidifying agent is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, lactic acid, phosphoric acid, citric acid, malic acid, fumaric acid, stearic acid, tartaric acid, boric acid, borax, benzoic acid, and combinations thereof.
15. The unit dose formulation of claim 14 , wherein said at least one acidifying agent is fumaric acid and/or citric acid.
16. The unit dose formulation of claim 1 , wherein said at least one actuator comprises at least one acid labile substance.
17. The unit dose formulation of claim 16 , wherein said at least one acid labile substance is selected from the group consisting of sulfonamide-based polymers and copolymers, amine functional polymers and copolymers, polysaccharides, poly(vinylpyrrolidone-co-dimethylmaleic anhydride) (PVD), dimethylaminoethyl methacrylate copolymers, and combinations thereof.
18. The unit dose formulation of claim 17 , wherein the amine functional polymers is selected from the group consisting of polyvinyl pyridine polymers and copolymers.
19. The unit dose formulation of claim 17 , wherein the polysaccharides is chitosan.
20. The unit dose formulation of claim 17 , wherein the dimethylaminoethyl methacrylate copolymers are selected from the group consisting of 2-propenoic acid, 2-methyl-, butyl ester, polymer with 2-(dimethylamino)ethyl 2-methyl-2-propenoate and methyl 2-methyl-2-propenoate (Eudragit™ E, CAS Registry Number 24938-16-7), 2-propenoic acid, 2-methyl-, butyl ester, polymer with 2-(dimethylamino)ethyl 2-methyl-2-propenoate and methyl 2-methyl-2-propenoate interpolyelectrolyte complex (Eudragit™ E interpolyelectrolyte complex), 2-propenoic acid, 2-methyl-, butyl ester, polymer with 2-(dimethylamino)ethyl 2-methyl-2-propenoate and methyl 2-methyl-2-propenoate polyamopholyte complex (Eudragit™ E polyamopholyte complex), 2-propenoic acid, 2-methyl-, butyl ester, polymer with 2-(dimethylamino)ethyl 2-methyl-2-propenoate and methyl 2-methyl-2-propenoate complex with methacrylic acid and methyl methacrylate copolymer (1:2) (Eudragit™ E interpolyelectrolyte complex with Eudragit™ L), methacrylic acid and methyl methacrylate copolymer (1:2) (Eudragit™ S), derivatives thereof, and combinations thereof.
21. The unit dose formulation of claim 20 , wherein said at least one acid labile substance comprises 2-propenoic acid, 2-methyl-, butyl ester, polymer with 2-(dimethylamino)ethyl 2-methyl-2-propenoate and methyl 2-methyl-2-propenoate (Eudragit™ E, CAS Registry Number 24938-16-7).
22. The unit dose formulation of claim 1 , wherein said at least one actuator comprises at least one base labile substance.
23. The unit dose formulation of claim 22 , wherein said at least one base labile substance is selected from the group consisting of pharmaceutically acceptable ethers, esters, ketones, epoxies, polyamides, polysiloxanes, enteric polymers, anionic copolymers based on methacrylic acid and methyl methacrylate, and combinations thereof.
24. The unit dose formulation of claim 23 , wherein said at least one base labile substance comprises at least one enteric polymer.
25. The unit dose formulation of claim 24 , wherein said at least one enteric polymer is methacrylic acid and methyl methacrylate copolymer (1:1) (Eudragit™ L) or methacrylic acid and methyl methacrylate copolymer (1:2) (Eudragit™ S).
26. The unit dose formulation of claim 1 , wherein dissolution of said at least one actuator and release of said at least one active substance is reduced upon dissolution of a threshold amount of said at least one regulator.
27. The unit dose formulation of claim 1 , wherein dissolution of said at least one actuator and release of said at least one active substance decreases in the presence of increasing concentrations of at least one regulator.
28. The unit dose formulation of claim 1 , wherein the rate of dissolution of said at least one actuator is inversely proportional to the number of unit dose formulations ingested.
29. The unit dose formulation of claim 1 , wherein, when the number of unit dosage forms ingested exceeds a predetermined number, said at least one regulator increases the pH to inhibit dissolution of said at least one actuator and inhibit release of said at least one active substance.
30. The unit dose formulation of claim 1 , wherein, when the number of unit dosage forms ingested exceeds a predetermined number, said at least one regulator decreases the pH to inhibit dissolution of said at least one actuator and inhibit release of said at least one active substance.
31. The unit dose formulation of claim 1 , wherein the predetermined number is less than 20.
32. The unit dose formulation of claim 31 , wherein the predetermined number is 1, 2, 3, 4, or 5.
33. The unit dose formulation of claim 31 , wherein the predetermined number is 1 or 2.
34. The unit dose formulation of claim 1 , further comprising at least one agent selected from the group consisting of an abuse deterrent coloring agent; a controlled release agent; a viscosity imparting agent; a gelling agent; polyethylene oxide; crospovidone; N,N-dimethylmethanamine; 2-methylprop-2-enoic acid (Eudragit™ RL CAS Registry No. 51822-44-7); ethyl prop-2-enoate; methyl 2-methylprop-2-enoate trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium chloride (Eudragit™ RS CAS Registry No. 39316-06-8), and combinations thereof.
35. The unit dose formulation of claim 1 , further comprising at least one abuse deterrent coloring agent.
36. The unit dose formulation of claim 34 , wherein said at least one abuse deterrent coloring agent is brilliant blue.
37. The unit dose formulation of claim 34 , wherein said at least one abuse deterrent coloring agent is Aluminum Lake Blue#1.
38. The unit dose formulation of claim 1 , further comprising at least one agent selected from the group consisting of a chewing discouraging agent, a licking discouraging agent, an insufflation discouraging agent, a snorting discouraging agent, an inhalation discouraging agent, and combinations thereof.
39. The unit dose formulation of claim 38 , wherein the inhalation discouraging agent is selected from the group consisting of a coloring agent, a tussigenic agent, an irritant, and combinations thereof.
40. The unit dose formulation of claim 1 , wherein said at least one active substance is at least one addictive substance.
41. The unit dose formulation of claim 1 , wherein said at least one active substance is at least one opioid agonist and/or at least one narcotic analgesic.
42. The unit dose formulation of claim 1 , wherein said at least one active substance has an analgesic ceiling effect.
43. The unit dose formulation of claim 1 , in the form of a bead, tablet, capsule, granule, and/or pellet.
44. The unit dose formulation of claim 1 , wherein said at least one active substance is in an amount of from about 0.1 mg to about 1000 mg; said at least one actuator is in an amount of from about 0.5 mg to about 500 mg; and/or said at least one regulator is in an amount of from about 0.5 mg to about 500 mg.
45. The unit dose formulation of claim 1 , wherein said at least one actuator is present in an amount of from 0.5 mg/cm 2 to 200 mg/cm 2 or from 1 mg/cm 2 to 100 mg/cm 2 or from 2 mg/cm 2 to 150 mg/cm 2 or from about 4 mg/cm 2 to about 100 mg/cm 2 or from 8 mg/cm 2 to 50 mg/cm 2 .
46. The unit dose formulation of claim 1 , wherein said at least one actuator is used in an amount that yields from about 1% to about 200% weight gain, from about 1% to about 70% or from about 1% to about 50% weight gain based on the weight of the formulation.
47. The unit dose formulation of claim 1 , wherein said at least one regulator is used in an amount that yields from about 1% to about 200% weight gain, from about 5% to about 80%, from about 1% to about 70% weight gain, from about 1% to about 50% or from about 5% to about 50% weight gain based on the weight of the formulation.
48. The unit dosage formulation of claim 1 , wherein release of said at least one active substance is a lag time, delayed release, no release or insignificant release of said at least one active substance.