Methods and compositions for the self-controlled release of active pharmaceutical ingredients - Patents.com

Abstract

Such methods and compositions are provided that deter abuse and minimize or reduce the potential for physical or psychological dependence. The abuse-deterrent pharmaceutical composition includes an abuse-prone drug; a first acid-soluble component; a first buffer component; and a delayed-release buffer component.

Description

Related Applications

[0001]

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 479,822, filed March 31, 2017, No. 62 / 544,375, filed August 11, 2017, and No. 62 / 587,783, filed November 17, 2017, all of which are incorporated herein by reference in their entireties. [Background technology]

[0002]

[0003] Classes of drugs that exhibit opium- 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 areas of the central nervous system that appear to be involved in regulating pain perception, movement, mood and behavior, and neuroendocrine function. Three classical opioid receptor types, mu (μ), delta (δ), and kappa (κ), have been extensively studied. Each of these receptors has its own anatomical distribution in the brain, spinal cord, and periphery. The majority of 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 also interact with multiple receptor subtypes when administered at high enough doses, potentially resulting in altered pharmacological effects. This is especially true as opioid doses are escalated 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 that contain opioid analgesics.

[0004]

[0005] Attempts have been made to reduce the abuse potential of orally administered drugs, including opioids, and these attempts generally center around the inclusion in the oral dosage form of an opioid antagonist that is not orally active, but which substantially blocks the analgesic effect of the opioid when the opioid is dissolved and administered parenterally.

[0005]

[0006] However, despite all attempts, misuse and abuse of pharmaceuticals continues to increase. Due to the susceptibility of drugs to abuse, there is an increasing need for new and effective methods and compositions to deter abuse of pharmaceuticals (e.g., orally administered pharmaceuticals), including, but not limited to, immediate release, sustained or extended release, and delayed release formulations. In particular, such methods and compositions that deter abuse and minimize or reduce the potential for physical or psychological dependence would be useful for both opioid analgesics and patients seeking pharmacotherapy. Summary of the Invention

[0006]

[0007] In one aspect, the present invention provides a pharmaceutical composition comprising: a drug susceptible to abuse; a first acid soluble component; a first buffering ingredient; and a delayed release buffering component. The present invention relates to an abuse-deterrent pharmaceutical composition. 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 buffer component is calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the delayed release buffer component includes a second buffer component, an enteric agent, and a sustained release component. In some embodiments, the delayed release buffer component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core includes a second buffer component, the shell includes an enteric agent, and the subcoat includes a sustained release component. In some embodiments, the delayed release buffer component includes a second buffer component, an enteric agent, and a second acid-soluble component. In some embodiments, the delayed release buffer component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprises a second buffer component, the shell comprises an enteric agent, 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 buffer component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the second buffer component is the same as the first buffer 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 an abuse-deterrent pharmaceutical composition comprising an abuse-prone drug; a first acid-soluble component; a first buffer component; a delayed release buffer component; and 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 between 10-50% 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 buffer component is calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the delayed release buffer component includes a second buffer component, an enteric agent, and a sustained release component. In some embodiments, the delayed release buffer component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core includes the second buffer component, the shell includes the enteric agent, and the subcoat includes the sustained release component. In some embodiments, the delayed release buffer component includes a second buffer component, an enteric agent, and a second acid-soluble component. In some embodiments, the delayed release buffer component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core includes the second buffer component, the shell includes the enteric agent, and the subcoat includes 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 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 buffer component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the second buffer component is the same as the first buffer 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 an abuse-deterrent pharmaceutical composition comprising an abuse-prone drug; a first acid-soluble component; a first buffer component; a delayed release buffer component; and a component for extending gastric emptying time. In some aspects, the component for extending 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 aspects, the component for extending gastric emptying time is selected from the group consisting of loperamide, diphenoxylate, atropine, difenoxin, anticholinergics, antidepressants, opioids, antidiarrheal drugs, and gastroparesis-inducing drugs. In some aspects, when ingested by a subject, the component for extending gastric emptying time extends the gastric emptying time of the subject. In some aspects, 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 buffer component is calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or combinations thereof. In some embodiments, the delayed release buffer component includes a second buffer component, an enteric agent, and a sustained release component. In some embodiments, the delayed release buffer component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core includes a second buffer component, the shell includes an enteric agent, and the subcoat includes a sustained release component. In some embodiments, the delayed release buffer component includes a second buffer component, an enteric agent, and a second acid-soluble component. In some embodiments, the delayed release buffer component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core includes a second buffer component, the shell includes an enteric agent, and the subcoat includes a second acid-soluble component. In some embodiments, the second acid-soluble component includes calcium carbonate, a cationic copolymer, or combinations 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 buffer component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the second buffer component is the same as the first buffer 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.

[0009]

[0010] In one embodiment, the present invention relates to an abuse-deterrent pharmaceutical composition comprising an abuse-prone drug; a first acid-soluble component; a first buffer component; a delayed release buffer 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, difenoxin, anticholinergics, antidepressants, opioids, antidiarrheals, and gastroparesis-inducing drugs. In some embodiments, when ingested by 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 10-50% 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 buffer component is calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the delayed release buffer component comprises a second buffer component, an enteric agent, and a sustained release component. In some embodiments, the delayed release buffer component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprises a second buffer component, the shell comprises an enteric agent, and the subcoat comprises a sustained release component. In some embodiments, the delayed release buffer component comprises a second buffer component, an enteric agent, 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 comprising a second buffering component, the shell comprising an enteric agent, and the subcoat comprising 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 buffer component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the second buffer component is the same as the first buffer 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.

[0010]

[0011] In some embodiments, the present invention relates to a dosage form comprising an abuse-deterrent pharmaceutical composition comprising an abuse-prone drug; a first acid-soluble component; a first buffer component; and a delayed release buffer 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 10-50% of the minimum therapeutic dose of the H2-antagonist for reducing gastric acid secretion. In some embodiments, the composition further comprises a component for increasing gastric emptying time. In some embodiments, the component for increasing 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 extending gastric emptying time is selected from the group consisting of loperamide, diphenoxylate, atropine, difenoxin, anticholinergics, antidepressants, opioids, antidiarrheals, and gastroparesis-inducing drugs. In some embodiments, when ingested by a subject, the component for extending 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 buffer component is calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the delayed release buffer component includes a second buffer component, an enteric agent, and a sustained release component. In some embodiments, the delayed release buffer component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprises a second buffer component, the shell comprises an enteric agent, and the subcoat comprises a sustained release component, hi some embodiments, the delayed release buffer component comprises a second buffer component, an enteric agent, and a second acid-soluble component.In some embodiments, the delayed release buffer component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprises a second buffer component, the shell comprises an enteric agent, 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 buffer component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the second buffer component is the same as the first buffer 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 a drug susceptible to abuse, the method comprising administering to a subject in need thereof an abuse-deterrent pharmaceutical composition comprising the drug susceptible to abuse; a first acid-soluble component; a first buffer component; and a delayed release buffer 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 10-50% 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 10-50% 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 increasing 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 increasing gastric emptying time is selected from the group consisting of loperamide, diphenoxylate, atropine, difenoxin, anticholinergics, antidepressants, opioids, antidiarrheal drugs, and gastroparesis-inducing drugs. In some embodiments, when ingested by a subject, the component for increasing gastric emptying time increases 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 buffer component is calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the delayed release buffer component comprises a second buffer component, an enteric agent, and a sustained release component.In some embodiments, the delayed release buffer component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprises a second buffer component, the shell comprises an enteric agent, and the subcoat comprises a sustained release component. In some embodiments, the delayed release buffer component comprises a second buffer component, an enteric agent, and a second acid-soluble component. In some embodiments, the delayed release buffer component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprises a second buffer component, the shell comprises an enteric agent, 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 buffer component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the second buffer component is the same as the first buffer 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 increasing gastric emptying time, and the abuse-deterrent pharmaceutical composition is administered before the composition for increasing gastric emptying time, after the composition for increasing gastric emptying time, or simultaneously with the composition for increasing gastric emptying time. In some embodiments, the component for increasing 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 increasing gastric emptying time is. , loperamide, diphenoxylate, atropine, difenoxin, anticholinergics, antidepressants, opioids, antidiarrheals, and gastroparesis-inducing drugs. In some embodiments, the composition for increasing 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 that includes an abuse-prone 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 abuse-prone 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 buffer component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the buffer 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 abuse-prone drug, an acid-soluble component, a buffering component, and a component for prolonging gastric emptying time, which may be a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, an amino acid, a peptide, a protein, a fatty acid, a monoglyceride, a diglyceride, or a triglyceride. In one aspect, the present invention relates to an abuse-deterrent pharmaceutical composition comprising an abuse-prone drug, an acid-soluble component, a buffering component, and a component for prolonging gastric emptying time, which may be loperamide, diphenoxylate, atropine, difenoxin, an anticholinergic, an antidepressant, an opioid, an antidiarrheal agent, and a gastroparesis-inducing agent.

[0014]

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

[0015]

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

[0016]

[0018] In one aspect, the present invention relates to a dosage form comprising an abuse-deterrent pharmaceutical composition comprising an abuse-prone drug, an acid-soluble component, a buffering component, and a component for extending 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 an abuse-prone drug, the method comprising administering to a subject in need thereof an abuse-deterrent pharmaceutical composition comprising an abuse-prone drug, an acid-soluble component, a buffering component, and a component for extending gastric emptying time.

[0018]

[0020] In one aspect, the present invention relates to a method for treating a disease alleviated by a drug susceptible to abuse, the method comprising administering to a subject in need thereof a drug susceptible to abuse, an acid soluble component, a buffer, and a medicament for treating a disease. The method comprises administering a dosage form comprising an abuse-deterrent pharmaceutical composition comprising an antidote component and an ingredient for extending gastric emptying time, hi some embodiments, 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 a drug susceptible to abuse, the method comprising administering to a subject in need thereof an abuse-deterrent pharmaceutical composition comprising the drug susceptible to abuse, an acid-soluble component, and a buffer component, and a composition for prolonging gastric emptying time comprising a component for prolonging gastric emptying time. In some aspects, the abuse-deterrent pharmaceutical composition is administered before the composition for prolonging gastric emptying time. In some aspects, the abuse-deterrent pharmaceutical composition is administered after the composition for prolonging gastric emptying time. In some aspects, the abuse-deterrent pharmaceutical composition is administered simultaneously with the composition for prolonging gastric emptying time. In some aspects, the component for prolonging gastric emptying time is a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, an amino acid, a peptide, a protein, a fatty acid, a monoglyceride, a diglyceride, or a triglyceride. In some embodiments, the component to increase gastric emptying time is loperamide, diphenoxylate, atropine, difenoxin, an anticholinergic, an antidepressant, an opioid, an antidiarrheal, or a gastroparesis-inducing agent.

[0020]

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

[0021]

[0023] The present invention may be better understood by consideration of the following drawings, which illustrate certain features of the invention. [Brief description of the drawings]

[0022] [Figure 1]

[0024] FIG. 1 shows the Tmax of a formulation according to an embodiment of the invention compared to a control formulation. [Diagram 2]

[0025] FIG. 2 shows the Cmax of a formulation according to an embodiment of the invention compared to a control formulation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023]

[0026] The compositions and methods of the present invention relate to self-regulating dosing, particularly of drugs susceptible to abuse. The self-regulating dosing of the present invention relies on a number of technical approaches. The dosing is self-regulating, for example, by first adjusting, e.g., raising or lowering the pH of the surrounding medium, typically the stomach contents of the subject. 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 the dosing exceeds a certain limit, typically the limit for 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 by delaying or stopping the disintegration of the matrix elements containing the active ingredient, e.g., by encapsulating or sequestering the active ingredient. In some embodiments, the dosing further comprises a delayed release buffer component that extends the effect of delaying or stopping the release of the active ingredient from the matrix if an overdose is ingested. In some embodiments, the dosing further extends the gastric emptying time, making it available for the pH modulation self-regulation mechanism to operate. It self-regulates by increasing the time available and enhancing the overall effect.

[0024]

[0027] Self-regulating medications are designed to limit and prolong the absorption of drugs when an inadequate dose is taken or when the medication is abused. Ingredients in self-regulating tablets include antacids / buffers to alter, e.g., raise, the pH of the stomach when administered orally. In some embodiments, the abuse-prone drug is contained in a dosage form that is intended to dissolve in an acidic gastric medium having a pH below 5 and provide an immediate or extended release profile of the active ingredient drug when the intended dose, or typically the prescribed dose, e.g., 1 or 2 unit doses, is ingested. Conversely, self-regulating dosage forms are intended to neutralize the gastric pH as more tablets are ingested, slowing the release of the active ingredient at pHs above 5.

[0025]

[0028] In some embodiments, the formulations of the present invention are designed to block or prevent the effects caused by intentional or unintentional overdosing of a drug. Under normal dosing conditions, the formulations of the present invention may allow for complete oral delivery of the desired drug dose. However, if an overdose is taken, either intentionally or unintentionally, for example, a dose that exceeds the dose 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 excessive oral consumption, where a drug abuser consumes an excessive dose of the abused drug to experience a "high", the "high" will be significantly reduced with the formulations of the present invention compared to a dose that freely releases the excess abused drug. In this way, the formulations of the present invention can act as a deterrent to not abuse the formulations of the present invention for the purpose of obtaining a high. Nevertheless, patients who use 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 with one or more mechanisms to control the release and / or absorption of the active pharmaceutical 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 stomach environment based on whether the pharmaceutical composition is ingested in an appropriate dose or in an excess. The pH-modulating properties can be provided by including one or more buffering 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 pharmaceutical ingredient by inhibiting or releasing the active pharmaceutical ingredient depending on the pH of the stomach environment. The pH-dependent dissolution properties can be provided by including one or more acid-soluble components in the pharmaceutical composition. Pharmaceutical compositions comprising 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 by reference in their entireties.

[0027]

[0030] In some aspects, the compositions and methods of the present invention synergistically incorporate additional autoregulatory mechanisms including prolonging gastric emptying time in subjects ingesting the compositions disclosed herein.

[0028]

[0031] While not wishing to be bound by any particular theory, certain aspects of the present invention are believed to be based in part on the in vivo administration of one or more doses of a self-regulating composition that does not have a gastric emptying time extension mechanism, resulting in the observed C max For example, as described in Example 1, the C maxThe in vivo reduction in pH was approximately the same as with three tablets. This is despite the fact that eight tablets represents a 2.7-fold greater buffering capacity of the gastric environment compared to three tablets. Thus, while a sufficient buffering level can be provided with a certain number of tablets, the effect and duration of the autoregulatory buffering level in vivo can be synergistically influenced by additional mechanisms such as gastric emptying time. If the buffering agent on which the first autoregulatory mechanism is based has a relatively short duration in the stomach, for example about 25 minutes, in some cases the buffering agent may be emptied from the stomach before it can further neutralize the newly generated gastric acid. Thus, the sufficient buffering effect of a large number of tablets may not be achieved in some cases, and the gastric juice may be acidic in the same time as with a small number of tablets. In some embodiments, an acid neutralization model is used to show that prolonging high gastric pH (>5) can be achieved when gastric emptying time is extended. In some embodiments, a delayed release buffer composition model is used to prolong high gastric pH (>5). In the present invention, the peak plasma drug concentration (C max DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Methods and compositions for extending gastric emptying time to facilitate better performance for reducing urinary incontinence are described.

[0029] definition

[0032] As used herein, the term “C max " refers to the maximum (or peak) serum concentration that a drug achieves in a particular 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 " is C max This refers to the time during which the

[0030]

[0033] As used herein, the term "bioequivalence" refers to max or the area under the concentration curve "AUC" of a drug is within 80% to 125% of that of the same marker for a reference drug.

[0031]

[0034] As used herein, a compound or drug with a "narrow therapeutic index" (NTI) refers to a compound or drug that falls within any definition of a narrow therapeutic index promulgated by the U.S. Food and Drug Administration, or any successor thereto, such as a substance with less than a two-fold difference between its median toxic dose (TD50) and median effective dose (ED50) values, or a substance with less than a two-fold difference between its minimum toxic concentration and its minimum effective concentration in the blood.

[0032]

[0035] When ranges are used herein, for example to describe concentrations or amounts, all combinations and subcombinations of the ranges and specific embodiments contained therein are also intended to be included in the ranges. When referring to a number or numerical range, the use of the term "about" means that the number or numerical range may vary, since the number or numerical range being referred to is an approximation within experimental variation or within statistical experimental error. The variation is typically 0% to 5%, 0% to 10%, 0% to 15%, etc., of the stated number or numerical range. For example, "about 45%" is understood to include 40.5% to 49.5%.

[0033]

[0036] The terms "comprising", "comprise", "comprises", " Related terms such as "having" or "including" are used to refer to, for example, Feature "consist of" or "consist essentially of" This includes aspects such as any composition, method or process aspects.

[0034]

[0037] The term "gastric emptying time" refers to the time it takes for an ingested substance to empty or move out of the stomach. The time is measured from when the substance is swallowed until the substance moves into the small intestine. Similarly, the term "gastric residence time" refers to the time that a substance remains in the stomach from when it is ingested until it moves into the small intestine.

[0035] Abuse-deterrent pharmaceutical compositions

[0038] In one aspect, the present invention relates to an abuse-deterrent pharmaceutical composition that includes an abuse-prone drug, a first acid-soluble component, a first buffer component, and a delayed-release buffer component.

[0036]

[0039] In one aspect, the present invention relates to an abuse-deterrent pharmaceutical composition that includes an abuse-prone drug, an acid-soluble component, a buffering component, and a component for extending gastric emptying time.

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

[0037]

[0041] In one aspect, the present invention provides a pharmaceutical composition comprising a drug susceptible to abuse, a first acid-soluble component, a first The present invention relates to an abuse-deterrent pharmaceutical composition that includes a buffering component, a component for reducing stomach acid production, and a delayed release buffering component.

[0038]

[0042] In one aspect, the present invention relates to an abuse-deterrent pharmaceutical composition that includes an abuse-prone drug, a first acid-soluble component, a first buffering component, a component for extending gastric emptying time, and a delayed release buffering component.

[0039]

[0043] In one aspect, the present invention relates to an abuse-deterrent pharmaceutical composition that includes an abuse-prone drug, a first acid-soluble component, a first buffering component, a component for reducing gastric acid production, and a component for prolonging gastric emptying time.

[0040]

[0044] In one aspect, the invention relates to a pharmaceutical composition comprising a drug (e.g., a drug susceptible to abuse) and one or more of: a) a first acid-soluble component, b) a first buffering component, c) a component for extending gastric emptying time, d) a component for reducing gastric acid production, and e) a delayed release buffering component.

[0041] Active Pharmaceutical Ingredients

[0045] Any drug, therapeutically acceptable drug salt, drug derivative, drug analog, drug congener, prodrug, or polymorph may be used in the present invention. Drugs suitable for use in the present invention may be found in the Physician's Desk Reference, 59th Edition, including, but not limited to, the following references: The contents of which are incorporated herein by reference. In one embodiment, the drug is an orally administered drug. In some embodiments, the pharmaceutical compositions according to the present invention may include one or more drugs, therapeutically acceptable drug salts, drug derivatives, drug analogues, drug congeners, or polymorphic mixtures, coated particles, or granules.

[0042]

[0046] In certain embodiments, drugs that are prone to abuse are used.Drugs that are commonly prone to abuse include psychotropic drugs and analgesics, such as, but not limited to, opioids, opiates, stimulants, tranquilizers, sedatives, anxiolytics, anesthetics, and drugs that can cause psychological and / or physical dependence.In one embodiment, the drug for use in the present invention can include amphetamines, amphetamine-like compounds, benzodiazepines, and methylphenidate or combinations thereof.In another embodiment, the present invention can include any of the decomposition isomers of drugs described herein and / or their salts.

[0043]

[0047] The drug for use in the present invention may be a drug with a narrow therapeutic range. After administration, too little of a drug with a narrow therapeutic range in the bloodstream may result in insufficient therapeutic activity, while too much of a drug with a narrow therapeutic range may result in excessive therapeutic activity or toxicity, both of which may be harmful. As a result, the use of drugs with narrow therapeutic ranges must be carefully monitored to prevent their potential for abuse.

[0044]

[0048] Drugs for use in the present invention may be drugs susceptible to abuse. Drugs for use in the present invention that may be susceptible to abuse may be one or more of the following: alfentanil, amphetamines, buprenorphine, butorphanol, carfentanil, codeine, cyclospor ... codeine, dezocine, diacetylmorphine, dihydromorphine Dihydrocodeine, dihydromorphine, diphenoxyacetate diphenoxylate, diprenorphine, etorphine, Fentanyl, hydrocodone, hydromorphone, β-hydroxy-3-methylfentanyl, levo-α - Acetylmethadol (levo-α-acetylmethadol), levorphanol, Fentanyl (lofentanil), meperidine, methadone, methyl Methylphenidate, morphine, nalbuphine, nal Nalmefene, oxycodone, oxymorphone, penicillin pentazocine, pethidine, propoxyphene, remifentanil, sufentanil, tilidine, and tramodol, their salts, derivatives, analogs, congeners, polymorphs, and mixtures of any of the foregoing.

[0045]

[0049] In another embodiment, potentially abuse-prone drugs for use in the present invention include one or more of the following: 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 (amphepramone), (±)-α-methylphenethylamine (amphetamine), 2-( α-Methylphenethyl-amino)-2-phenylacetonitrile (amphetaminil), 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 (protizolam), 17-cyclopropylmethyl-4,5α-epoxy-7 α[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol (buprenorphine), 5-butyl-5-ethylbarbituric acid (butobarbital), butorphanol, (7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)-dimethylcarbamate (camazepam), (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-benzodiazepine-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 (clotiazepam), 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)-tropanecarboxylate (cocaine), 4,5α-epoxy-3-methoxy-17-methyl-7-morphinen-6α-ol (codeine), 5-(1-cyclohexenyl)-5-ethylbarbituric acid (cyclobarbital), cyclorphan, cyprin, Renorphin, 7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2(3H)-one (delorazepam), desomorphine, dextromoramide, (+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate (dextropropoxyphene), dezocine, diampromide, diamorphone, 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-morphinanediol (dihydromorphine), Dimenoxadol, Dimefetamol [sic-Tr.Ed.], Dimethylthiambutene, Dioxaphetyl 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), Ethoheptadine, Ethylmethylthiambutene, Ethyl-[7-chloro-5-(2-fluoro) phenyl)-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-trinorbornane-2-yl 7-[2-(α-methylphenethylamino)-ethyl]theophylline (fenethylline), 3-(α-methylphenethylamino)propionitrile (fenproporex), N-(1-phenethyl-4-piperidyl)propionanilide (fentanyl), 7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one (fludiazepam), 5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepin-2-(3H)-one (fludiazepam), flunitrazepam, 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2(3H)-one (flurazepam), 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one (halazepam), 10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolo[3,2-d][1,4]benzodiazepin-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]benzodiazepine-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-morphinanol (levorphanol), levophenacylmorphan (levophenacyl morphan), lofentanil, 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 (lormetazepam), 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 (mefenorex), meperidine, 2-methyl-2-propyltrimethylenedicarbamate (meprobamate), meptazinol, metazocine, 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 (methyprylon), 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-morphine-3,6α-diol (morphine), myrophine, (±)-trans-3-(1,1-dimethylethyl) nabilone, nalbuphen, nalorphine, narceine, nicomorphine, 1-methyl-7-nitro-5 -phenyl-1H-1,4-benzodiazepin-2(3H)-one (nimetazepam), 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, opium poppy species 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 plant parts of plants belonging to the Papaver species (including the subspecies setigerum), papaveretum , 2-imino-5-phenyl-4-oxazolidinone (pernoline), 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'-bipyridyl] 4'-carboxamide (piritramide), 7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (prazepam), profadol, proheptadine, promedol, properidine, propoxyphene, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl-{3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]propanoate}(leucine), mifentanil), 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) (1R)-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 (vinylbital), * ,2R * )-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (1R,2R,4S)-2-[dimethylamino]methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl l) cyclohexanol, in each case optionally in the form of the corresponding stereoisomeric compounds and also the corresponding derivatives, in particular esters or ethers, and in any case physiologically compatible compounds, in particular salts and solvates.

[0046]

[0050] In one embodiment, the pharmaceutical compositions of the present invention comprise, as the therapeutically active ingredient, one or more opioids, such as hydrocodone, morphine, oxycodone, hydromorphone and / or salts thereof.

[0047]

[0051] Typically, when processed into a suitable dosage form as described in more detail below, the drug will be present in such a dosage form in an amount normally prescribed therein, typically in an amount of from about 0.5 to about 25 percent on a dry weight basis based on the total weight of the formulation. In some embodiments, such amounts may 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 may 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 embodiments, the dosage form contains an amount of drug appropriate to provide a therapeutic effect.

[0048]

[0052] In some embodiments, the compositions of the present invention contain 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%, about 100%, about 101%, about 2%, 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] Components soluble in acidic solutions

[0053] In some embodiments, the pharmaceutical compositions of the present invention include one or more components that are soluble in acidic solutions. Acidic solutions are considered to be solutions with a pH of less than 7, from about 1 to about 4, from about 2 to about 5, 5 or less, etc. 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 solutions having a pH greater 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 particle matrix with the active pharmaceutical ingredient. The acid soluble component may 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 may affect the release of the active pharmaceutical ingredient depending on the pH of the environment. The pH of this environment may be increased or maintained by a buffer component and / or an antacid component depending on the amount of pharmaceutical composition ingested. When the pharmaceutical composition is ingested in an appropriate dosage, the active pharmaceutical ingredient may be released from the acid soluble component. When the pharmaceutical composition is ingested in excess, the pH buffering component is present in an amount that is not large enough to affect the gastrointestinal pH, thereby preventing the acid soluble component from dissolving and releasing the active pharmaceutical ingredient. When the pharmaceutical composition is ingested in excess, the pH buffering component is present in an amount that raises the gastrointestinal pH, thereby preventing the acid soluble component from dissolving and releasing the active pharmaceutical ingredient.

[0051]

[0055] In some embodiments, the acid soluble component forms a matrix and a substantial portion of the abuse-prone 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.

[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 28 wt%, about 18 wt% to about 28 wt%, about 20 wt% to about 28 wt%, about 22 wt% to about 28 wt%, about 24 wt% to about 28 wt%, about 26 wt% to about 28 wt%, about 28 ...%, about 28 wt%, about 28 wt%, about % 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 compositions of the present invention contain 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%, about 100%, about 101%, about %, 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%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121%, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131%, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 141%, about 1 6%, 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 are calcium carbonate, chitosan, polymers and copolymers such as polymethacrylates, for example Eudragit® (a cationic polymer having dimethylaminoethyl methacrylate as a functional group).

[0056] Buffering and / or antacid ingredients

[0060] In some embodiments, the pharmaceutical compositions of the present invention include one or more buffering and / or antacid components. Such components may increase the pH of the stomach if the pharmaceutical composition is consumed in inappropriate amounts and / or in amounts greater than typically prescribed for normal therapeutic use. In some embodiments, such ingredients can rapidly and sustainably raise the gastric pH to a pH above about 4 when the pharmaceutical composition is consumed in inappropriate amounts and / or in amounts greater than those typically prescribed for normal therapeutic use.

[0057]

[0061] Examples of suitable buffer components (e.g., first buffer component, second buffer component, or both first and second buffer 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, dihydroxyaluminum aminoacetate, sodium dihydroxyaluminum carbonate, glycine, magnesium glycinate, magnesium hydroxide, magnesium oxide, potassium bicarbonate, sodium bicarbonate, sodium potassium tartrate, tribasic sodium phosphate, and tricalcium phosphate.

[0058]

[0062] In some embodiments, the buffer component (e.g., the first buffer component, the second buffer component, or both the first and second buffer components) comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. In some embodiments, the buffer 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 buffer component (e.g., the first buffer component, the second buffer component, or both the first and second buffer components) and / or the antacid component may be included in an amount that does not affect gastric pH when the pharmaceutical composition is taken in an appropriate therapeutic amount, but that raises gastric pH when the pharmaceutical composition is taken in an excess amount, e.g., an amount greater than that typically prescribed for normal therapeutic use. In some embodiments, an appropriate therapeutic amount refers to one or two tablets or doses, while an excess amount refers to three or more tablets or doses. In some embodiments, the buffer component and / or antacid component is 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 compositions of the present invention comprise a buffer component (e.g., a first buffer component, a second buffer component, or each of the first and second buffer 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% of the pharmaceutical composition. ,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%, Approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 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.

[0061]

[0065] In some embodiments, a component may be an acid-soluble component, a buffer component (e.g., a first buffer component, a second buffer component, or both the first and second buffer components) and / or a control component. It may also act as an acid component. Examples of suitable such components are calcium carbonate, di- and tribasic calcium phosphate, and magnesium hydroxide.

[0062]

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

[0063]

[0067] In some embodiments, the delayed release buffer component is in solid form, hi some embodiments, the delayed release buffer 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 buffer 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 buffer component (e.g., the delayed release buffer 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., >pH 5).

[0065]

[0069] In some embodiments, the delayed release buffer component is insoluble at a pH of 5 or less, 4.5 or less, 4 or less, about 1 to about 5, about 1 to about 4.5, about 1 to about 4, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5. In some embodiments, the delayed release buffer component is soluble at a pH of 5 or more, 5.5 or more, 6 or more, 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.

[0066]

[0070] In some embodiments, the delayed release buffer component comprises an enteric agent 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 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 buffer component comprises a core and a shell surrounding or substantially surrounding the core. In some embodiments, the shell comprises an enteric coating of the delayed release buffer component. In some embodiments, the core comprises a second buffer component of the delayed release buffer component.

[0068]

[0072] In some embodiments, the delayed release buffer component further comprises a subcoating. The subcoating can provide sustained release to the material in the core, such as the second buffer component in the core. Suitable materials for the subcoating include, but are not limited to, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, povidone, and mixtures thereof. In some embodiments, the subcoating is used to separate the enteric agent from the second buffer component. In certain embodiments that include a shell that includes an enteric agent and a core that includes 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 yet 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 interspersed with, coated with, surrounds, or substantially coats or substantially surrounds the second buffer component. In some embodiments that include a core that includes a second buffer component, the core may further include 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 buffer component in the same way that the first acid-soluble component delays the release of the active pharmaceutical ingredient. For example, the acid-soluble component (e.g., the second acid-soluble component) can delay the release of the second buffer component until the first buffer component has passed through the stomach environment and / or until gastric acid secretion lowers the pH to acidic conditions again, e.g., 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 amino methacrylate 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] Ingredients that extend gastric emptying time

[0075] In some embodiments, it has been found that combining an extended gastric emptying time (i.e., increasing the amount of time the components of the dosage form reside in the stomach before passing into the small intestine) with a self-regulating abuse-deterrent dosage form synergistically improves the abuse-deterrent properties of the dosage form.

[0072]

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

[0073]

[0077] The ingredient useful for increasing gastric emptying time may be any drug or active ingredient known to act as a gastric emptying time extender. In some embodiments, the ingredient for increasing gastric emptying time may be loperamide, diphenoxylate, atropine, difenoxin, anticholinergics, antidepressants, opioids, antidiarrheals, and / or gastroparesis-inducing drugs.

[0074]

[0078] In some embodiments, a component useful for increasing 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 may be locally delivered from the dosage form, preferably in an amount that does not result in any substantial systemic effect on the subject, are anticholinergics, such as propantheline, and other drugs, including, but not limited to, methylcellulose, guar gum, triglyceride esters, fats, such as triethanol myristate, fatty acids of 10 to 15 carbon atoms.

[0075]

[0079] In some embodiments, the present invention provides a method for treating a pulmonary circulation disorder (PCH) in a dosage form that, when abused, max and / or C maxIn one embodiment, this occurs when three or more dosage forms are consumed simultaneously or at about the same time.

[0076]

[0080] In some embodiments, the compositions of the present invention comprise 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 emptying time extending component by weight percentage of the composition or final dosage form.

[0077]

[0081] In some embodiments, the compositions of the present invention may be present in an amount, by weight percentage of the composition or final dosage form, 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 2%, 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 emptying time extending component.

[0078] Ingredients that reduce stomach acid production

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

[0079]

[0083] In some embodiments, the pharmaceutical compositions of the present invention include one or more ingredients that reduce the production of gastric acid (i.e., gastric acid secretion inhibitors). In some embodiments, the inclusion of a gastric acid production reducing ingredient synergistically improves the abuse-deterrent properties of the dosage form. In some embodiments, the gastric acid production reducing ingredient is present in a sub-therapeutic amount when taken at the intended dose (e.g., 1 or 2 tablets), but is present in a therapeutic amount when taken at greater than the intended dose (e.g., 3 or more tablets, e.g., 4, 5, 6, 7, or 8 tablets). The pharmaceutical compositions of some embodiments of the present invention are intended to Therapeutic doses of gastric acid secretion inhibitors, as provided when taken in larger doses, can delay the time until stomach reacidification.

[0080]

[0084] In some embodiments, the component that reduces gastric acid production is in a core that is surrounded or substantially surrounded by a shell. In some embodiments, the shell comprises an enteric coating. The enteric coating 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 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.

[0081]

[0085] In some embodiments, the inclusion of one or more ingredients that reduce stomach acid production results in a reduction in acid 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 compositions of the present invention may be present in a weight percentage of the composition or final dosage form of about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 1%, about 0.05% to about 0.5%, about 0.05% to about 0.1%, about 1% to about 15%, about 2.5% to about 25%, or a mixture thereof. %, 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 a gastric acid production reducing component.

[0083]

[0087] In some embodiments, the compositions of the present invention may be present in an amount of 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 %, approx. 32%, approx. 33%, approx. 34%, approx. 35%, approx. 36%, approx. 37%, approx. 38%, approx. 39%, approx. 40%, approx. 41%, approx. 42%, approx. 43%, approx. 44%, approx. 45%, approx. 46%, approx. 47%, approx. 48%, approx. 49%, approx. 50%, approx. 51%, approx. 52%, approx. 53%, approx. 54%, approx. 55%, approx. 56%, approx. 57%, approx. 58%, approx. 59%, approx. 60%, approx. 61%, approx. 62%, approx. 63%, approx. 64%, approx. 65%, approx. 66%, approx. 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 acid production reducing component.

[0084] Additional Ingredients

[0088] The present invention optionally includes other ingredients for enhancing the manufacture of a dosage form from the pharmaceutical composition of the present invention and / or for modifying the release profile of a dosage form comprising the pharmaceutical composition of the present invention. It can also include:

[0085]

[0089] Some embodiments of the present invention include one or more pharma- ceutically acceptable fillers / diluents. In one embodiment, Avicel PH (microcrystalline cellulose) is the filler used in the formulation. Avicel PH may have an average particle size ranging from 20 to about 200 μm, preferably about 100 μm. The density is 1.512 to 1.668 g / cm. 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 by weight of the solid basis of the formulation. Typical bulking agents may be present in an amount of 10 to 65 percent by weight based on the dry weight of the total composition. Other ingredients may include sugars and / or polyols. Lactose may also be included, having a particle size of about 20 to about 400 microns and a density of about 0.3 to about 0.9 g / ml.

[0086]

[0090] In some embodiments of the present invention, the filler not only imparts cohesiveness to the materials in the formulation, but also functions as a binder in that it can increase the bulk weight of the directly compressible formulation (described below) to achieve a formulation weight acceptable for direct compression (tabletting) processes. In some embodiments, the additional filler does not need to provide the same level of cohesiveness as the selected binder, but can contribute to the uniformity of the formulation as well as make the formulation less likely to separate once blended. Additionally, suitable fillers do not adversely affect the flow properties of the composition or the dissolution profile of the formed tablets.

[0087]

[0091] In one embodiment, the present invention can include one or more pharma- ceutically acceptable disintegrants. Such disintegrants are known to those skilled in the art. In the present invention, the disintegrants can be, 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 to 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. Additionally, the disintegrant can minimize segregation and provide an immediate release profile to the formulation. In some embodiments, the disintegrant is present in an amount of about 2 to about 25 weight percent based on the solids of the directly compressible formulation. Furthermore, the antacid added to the formulation can also aid in tablet disintegration through effervescence of the antacid component when the tablet is introduced to a low pH environment, potentially reducing the need for additional disintegrants.

[0088]

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

[0089]

[0093] In one embodiment, the present invention can include one or more pharma- ceutically acceptable lubricants, such as, but not limited to, magnesium stearate. In one embodiment, 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 embodiment, the lubricant, such as stearate, Magnesium phosphate can aid in processing by contributing to reduced friction between the die wall and the pharmaceutical composition of the present invention during compression (tabletting), and also making the tablet easier to eject. In some embodiments, the lubricant also reduces adhesion to the punch and die and / or aids in the flow of the powder into the hopper and / or die. In embodiments of the present invention, a lubricant having a particle size of about 5 to about 50 microns and a density of about 0.1 to about 1.1 g / ml, such as magnesium stearate, is used in the pharmaceutical composition. In certain embodiments, the lubricant should comprise about 0.1 to about 2 weight percent of the formulation on a solids basis. Suitable lubricants are stable and do not polymerize within the formulation once mixed. Other lubricants known or being developed in the art that exhibit acceptable or equivalent properties include stearic acid, hydrogenated oils, sodium stearyl fumarate, polyethylene glycol, and Lubritab®.

[0090] Dosage form functionality

[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 excess dose of the active pharmaceutical ingredient. In some embodiments, the pharmaceutical formulations can be designed to have pH-modulating 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 stomach environment based on whether the pharmaceutical composition is ingested in an appropriate dose or in an excess. The pH-modulating properties can be provided by including one or more buffering 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 inhibiting or releasing the active pharmaceutical ingredient depending on the pH of the stomach 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 ingested in an appropriate amount, the pH adjusting property has a minimal effect (i.e., the pH of the stomach environment is not substantially adjusted or is maintained at a desired level) and the pH dependent solubility property has a minimal effect (i.e., the active pharmaceutical ingredient is released), thereby allowing the release and / or absorption of the active ingredient. However, when the pharmaceutical composition is ingested in an excessive amount, in some embodiments, the composition is formulated such that the pH adjusting property has a maximal effect (i.e., increases the pH of the stomach environment) and the pH dependent solubility property has a maximal effect (i.e., the acid soluble ingredient does not dissolve because it is not soluble), thereby 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 surrounding the matrix at the time the pharmaceutical composition is ingested: in a low pH environment (i.e., pH 1-4), the matrix is ​​likely to dissolve and release the drug rapidly, whereas in a high pH environment (i.e., pH > 4), the matrix is ​​likely to become insoluble and release of the drug is delayed and perhaps incomplete, thereby reducing the levels of drug absorbed.

[0093]

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

[0094]

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

[0095]

[0099] Under conditions where an overdose is ingested (e.g., 3 tablets or more), the amount of buffering and / or antacid components from the overdose may in turn be sufficient to rapidly and persistently raise the gastric pH (e.g., pH > 4), and thus the acid-soluble drug matrix may be less likely to dissolve in the high pH gastric environment, inhibiting drug release from the matrix.

[0096]

[0100] In some embodiments, the inhibition of the drug from the acid-soluble matrix is This is further aided by gastrointestinal transit which may move the acid-soluble matrix particles into the intestine and lower gastrointestinal tract, which has a controlled high pH environment (ie, pH 5.5-8).

[0097]

[0101] In some embodiments, the overall inhibition of drug release upon overdose is greater than or equal to normal gastric pH (i.e., pH 1-4) compared to an equivalent oral dose that releases drug at max Increase in and / or C maxThis results in a pharmacokinetic profile having a decrease in

[0098]

[0102] In some embodiments, the component that reduces gastric acid production slows the time to stomach reacidification. As a result, the high pH of the stomach environment is prolonged, enhancing the inhibition of active drug release in the event of overdosing (ie, 3 or more doses or tablets).

[0099]

[0103] In some embodiments, the component that reduces stomach acid is the p of the surrounding medium (e.g., the stomach environment). It is not released from the pharmaceutical composition until H is high, e.g., greater than about 4, greater than about 4.5, or greater than about 5. At such high pH, ​​components in contact with or coating the stomach acid reducing component dissolve.

[0100]

[0104] In some embodiments, the second buffer component is a buffer that is The delayed release buffer component is not released from the delayed release buffer component until the pH is high, e.g., greater than about 4, greater than about 4.5, or greater than about 5. At such high pH, ​​the enteric agent in the delayed release buffer component dissolves. In some embodiments, the release of the second buffer component can be further delayed by including an acid soluble component, as previously described herein.

[0101]

[0105] In some embodiments, the delayed release buffer component is released when the high pH of the stomach environment is maintained. By extending the time between the release of the active agent and the release of the active agent, the inhibition of the release of the active agent in the case of an overdose (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, an active pharmaceutical 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 coating. In some such embodiments, the delayed release buffering component serves to prevent re-acidification for a period of 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 a second buffering component and an enteric coating prevents re-acidification of the stomach environment for more than 1 hour, more than 2 hours, or more than 3 hours. In some embodiments, the combination of the first buffering component and the delayed release buffering component comprising a second buffering component and an enteric coating prevents re-acidification of the stomach for a period of time longer than the first buffering component alone.

[0102] Manufacturing method

[0106] In some embodiments, the pharmaceutical composition comprises an active pharmaceutical ingredient in an acid-soluble component and optionally It can be prepared by intimate mixing by any suitable method. In one embodiment, the method is a dry or wet granulation method. In some embodiments, the particle matrix is ​​particulate or In another embodiment, the method is hot melt extrusion. Without wishing to be bound by theory, hot melt extrusion may provide more intimate contact between two or more components used in the present invention than mixing or other composite forming methods.

[0103]

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

[0104]

[0108] In one aspect, the present invention provides a pharmaceutical composition comprising a drug susceptible to abuse, an acid soluble component, a buffer component, and a dosage form comprising an abuse-deterrent pharmaceutical composition comprising a component that extends gastric emptying time, the dosage form being 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 made from the pharmaceutical composition of the present invention. The dosage form can be any shape, including regular or irregular, depending on the needs of the practitioner.

[0105]

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

[0106]

[0110] dosage forms, including various controlled release dosage forms, and / or methods of making abuse-deterrent pharmaceutical compositions; and the incorporation of one or more layers is known in the art and is described, for example, in U.S. Pat. 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 entireties.

[0107]

[0111] The one or more components may be any of those described herein with respect to certain components. The nanoparticles may be present in layers, through-holes or in a "core-shell" type arrangement.

[0112] In some embodiments, one or more of the components or particles, granules, or layers are described in U.S. Pat. The active ingredient may be sequestered as described in Publication No. 20120202839, which is incorporated herein by reference in its entirety. Abuse-deterrent pharmaceutical compositions comprising an immediate release unit dose of a pharma- ceutical active ingredient, an acid-soluble ingredient, and a buffering ingredient are described in U.S. Patent No. 9,101,636, which is incorporated herein by reference in its entirety.

[0108]

[0113] The present invention can be used to prepare immediate release formulations as well as controlled drug release formulations. Controlled release formulations can include delayed release, bimodal and tripadical release, extended and sustained release oral solid dosage formulations.

[0109] Usage

[0114] In one aspect, the present invention provides a method for treating a disease that is alleviated by a drug susceptible to abuse. With respect to therapy, the method includes administering to a subject in need thereof an abuse-deterrent pharmaceutical composition that includes an abuse-prone drug, an acid-soluble component, a buffering component, and a gastric emptying time-prolonging component.

[0110]

[0115] In one aspect, the present invention provides a method for treating a disease that is alleviated by a drug susceptible to abuse. With respect to therapy, the method includes administering to a subject in need thereof a dosage form comprising an abuse-deterrent pharmaceutical composition comprising an abuse-prone drug, an acid-soluble component, a buffering component, and a gastric emptying time extending component, the dosage form being a food bar or a beverage.

[0111]

[0116] In one aspect, the present invention provides a method for treating a disease that is alleviated by a drug susceptible to abuse. For therapy, the method includes administering to a subject in need thereof an abuse-deterrent pharmaceutical composition comprising an abuse-prone drug, an acid-soluble component, and a buffer component, and a composition for extending gastric emptying time comprising a component for extending gastric emptying time. In some embodiments, the abuse-deterrent pharmaceutical composition is administered before the composition for extending gastric emptying time, after the composition for extending gastric emptying time, or simultaneously with the composition for extending gastric emptying time. In some embodiments, the component for extending gastric emptying time is a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, an amino acid, a peptide, a protein, a fatty acid, a monoglyceride, a diglyceride, or a triglyceride. In some embodiments, the component for extending gastric emptying time is loperamide, diphenoxylate, atropine, difenoxin, an anticholinergic, an antidepressant, an opioid, an antidiarrheal agent, or a gastroparesis-inducing agent.

[0112]

[0117] In one aspect, the present invention provides a method for treating a disease that is alleviated by a drug susceptible to abuse. With respect to therapy, the method includes administering to a subject in need thereof an abuse-deterrent pharmaceutical composition comprising an abuse-prone drug, an acid-soluble component, and a buffering component, and a dosage form comprising a composition for prolonging gastric emptying time, the composition comprising an ingredient for prolonging gastric emptying time, the dosage form being a food bar or a beverage.

[0113]

[0118] The uses include drugs susceptible to abuse, acid-soluble components, buffer components, and gastric emptying. The present invention also includes a method of deterring abuse of a pharmaceutical composition comprising an ingredient for increasing gastric emptying time and / or increasing gastric residence time, the method comprising increasing gastric emptying time and / or increasing gastric residence time in a subject who has ingested more dosage units of the composition than recommended or prescribed.

[0114]

[0119] In some embodiments, the gastric The drainage time can be extended in a subject 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.

[0115]

[0120] Similarly, in some embodiments, the composition or dosage form may be more effective than one that does not include the features of the present invention. Thus, gastric emptying time or residence time can be increased 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] The method to deter abuse is to ensure that the drug taken is taken at a higher dose than recommended or prescribed. It may also include an increase in the gastric residence time of a certain percentage of the drug when it is part of a composition of the invention in a subject who ingests a dosage unit (e.g., 3, 4, 5, 6, 7, 8, etc., or more dosage units) of the composition.

[0117]

[0122] In some embodiments, the drug may reduce gastric upset compared to compositions or dosage forms that do not include the features of the invention. The residence time is 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%, about 100%, about 101%, about 102%, about 1 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%, It can be extended to 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, the drug may reduce gastric upset compared to compositions or dosage forms that do not include the features of the invention. The residence 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 drug taken at one time.

[0119]

[0124] In some embodiments, the drug may reduce gastric upset compared to compositions or dosage forms that do not include the features of the invention. The 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% relative to a certain percentage of the total amount of drug ingested at one time.

[0120]

[0125] Certain aspects of the present invention can be better understood as illustrated by the following examples. It will be understood that these examples are illustrative and not intended to be limiting. EXAMPLES

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

[0126] Clinical Study AP-LTX-400 (Study 400) Hydromorphone HCL 2 mg formulations were used: LTX-04S and LTX-04P. Both were the same microparticle formulation but with different amounts of buffering agent (5 and 9 mEq buffer capacity, respectively). Study 400 was designed for two sequential cohorts. In cohort 1, the two test formulations were compared against the reference product, Dilaudid® tablets 2 mg, at 1, 2, and 3 tablets. In cohort 2, the LTX-04P test formulation was tested and compared against the reference product at 4, 6, and 8 tablets, representing excess oral consumption.

[0122]

[0127] In cohort 1, microparticles were sufficient to deliver hydromorphone to intended levels. In addition, the peak plasma drug concentration (C max It was also observed that approximately a 20% reduction in peak plasma drug concentration (C ) was achieved. Furthermore, three tablets of LTX-04P (27 mEq buffer) achieved a significantly higher peak plasma drug concentration (C ) than three tablets of LTX-04S (15 mEq buffer). max) was also observed to demonstrate a 28% reduction in pH, indicating that a threshold buffer concentration had been achieved to facilitate the intentional reduction of peak drug concentrations. Subject in vivo pH monitoring demonstrated that three LTX-04P tablets rapidly raised gastric pH above pH 4 within minutes of administration and back to baseline low pH approximately 30 minutes later, whereas three LTX-04S tablets did not significantly raise the pH above 3 over the same time course.

[0123]

[0128] In cohort 2 of study 400, LTX-04P tablets were compared with the reference product and Similar to the three LTX-04P tablets in cohort 1, four, six, and eight tablets also showed approximately 20% reduction in peak plasma drug concentrations compared to a single dose of LTX-04P. These results are consistent with the in vitro multi-tablet acid challenge analysis, which showed a gradual decrease in drug release with increasing tablet number. For example, the drug release of 8 tablets after 1 hour was reduced by approximately 70% compared to 100% drug release of 1 tablet at 1 hour. However, the C max The in vivo reduction in was approximately the same as for the three tablets, despite the introduction of 2.7-fold greater buffering capacity to the gastric environment.

[0124] Example 2: Self-regulating formulation with extended gastric emptying time

[0129] To demonstrate the synergistic effect of prolonged gastric emptying time with the autoregulating formulation, AP-LTX-401 compared the human pharmacokinetics of an autoregulatory hydromorphone HCl 2 mg formulation, LTX-04P3, in a prolonged gastric emptying model. A first group of 13 subjects received seven LTX-04P3 tablets with 240 mL of water. A second group of 15 subjects received seven LTX-04P3 tablets with 240 mL of 20% w / v glucose in water, a solution known to prolong gastric emptying. A control group of 30 subjects received seven tablets of generic hydromorphone HCl, 2 mg, with 240 mL of water.

[0125]

[0130] Coadministration of seven tablets of LTX-04P3 with glucose increased peak plasma hydrochloride Geometric mean time to sulfonate concentration (T max ) is the T of LTX-04P3 taken with water. max A significant increase in T was observed in subjects treated with glucose compared to subjects without glucose, from 1.22 h to 2.05 h (Figure 1). max represents a 168% increase in the release of the drug. Because glucose delayed gastric emptying (prolonged gastric retention), the autoregulatory buffer components remained in the stomach for a longer period, enhancing the delayed release of the drug (improving the efficacy of autoregulation).

[0126]

[0131] The effect of prolonging gastric retention was measured by the geometric mean peak hydromorphone plasma concentration (C max The glucose-mediated C of LTX-04P3 tablets was not adversely affected by the ability of the autoregulatory formulation to reduce max C compared with generic hydromorphone, as well as LTX-04P3 coadministered with water. max The compound retained its ability to provide a reduction in

[0127] Example 3: Exemplary Formulations and Methods

[0132] An example of a formulation and method for producing acid-soluble granules is as follows.

[0133] acid soluble granules

[0128] [Table 1]

[0129]

[0134] Preparation of acid soluble granules:

[0135] 1. Blend oxycodone and Eudragit E homogeneously;

[0136] 2.Hot melt extrusion of the blend at 160℃; Recover the extruded material;

[0137] 3. Oxycodone-Eudragit E extrudate is mixed with cyclodextrin by vibratory granulator. sieving; collecting the sieved granules (<600 μm);

[0138] Examples of formulations and methods for producing delayed release buffer components containing a gastric acid reducing agent are as follows: That is correct.

[0130]

[0139] Delayed release buffer component having a stomach acid reducer

[0131] [Table 2]

[0132]

[0140] Method for preparing delayed release buffer composition having gastric acid reducing agent

[0141] 1. Blend magnesium oxide and microcrystalline cellulose evenly;

[0142] 2. The blend is roller compacted and sized by an oscillating granulator. The dried granules (>250 μm) are collected.

[0133]

[0143] 3. Add Eudragit E PO subcoating A dispersion to a sufficient amount of water. Manufactured using and maintain constant mixing

[0144] 4. Apply Opadry Clear / Famotidine subcoating B solution. First prepare the Opadry Clear by mixing it with a sufficient amount of water. Then add the Famotidine to Subcoating B and distribute evenly while maintaining constant mixing.

[0134]

[0145] 5. Add the Eudragit L 30D enteric coating dispersion to a sufficient amount of water. The mixture is prepared using a mixing roller to maintain constant mixing.

[0146] 6. Place the dried granules in a fluid bed coater and coat with approximately 10% Eudragit E. PO subcoating A is applied to the buffer granules by bottom spray technique. Once applied, the Eudragit E PO subcoating A is allowed to dry thoroughly. Then, using the same fluid bed technique, apply sufficient Opadry Clear / Famotidine subcoating B solution to provide 2 mg of Famotidine per dose. Once applied, the Opadry Clear / Famotidine subcoating B is allowed to dry thoroughly. Then, using the same fluid bed technique, approximately 10% (w / w) of Eudragit L 30% dispersion is applied to the subcoat A&B granules and allowed to dry thoroughly.

[0135]

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

[0148] An example of a formulation and process for producing oxycodone self-regulating tablets is as follows: do.

[0136]

[0149] Oxycodone self-regulating tablets

[0137] [Table 3]

[0138]

[0150] Method for manufacturing oxycodone self-regulating tablets

[0151] 1. Oxycodonic acid soluble granules, Effersoda 12, enteric coated The mixed magnesium oxide / famotidine granules, glycine and crospovidone are homogeneously blended.

[0139]

[0152] 2. Add magnesium stearate to the blend and final blend for an additional 3 minutes. do.

[0153] 3. The final blend is then pressed into a modified oval tablet tooling. Transfer the mixture to a rotary tablet press equipped with a press-type press. Compress tablets to a hardness of 8-12 kP.

[0140] Aspects of the present invention also include the following. Aspect 1. An abuse-deterrent pharmaceutical composition comprising: Drugs that are prone to abuse; a first acid soluble component; a first buffer component; and A delayed release buffer component; A composition comprising: Aspect 2. The composition of aspect 1, wherein the first acid-soluble component comprises calcium carbonate, a cationic copolymer, or a combination thereof. Example 3. The composition of example 2, wherein the cationic copolymer comprises one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. Aspect 4 The composition of any of Aspects 1-3, wherein the first buffer component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. Aspect 5. The composition of any of Aspects 1-4, wherein the delayed release buffer component comprises a second buffer component, an enteric agent, and a sustained release component. Embodiment 6. The composition of embodiment 5, wherein the delayed release buffer component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, wherein the core comprises a second buffer component, the shell comprises an enteric agent, and the subcoat comprises a sustained release component. Aspect 7 The composition of any of Aspects 1-4, wherein the delayed release buffer component comprises a second buffer component, an enteric agent, and a second acid-soluble component. Embodiment 8. The composition of embodiment 7, wherein the delayed release buffer component comprises a core, a shell surrounding the core, and a subcoat between the core and the shell, wherein the core comprises a second buffer component, the shell comprises an enteric agent, and the subcoat comprises a second acid-soluble component.

[0023] Aspect 9. The composition of aspect 8, wherein the second acid-soluble component comprises calcium carbonate, a cationic copolymer, or a combination thereof. Example 10. The composition of example 9, wherein the cationic copolymer comprises one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. Embodiment 11 The composition of any of embodiments 10-13, wherein the second acid-soluble component is the same as the first acid-soluble component. Aspect 12. The composition of any of aspects 5-11, wherein the second buffer component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. Embodiment 13 The composition of any of embodiments 5 to 12, wherein the second buffer component is the same as the first buffer component. Aspect 14. The composition of any of aspects 5-13, wherein 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. Aspect 15. The composition of any of aspects 1 to 14, further comprising an ingredient for reducing gastric acid production. Embodiment 16. The composition according to embodiment 15, wherein the component for reducing gastric acid production comprises an H2-antagonist. Embodiment 17. A composition according to embodiment 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. Embodiment 18. The composition of any of embodiments 1-17, further comprising a component for increasing gastric emptying time. Aspect 19. The composition of aspect 18, wherein the ingredient for increasing gastric emptying time is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, amino acids, peptides, proteins, fatty acids, monoglycerides, diglycerides, and triglycerides. Aspect 20. The composition of aspect 18, wherein the ingredient for increasing gastric emptying time is selected from the group consisting of loperamide, diphenoxylate, atropine, difenoxin, anticholinergics, antidepressants, opioids, antidiarrheals, and gastroparesis-inducing agents. Aspect 21 The composition of any of aspects 18-20, wherein when ingested by a subject, the component for increasing gastric emptying increases gastric emptying time in the subject. Aspect 22. A dosage form comprising the composition of any one of aspects 1 to 21. Aspect 23. The dosage form of aspect 22, wherein the dosage form is a food bar or a beverage. A method for treating a disease alleviated by a drug susceptible to abuse, comprising: A method comprising administering to a subject in need thereof a composition according to any one of aspects 1 to 21. Aspect 25. The method of aspect 24, further comprising administering a composition for increasing gastric emptying time, wherein the abuse-deterrent pharmaceutical composition is administered before the composition for increasing gastric emptying time, after the composition for increasing gastric emptying time, or simultaneously with the composition for increasing gastric emptying time. Aspect 26. The method of aspect 25, wherein the component for increasing gastric emptying time is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, amino acids, peptides, proteins, fatty acids, monoglycerides, diglycerides, and triglycerides. Aspect 27. The method of aspect 25, wherein the ingredient for increasing gastric emptying time is selected from the group consisting of loperamide, diphenoxylate, atropine, difenoxin, anticholinergics, antidepressants, opioids, antidiarrheals, and gastroparesis-inducing agents. Aspect 28. The method of any of aspects 25 to 27, wherein the ingredient for increasing gastric emptying time is included in a dosage form, and the dosage form is a food bar or a beverage.

[0154] Those skilled in the art will appreciate that numerous variations and / or modifications to the invention as shown in the specific embodiments are possible without departing from the spirit and scope of the invention as broadly described. Additionally, each and every reference cited above is incorporated herein by reference as if fully set forth herein.

Claims

1. 1. An abuse-deterrent pharmaceutical composition comprising: Opioid drugs that are prone to overdose; a first acid soluble component; a first buffer component; a delayed release buffer component; and Ingredients to extend gastric emptying time Including, wherein the first acid-soluble component forms a matrix to isolate the opioid drug susceptible to overdose from the delayed release buffer component and the component for extending gastric emptying time, and the first acid-soluble component is a cationic polymer or copolymer; the delayed release buffer component constitutes a core, a shell surrounding the core, and a subcoat between the core and the shell, the core comprises a second buffer component, the shell comprises an enteric component, the subcoat comprises a second acid-soluble component, and the second acid-soluble component comprises a cationic polymer or copolymer, and the component for extending gastric emptying time is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, amino acids, peptides, proteins, fatty acids, monoglycerides, diglycerides, and triglycerides. composition.

2. 10. The composition of claim 1, wherein the cationic polymer or copolymer comprises one or more of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

3. 3. The composition of claim 1 or 2, wherein the first buffer component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof.

4. The composition of any one of claims 1 to 3, wherein the ingredient for increasing gastric emptying time is selected from the group consisting of loperamide, diphenoxylate, atropine, difenoxin, anticholinergics, antidepressants, opioids, antidiarrheals, and gastroparesis-inducing agents.

5. The composition of any one of claims 1 to 4, wherein the second acid-soluble component is the same as the first acid-soluble component.

6. The composition of any one of claims 1 to 5, wherein the second buffer component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof.

7. The composition of any one of claims 1 to 6, wherein the second buffer component is the same as the first buffer component.

8. 8. The composition of any one of claims 1 to 7, wherein 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.

9. The composition of any one of claims 1 to 8, further comprising an ingredient for reducing stomach acid production.

10. The composition of claim 9, wherein the component for reducing stomach acid production comprises an H2-antagonist.

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

12. 12. The composition of any one of claims 1 to 11, wherein when ingested by a subject, the component for increasing gastric emptying increases the gastric emptying time of the subject.

13. A formulation comprising a composition according to any one of claims 1 to 12.

14. A composition according to any one of claims 1 to 12 for use in treating a disease alleviated by an opioid drug susceptible to overdose.

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