Methods and compositions for self-regulated release of active pharmaceuticals ingredients

Abstract

To provide a composition that deters abuse and minimizes or reduces the potential for physical or psychological dependency.SOLUTION: An abuse deterrent pharmaceutical composition includes a drug susceptible to abuse, a first acid soluble ingredient, a first buffering ingredient, and a delayed release buffering component.SELECTED DRAWING: Figure 1

Description

Related Applications

[0001]

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 479,822, filed Mar. 31, 2017; U.S. Provisional Patent Application No. 62 / 544,375, filed Aug. 11, 2017; and U.S. Provisional Patent Application No. 62 / 587,783, filed Nov. 17, 2017, the entire contents of each of which are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION

[0002]

[0003] A class of drugs that exhibit morphine- or morphine-like properties are called opioids, or opioid agonists. As agonists, certain drugs are characterized by interacting with stereospecific and saturable binding sites in the brain and other body tissues and organs. Endogenous opioid-like peptides are present in regions of the central nervous system that are thought to be involved in the regulation of pain perception, movement, mood and behavior, and neuroendocrine function. Three classical opioid receptor types, mu (μ), delta (δ), and kappa (κ), have been widely studied. Each of these receptors has a unique anatomical distribution in the brain, spinal cord, and periphery. Most clinically used opioids are relatively selective for the μ receptor, reflecting their similarity to morphine. However, opioid-containing drugs that are relatively selective for a particular receptor subtype at standard therapeutic doses often interact with multiple receptor subtypes when administered at sufficiently high doses, which can lead to changes in their pharmacological effects. This is particularly true since opioid doses escalate to overcome tolerance.

[0003]

[0004] Repeated use of opioids can lead to the development of tolerance, physical and / or psychological dependence, i.e., addiction, which is a characteristic of most drugs containing opioid analgesics.

[0004]

[0005] Attempts have been made to reduce the potential for abuse of orally administered drugs containing opioids. These attempts generally center around including in an oral dosage form an opioid antagonist that is not orally active but substantially blocks the analgesic effect of the opioid when attempting to dissolve the opioid for parenteral administration.

[0005]

[0006] However, despite all attempts, the misuse and abuse of pharmaceuticals continue to increase. There is an ever-growing need for new and effective methods and compositions for deterring the abuse of pharmaceuticals (e.g., orally administered pharmaceuticals) such as, but not limited to, immediate release, sustained or extended release, and delayed release formulations, particularly for drugs that are prone to abuse. Such methods and compositions that deter abuse and minimize or reduce the potential for physical or psychological dependence would be useful for opioid analgesics as well as for patients seeking drug therapy.

SUMMARY OF THE INVENTION

[0006]

[0007] In one aspect, the present invention relates to an abuse deterrent pharmaceutical composition comprising an abuse-prone drug; a first acid-soluble component; a first buffering ingredient; and a delayed release buffering component. In some aspects, the first acid-soluble component is, for example, calcium carbonate, a cationic copolymer, or a combination thereof. In some aspects, the cationic copolymer is, for example, one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In some aspects, the first buffering component is, for example, calcium carbonate, sodium bicarbonate, magnesium oxide, trisodium phosphate, or a combination thereof. In some aspects, the delayed release buffering component comprises a second buffering component, an enteric coating, and a sustained release component. In some aspects, the delayed release buffering ​The composition comprises a core, a shell surrounding the core, and a subcoat between the core and the shell. The core contains a second buffering component, the shell contains an enteric solvent, and the subcoat contains a sustained release component. In some embodiments, the delayed release buffering component comprises a second buffering component, an enteric solvent, and a second acid-soluble component. In some embodiments, the delayed release buffering component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell. The core contains a second buffering component, the shell contains an enteric solvent, and the subcoat contains a second acid-soluble component. In some embodiments, the second acid-soluble component comprises calcium carbonate, a cationic copolymer, or a combination thereof. In some embodiments, the cationic copolymer comprises one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In some embodiments, the second acid-soluble component is the same as the first acid-soluble component. In some embodiments, the second buffering component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the second buffering component is the same as the first buffering component. In some embodiments, the enteric component comprises one or more of shellac, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, sodium alginate, and zein.

[0007]

[0008] In one aspect, the present invention relates to a drug abuse deterrent pharmaceutical composition comprising a drug prone to abuse; a first acid-soluble component; a first buffering component; a delayed release buffering component; and a component for reducing gastric acid production. In some aspects, the component for reducing gastric acid production comprises an H2-antagonist. In some aspects, the H2-antagonist is present in an amount of 10 to 50% of the minimum therapeutic dose of the H2 antagonist for reducing gastric acid secretion. In some aspects, the first acid-soluble component is calcium carbonate, a cationic copolymer, or a combination thereof. In some aspects, the cationic copolymer is one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In some aspects, the first buffering component is calcium carbonate, sodium bicarbonate, magnesium oxide, trisodium phosphate, or a combination thereof. In some aspects, the delayed release buffering component comprises a second buffering component, an enteric coating, and a sustained release component. In some aspects, the delayed release buffering component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprising the second buffering component, the shell comprising the enteric coating, and the subcoat comprising the sustained release component. In some aspects, the delayed release buffering component comprises a second buffering component, an enteric coating, and a second acid-soluble component. In some aspects, the delayed release buffering component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprising the second buffering component, the shell comprising the enteric coating, and the subcoat comprising the second acid-soluble component. In some aspects, the second acid-soluble component comprises calcium carbonate, a cationic copolymer, or a combination thereof. In some aspects, the cationic copolymer comprises one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In some aspects, the second acid-soluble component is the same as the first acid-soluble component. In some aspects, the second buffering component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, trisodium phosphate, or a combination thereof. In some aspects, the second buffering component is the same as the first buffering component.In some embodiments, the enteric component comprises one or more of shellac, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, sodium alginate, and zein.

[0008]

[0009] In one aspect, the present invention relates to a drug abuse deterrent pharmaceutical composition comprising a drug prone to abuse; a first acid-soluble component; a first buffering component; a delayed release buffering component; and a component for extending the gastric emptying time. In some embodiments, the component for extending the gastric emptying time is It is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, amino acids, peptides, proteins, fatty acids, monoglycerides, diglycerides, and triglycerides. In some embodiments, the component for extending the gastric emptying time is selected from the group consisting of loperamide, diphenoxylate, atropine, diphenoxin, anticholinergic agents, antidepressants, opioids, antidiarrheal agents, and agents that induce gastric hypomotility. In some embodiments, when ingested by a subject, the component for extending the gastric emptying time extends the gastric emptying time of the subject. In some embodiments, the first acid-soluble component is calcium carbonate, a cationic copolymer, or a combination thereof. In some embodiments, the cationic copolymer is one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In some embodiments, the first buffering component is calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the delayed-release buffering component includes a second buffering component, an enteric solvent, and a sustained-release component. In some embodiments, the delayed-release buffering component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core contains the second buffering component, the shell contains the enteric solvent, and the subcoat contains the sustained-release component. In some embodiments, the delayed-release buffering component includes a second buffering component, an enteric solvent, and a second acid-soluble component. In some embodiments, the delayed-release buffering component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core contains the second buffering component, the shell contains the enteric solvent, and the subcoat contains the second acid-soluble component. In some embodiments, the second acid-soluble component includes calcium carbonate, a cationic copolymer, or a combination thereof. In some embodiments, the cationic copolymer includes one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In some embodiments, the second acid-soluble component is the same as the first acid-soluble component. In some embodiments, the second buffering component includes calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the second buffering component is the same as the first buffering component.In some embodiments, the enteric component includes one or more of shellac, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, sodium alginate, and zein.

[0009]

[0010] In one aspect, the present invention relates to a drug abuse deterrent pharmaceutical composition comprising a drug prone to abuse; a first acid-soluble component; a first buffering component; a delayed release buffering component; a component for reducing gastric acid production; and a component for prolonging gastric emptying time. In some embodiments, the component for prolonging gastric emptying time is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, amino acids, peptides, proteins, fatty acids, monoglycerides, diglycerides, and triglycerides. In some embodiments, the component for prolonging gastric emptying time is selected from the group consisting of loperamide, diphenoxylate, atropine, diphenoxine, anticholinergic agents, antidepressants, opioids, antidiarrheal agents, and agents that induce gastric atony. In some embodiments, when administered to a subject, the component for prolonging gastric emptying time prolongs the gastric emptying time of the subject. In some embodiments, the component for reducing gastric acid production comprises an H2-antagonist. In some embodiments, the H2-antagonist is present in an amount of 10 to 50% of the minimum therapeutic dose of the H2 antagonist for reducing gastric acid secretion. In some embodiments, the first acid-soluble component is calcium carbonate, a cationic copolymer, or a combination thereof. In some embodiments, the cationic copolymer is one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In some embodiments, the first buffering component is calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the delayed release buffering component includes a second buffering component, an enteric solvent, and a sustained release component. In some embodiments, the delayed release buffering component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprising the second buffering component and the shell comprising the enteric solvent And the subcoat contains a sustained-release component. In some embodiments, the delayed-release buffering component includes a second buffering component, an enteric solvent, and a second acid-soluble component. In some embodiments, the delayed-release buffering component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core contains the second buffering component, the shell contains the enteric solvent, and the subcoat contains the second acid-soluble component. In some embodiments, the second acid-soluble component includes calcium carbonate, a cationic copolymer, or a combination thereof. In some embodiments, the cationic copolymer includes one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In some embodiments, the second acid-soluble component is the same as the first acid-soluble component. In some embodiments, the second buffering component includes calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the second buffering component is the same as the first buffering component. In some embodiments, the enteric component includes one or more of shellac, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, sodium alginate, and zein.

[0010]

[0011] In some embodiments, the present invention relates to a dosage form comprising an abuse-deterrent pharmaceutical composition comprising a drug prone to abuse, a first acid-soluble component, a first buffering component, and a delayed-release buffering component. In some embodiments, the composition further comprises a component for reducing gastric acid production. In some embodiments, the component for reducing gastric acid production comprises an H2-antagonist. In some embodiments, the H2-antagonist is present in an amount of 10 to 50% of the minimum therapeutic dose of the H2 antagonist for reducing gastric acid secretion. In some embodiments, the composition further comprises a component for prolonging the gastric emptying time. In some embodiments, the component for prolonging the gastric emptying time is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, amino acids, peptides, proteins, fatty acids, monoglycerides, diglycerides, and triglycerides. In some embodiments, the component for prolonging the gastric emptying time is selected from the group consisting of loperamide, diphenoxylate, atropine, diphenoxine, anticholinergic agents, antidepressants, opioids, antidiarrheal agents, and agents that induce gastric atony. In some embodiments, when ingested by a subject, the component for prolonging the gastric emptying time prolongs the gastric emptying time of the subject. In some embodiments, the first acid-soluble component is calcium carbonate, a cationic copolymer, or a combination thereof. In some embodiments, the cationic copolymer is one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In some embodiments, the first buffering component is calcium carbonate, sodium bicarbonate, magnesium oxide, trisodium phosphate, or a combination thereof. In some embodiments, the delayed-release buffering component comprises a second buffering component, an enteric coating, and a sustained-release component. In some embodiments, the delayed-release buffering component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprising the second buffering component, the shell comprising the enteric coating, and the subcoat comprising the sustained-release component. In some embodiments, the delayed-release buffering component comprises a second buffering component, an enteric coating, and a second acid-soluble component.In some embodiments, the delayed-release buffering component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprises a second buffering component, the shell comprises an enteric solvent, and the subcoat comprises a second acid-soluble component. In some embodiments, the second acid-soluble component comprises calcium carbonate, a cationic copolymer, or a combination thereof. In some embodiments, the cationic copolymer comprises one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In some embodiments, the second acid-soluble component is the same as the first acid-soluble component. In some embodiments, the second buffering component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the second buffering component is the same as the first buffering component. In some embodiments, the enteric component comprises one or more of shellac, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, sodium alginate, and zein. In some embodiments, the dosage form is a food bar or a beverage.

[0011]

[0012] In some embodiments, the present invention relates to a method for treating a disease alleviated by an easily abused drug, the method comprising administering to a subject in need thereof an abuse deterrent pharmaceutical composition comprising an easily abused drug; a first acid-soluble component; a first buffering component; and a delayed-release buffering component. In some embodiments, the composition further comprises a component for reducing gastric acid production. In some embodiments, the component for reducing gastric acid production comprises an H2-antagonist. In some embodiments, the H2-antagonist is present in an amount of 10 to 50% of the minimum therapeutic dose of the H2 antagonist for reducing gastric acid secretion. In some embodiments, the component for reducing gastric acid production comprises an H2-antagonist. In some embodiments, the H2-antagonist is present in an amount of 10 to 50% of the minimum therapeutic dose of the H2 antagonist for reducing gastric acid secretion. In some embodiments, the composition further comprises a component for prolonging gastric emptying time. In some embodiments, the component for prolonging gastric emptying time is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, amino acids, peptides, proteins, fatty acids, monoglycerides, diglycerides, and triglycerides. In some embodiments, the component for prolonging gastric emptying time is selected from the group consisting of loperamide, diphenoxylate, atropine, diphenoxine, anticholinergic agents, antidepressants, opioids, antidiarrheal agents, and agents that induce gastric hypomotility. In some embodiments, when ingested by the subject, the component for prolonging gastric emptying time prolongs the gastric emptying time of the subject. In some embodiments, the first acid-soluble component is calcium carbonate, a cationic copolymer, or a combination thereof. In some embodiments, the cationic copolymer is one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In some embodiments, the first buffering component is calcium carbonate, sodium bicarbonate, magnesium oxide, trisodium phosphate, or a combination thereof. In some embodiments, the delayed-release buffering component comprises a second buffering component, an enteric solvent, and a sustained-release component.In some embodiments, the delayed-release buffering component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprises a second buffering component, the shell comprises an enteric solvent, and the subcoat comprises a sustained-release component. In some embodiments, the delayed-release buffering component comprises a second buffering component, an enteric solvent, and a second acid-soluble component. In some embodiments, the delayed-release buffering component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprises a second buffering component, the shell comprises an enteric solvent, and the subcoat comprises a second acid-soluble component. In some embodiments, the second acid-soluble component comprises calcium carbonate, a cationic copolymer, or a combination thereof. In some embodiments, the cationic copolymer comprises one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In some embodiments, the second acid-soluble component is the same as the first acid-soluble component. In some embodiments, the second buffering component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the second buffering component is the same as the first buffering component. In some embodiments, the enteric component comprises one or more of shellac, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, sodium alginate, and zein. In some embodiments, the method further comprises administering a composition for prolonging gastric emptying time, and the substance abuse deterrent pharmaceutical composition is administered before, after, or simultaneously with the composition for prolonging gastric emptying time. In some embodiments, the component for prolonging gastric emptying time is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, amino acids, peptides, proteins, fatty acids, monoglycerides, diglycerides, and triglycerides. In some embodiments, the component for prolonging gastric emptying time is... , selected from the group consisting of loperamide, diphenoxylate, atropine, difenoxin, anticholinergic agents, antidepressants, opioids, antidiarrheal agents, and agents that induce gastric atony. In some embodiments, the composition for extending gastric emptying time is included in a dosage form, and the dosage form is a food bar or a beverage.

[0012]

[0013] In one aspect, the present invention relates to an abuse-deterrent pharmaceutical composition comprising an easily abused drug, an acid-soluble component, a buffering component, and a component for extending gastric emptying time.

[0014] In some embodiments, the acid-soluble component forms a matrix, and a substantial portion of the easily abused drug is contained within the matrix. In some embodiments, the acid-soluble component comprises calcium carbonate, a cationic copolymer, or a combination thereof. In some embodiments, the cationic copolymer comprises one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In some embodiments, the acid-soluble component is present in an amount of about 1 wt% to about 40 wt% of the pharmaceutical composition. In some embodiments, the buffering component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the buffering component is present in an amount of about 45 wt% to about 95 wt%.

[0013]

[0015] In one aspect, the present invention relates to an abuse-deterrent pharmaceutical composition comprising an easily abused drug, an acid-soluble component, a buffering component, and a component for extending gastric emptying time which can be a monosaccharide, disaccharide, oligosaccharide, polysaccharide, amino acid, peptide, protein, fatty acid, monoglyceride, diglyceride, or triglyceride. In one aspect, the present invention relates to an abuse-deterrent pharmaceutical composition comprising an easily abused drug, an acid-soluble component, a buffering component, and a component for extending gastric emptying time which can be loperamide, diphenoxylate, atropine, difenoxin, anticholinergic agents, antidepressants, opioids, antidiarrheal agents, and agents that induce gastric atony.

[0014]

[0016] In one aspect, the present invention relates to an abuse-deterrent pharmaceutical composition comprising a drug prone to abuse, an acid-soluble component, a buffering component, and a component for extending the gastric emptying time, wherein when ingested by a subject, the component for extending the gastric emptying time extends the gastric emptying time of the subject. In one aspect, the present invention relates to an abuse-deterrent pharmaceutical composition comprising a drug prone to abuse, an acid-soluble component, a buffering component, and a component for extending the gastric emptying time, wherein when ingested by a subject, the component for extending the gastric emptying time extends the gastric emptying time of the composition.

[0015]

[0017] In one aspect, the present invention relates to an abuse-deterrent pharmaceutical composition comprising a drug prone to abuse, an acid-soluble component, a buffering component, and a component for extending the gastric emptying time, wherein when the composition is ingested in excess of the intended dose, the acid-soluble component and the buffering component slow the release of the drug.

[0016]

[0018] In one aspect, the present invention relates to a dosage form comprising an abuse-deterrent pharmaceutical composition comprising a drug prone to abuse, an acid-soluble component, a buffering component, and a component for extending the gastric emptying time. In some aspects, the dosage form is a food bar or a beverage.

[0017]

[0019] In one aspect, the present invention relates to a method for treating a disease alleviated by a drug prone to abuse, the method comprising administering to a subject in need thereof an abuse-deterrent pharmaceutical composition comprising a drug prone to abuse, an acid-soluble component, a buffering component, and a component for extending the gastric emptying time.

[0018]

[0020] In one aspect, the present invention relates to a method for treating a disease alleviated by a drug prone to abuse, the method comprising administering to a subject in need thereof a dosage form comprising an abuse-deterrent pharmaceutical composition comprising a drug prone to abuse, an acid-soluble component, a buffering component, and a component for extending the gastric emptying time. In some aspects, the dosage form is a food bar or a beverage. and a component for extending the gastric emptying time. In some aspects, the dosage form is a food bar or a beverage.

[0019]

[0021] In one aspect, the present invention relates to a method for treating a disease alleviated by an easily abused drug, the method comprising administering to a subject in need thereof an abuse deterrent pharmaceutical composition comprising an easily abused drug, an acid-soluble component, and a buffering component, and a composition for extending the gastric emptying time comprising a component for extending the gastric emptying time. In some aspects, the abuse deterrent pharmaceutical composition is administered before the composition for extending the gastric emptying time. In some aspects, the abuse deterrent pharmaceutical composition is administered after the composition for extending the gastric emptying time. In some aspects, the abuse deterrent pharmaceutical composition is administered simultaneously with the composition for extending the gastric emptying time. In some aspects, the component for extending the gastric emptying time is a monosaccharide, disaccharide, oligosaccharide, polysaccharide, amino acid, peptide, protein, fatty acid, monoglyceride, diglyceride, or triglyceride. In some aspects, the component for extending the gastric emptying time is loperamide, diphenoxylate, atropine, diphenoxine, an anticholinergic agent, an antidepressant, an opioid, an antidiarrheal agent, or a drug that induces gastric paresis.

[0020]

[0022] In one aspect, the present invention relates to a method for treating a disease alleviated by an easily abused drug, the method comprising administering to a subject in need thereof a dosage form comprising an abuse deterrent pharmaceutical composition comprising an easily abused drug, an acid-soluble component, and a buffering component, and a composition for extending the gastric emptying time comprising a component for extending the gastric emptying time, the dosage form being a food bar or a beverage.

[0021]

[0023] The present invention will be better understood by considering the following drawings which illustrate certain characteristics of the present invention.

Brief Description of the Drawings

[0022]

Figure 1

[0024] Figure 1 shows a comparison of the Tmax of the formulation according to an aspect of the present invention with that of a control formulation.

Figure 2

[0025] Figure 2 shows a comparison of the Cmax of the formulation according to an aspect of the present invention with that of a control formulation.

Mode for Carrying Out the Invention

[0023]

[0026] The compositions and methods of the present invention relate to self-regulated dosing, particularly self-regulated dosing of drugs that are prone to abuse. The self-regulated dosing of the present invention relies on a number of technical techniques. The dosing is first self-regulated by making adjustments such as raising or lowering the pH of the ambient medium, typically the pH of the subject's gastric contents. The change in pH then controls the release of the active ingredient from the composition contained in the dosing. Thus, when the total amount of dosing exceeds a certain limit, typically the limit at which the drug or active ingredient is prescribed for its normal therapeutic use, the change in pH compared to the normal pH range slows down the release of the active ingredient. This is typically done, for example, by delaying or stopping the disintegration of the matrix element containing the active ingredient by encapsulating or isolating the active ingredient. In some embodiments, the dosing further includes a delayed-release buffer component that extends the effect of delaying or stopping the release of the active ingredient from the matrix when an overdose is ingested. In some embodiments, the dosing is further self-regulated by extending the gastric emptying time to increase the time available for the pH modulation self-regulation mechanism to act and enhance its overall effect. It is self-regulated by increasing the time available for the pH modulation self-regulation mechanism to act and enhance its overall effect.

[0024]

[0027] Self-regulated dosing is designed to limit and extend the absorption of a drug when an inappropriate dose is ingested or when the dosing is abused. The components in the self-regulated tablets include antacids / buffers for changing, for example, raising the pH of the stomach when orally administered. One In some embodiments, drugs that are prone to abuse are incorporated into dosage forms that are intended to dissolve in an acidic gastric medium having a pH of 5 or less when an intended dose, or a typically prescribed dose, e.g., one or two unit doses, is ingested, and to provide immediate release, or an extended release profile, of the active ingredient drug. In contrast, self-regulating dosage forms are intended to neutralize the gastric pH and slow the release of the active ingredient at a pH higher than 5 when more tablets are ingested.

[0025]

[0028] In some embodiments, the formulations of the present invention are designed to block or prevent the effects caused by intentional or unintentional overdose of a drug. Under normal dosage conditions, the formulations of the present invention may enable complete oral delivery of the desired drug dosage. However, when an overdose is intentionally or unintentionally ingested, e.g., a dosage exceeding that typically prescribed for normal therapeutic use, the formulations of the present invention can act to slow or block the release and subsequent absorption of the overdose. Thus, in the case of intentional oral overconsumption where a drug abuser consumes an overdose of an abused drug to experience a "high", that "high" will be significantly reduced in the formulations of the present invention compared to a dosage that freely releases the excess abused drug. In this way, the formulations of the present invention can act as a deterrent to prevent abuse of the formulations of the present invention for the purpose of obtaining a high. Nevertheless, a patient using the present invention as directed or prescribed can enjoy the desired therapeutic effect or treatment.

[0026]

[0029] Generally, and as described in more detail herein, the pharmaceutical formulations of the present invention can be designed using one or more mechanisms to control the release and / or absorption of the pharmaceutical active ingredient. In some embodiments, the pharmaceutical formulations can be designed to have pH modulating properties and / or pH-dependent dissolution properties. The pH modulating properties can affect the release and / or absorption of the active ingredient by adjusting the pH of the gastric environment based on whether the pharmaceutical composition has been ingested in an appropriate dosage or has been over-ingested. The pH modulating properties can be provided by including one or more buffering components and / or antacid components in the pharmaceutical composition. The pH modulating properties can be provided by including buffering components (e.g., immediate release buffering components and delayed release buffering components). The pH-dependent dissolution properties can affect the release and / or absorption of the active ingredient by suppressing or releasing the pharmaceutical active ingredient in response to the pH of the gastric environment. The pH-dependent dissolution properties can be provided by including one or more acid-soluble components in the pharmaceutical composition. Pharmaceutical compositions containing acid-soluble components are described in U.S. Pat. Nos. 9,662,393, 9,320,796, and 9,101,636, and U.S. Patent Application Publication No. 20170056501, all of which are incorporated herein by reference in their entireties.

[0027]

[0030] In some embodiments, the compositions and methods of the present invention synergistically incorporate additional self-regulatory mechanisms including extending the gastric emptying time in a subject that has ingested the compositions disclosed herein.

[0028]

[0031] Without wishing to be bound by any particular theory, certain aspects of the present invention rely, in part, on the observation that in vivo administration of one or more doses of a self-regulatory composition lacking a gastric emptying time extension mechanism results in a non-linear response with respect to the observed C max of the corresponding active ingredient. For example, as described in Example 1, the C maxThe in vivo decline was approximately the same as that of three tablets. Despite the fact that eight tablets corresponded to a gastric environment buffering capacity 2.7 times greater than that of three tablets, this was the case. Thus, a sufficient buffering level can be provided by a certain number of tablets, but the effect and duration of the self-regulating buffering level in vivo can be synergistically affected by additional mechanisms such as gastric content evacuation time. If the buffering agent on which the first self-regulating mechanism relies has a relatively short duration in the stomach, for example, about 25 minutes, then in some cases, the buffering agent may be excreted from the stomach before it can further neutralize newly generated gastric acid. Therefore, the sufficient buffering effect of a large number of tablets may not be achieved in some cases, and the gastric juice returns to an acidic pH within the same time as that of a small number of tablets. In some embodiments, it has been shown that using an acid neutralization model and prolonging the gastric content evacuation time can achieve an extended high gastric pH (>5). In some embodiments, a delayed release buffering composition model is used to extend the high gastric pH (>5). In the present invention, a method and composition for prolonging the gastric content evacuation time are described to promote better performance for reducing the peak plasma drug concentration (C max ) in the case of multiple tablet administrations with self-regulating dosing.

[0029] Definition

[0032] As used herein, the term "C max " refers to the maximum (or peak) serum concentration achieved by a drug in a specific compartment or test area of the body after administration of the drug and before administration of a second dose. As used herein, the term "T max " refers to the time at which C max is observed.

[0030]

[0033] As used herein, the term "bioequivalence" is understood to mean one or more of the 90% confidence interval (log-transformed) of C max or the area under the drug concentration curve "AUC" being within 80% to 125% of the same marker of the reference drug.

[0031]

[0034] As used herein, a compound or drug having a "narrow therapeutic index" (NTI) means a compound or drug that falls within any definition of narrow therapeutic index promulgated by the U.S. Food and Drug Administration, or any successor agency thereof. For example, a substance in which the difference between the 50% toxic dose (TD50) and the 50% effective dose (ED50) values is less than 2-fold, or the difference between the minimum toxic concentration and the minimum effective concentration in the blood is less than 2-fold.

[0032]

[0035] As used herein, when ranges are used, for example, to describe a concentration or amount, all combinations and sub-combinations of the range and specific embodiments included therein are also to be considered as being included in the range. When referring to a number or numerical range, the use of the term "about" means that the number or numerical range can vary because the recited number or numerical range is an approximation within the range of experimental variation or within the range of statistical experimental error. The variation is typically 0% to 5%, 0% to 10%, 0% to 15%, etc. of the recited number or numerical range. For example, "about 45%" is understood to include 40.5% to 49.5%.

[0033]

[0036] The terms "comprising" and related terms such as "comprise", "comprises", "having" or "including" include, for example, the recited features "consisting of" or "consisting essentially of" in any embodiment, such as an embodiment of any composition, method or process.

[0034]

[0037] The term "gastric emptying time" means the time required to empty or move the ingested substance from the stomach. The time is measured from when the substance is swallowed until it moves into the small intestine. Similarly, the term "gastric residence time" means the time that the substance remains in the stomach from when it is ingested until it moves into the small intestine.

[0035] Abuse-deterrent pharmaceutical composition

[0038] In one aspect, the present invention relates to a drug abuse deterrent pharmaceutical composition comprising a drug that is easily abused, a first acid-soluble component, a first buffering component, and a delayed-release buffering component.

[0036]

[0039] In one aspect, the present invention relates to a drug abuse deterrent pharmaceutical composition comprising a drug that is easily abused, an acid-soluble component, a buffering component, and a component for extending the gastric content excretion time.

[0040] In one aspect, the present invention relates to a drug abuse deterrent pharmaceutical composition comprising a drug that is easily abused, an acid-soluble component, a buffering component, and a component for reducing gastric acid production.

[0037]

[0041] In one aspect, the present invention relates to a drug that is easily abused, a first acid-soluble component, a first buffering component, a component for reducing gastric acid production, and a delayed-release buffering component. The present invention relates to a drug abuse deterrent pharmaceutical composition.

[0038]

[0042] In one aspect, the present invention relates to a drug abuse deterrent pharmaceutical composition comprising a drug that is easily abused, a first acid-soluble component, a first buffering component, a component for extending the gastric content excretion time, and a delayed-release buffering component.

[0039]

[0043] In one aspect, the present invention relates to a drug abuse deterrent pharmaceutical composition comprising a drug that is easily abused, a first acid-soluble component, a first buffering component, a component for reducing gastric acid production, and a component for extending the gastric content excretion time.

[0040]

[0044] In one aspect, the present invention relates to a pharmaceutical composition comprising a drug (such as a drug that is easily abused) and one or more of a) a first acid-soluble component, b) a first buffering component, c) a component for extending the gastric content excretion time, d) a component for reducing gastric acid production, and e) a delayed-release buffering component.

[0041] Active pharmaceutical ingredient

[0045] Any drug, pharmaceutically acceptable salt, drug derivative, drug analog, drug homolog, prodrug, or polymorph can be used in the present invention. Suitable drugs for use in the present invention can be found in the Physician’s Desk Reference, 59th Edition, the contents of which are incorporated herein by reference. In one aspect, the drug is an orally administered drug. In some aspects, the pharmaceutical composition according to the present invention may comprise a mixture, coated particles, or granules of one or more drugs, pharmaceutically acceptable salts, drug derivatives, drug analogs, drug homologs, or polymorphs.

[0042]

[0046] In certain aspects, drugs that are prone to abuse are used. Commonly abused drugs are psychotropic drugs and analgesics, for example, but not limited to, opioids, cannabis, stimulants, psychotropics, sedatives, anti-anxiety drugs, anesthetics, and drugs that can cause mental and / or physical dependence. In one aspect, the drugs for use in the present invention can be amphetamines, amphetamine-like compounds, benzodiazepines, and methylphenidate or combinations thereof. In another aspect, the present invention may comprise any of the degradation isomers of the drugs described herein, and / or salts thereof.

[0043]

[0047] The drugs for use in the present invention can be drugs having a narrow therapeutic range. After administration, if a drug having a narrow therapeutic range is too low in the bloodstream, it may only result in insufficient therapeutic activity, while if the dose of a drug with a narrow therapeutic range is too high, it may result in excessive therapeutic activity or toxicity, both of which can be harmful. As a result, the use of drugs with a narrow therapeutic range is carefully monitored and their potential for abuse must be deterred.

[0044]

[0048] The drug for use in the present invention can be a drug that is prone to abuse. The drug that may be prone to abuse for use in the present invention can be one or more of the following. That is, alfentanil, amphetamines, buprenorphine, butorphanol, carfentanil, codeine, dezocine, diacetylmorphine, dihydrocodeine, dihydromorphine, diphenoxylate, diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone, β-hydroxy-3-methylfentanyl, levo-α-acetylmethadol, levorphanol, lofentanil, meperidine, methadone, methylphenidate, morphine, nalbuphine, nalmefene, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil, sufentanil, tilidine, and tramadol, their salts, derivatives, analogs, homologs, polymorphs, and mixtures of any of the foregoing. codeine, dezocine, diacetylmorphine, dihydro codeine, dihydromorphine, diphenoxylate diphenoxylate, diprenorphine, etorphine, f entanyl, hydrocodone, hydromorphone, β-hydroxy-3-methylfentanyl, levo-α -acetylmethadol, levorphanol, l ofentanil, meperidine, methadone, methylf enidate, morphine, nalbuphine, nal mefene, oxycodone, oxymorphone, p entazocine, pethidine, propoxyphene, remifentanil, sufentanil, tilidine, and tramadol, their salts, derivatives, analogs, homologs, polymorphs, and mixtures of any of the foregoing.

[0045]

[0049] In another aspect, the drug that is likely to be misused for use in the present invention includes one or more of the following. That is, dextromethorphan (3-methoxy-17-methyl-9a,13a,14a-morphinan hydrobromide monohydrate), N-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)-ethyl]-4-methoxymethyl-4-piperidyl} propionanilide (alfentanil), 5,5-diallylbarbituric acid (allobarbital), allylprodine, alpha-prodine, 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine (alprazolam), 2-diethylaminopropiophenone (amfepramone), (±)-α-methylphenethylamine (amphetamine), 2-( α-Methylphenethyl-amino)-2-phenylacetonitrile (amphetamine), 5-ethyl-5-isopentylbarbituric acid (amobarbital), anileridine, apocodeine, 5,5-diethylbarbituric acid (barbital), benzylmorphine, bezitramide, 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepin-2(3H)-one (bromazepam), 2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine (prothipendyl), 17-cyclopropylmethyl-4,5α-epoxy-7α[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol (buprenorphine), 5-butyl-5-ethylbarbituric acid (butabarbital), butorphanol, (7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)-dimethylcarbamate (carbamazepam), (1S,2S)-2-amino-1-phenyl-1-propanol (cathine / D-norpseudoephedrine), 7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-ylamine-4 oxide (chlordiazepoxide), 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (clobazam), 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepin-2(3H)-one (clonazepam), clonitazene, 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid (clorazepate) , 5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-one (chlotiazepate), 10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one (cloxazolam), (-)-methyl-[3β-benzoyloxy-2β(1αH,5αH)-tropane carboxylate (cocaine), 4,5α-epoxy-3-methoxy-17-methyl-7-morphinen-6α-ol (codeine), 5-(1-cyclohexenyl)-5-ethylbarbituric acid (cyclobarbital), cyclophosphane, cyclorphan, 7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2(3H)-one (diazepam), desomorphine, dextromoramide, (+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl) propionate (dextropropoxyphene), desocine, diampromide, diamorphine, 7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (diazepam), 4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol (dihydrocodeine), 4,5α-epoxy-17-methyl-3,6a-morphinane-diol (dihydromorphine), Dimenoxadol, Dimepheptanol [sic - Tr.Ed.], Dimethylthiambutene, Dioxyfedyl butyrate, Dipipanone, (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (Dronabinol), Eptazocine, 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (Estazolam), Ethoheptazine, Ethylmethylthiambutene, Ethyl - [7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate] (Ethyl loflazepate), 4,5α-epoxy-3-ethoxy-17-methyl-7-morphinen-6α-ol (Ethylmorphine), Etonitrazene, 4,5α-epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol (Etorphine), N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine (Phencyclamine), 7-[2-(α-methylphenethylamino)-ethyl]theophylline (Phenethylamine), 3-(α-methylphenethylamino)propionitrile (Phenproporex), N-(1-phenethyl-4-piperidyl)propionanilide (Fentanyl), 7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepine-2(3H)-one (Fludiazepam), 5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepine-2-(3H)-one (Flunitrazepam), 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2(3H)-one (Flurazepam), 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepine-2(3H)-one (Halazepam), 10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolo[3,2-d][1,4]benzodiazepine-6(5H)-one (Haloxazolam), Heroin, 4,5α-Epoxy-3-methoxy-17-methyl-6-morphinanone (hydrocodone), 4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanone (hydromorphone), hydroxypethidine, isomethadone, hydroxymethylmorphinan, 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2-d][1,4]benzodiazepin-4,7(6H)-dione (ketazolam), 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone (ketobemidone), (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate (levacetylmethadol (LAAM)), (-)-6-dimethylamino-4,4-diphenyl-3-heptanone (levomethadone), (-)-17-methyl-3-morphanol (levorphanol), levophenacylmorphan, lofentanyl, 6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2a][1,4]benzodiazepin-1(4H)-one (loprazolam), 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepin-2(3H)-one (lorazepam), 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepin-2(3H)-one (lorazepam), 5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol (mazindol), 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine (medazepam), N-(3-chloropropyl)-α-methylphenethylamine (mephenorex), meperidine, 2-methyl-2-propyltrimethylenedicarbamate (meprobamate), meptazinol, metazosin, methylmorphine, N,α-dimethylphenethylamine (methamphetamine), (±)-6-dimethylamino-4,4-Diphenyl-3-heptanone (methadone), 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone), methyl-[2-phenyl-2-(2-piperidyl)acetate] (methylphenidate), 5-ethyl-1-methyl-5-phenylbarbituric acid (methylphenobarbital), 3,3-diethyl, -5-methyl-2,4-piperidinedione (methiprylon), metopon, 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam), 2-(benzhydrylsulfinyl)acetamide (modafinil), 4,5α-epoxy-17-methyl-7-morphinen-3,6α-diol (morphine), myrophine, (±)-trans-3-(1,1-dimethyl heptyl)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9(6αH)-one (naloxone), nalbuphine, nalorphine, narceine, nicomorphine, 1-methyl-7-nitro-5 -phenyl-1H-1,4-benzodiazepin-2(3H)-one (nitrazepam), 7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nitrazepam), 7-chloro-5-phenyl-1H-1,4-benzodiazepin-2-(3H)-one (nordazepam), norlevorphanol, 6-dimethylamino-4,4-diphenyl-3-hexanone (normethadone), normorphine, norpipanone, keshi species The coagulated juice of plants belonging to Papaver somniferum (opium), 7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2-(3H)-one (oxazepam), (cis-trans)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(5H)-one (oxazolam), 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone (oxycodone), oxymorphone, plants and parts of plants belonging to the genus Papaver (including the subspecies Papaver setigerum), papaveretum , 2-imino-5-phenyl-4-oxazolidinone (pernolide), 1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol (pentazocine), 5-ethyl-5-(1-methylbutyl)barbituric acid (pentobarbital), ethyl-(1-methyl-4-phenyl-4-piperidine-carboxylate) (pethidine), phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, pholcodeine, 3-Methyl-2-phenylmorpholine (phenmetrazine), 5-Ethyl-5-phenylbarbituric acid (phenobarbital), α,α-Dimethylphenethylamine (phentermine), 7-Chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepin-2(3H)-one (pinazepam), α-(2-Piperidyl)benzhydryl alcohol (pipradol), 1’-(3-Cyano-3,3-diphenylpropyl)[1,4’-bipiperidine]-4’-carboxamide (piritramide), 7-Chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (prazepam), profadol, proheptazine, promedol, properidine, propoxyphene, N-(1-Methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, Methyl-{3-[4-Methoxycarbonyl-4-(N-phenylpropanamide)piperidino]propanoate} (remifentanil), 5-sec.-Butyl-5-ethylbarbituric acid (secbutabarbital), 5-Allyl-5-(1-methylbutyl)barbituric acid (secobarbital), N-{4-Methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide (sufentanil), 7-Chloro-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepin-2-(3H)-one (temazepam), 7-Chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one (tetrazepam), Ethyl-(2-dimethylamino-1-phenyl-3-cyclohexane-1-carboxylate) (tilidine (cis and trans)), tramadol, 8-Chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (triazolam), 5-(1-Methylbutyl)-5-vinylbarbituric acid (vinylbarbital), (1R * ,2R * )-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)phenol, (1R,2R,4S)-2-[(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl (a) cyclohexanol, in the form of the corresponding stereoisomeric compounds, respectively, optionally, and corresponding derivatives, in particular esters or ethers, and both physiologically compatible compounds, in particular salts and solvates.

[0046]

[0050] In one aspect, the pharmaceutical composition of the present invention contains, as a therapeutically active ingredient, one or more opioids such as hydrocodone, morphine, oxycodone, hydromorphone and / or their salts.

[0047]

[0051] Typically, when processed into a suitable dosage form as described in more detail below, the drug can be present in such a dosage form in an amount that is usually formulated, typically about 0.5 to about 25 percent by dry weight based on the total weight of the formulation. In some aspects, such amounts can typically be about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.5 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg. More typically, the drug can be present in an amount of about 1 mg to about 10 mg, about 2 mg to about 25 mg, about 5 mg to about 75 mg, about 10 mg to about 200 mg, about 125 mg to about 250 mg, or about 250 mg to about 500 mg. In other aspects, the dosage form contains an appropriate amount of the drug to provide a therapeutic effect.

[0048]

[0052] In some embodiments, the composition of the present invention contains a drug or active ingredient in an amount, by weight, of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9%.

[0049] Component soluble in acidic solution

[0053] In some embodiments, the pharmaceutical composition of the present invention contains one or more components that are soluble in an acidic solution. The acidic solution can be considered a solution having a pH less than 7, such as about 1 to about 4, about 2 to about 5, or 5 or less. In some embodiments, the acid-soluble component is poorly soluble in weakly acidic, neutral, and / or basic solutions. In some embodiments, the acid-soluble component is poorly soluble in a solution having a pH higher than about 4 or 5.

[0050]

[0054] In some embodiments, the acid-soluble component is included in the pharmaceutical composition in the form of a particulate matrix having a pharmaceutical active ingredient. The acid-soluble component can be included in the pharmaceutical composition in an amount sufficient to form this matrix. In some embodiments, the active ingredient is sequestered within the acid-soluble component. The acid-soluble component can affect the release of the pharmaceutical active ingredient depending on the pH of the environment. This environmental pH is increased or maintained by a buffering component and / or an antacid component depending on the amount of the administered pharmaceutical composition. When the pharmaceutical composition is administered in an appropriate dosage the pH buffering component is not present in a large enough amount to affect the gastrointestinal pH, so the acid-soluble component dissolves and releases the pharmaceutical active ingredient. When the pharmaceutical composition is administered in an excessive amount, the pH buffering component is present in an amount that raises the gastrointestinal pH, thereby preventing the dissolution of the acid-soluble component and the release of the pharmaceutical active ingredient.

[0051]

[0055] In some embodiments, the acid-soluble component forms a matrix and a substantial portion of the drug that is prone to abuse is contained within the matrix. In some embodiments, the acid-soluble component includes calcium carbonate, a cationic copolymer, or a combination thereof. In some embodiments, the cationic copolymer includes one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

[0052]

[0056] In some embodiments, the acid-soluble component is present in an amount of about 1 wt% to about 40 wt%, about 5 wt% to about 50 wt%, about 7.5 wt% to about 65 wt%, about 10 wt% to about 75 wt%, or about 25 wt% to about 95 wt% of the pharmaceutical composition.

[0053]

[0057] In some embodiments, the acid-soluble component is present in the pharmaceutical composition in an amount of about 1 wt% to about 50 wt%, about 1 wt% to about 48 wt%, about 1 wt% to about 46 wt%, about 1 wt% to about 44 wt%, about 1 wt% to about 42 wt%, about 1 wt% to about 40 wt%, about 2 wt% to about 38 wt%, about 4 wt% to about 36 wt%, about 6 wt% to about 34 wt%, about 8 wt% to about 32 wt%, about 10 wt% to about 30 wt%, about 12 wt% to about 28 wt%, about 14 wt% to about 26 wt%, about 16 wt% to about 24 wt%, about 18 wt% to about 22 wt%, about 1 wt%, about 2 wt%, about 4 wt%, about 6 wt%, about 8 wt%, about 10 wt%, about 12 wt%, about 14 wt%, about 16 wt%, about 18 wt%, about 20 wt%, about 22 wt%, about 24 wt%, about 26 wt%, about 28 wt%, about 30 wt%, about 32 wt%, about 34 wt%, about 36 wt%, about 38 wt%, about 40 wt%, about 42 wt%, about 44 wt%, about 46 wt%, about 48 wt%, or about 50 wt%.

[0054]

[0058] In some embodiments, the composition of the present invention comprises the acid-soluble component in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9%.

[0055]

[0059] Examples of suitable acid-soluble components include polymers and copolymers such as calcium carbonate, chitosan, polymethacrylate, for example, Eudragit® (a cationic polymer having dimethylaminoethyl methacrylate as a functional group), and the like.

[0056] Buffer component and / or antacid component

[0060] In some embodiments, the pharmaceutical composition of the present invention comprises one or more buffering components and / or antacid components. Such components can increase the gastric pH when the pharmaceutical composition is consumed in an inappropriate amount and / or in an amount greater than the amount typically prescribed for normal therapeutic use. In some embodiments, such components can rapidly and continuously increase the gastric pH to a pH higher than about 4 when the pharmaceutical composition is consumed in an inappropriate amount and / or in an amount greater than the amount typically prescribed for normal therapeutic use.

[0057]

[0061] Examples of suitable buffering components (e.g., a first buffering component, a second buffering component, or both the first and second buffering components) and / or antacid components include, but are not limited to, aluminum hydroxide, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, calcium carbonate, calcium phosphate, dibasic calcium phosphate, aluminum dihydroxyaminoacetate, sodium aluminum carbonate dihydroxide, glycine, magnesium glycinate, magnesium hydroxide, magnesium oxide, potassium bicarbonate, sodium bicarbonate, potassium sodium tartrate, trisodium phosphate, and tricalcium phosphate, and the like.

[0058]

[0062] In some embodiments, the buffering component (e.g., the first buffering component, the second buffering component, or both the first and second buffering components) comprises calcium carbonate, sodium bicarbonate, magnesium oxide, trisodium phosphate, or combinations thereof. In some embodiments, the buffering component is present in an amount of about 25 wt% to about 65 wt%, about 35 wt% to about 75 wt%, about 45 wt% to about 95 wt%, about 50 wt% to about 90 wt%, or about 55 wt% to about 75 wt% of the pharmaceutical composition.

[0059]

[0063] In some embodiments, the buffering component (e.g., the first buffering component, the second buffering component, or both the first and second buffering components) and / or the antacid component are included in an amount such that the pH of the stomach is not affected when the pharmaceutical composition is taken in a proper therapeutic amount, but the pH of the stomach is increased when the pharmaceutical composition is taken in an excessive amount, e.g., an amount greater than the amount typically prescribed for normal therapeutic use. In some embodiments, a proper therapeutic amount refers to 1 or 2 tablets or doses, while an excessive amount refers to 3 or more tablets or doses. In some embodiments, the buffering component and / or the antacid component are included in the pharmaceutical composition in an amount of about 45 wt% to about 95 wt%, about 50 wt% to about 90 wt%, about 55 wt% to about 85 wt%, about 60 wt% to about 80 wt%, about 65 wt% to about 75 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, or about 95 wt% of the pharmaceutical composition.

[0060]

[0064] In some embodiments, the composition of the present invention comprises a buffering component (e.g., a first buffering component, a second buffering component, or each of the first and second buffering components) and / or an antacid component in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9% by weight of the pharmaceutical composition.

[0061]

[0065] In some embodiments, one component can act as both an acid-soluble component and a buffering component (e.g., a first buffering component, a second buffering component, or both the first and second buffering components) and / or an antacid component. Examples of such suitable components include calcium carbonate, dibasic and tribasic calcium phosphate, and magnesium hydroxide.

[0062]

[0066] In some embodiments, the pharmaceutical composition of the present invention further comprises a delayed-release buffering component. In some embodiments, the delayed-release buffering component comprises a second buffering component. In some embodiments, the second buffering component has the same chemical composition as the first buffering component, while in other embodiments, the second buffering component has a chemical composition different from that of the first buffering component. The delayed-release buffering component can be designed to provide a back-up reservoir of buffering components that are not easily released by the stomach. In some embodiments, the delayed-release buffering component is different from the first buffering component (immediate-release buffering component) and is insoluble in the gastric environment after ingestion of the intended dose (i.e., 1 or 2 tablets). For example, in some embodiments, the delayed-release buffering component can be designed to act in any one or more of the following ways: that is, maintain a solid form, shape, and / or particle size for a certain period of time after administration so as not to be easily released by the stomach, like a micronized or solubilized immediate-release buffering agent; or remain intact in an acidic environment such as the stomach after ingestion of the intended dose (i.e., 1 or 2 tablets), and be released in a neutral gastric environment such as the stomach after ingestion of an excessive dose (i.e., 3 or more tablets).

[0063]

[0067] In some embodiments, the delayed-release buffering component is in solid form. In some embodiments, the delayed-release buffering component remains solid in a neutral gastric environment (e.g., pH less than 5) for at least 1 minute, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, or at least 120 minutes.

[0064]

[0068] In some embodiments, the delayed-release buffering component has an average particle size of 250 μm or more, about 250 μm to about 1.2 mm, or about 400 μm. In some embodiments, the second buffering component (e.g., the delayed buffering component) maintains its average particle size of at least 250 μm, about 250 μm to about 1.2 mm, or about 400 μm in a neutral gastric environment (e.g., >pH5).

[0065]

[0069] In some embodiments, the delayed-release buffering component is insoluble at a pH of 5 or less, 4.5 or less, 4 or less, from about 1 to about 5, from about 1 to about 4.5, from about 1 to about 4, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or about 5. In some embodiments, the delayed-release buffering component is soluble at a pH of 5 or greater, 5.5 or greater, 6 or greater, from about 5 to about 14, from about 5 to about 12, from about 6 to about 12, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, or about 14.

[0066]

[0070] In some embodiments, the delayed-release buffering component includes an enteric agent. The enteric agent is soluble at a pH of 5 or greater, 5.5 or greater, 6 or greater, from about 5 to about 14, from about 5 to about 12, from about 6 to about 12, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, or about 14. Examples of suitable enteric agents include, but are not limited to, one or more of shellac, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, sodium alginate, shellac, and zein.

[0067]

[0071] In some embodiments, the delayed-release buffering component includes a core and a shell surrounding or substantially surrounding the core. In some embodiments, the shell includes an enteric agent of the delayed-release buffering component. In some embodiments, the core includes a second buffering component of the delayed-release buffering component.

[0068]

[0072] In some embodiments, the delayed-release buffer component further comprises a subcoating. The subcoating can provide sustained release to materials within the core, such as a second buffer component within the core. Suitable materials for the subcoating include, but are not limited to, copovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone, and mixtures thereof. In some embodiments, the subcoating is used to separate the enteric solvent from the second buffer component. In certain embodiments comprising a shell containing an enteric solvent and a core containing a second buffer component, the subcoating can separate the shell and the core.

[0069]

[0073] In some embodiments, the second buffer component comprises a plurality of particles. In other embodiments, the second buffer component comprises a plurality of granules. In still other embodiments, the second buffer component comprises a tablet.

[0070]

[0074] In some embodiments, the acid-soluble component (e.g., the second acid-soluble component) is dispersed in, coated with, surrounding, or substantially coating or substantially surrounding the second buffering component. In some embodiments comprising a core containing the second buffering component, the core may further contain an acid-soluble component (e.g., the second acid-soluble component). Such an acid-soluble component (e.g., the second acid-soluble component) can delay the complete release of the second buffering component in the same manner as the first acid-soluble component delays the release of the pharmaceutical active ingredient. For example, the acid-soluble component (e.g., the second acid-soluble component) can delay the release of the second buffering component until the first buffering component passes through the gastric environment and / or until gastric acid secretion lowers the pH back to acidic conditions, such as less than about 5, less than about 4.5, less than about 4, etc. In some embodiments, the acid-soluble component (e.g., the second acid-soluble component) is a neutral or acid-soluble polymer. Suitable neutral or acid-soluble polymers include, but are not limited to, methacrylate copolymers such as aminomethacrylate copolymers (Eudragit RS and RL), butyl methacrylate, methyl methacrylate, dimethylaminoethyl methacrylate copolymer (Eudragit E), ethyl cellulose, and ethyl acrylate-methyl methacrylate copolymer (Eudragit NE).

[0071] Component for prolonging gastric content evacuation time

[0075] In some embodiments, it has been found that associating an extended gastric emptying time (i.e., extending the time the dosage form components remain in the stomach before moving to the small intestine) with an abuse deterrent dosage form synergistically improves the abuse deterrent properties of the dosage form.

[0072]

[0076] Generally, any component suitable for prolonging gastric emptying time can be used in the compositions and methods of the present invention. In some embodiments, the component for prolonging gastric emptying time can be a monosaccharide, disaccharide, oligosaccharide, polysaccharide, amino acid, peptide, protein, fatty acid, monoglyceride, diglyceride, or triglyceride. Generally, most foods, including polysaccharides such as starch, fats such as plant or animal fats, and proteins such as plant or animal proteins, are suitable as components for prolonging gastric emptying time.

[0073]

[0077] The component useful for prolonging gastric emptying time may be any drug or active ingredient known to act as a gastric emptying time extender. In some embodiments, the component for prolonging gastric emptying time can be loperamide, diphenoxylate, atropine, diphenoxine, anticholinergic agents, antidepressants, opioids, antidiarrheal agents, and / or agents that induce gastric hypomotility.

[0074]

[0078] In some embodiments, the component useful for prolonging gastric emptying time can be a substance that delays the onset of the housekeeping wave (strong and frequent contractions) of the interdigestive myoelectric motor cycle (IMMC). Examples of drugs that delay the onset of the housekeeping wave and are preferably locally delivered from the dosage form in an amount that causes no substantial systemic effect on the subject are, for example, anticholinergic agents such as propantheline, and, without limitation, other drugs such as methylcellulose, guar gum, triglyceride esters, fats such as triethanol myristate, and fatty acids having 10 to 15 carbon atoms. without causing, preferably, any substantial systemic effect on the subject and are locally delivered from the dosage form in an amount that delays the onset of the housekeeping wave are, for example, anticholinergic agents such as propantheline, and, without limitation, other drugs such as methylcellulose, guar gum, triglyceride esters, fats such as triethanol myristate, and fatty acids having 10 to 15 carbon atoms.

[0075]

[0079] In some embodiments, the present invention reduces C max and / or C maxIt contains an amount of gastric content discharge time extension component sufficient to delay the start by 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes. In one aspect, this occurs when three or more dosage forms are consumed simultaneously or almost simultaneously.

[0076]

[0080] In some aspects, the composition of the present invention contains, by weight percentage of the composition or the final dosage form, about 1% to about 15%, about 2.5% to about 25%, about 5% to about 35%, about 7.5% to about 45%, about 10% to about 50%, about 12.5% to about 60%, about 15% to about 65%, about 17.5% to about 70%, about 20% to about 75%, about 22.5% to about 80%, about 25% to about 90%, about 35% to about 95%, about 50% to about 99%, or about 75% to about 99.9% of the gastric content discharge time extension component.

[0077]

[0081] In some aspects, the composition of the present invention contains, by weight percentage amount of the composition or the final dosage form, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9% of the gastric content discharge time extension component.

[0078] Component for reducing gastric acid production

[0082] Generally, any component suitable for reducing gastric acid production can be used in the compositions and methods of the present invention. In some embodiments, the component for reducing gastric acid production can be a histamine 2 receptor (H2) antagonist. In some embodiments, the H2 antagonist can be one or more of nizatidine, famotidine, ranitidine, and cimetidine. In some embodiments, the component for reducing gastric acid production can be a proton pump inhibitor. In some embodiments, the proton pump inhibitor can be one or more of ilaprazole, rabeprazole, pantoprazole, esomeprazole, dexlansoprazole, lansoprazole, and omeprazole.

[0079]

[0083] In some embodiments, the pharmaceutical composition of the present invention comprises one or more components that reduce gastric acid production (i.e., gastric acid secretion inhibitors). In some embodiments, including a gastric acid production reducing component synergistically improves the abuse deterrent properties of the dosage form. In some embodiments, the gastric acid production reducing component is present in an amount below the therapeutic amount when taken at the intended dosage (e.g., 1 or 2 tablets), but is present in a therapeutic amount when taken in an amount greater than the intended dosage (e.g., 3 or more tablets, e.g., 4, 5, 6, 7, or 8 tablets). The therapeutic dosage of the gastric acid secretion inhibitor provided when the pharmaceutical composition of some embodiments of the present invention is taken in an amount greater than the intended dosage can delay the time to gastric re-acidification.

[0080]

[0084] In some embodiments, the component that reduces gastric acid production is within a core that is surrounded or substantially surrounded by a shell. In some embodiments, the shell contains an enteric solvent. The enteric solvent can be a material that is soluble at a pH of 5 or greater, 5.5 or greater, 6 or greater, about 5 to about 14, about 5 to about 12, about 6 to about 12, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, about 13.5, or about 14. Examples of suitable enteric solvents include, but are not limited to, one or more of shellac, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, sodium alginate, shellac, and zein.

[0081]

[0085] In some embodiments, by including one or more components that reduce gastric acid production, acid reduction is caused at about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, or about 45 minutes after administration.

[0082]

[0086] In some embodiments, the composition of the present invention contains from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% to about 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 1% to about 15%, from about 2.5% to about 25%, from about 5% to about 35%, from about 7.5% to about 45%, from about 10% to about 50%, from about 12.5% to about 60%, from about 15% to about 65%, from about 17.5% to about 70%, from about 20% to about 75%, from about 22.5% to about 80%, from about 25% to about 90%, from about 35% to about 95%, from about 50% to about 99%, or from about 75% to about 99.9% of a gastric acid production reducing component, by weight percent of the composition or final dosage form.

[0083]

[0087] In some embodiments, the composition of the present invention comprises, in weight percent amounts of the composition or the final dosage form, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9% of an anti-gastric acid component.

[0084] Additional component

[0088] The present invention optionally further comprises other components for enhancing the manufacture of the pharmaceutical composition of the present invention into a dosage form and / or for modifying the release profile of the dosage form comprising the pharmaceutical composition of the present invention and can also include.

[0085]

[0089] Some aspects of the present invention include one or more pharmaceutically acceptable fillers / diluents. In one aspect, Avicel PH (microcrystalline cellulose) is the filler used in the formulation. Avicel PH can have an average particle size in the range of 20 to about 200 μm, preferably about 100 μm. The density ranges from 1.512 to 1.668 g / cm 3 ³. Avicel PH should have a molecular weight of about 36,000. The effectiveness of Avicel PH is optimal when present in an amount of about 10 to 65 percent based on the solid-based weight of the formulation. A typical filler can be present in an amount of 10 to 65 weight percent based on the dry weight of the total composition. Other components can be sugars and / or polyols, etc. Lactose having a particle size of about 20 to about 400 microns and a density of about 0.3 to about 0.9 g / ml can also be included.

[0086]

[0090] In some aspects of the present invention, the filler not only imparts cohesiveness to the materials within the formulation but also functions as a binder in that it can increase the bulk weight of the direct compression (tableting) formulation (described below) to achieve an acceptable formulation weight for the direct compression method. In some aspects, an additional filler need not provide the same level of cohesiveness as the selected binder, but can contribute to the uniformity of the formulation and also make the blended formulation less likely to separate. Further, a suitable filler does not adversely affect the flowability of the composition or the dissolution profile of the formed tablets.

[0087]

[0091] In one aspect, the present invention can include one or more pharmaceutically acceptable disintegrants. Such disintegrants are known to those skilled in the art. In the present invention, the disintegrants include, but are not limited to, sodium starch glycolate (Explotab®) having a particle size of about 104 microns and a density of about 0.756 g / ml, starch (e.g., Starch 21) having a particle size of about 2 - 32 microns and a density of about 0.462 g / ml, Crospovidone® having a particle size of about 400 microns and a density of about 1.22 g / ml, and croscarmellose sodium (Ac-Di-Sol) having a particle size of about 37 - about 73.7 microns and a density of about 0.529 g / ml. The selected disintegrant should contribute to the compressibility, flowability, and uniformity of the formulation. Further, the disintegrant can minimize separation and provide an immediate release profile to the formulation. In some aspects, the disintegrant is present in an amount of about 2 - about 25 weight percent based on the solids of the direct compressible formulation. Additionally, antacids added to the formulation can also assist in tablet disintegration through the foaming of the antacid component when the tablet is introduced into a low pH environment, thus likely reducing the need for additional disintegrants.

[0088]

[0092] In one aspect, the present invention can include one or more pharmaceutically acceptable glidants, such as, but not limited to, colloidal silicon dioxide. In one aspect, colloidal silicon dioxide (Cab-O-Sil®) having a density of about 0.029 - about 0.040 g / ml can be used to improve the flow characteristics of the formulation. Such glidants can be supplied in an amount of about 0.1 - about 1 weight percent of the formulation on a solid basis. However, based on the present invention, while colloidal silicon dioxide is one particular glidant, it will be understood that other known or developing glidants having similar properties can be used if they are compatible with other excipients and active ingredients in the formulation and do not significantly affect the flowability, uniformity, and compressibility of the formulation.

[0089]

[0093] In one aspect, the present invention can include one or more pharmaceutically acceptable lubricants, such as, but not limited to, magnesium stearate. In one aspect, the lubricant, such as magnesium stearate, has a particle size of about 450 to about 550 microns and a density of about 1.00 to about 1.80 g / ml. In one aspect, the lubricant, such as stear Magnesium phosphate can contribute to reducing the friction between the die wall and the pharmaceutical composition of the present invention during compression (tableting), making it easier to remove the tablets, and thus promoting processing. In some aspects, the lubricant makes it difficult to adhere to the punches and dies and / or also aids in the flow of the powder into the hopper and / or die. In an aspect of the present invention, a lubricant, such as magnesium stearate, having a particle size of about 5 to about 50 microns and a density of about 0.1 to about 1.1 g / ml is used in the pharmaceutical composition. In certain aspects, the lubricant should constitute about 0.1 to about 2 weight percent of the formulation on a solid basis. Suitable lubricants are stable and do not polymerize within the formulation once mixed. Other lubricants known or under development in the art that exhibit acceptable or equivalent properties include stearic acid, hydrogenated oils, sodium stearyl fumarate, polyethylene glycol, and Lubritab®.

[0090] Functionality of dosage form

[0094] As described herein, the pharmaceutical formulations of the present invention can be formulated to slow or block the release and subsequent absorption of an overdose of a pharmaceutical active ingredient. In some embodiments, the pharmaceutical formulations can be designed to have pH modulating properties and / or pH-dependent dissolution properties. The pH modulating properties can affect the release and / or absorption of the active ingredient by adjusting the pH of the gastric environment based on whether the pharmaceutical composition is taken at an appropriate dose or overdosed. The pH modulating properties can be provided by including one or more buffering components and / or antacid components in the pharmaceutical composition. The pH-dependent dissolution properties can affect the release and / or absorption of the active ingredient by suppressing or releasing the pharmaceutical active ingredient in response to the pH of the gastric environment. The pH-dependent dissolution properties can be provided by including one or more acid-soluble components in the pharmaceutical composition.

[0091]

[0095] In some embodiments, the pharmaceutical composition can be formulated such that when the composition is taken in an appropriate amount, the pH modulating properties have a minimal effect (i.e., the pH of the gastric environment is not substantially adjusted or is maintained at a desirable level) and the pH-dependent dissolution properties also have a minimal effect (i.e., the pharmaceutical active ingredient is released), allowing for the release and / or absorption of the active ingredient. However, when the pharmaceutical composition is overdosed, in some embodiments, the composition is formulated such that the pH modulating properties have a maximal effect (i.e., raising the pH of the gastric environment) and the pH-dependent dissolution properties also have a maximal effect (i.e., the acid-soluble component is insoluble and does not dissolve), preventing the release and / or absorption of the active ingredient.

[0092]

[0096] The release of the drug from the matrix can then be controlled by the pH environment at that time surrounding the matrix upon ingestion of the pharmaceutical composition. In a low pH environment (i.e., pH 1-4), the matrix is more soluble and releases the drug rapidly, while in a high pH environment (i.e., pH > 4), the matrix is more likely to be insoluble, delaying the release of the drug and perhaps making it incomplete, such that the level of drug absorbed is diminished.

[0093]

[0097] In some embodiments, for a single dosage unit, the required amount of acid-soluble drug matrix is further mixed with a buffering component and / or an antacid component in an amount sufficient to neutralize the gastric pH to the point where, when a single dosage unit is ingested, the buffering component and / or the antacid component maintains the gastric pH in the range of pH 1 to 4. The blend of acid-soluble drug matrix / antacid / buffer can be formed into an oral solid dosage form such as a tablet or capsule, but is not limited to such dosage forms.

[0094]

[0098] As a result, the pharmaceutical composition can be formulated to have pH-regulating properties and pH-dependent dissolution properties such that, under normal dosing conditions (i.e., 1 or 2 tablets), when a single dose is ingested, the buffering component and / or the antacid component neutralizes a portion of the gastric acid, but the acidity of the stomach remains in the range of pH 1 to 4. Under these conditions, since the acid-soluble drug matrix is soluble in the acidic gastric environment, the drug is rapidly released into the stomach and can be absorbed into the bloodstream. soluble, so the drug is rapidly released into the stomach and can be absorbed into the bloodstream.

[0095]

[0099] Under conditions where an overdose is ingested (e.g., 3 or more tablets), the amount of buffering component and / or antacid component due to the overdose may be sufficient to rapidly and continuously increase the gastric pH (e.g., pH > 4). Accordingly, the acid-soluble drug matrix is less likely to dissolve in the high pH gastric environment, and drug release from the matrix can be suppressed.

[0096]

[0100] In some embodiments, the suppression of drug from the acid-soluble matrix is further assisted by gastrointestinal transit that can move the acid-soluble matrix particles to the intestine and lower gastrointestinal tract having a biologically controlled high pH environment (i.e., pH 5.5 to 8). In some embodiments, the overall suppression of drug release due to overdose, when compared to an oral dose of equal amount that releases the drug at normal gastric pH (i.e., pH 1 to 4), is an increase in T

[0097]

[0101] In some embodiments, the overall suppression of drug release due to overdose, when compared to an oral dose of equal amount that releases the drug at normal gastric pH (i.e., pH 1 to 4), is an increase in T max and / or C maxresulting in a pharmacokinetic profile having a decrease.

[0098]

[0102] In some embodiments, the component that reduces gastric acid production delays the time until gastric re-acidification, so that the high pH of the gastric environment is extended, and the suppression of active drug release in the case of over - ingestion (i.e., 3 or more doses or tablets) is enhanced.

[0099]

[0103] In some embodiments, the component that reduces gastric acid is not released from the pharmaceutical composition until the pH of the surrounding medium (e.g., the gastric environment) becomes high, e.g., higher than about 4, higher than about 4.5, higher than about 5. When such a high pH is reached, the component that is in contact with or coats the component that reduces gastric acid dissolves.

[0100]

[0104] In some embodiments, the second buffering component is not released from the delayed - release buffering component until the pH of the surrounding medium (e.g., the gastric environment) becomes high, e.g., higher than about 4, higher than about 4.5, higher than about 5. When such a high pH is reached, the enteric solvent of the delayed - release buffering component dissolves. In some embodiments, the release of the second buffering component can be further delayed by including an acid - soluble component, as described above herein.

[0101]

[0105] In some embodiments, the delayed - release buffering component is when the high pH of the gastric environment is maintained By extending the interval, suppression of active drug release in case of over - intake (i.e., 3 or more doses or tablets) is extended. In some embodiments, the present invention relates to a dosage form comprising an acid - soluble component, a pharmaceutically active ingredient, a first buffering component, a component for reducing gastric acid production, and a delayed - release buffering component comprising a second buffering component and an enteric solvent. In some such embodiments, the delayed - release buffering component serves to prevent re - acidification for a time sufficient for the component for reducing gastric acid production to reach a sufficient or maximum plasma concentration. For example, in some embodiments, the combination of the first buffering component and the delayed - release buffering component comprising the second buffering component and the enteric solvent prevents re - acidification of the gastric environment for longer than 1 hour, longer than 2 hours, or longer than 3 hours. In some embodiments, the combination of the first buffering component and the delayed - release buffering component comprising the second buffering component and the enteric solvent prevents re - acidification of the stomach for a longer time than the first buffering component alone.

[0102] Manufacturing method

[0106] In some embodiments, the pharmaceutical composition can be manufactured by homogeneously mixing the pharmaceutically active ingredient with the acid - soluble component and any suitable method. In one embodiment, the method is a dry or wet granulation method. In some embodiments, the particle matrix is formed in particulate or granular form. In another embodiment, the method is hot - melt extrusion. Without wishing to be bound by theory, hot - melt extrusion can provide closer contact between two or more components used in the present invention than mixing or other composite - material - forming methods.

[0103]

[0107] The compressed tablets containing the pharmaceutical composition of the present invention can be direct - compression tablets or non - direct - compression tablets. In one embodiment, the dosage form of the present invention can be manufactured by wet granulation methods and dry granulation methods (e.g., slugging or roller compression). The manufacturing method and the type of excipient are selected to impart desirable physical properties to the tablets that enable rapid compression of the tablets. After compression, the tablets must have several additional attributes such as appearance, hardness, disintegration ability, and an acceptable dissolution profile.

[0104]

[0108] In one aspect, the present invention relates to a dosage form comprising a drug that is prone to abuse, an acid-soluble component, a buffering component, and a gastric emptying time prolonging component, and the dosage form is a food bar or a beverage. Suitable formulations and dosage forms of the present invention include, but are not limited to, powders, caplets, pills, suppositories, gels, soft gelatin capsules, capsules, and compressed tablets produced from the pharmaceutical composition of the present invention. The dosage form may be of any shape, including regular or irregular shapes, depending on the needs of the expert.

[0105]

[0109] The selection of fillers and other excipients typically depends on the chemical and physical properties of the drug, the behavior of the mixture during processing, and the properties of the final tablet. It is understood that the adjustment of such parameters is within the general understanding of those skilled in the relevant art. Suitable fillers and excipients are described in more detail above.

[0106]

[0106]

[0110] Dosage forms comprising various controlled release dosage forms, and / or methods of manufacturing a drug abuse deterrent pharmaceutical composition, and the incorporation of one or more layers are known in the art and are described, for example, in U.S. Patent No. 9,522,119, U.S. Patent Application Publication Nos. 2009023288 and 20060210633, and International Patent Application Publication Nos. WO2014059512, WO2016023108, WO2007072495, WO2005101983, WO2003011255, WO2005039481, and WO2006123364, the contents of which are incorporated herein by reference in their entirety.

[0107]

[0111] One or more components may be present during the layering or "core-shell" type of arrangement as described herein with respect to certain components.

[0112]

[0112] In some aspects, one or more components or particles, granules or layers are described in U.S. Patent It can be isolated as described in Application Publication No. 20120202839 (the entire text of which is incorporated herein by reference). An abuse-deterrent pharmaceutical composition containing an immediate-release unit dose of a pharmaceutically active ingredient, an acid-soluble component, and a buffering component is described in U.S. Patent No. 9,101,636 (the entire text of which is incorporated herein by reference).

[0108]

[0113] The present invention can be used to manufacture immediate-release formulations and controlled drug release formulations. The controlled release formulations can include oral solid dosage forms of delayed release, biphasic and triphasic release, extended and sustained release.

[0109] Method of use

[0114] In one aspect, the present invention relates to a treatment method for a disease alleviated by an easily abused drug, the method comprising administering to a subject in need thereof an abuse-deterrent pharmaceutical composition comprising an easily abused drug, an acid-soluble component, a buffering component, and a component for extending the gastric emptying time. In one aspect, the present invention relates to a treatment method for a disease alleviated by an easily abused drug, the method comprising administering to a subject in need thereof a dosage form comprising an abuse-deterrent pharmaceutical composition comprising an easily abused drug, an acid-soluble component, a buffering component, and a component for extending the gastric emptying time, wherein the dosage form is a food bar or a beverage.

[0110]

[0115] In one aspect, the present invention relates to a treatment method for a disease alleviated by an easily abused drug, the method comprising administering to a subject in need thereof a dosage form comprising an abuse-deterrent pharmaceutical composition comprising an easily abused drug, an acid-soluble component, a buffering component, and a component for extending the gastric emptying time. In one aspect, the present invention relates to a treatment method for a disease alleviated by an easily abused drug, the method comprising administering to a subject in need thereof a dosage form comprising an abuse-deterrent pharmaceutical composition comprising an easily abused drug, an acid-soluble component, a buffering component, and a component for extending the gastric emptying time, wherein the dosage form is a food bar or a beverage.

[0111]

[0116] In one aspect, the present invention relates to a treatment method for a disease alleviated by an easily abused drug, the method comprising administering to a subject in need thereof a dosage form comprising an abuse-deterrent pharmaceutical composition comprising an easily abused drug, an acid-soluble component, a buffering component, and a component for extending the gastric emptying time. Regarding a therapy, the method includes administering to a subject in need thereof a substance abuse deterrent pharmaceutical composition comprising an easily abused drug, an acid-soluble component, and a buffering component, and a composition for extending the gastric emptying time comprising a component for extending the gastric emptying time. In some embodiments, the substance abuse deterrent pharmaceutical composition is administered before, after, or simultaneously with the composition for extending the gastric emptying time. In some embodiments, the component for extending the gastric emptying time is a monosaccharide, disaccharide, oligosaccharide, polysaccharide, amino acid, peptide, protein, fatty acid, monoglyceride, diglyceride, or triglyceride. In some embodiments, the component for extending the gastric emptying time is loperamide, diphenoxylate, atropine, diphenoxine, an anticholinergic agent, an antidepressant, an opioid, an antidiarrheal agent, or a gastric hypomotility inducing agent.

[0112]

[0117] In one embodiment, the present invention relates to a treatment for a disease alleviated by an easily abused drug Regarding a therapy, the method includes administering to a subject in need thereof a dosage form comprising a substance abuse deterrent pharmaceutical composition comprising an easily abused drug, an acid-soluble component, and a buffering component, and a composition for extending the gastric emptying time comprising a component for extending the gastric emptying time, the dosage form being a food bar or a beverage.

[0113]

[0118] The method of use also includes a method for deterring abuse of a pharmaceutical composition comprising an easily abused drug, an acid-soluble component, a buffering component, and a component for extending the gastric emptying time and / or extending the gastric retention time, the method including extending the gastric emptying time and / or extending the gastric retention time in a subject who has ingested more dosage units of the composition than recommended or prescribed.

[0114]

[0119] In some embodiments, compared to a composition or dosage form that does not include the features of the present invention, in the stomach The gastric emptying time can be extended by about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, about 2.5 hours, or about 3 hours in the subject.

[0115]

[0120] Similarly, compared to a composition or dosage form that does not include the features of the present invention, in some embodiments the gastric emptying time or residence time can be extended by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 175%, or about 200%.

[0116]

[0121] A method of deterring abuse may also include an extension of the gastric residence time of a certain proportion of the drug when the drug ingested is a part of the composition of the present invention in a subject who has ingested a composition in a larger number of dosage units (e.g., 3, 4, 5, 6, 7, 8, etc., or more dosage units) than recommended or prescribed.

[0117]

[0122] In some embodiments, compared to a composition or dosage form that does not include the features of the present invention, the gastric residence The retention time can be extended for about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70% of the total amount of the drug ingested at one time. It can be extended for about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9%.

[0118]

[0123] In some embodiments, compared to a composition or dosage form that does not include the features of the present invention, the gastric retention time can be extended by about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, about 2.5 hours, or about 3 hours for a certain percentage of the total amount of the drug ingested at one time.

[0119]

[0124] In some embodiments, compared to a composition or dosage form that does not include the features of the present invention, the gastric retention The retention time can be extended by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 175%, or about 200% with respect to a certain percentage of the total amount of the drug taken at one time.

[0120]

[0125] Certain aspects of the present invention will be better understood as shown by the following examples. These examples are for illustrative purposes only and are not intended to be limiting. These examples are for illustrative purposes only and are not intended to be limiting.

Example

[0121] Example 1: Limits of self-regulating formulations

[0126] As Clinical Study AP-LTX-400 (Study 400), two prototype hydrocodone HCL 2 mg formulations: LTX-04S and LTX-04P were used. Both were the same microparticle formulations, but differed in the amount of buffer (5 and 9 mEq buffering capacity, respectively). Study 400 was designed for two consecutive cohorts. In Cohort 1, the two test formulations were compared with 1, 2, and 3 tablets against the reference product, namely Dilaudid® tablets 2 mg. In Cohort 2, the LTX-04P test formulation was tested and compared with 4, 6, and 8 tablets representing excessive oral consumption against the reference product.

[0122]

[0127] In Cohort 1, it was observed that the microparticles did not release the hydrocodone sufficiently to the intended level. Also, in the case of 3 tablets of LTX-04P, it was also observed that an approximately 20% reduction was achieved in the peak plasma drug concentration (C ) compared to a single dose of LTX-04P. Furthermore, 3 tablets of LTX-04P (27 mEq buffer) had a lower peak plasma drug concentration (C max ) compared to 3 tablets of LTX-04S (15 mEq buffer). max) also showed a 28% reduction, indicating that the threshold buffer concentration was achieved and promoting an intentional reduction in peak drug concentration. In in vivo pH monitoring of the subjects, three tablets of LTX-04P tablets rapidly raised the gastric pH above pH 4 within minutes of administration and lowered it to the baseline low pH approximately 30 minutes later, while three tablets of LTX-04S were shown not to raise the pH much above pH 3 over the same time course.

[0123]

[0128] In cohort 2 of study 400, LTX-04P tablets were compared to the reference product at doses of 4, 6, and 8 tablets. Similar to the case of three tablets of LTX-04P in cohort 1, a reduction of approximately 20% in peak plasma drug concentration was also seen at 4, 6, and 8 tablets compared to a single dose of LTX-04P. These results were unexpected since in vitro multi-tablet acid challenge analysis had shown a gradual decrease in drug release with an increase in the number of tablets. For example, in the case of 8 tablets, in vitro release after 1 hour resulted in a decrease of approximately 70% compared to 100% drug release in 1 hour for a single tablet. However, the in vivo reduction of C for 8 tablets was almost the same as that for three tablets, despite the introduction of a buffer capacity 2.7 times greater for the gastric environment. max

[0124] Example 2: Self-regulating formulations with an extended gastric content evacuation time

[0129] To demonstrate the synergistic effect of the extended gastric emptying time by the self-regulating formulation, in study AP-LTX-401, the human pharmacokinetics of the self-regulating hydromorphone HCl 2mg formulation LTX-04P3 were compared in a gastric emptying time extension model. The first group of 13 subjects was administered seven tablets of LTX-04P3 tablets with 240 mL of water. The second group of 15 subjects was administered seven tablets of LTX-04P3 tablets with 240 mL of 20% w / v glucose in water, a solution known to extend the gastric emptying time. A control group of 30 subjects was administered seven tablets of generic hydromorphone HCl, 2 mg with 240 mL of water.

[0125]

[0130] Co - administration of glucose with 7 tablets of LTX - 04P3 resulted in a geometric mean time (T ) to the peak plasma hydromorphone concentration that was significantly increased to 2.05 hours compared to 1.22 hours for LTX - 04P3 taken with water (Figure 1). This represents a 168% increase in T max for the glucose - treated subjects compared to the subjects without glucose. Since glucose delayed gastric emptying (prolonged gastric retention), the self - regulating buffer component remained in the stomach for a longer time, enhancing the delay in drug release (improving the effectiveness of self - regulation). max max

[0126]

[0131] The effect of prolonged gastric retention did not adversely affect the ability of the self - regulating formulation to reduce the geometric mean peak hydromorphone plasma concentration (C max ). The C max of the glucose - mediated LTX - 04P3 tablets retained its ability to provide a reduction in C max compared to generic hydromorphone, similar to that of LTX - 04P3 co - administered with water (as shown in Figure 2).

[0127] Example 3: Exemplary formulations and methods

[0132] Examples of formulations and methods for producing acid - soluble granules are as follows.

[0133] Acid - soluble granules

[0128]

Table 1

[0129]

[0134] Method for producing acid - soluble granules:

[0135] 1. Uniformly blend oxycodone and Eudragit E;

[0136] 2. Hot - melt extrude the blend at 160 °C; recover the extruded material;

[0137] ​​3. Size the oxycodone-Eudragit E extrudate using a vibrating granulator; collect the sieved granules (<600 μm);

[0138] Examples of formulations and methods for producing a delayed release buffer component containing an antihyperacid agent are as follows

[0130]

[0139] Delayed release buffer component having an antihyperacid agent

[0131]

Table 2

[0132]

[0140] Method for producing a delayed release buffer component having an antihyperacid agent

[0141] 1. Uniformly blend magnesium oxide and microcrystalline cellulose;

[0142] 2. Compress the blend using a roller and size it using a vibrating granulator. Collect the sieved dry granules (>250 μm).

[0133]

[0143] 3. Produce a subcoating A dispersion of Eudragit E PO using a sufficient amount of water and maintain a steady mixing

[0144] 4. Produce a subcoating B solution of Opadry Clear / famotidine by first mixing Opadry Clear with a sufficient amount of water. Next, add famotidine to the subcoating B and disperse it uniformly while maintaining a steady mixing.

[0134]

[0145] 5. Produce an enteric coating dispersion of Eudragit L 30D using a sufficient amount of water and maintain a steady mixing

[0146] 6. Place the dry granules in a fluidized bed coater and apply approximately 10% of Eudragit E ​​​​​​Apply PO subcoating A to the buffer granules by the bottom spray method. After application, thoroughly dry the Eudragit E PO subcoating A. Next, apply a sufficient amount of the Opadry Clear / famotidine subcoating B solution by the same fluid bed method to obtain 2 mg of famotidine per dose. After application, thoroughly dry the Opadry Clear / famotidine subcoating B. Next, apply an approximately 10% (w / w) Eudragit L 30% dispersion to the subcoated A&B granules by the same fluid bed method and dry completely.

[0135]

[0147] 7. Sieved enteric-coated delayed release buffer / gastric acid reducing granules (>250 μm) are collected.

[0148] Examples of formulations and methods for manufacturing oxycodone self-regulating tablets are as follows as follows.

[0136]

[0149] Oxycodone self-regulating tablets

[0137]

Table 3

[0138]

[0150] Method for manufacturing oxycodone self-regulating tablets

[0151] 1. Uniformly blend oxycodone acid-soluble granules, Effersoda 12, enteric-coated magnesium oxide / famotidine granules, glycine, and crospovidone. 2. Add magnesium stearate to the blend and perform a final blend for an additional 3 minutes.

[0139]

[0152] 3. Transfer the final blend to a rotary tablet press equipped with modified oval tablet tooling. Compress the tablets to a hardness of 8 - 12 kP. 4.

[0153] 3. Transfer the final blend to a rotary tablet press equipped with modified oval tablet tooling. Compress the tablets to a hardness of 8 - 12 kP. Compress the tablets to a hardness of 8 - 12 kP.

[0140]

[0154] One skilled in the art will recognize that numerous variations and / or modifications can be made to the invention as presented in the specific embodiments without departing from the spirit and scope of the invention as broadly described. Further, each of the references cited above is hereby incorporated by reference into this specification as if fully set forth herein.

Claims

**Claim 1** A misuse deterrent pharmaceutical composition comprising: a drug prone to misuse; a first acid-soluble component; a first buffering component; and a delayed-release buffering component . **Claim 2** The composition according to claim 1, wherein the first acid-soluble component comprises calcium carbonate, a cationic copolymer, or a combination thereof. **Claim 3** The composition according to claim 2, wherein the cationic copolymer comprises one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. **Claim 4** The composition according to any one of claims 1 to 3, wherein the first buffering component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, trisodium phosphate, or a combination thereof. **Claim 5** The composition according to any one of claims 1 to 4, wherein the delayed-release buffering component comprises a second buffering component, an enteric coating agent, and a sustained-release component. **Claim 6** The composition according to claim 5, wherein the delayed-release buffering component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprises the second buffering component, the shell comprises the enteric coating agent, and the subcoat comprises the sustained-release component. **Claim 7** The composition according to any one of claims 1 to 4, wherein the delayed-release buffering component comprises a second buffering component, an enteric coating agent, and a second acid-soluble component. **Claim 8** The composition according to claim 7, wherein the delayed-release buffering component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprises the second buffering component, the shell comprises the enteric coating agent, and the subcoat comprises the second acid-soluble component. **Claim 9** The composition according to claim 8, wherein the second acid-soluble component comprises calcium carbonate, a cationic copolymer, or a combination thereof. **Claim 10** The composition according to claim 9, wherein the cationic copolymer comprises one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. **Claim 11** The composition according to any one of claims 10 to 13, wherein the second acid-soluble component is the same as the first acid-soluble component. **Claim 12** The composition according to any one of claims 5 to 11, wherein the second buffering component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, trisodium phosphate, or a combination thereof. **Claim 13** The composition according to any one of claims 5 to 12, wherein the second buffering component is the same as the first buffering component. **Claim 14** The enteric component contains one or more of shellac, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, sodium alginate, and zein, and the composition according to any one of claims 5 to 13.

15. The composition according to any one of claims 1 to 14, further comprising a component for reducing gastric acid production.

16. The composition according to claim 15, wherein the component for reducing gastric acid production contains an H2-antagonist.

17. The composition according to claim 16, wherein the H2-antagonist is present in an amount of 10 to 50% of the minimum therapeutic dose of the H2 antagonist for reducing gastric acid secretion.

18. The composition according to any one of claims 1 to 17, further comprising a component for extending the gastric emptying time.

19. The composition according to claim 18, wherein the component for extending the gastric emptying time is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, amino acids, peptides, proteins, fatty acids, monoglycerides, diglycerides, and triglycerides.

20. The composition according to claim 18, wherein the component for extending the gastric emptying time is selected from the group consisting of loperamide, diphenoxylate, atropine, diphenoxine, anticholinergic agents, antidepressants, opioids, antidiarrheal agents, and agents inducing gastric atony.

21. The composition according to any one of claims 18 to 20, wherein the component for extending the gastric emptying time extends the gastric emptying time of the subject when ingested by the subject.

22. A dosage form comprising the composition according to any one of claims 1 to 21.

23. The dosage form according to claim 22, wherein the dosage form is a food bar or a beverage.

24. A method for treating a disease alleviated by a drug prone to abuse, comprising administering to a subject in need thereof the composition according to any one of claims 1 to 21.

25. Further comprising administering a composition for extending the gastric emptying time, and the abuse deterrent pharmaceutical composition is administered before, after, or simultaneously with the composition for extending the gastric emptying time. The method according to claim 24.

26. The method according to claim 25, wherein the component for extending the gastric emptying time is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, amino acids, peptides, proteins, fatty acids, monoglycerides, diglycerides, and triglycerides. **Claim 27** The method according to claim 25, wherein the component for extending the gastric emptying time is selected from the group consisting of loperamide, diphenoxylate, atropine, difenoxin, anticholinergic agents, antidepressants, opioids, antidiarrheal agents, and agents that induce gastric hypomotility. **Claim 28** The method according to any one of claims 25 to 27, wherein the component for extending the gastric emptying time is included in a dosage form, and the dosage form is a food bar or a beverage.

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