Self-regulated release of active pharmaceutical ingredient

Abstract

To provide a composition that deters abuse and minimizes or reduces the potential for physical or physiological dependency.SOLUTION: An abuse deterrent pharmaceutical composition comprises: a. a pharmaceutically active ingredient; b. an acid soluble ingredient comprising a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate; and c. a buffering ingredient. The buffering ingredient is present in an amount sufficient to suppress peak plasma concentration (Cmax) of the pharmaceutically active ingredient, when the composition is ingested in excess of a dosage appropriate for providing a therapeutic effect. The pharmaceutically active ingredient is a psychoactive drug or analgesic.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 61 / 731,901, filed on November 30, 2012, with the title "Methods and Compositions for Self - Regulated Release of Active Pharmaceutical Ingredients", the entire content of which is incorporated herein by reference.

Background Art

[0002] The class of drugs that exhibit opioid or morphine - like properties are referred to as opioids or opioid agonists. As agonists, certain drugs are characterized by interacting with stereospecific and saturable binding sites in the brain, as well as in other body tissues and organs. Endogenous opioid - like peptides are present in regions of the central nervous system that are presumed to be involved in the regulation of pain perception; movement, mood, and behavior; and neuroendocrine functions. Three classical opioid receptor types, mu (μ), delta (δ), and kappa (κ), have been widely studied. Each of these three receptors shows a unique anatomical distribution in the brain, spinal cord, and periphery. Most clinically utilized opioids are relatively selective for the μ - receptor, reflecting their similarity to morphine. However, opioid - containing drugs that are relatively selective for a particular receptor subtype at standard therapeutic doses often interact with multiple receptor subtypes when given at sufficiently high doses, which can lead to a change in their pharmacological effects. This is especially true when opioid doses are gradually increased and tolerance is exceeded.

[0003] The potential for the development of tolerance, physical and / or physiological dependence (i.e., habituation) due to repeated use of opioids is a characteristic feature of most drugs containing opioid analgesics. The potential for habituation is one of the main concerns in the use of opioids for pain management. Another major concern associated with the use of opioids is the diversion of these drugs from patients who legitimately have pain to other individuals (non-patients) for recreational purposes.

[0004] Drug abusers and / or addicts typically obtain a solid dosage form intended for oral administration containing one or more opioid analgesics and, by 1) injection, 2) inhalation, and / or 3) oral ingestion in amounts exceeding typical therapeutic dosages for such drugs, perform crushing, shearing, grinding, chewing, dissolving and / or heating, extraction, or other improper processing or destruction of the unit dosage form so that most or even all of the active drug can be administered.

[0005] There are three basic behavioral patterns leading to opioid abuse. The first involves individuals who start using opioid drugs in the context of legitimate medical treatment and initially receive the drugs from a properly authorized healthcare provider by prescription. Through devious means, such individuals may ultimately seek prescriptions for drug supplies far exceeding their legitimate medical needs from illicit sources that are diversions from multiple healthcare providers and / or pharmacies and / or other legal drug distribution channels. The second pattern of abuse starts with experimental or "recreational" drug users who do not have a legitimate medical indication for drugs prone to abuse and who seek a "high". The third pattern of abuse involves users who start using by any of the methods described above and ultimately switch to orally administered drugs obtained from an organized legitimate addiction treatment program.

[0006] The routes of administration commonly available to abusers for the abuse of opioid-containing drug formulations are various There are. As the most common methods, 1) parenteral (e.g., intravenous injection), 2) intranasal (e.g., nasal aspiration), and 3) repeated oral ingestion of an excessive amount, such as oral administration of tablets or capsules, can be cited. One mode of abuse of oral solid drugs is to first mix the dosage form with a suitable solvent (e.g., water), and then extract the opioid component from the mixture for use as a solution suitable for intravenous injection of an opioid to obtain a "euphoric state".

[0007] Attempts have been made to reduce the potential for abuse of drugs administered orally. Such attempts have generally focused on including in the oral dosage form an antagonist that is inactive orally but substantially blocks the effect of the drug when an attempt is made to dissolve the drug and administer it parenterally.

Summary of the Invention

[0008] Despite all attempts, the misuse and abuse of pharmaceuticals continue to increase. There is an ongoing and clear need for new and effective methods and compositions for deterring the abuse of pharmaceuticals (e.g., orally administered pharmaceuticals), including but not limited to immediate release, sustained release or extended release, and delayed release formulations of drugs that are prone to abuse. In particular, methods and compositions that deter abuse and minimize or reduce the potential for physical or physiological dependence would be useful for opioid analgesics for patients seeking drug therapy.

[0009] According to an embodiment of the present invention, an abuse-deterrent pharmaceutical composition comprises a pharmaceutically active ingredient; an acid-soluble ingredient; and a buffering ingredient. In certain embodiments, the acid-soluble ingredient and the buffering ingredient suppress the release of the pharmaceutically active ingredient when the composition is ingested in amounts exceeding the intended dosage.

[0010] In certain embodiments, the pharmaceutically active ingredient is a drug that is prone to abuse. In certain embodiments, the pharmaceutically active ingredient is a drug having a narrow therapeutic index. In certain embodiments, the acid-soluble component can include calcium carbonate, a cationic copolymer, or a combination thereof. In certain embodiments, the acid-soluble component includes a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. The acid-soluble component may be present in an amount of from about 1 wt% to about 40 wt% of the pharmaceutical composition.

[0011] In certain embodiments, the pharmaceutically active ingredient is housed within the matrix of the acid-soluble component. In certain embodiments, the buffering component can include calcium carbonate, sodium bicarbonate, magnesium oxide, trisodium phosphate, or a combination thereof. The buffering component may be present in an amount of from about 45 wt% to about 95 wt%.

[0012] The present invention will be understood in more detail by examining the following drawings that illustrate certain characteristics of the present invention.

Brief Description of the Drawings

[0013]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Modes for Carrying Out the Invention

[0014] Regarding the drawings, features that are the same throughout the drawings are denoted by the same reference numerals. In one embodiment, the formulations of the present invention are designed to block or prevent the effects caused by intentional or unintentional overdose of pharmaceutical products. Under normal dosing conditions, the formulations of the present invention can enable complete and / or bioequivalent oral delivery of the desired drug dose. However, when an intentional or unintentional overdose is ingested, the formulations of the present invention can act to delay or block the release and subsequent absorption of the overdose. Thus, in the case of intentional overdose where a drug abuser ingests an overdose of a drug to experience the intoxicating effect, the effect will be greatly reduced in the formulations of the present invention compared to a dose where the excessive drug is released freely. In this way, the formulations of the present invention can act as an inhibitor of the abuse of the formulations of the present invention for the purpose of obtaining an intoxicating effect. However, patients who use the present invention as directed will receive the desired therapeutic treatment.

[0015] Generally, and as described in more detail herein, the pharmaceutical formulations of the present invention can be designed using one or more components that control the release and / or absorption of the active pharmaceutical ingredient. In one embodiment, the pharmaceutical formulation can be designed to have a pH-modifying feature and / or a pH-dependent solubility feature. The pH-modifying feature can affect the release and / or absorption of the active ingredient by modifying the pH of the gastric environment based on whether the pharmaceutical composition is taken at an appropriate dose or an excessive dose. The pH-modifying feature can be provided by including one or more buffering components and / or antacid components in the pharmaceutical composition. The pH-dependent solubility feature can affect the release and / or absorption of the active ingredient by containing or releasing the active pharmaceutical ingredient depending on the pH of the gastric environment. The pH-dependent solubility feature can be provided by including one or more acid-soluble components in the pharmaceutical composition.

[0016] Component Active pharmaceutical ingredient Any drug, pharmaceutically acceptable salt, drug derivative, drug analog, drug homolog, or polymorph can also be used in the present invention. Drugs suitable for use in the present invention can be found in the Physician's Desk Reference, 59th Edition, the content of which is incorporated herein by reference. In one embodiment, the drug is a drug administered orally.

[0017] In certain embodiments, drugs that are prone to abuse are used. Commonly abused drugs include, but are not limited to, psychoactive drugs and analgesics, such as opioids, opiates, stimulants, tranquilizers, sedatives, anti-anxiety agents, narcotics, and drugs that can cause physiological and / or physical dependence. In one embodiment, the drugs used in the present invention can include amphetamine, amphetamine-like compounds, benzodiazepines, and methylphenidate, or combinations thereof. In another embodiment, the present invention may include any of the resolved isomers of the drugs described herein, and / or their salts.

[0018] The drugs used in the present invention that may be prone to abuse may be one or more of the following: alfentanil, amphetamine, buprenorphine, butorphanol, carfentanil, codeine, desocine, diacetylmorphine, dihydrocodeine, dihydromorphine, diphenoxylate, diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone, β-hydroxy-3-methylfentanyl, levo-α-acetylmethadol, levorphanol, lofentanil, meperidine, methadone, methylf enidate, morphine, nalbuphine, naloxone, nalorphine, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil, sufentanil, tilidine, and tramadol, their salts, derivatives, analogs, homologs, polymorphs, and mixtures of any of the aforementioned drugs.

[0019] In another embodiment, drugs used in the present invention that may be prone to abuse include one or more of the following: dextromethorphan (3-methoxy-17-methyl-9a,13a,14a-morphinan hydrobromide monohydrate (3-Methoxy-17-methyl-9a,13a,14a-morphinan hydrobromide monohydrate)), N-{1-[2-(4-ethyl-5 -oxo-2-tetrazolin-1-yl)-ethyl]-4-methoxymethyl-4-piperidyl}propionanilide (alfentanil), 5,5-diallylbarbituric acid (allobarbital), allylprodine, alpha-prodine, 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine (alprazolam), 2-diethylaminopropiophenone (amfepramone), (±)-alpha-methylphenethylamine (amphetamine), 2-(alpha-methylphenethyl-amino)-2-phenylacetonitrile (amphetaminil), 5-ethyl-5-isopentylbarbituric acid (amobarbital), anileridine, apocodeine, 5,5-diethylbarbituric acid (barbital), benzylmorphine, vedotramide, 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 (brotizolam), 17-cyclopropylmethyl-4,5α-epoxy-7α[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol (buprenorphine), 5-butyl-5-ethylbarbituric acid (butabarbital), butorphanol, (7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)-dimethylcarbamate (carbamazepam), (1S,2S)-2-amino-1-phenyl-1-propanol (cathine / D-norpseudoephedrine), 7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-ylamine-oxide (chlordiazepoxide), 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (clobazam), 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepin-2(3H)-one (clonazepam), clonitazene, 7-chloro-2,3-dihydro -2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid (chlorazepic acid), 5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]-diazepin-2(3H)-one (chlotiazepame), 10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one (cloxazolam), (-)-methyl-[3β-benzoyloxy-2β(1αΗ,5αH)-tropane carboxylate (cocaine), 4,5α-epoxy-3-methoxy-17-methyl-7-morphinen-6α-ol (codeine), 5-(1-cyclohexenyl)-5-ethylbarbituric acid (cyclobarbital), cyclorphan, cyprenorphine, 7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiaz pin-2(3H)-one (delorazepam), desomorphine, dextromoramide, (+)-(1-benzyl-3-dimethylamino-2-methyl -1-phenylpropyl)propionate (dextropropoxyphene), dezocine, diampromide, diamorphine, 7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (diazepam), 4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol (dihydrocodeine), 4,5α-epoxy-17-methyl-3,6a-morphinane diol (dihydromorphine), dimenoxadol, dimephetamol [sic-Tr.Ed.], dimethylthiambutene, dioxaphetylbut Rate, dipipanone, (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (dronabinol), eptazocine, 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (estazolam), ethoheptazine, ethylmethylthiambutene, ethyl-[7-chloro-5 -(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate] (ethyl loflazepate), 4,5α-epoxy-3-ethoxy-17-methyl-7-morphinen-6α-ol (ethylmorphine), etonitrazene, 4,5α-epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol (etorphine), N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine (fencamfamine), 7-[2-(α-methylphenethylamino)-ethyl]theophylline (fenetylline), 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 (flurazepam), 5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepin-2-(3H)-one (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]benzodiazepin-4,7(6H)-dione (ketazolam), 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone (ketobemidone), (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate (levacetylmethadol (LAAM)), (-)-6-dimethylamino-4,4-diphenyl-3-heptanone (levomethadone), (-)-17- Methyl-3-morphanol (levorphanol), levophenacyl morphan, lofentanyl, 6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]benzodiazepin-1(4H)-one (lorazepam), 7-chloro-5-(2-chlorophenyl)-3-hydroxy-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 (mephenorex), meperidine, 2-methyl-2-propyltrimethylenedicarbamate (meprobamate), meptazinol, metazocine, methylmorphine, N,α-dimethylphenethylamine (methamphetamine), (±)-6-dimethylamino-4,4-diphenyl-3-heptanone (mesadone), 2-methyl-3-o-tolyl-4(3H)-quinazolinone (metacolon), 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-α][1,4]benzodiazepine (midazolam), 2-(benzohydrylsulfinyl)acetamide (modafinil), 4,5α-epoxy-17-methyl-7-morphinen-3,6α-diol (morphine), myrophine, (±)-trans-3-(1 ​,1-dimethylheptyl)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9(6αH)-one (navolone), nalbuphen, nalorphine, narceine, nicomorphine , 1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nitrazepam), 7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nitrazepam), 7-chloro-5-phenyl-1H-1,4-benzodiazepin-2-(3H)-one (nordazepam), norlevorphanol, 6-dimethylamino-4,4-diphenyl-3-hexanone (normethadone), normorphine, norpipanone, extract of plants belonging to the species Papaver somniferum) coagulated (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 of the species Papaver and plant parts (Papaver somniferum), papaveretum, 2-iminio-5-phenyl-4-oxazolidinone (pemoline), 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, phol codeine, 3-methyl-2-phenylmorpholine (phenmetrazine) , 5-ethyl-5-phenylbarbituric acid (phenobarbital), α,α-dimethylphenethylamine (phentermine), 7-chloro-5-phenyl-1-(2-propynyl)-1H-1, 4-benzodiazepin-2(3H)-one (pinazepam), α-(2-piperidyl)benzhydryl alcohol (pipradol), 1’-(3-cyano-3,3-diphenylpropyl)[1,4’-bipiperidine]-4’-carboxamide (piritramide), 7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-ben zodiazepin-2(3H)-one (prazepam), profadol, proheptazine, promedol, properidine, propoxyphene, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl-{3-[4-methoxycarbonyl-4-(N-phenylpropanamide)piperidino]propanoate} (remifentanil), 5-sec-butyl-5-ethylbarbituric acid (secbutabarbital), 5-allyl-5-( and plant parts (Papaver somniferum), papaveretum, 2-iminio-5-phenyl-4-oxazolidinone (pemoline), 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, phol (1-Methylbutyl)barbituric acid (secobarbital), N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide (sufentanil), 7-chloro-2-hydroxymethyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (temazepam), 7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one (tetrazepam), ethyl-(2-dimethylamino-1-phenyl-3-cyclohexane-1-carbo xylate)(chlordiazepoxide (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), (1R * ,2R * )-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (1R,2R,4S)-2-[(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol, each, optionally, the corresponding stereoisomeric compounds, and further, the corresponding derivatives, in particular, may be esters or ethers, and all, compounds having physiological compatibility, in particular, salts and solvates.

[0020] In one embodiment, the pharmaceutical composition of the present invention comprises, as a therapeutically active ingredient, one or more opioids such as hydrocodone, hydromorphone, morphine, and oxycodone, and / or salts thereof. Typically, as described in more detail below, when processed into a suitable dosage form, the drug may be present in such dosage form in the amounts customarily prescribed, typically, about 0.5 to about 25 percent on a dry weight basis based on the total weight of the formulation.

[0021] Regarding analgesics in unit dosage forms, such drugs may be present in pharmaceutically acceptable amounts; the standard dosages of such drugs are generally known in the art, which are disclosed, for example, in United States Pharmacopeia and National Formulary (USP 36-NF 31). Rockville, MD: United States Pharmacopeia Convention; 2013, the entire content of which is incorporated herein by reference. In certain embodiments, such drugs may be present in amounts of about 5, 25, 50, 75, 100, 125, 150, 175, or 200 mg. In certain embodiments, the drug may be present in an amount from about 5 to about 500 mg, or from about 5 to about 200 mg. In certain embodiments, the dosage form contains an amount of the drug suitable to provide a therapeutic effect.

[0022] In certain embodiments, the pharmaceutically active ingredient may include a drug having a narrow therapeutic index. Drugs having a narrow therapeutic index include, but are not limited to, aminophylline, carbamazepine, clindamycin, clonidine, digoxin, disopyramide, dyphylinne, guanthidine, isetharine mesylate, isoproterenol, levothyroxine, lithium carbonate, metaproterenol, minoxidil, oxytriphylline, phenytoin, pasosin, primidone, procaine Examples may include amide, quinine gluconate, theophylline, valproic acid, sodium valproate, and warfarin sodium. For drugs having a narrow therapeutic dose in unit dosage form, such drugs may be present in pharmaceutically acceptable amounts; the standard doses of such drugs are generally known in the art, which are disclosed, for example, in United States Pharmacopeia and National Formulary (USP 36 - NF 31). Rockville, MD: United States Pharmacopeia Convention; 2013, the entire content of which is incorporated herein by reference. In certain embodiments, such drugs may be present in amounts of about 0.025, 0.05, 0.1, 0.2, 0.3, 0.5, 1, 2, 2.5, 3, 4, 5, 6, 7.5, 10, 25, 50, 75, 100, 125, 150, 175, 200, and 250 mg. In certain embodiments, the drug may be present in an amount from about 0.01 to about 1000 mg, or from about 0.05 to about 500 mg. In certain embodiments, the dosage form contains an amount of the drug suitable to provide a therapeutic effect.

[0023] Components soluble in acidic solution In certain embodiments, the pharmaceutical composition of the present invention includes one or more components soluble in acidic solution. An acidic solution may be considered to be a solution having a pH of from about 1 to about 4. In certain embodiments, the acid - soluble component has low solubility in a solution that is slightly acidic, neutral, and / or basic, i.e., a solution having a pH greater than about 4.

[0024] In certain embodiments, the acid-soluble component is included in the pharmaceutical composition in the form of a particulate matrix, together 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 certain embodiments, the active ingredient is sequestered within the acid-soluble component. The acid-soluble component can be one that affects the release of the active pharmaceutical ingredient according to the pH of the environment that is raised or maintained according to the amount of the pharmaceutical composition ingested, by a buffering and / or antacid component: when the pharmaceutical composition is ingested in a proper dosage, the pH buffering component is not present in an amount that modifies or sufficiently raises the gastrointestinal pH, the acid-soluble component dissolves, and the active pharmaceutical ingredient is released; when the pharmaceutical composition is ingested in an excessive amount, the pH buffering component is present in an amount that raises the gastrointestinal pH, and thus, the dissolution of the acid-soluble component and the release of the active pharmaceutical ingredient are prevented.

[0025] In certain embodiments, the acid-soluble component is included in the pharmaceutical composition in an amount of from about 1% to about 50% by weight; from about 1% to about 48% by weight; from about 1% to about 46% by weight; from about 1% to about 44% by weight; from about 1% to about 42% by weight; from about 1% to about 40% by weight; from about 2% to about 38% by weight; from about 4% to about 36% by weight; from about 6% to about 34% by weight; from about 8% to about 32% by weight; from about 10% to about 30% by weight; from about 12% to about 28% by weight; from about 14% to about 26% by weight; from about 16% to about 24% by weight; from about 18% to about 22% by weight; about 1% by weight; about 2% by weight; about 4% by weight; about 6% by weight; about 8% by weight; about 10% by weight; about 12% by weight; about 14% by weight; about 16% by weight; about 18% by weight; about 20% by weight; about 22% by weight; about 24% by weight; about 26% by weight; about 28% by weight; about 30% by weight; about 32% by weight; about 34% by weight; about 36% by weight; about 38% by weight; about 40% by weight; about 42% by weight; about 44% by weight; about 46% by weight; about 48% by weight; or about 50% by weight.

[0026] Examples of suitable acid-soluble components include calcium carbonate, chitosan, cationic copolymers of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate such as Eudragit® E PO, Eudragit® E 12.5, dibasic and tribasic calcium phosphate, and magnesium hydroxide.

[0027] Buffering and / or antacid components In certain embodiments, the pharmaceutical compositions of the invention include one or more buffering and / or antacid components. Such components can bring about an increase in the gastric pH when the pharmaceutical composition is taken in an appropriate amount. In certain embodiments, such components can rapidly and continuously increase the gastric pH to a pH greater than about 4 when the pharmaceutical composition is taken in an appropriate amount.

[0028] In certain embodiments, the buffering and / or antacid components may be included in an amount such that the gastric pH is not affected when the pharmaceutical composition is taken in an appropriate therapeutic amount, but the gastric pH can be increased when the pharmaceutical composition is taken in an excessive amount. In certain embodiments, the buffering and / or antacid components are present in the pharmaceutical composition in an amount of from about 45 wt% to about 95 wt%; from about 50 wt% to about 90 wt%; from about 55 wt% to about 85 wt%; from about 60 wt% to about 80 wt%; from 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%.

[0029] Examples of suitable buffering 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, gly Examples include glycine magnesium, magnesium hydroxide, magnesium oxide, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium sodium tartrate, trisodium phosphate, and tricalcium phosphate.

[0030] In certain embodiments, one component can act as both an acid-soluble component and a buffering and / or antacid component. Examples of such suitable components include calcium carbonate, dibasic and tribasic calcium phosphate, and magnesium hydroxide.

[0031] Additional components The present invention may also optionally include other components in order to facilitate the manufacture of dosage forms from the pharmaceutical compositions of the present invention and / or to modify the release profile of dosage forms containing the pharmaceutical compositions of the present invention.

[0032] Certain embodiments of the present invention include one or more pharmaceutically acceptable fillers / diluents. In one embodiment, Avicel PH (microcrystalline cellulose) is the filler used in the formulation. Avicel PH can have an average particle size in the range of 20 to about 200 μm, preferably about 100 μm. The density ranges from 1.512 to 1.668 g / cm. 3 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 weight percent of the formulation on a solids basis. A typical filler may be present at 10 to 65 weight percent of the total composition on a dry weight basis. Other components may include sugars and / or polyols. Lactose having a particle size of about 20 to about 400 microns and a density of about 0.3 to about 0.9 g / mL may also be mentioned.

[0033] In certain embodiments of the present invention, a filler that may be present at about 10 to 65 weight percent on a dry weight basis not only imparts binding properties to the substances within the formulation, but also functions as a binder that can increase the bulk weight of a directly compressible formulation (described below) to obtain an acceptable formulation weight for direct compression. In certain embodiments, an additional filler need not provide the same level of binding properties as the selected binder, but can contribute to the homogeneity of the formulation and prevent separation from the formulation after blending. Further, preferred fillers do not have an adverse effect on the flowability of the composition or the dissolution profile of the formed tablets.

[0034] In one embodiment, the present invention may include one or more pharmaceutically acceptable disintegrants. Such disintegrants are known to those of skill in the art. In the present invention, disintegrants include, but are not limited to, sodium starch glycolate (Explotab®) having a particle size of about 104 microns and a density of about 0.756 g / mL, starch (e.g., Starch 21) having a particle size of about 2 to about 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 homogeneity of the formulation. Further, the disintegrant can minimize separation and provide an immediate release profile for the formulation. In certain embodiments, the (one or more) disintegrant is present in an amount of about 2 to about 25 weight percent on a solids basis of the directly compressible formulation. Further, an antacid added to the formulation can assist in the disintegration of the tablet when the tablet is introduced into a low pH environment by the foaming of the antacid component, and thus the need for an additional disintegrant may be reduced.

[0035] In one embodiment, the present invention includes, but is not limited to, colloidal silicon dioxide It may contain one or more pharmaceutically acceptable flow promoters. In one embodiment, colloidal silicon dioxide (Cab-O-Sil®) having a density of from about 0.029 to about 0.040 g / mL can be used to improve the flow characteristics of the formulation. Such a flow promoter may be provided in an amount of from about 0.1 to about 1 weight percent based on the solid content of the formulation. However, based on the present invention, although colloidal silicon dioxide is one specific flow promoter, other flow promoters known or developed in the future having similar properties may be used as long as they are compatible with other excipients and active ingredients in the formulation and do not have a significant impact on the fluidity, homogeneity, and compressibility of the formulation.

[0036] In one embodiment, the present invention may include one or more pharmaceutically acceptable lubricants including but not limited to magnesium stearate. In one embodiment, magnesium stearate has a particle size of from about 450 to about 550 microns and a density of from about 1.00 to about 1.80 g / mL. In one embodiment, magnesium stearate can contribute to reducing the friction between the die wall and the pharmaceutical composition of the present invention during the compression process, facilitating the ejection of the tablets, and thus promoting processing. In certain embodiments, the lubricant prevents adhesion to the punches and dies and / or aids in the flow of the powder in the hopper and / or into the die. In embodiments of the present invention, magnesium stearate having a particle size of from about 5 to about 50 microns and a density of from about 0.1 to about 1.1 g / mL is used in the pharmaceutical composition. In specific embodiments, the lubricant should constitute from 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 after mixing. Other lubricants known or developed in the art that exhibit acceptable or equivalent properties include stearic acid, hydrogenated oil, sodium stearyl fumarate, polyethylene glycol, and Lubritab®.

[0037] In certain embodiments, the most important criteria in the selection of excipients is that the excipients achieve good content uniformity and release the active ingredient as desired. By having very good binding properties, homogeneity, as well as good compressibility, cohesiveness, and flowability in the mixed form, the excipients minimize the separation of the powder in the hopper during the compression process.

[0038] Controlled drug release dosage forms As described herein, the pharmaceutical formulations of the present invention can be formulated to delay or block the release of an overdose of the active pharmaceutical ingredient and subsequent absorption. In certain embodiments, the pharmaceutical formulations can be designed to have pH-modifying characteristics and / or pH-dependent solubility characteristics. The pH-modifying characteristics can affect the release and / or absorption of the active ingredient by modifying the pH of the gastric environment based on whether the pharmaceutical composition is taken at an appropriate dose or in excess. The pH-modifying characteristics can be provided by including one or more buffering and / or antacid components in the pharmaceutical composition. The pH-dependent solubility characteristics can affect the release and / or absorption of the active ingredient by containing or releasing the active pharmaceutical ingredient depending on the pH of the gastrointestinal environment. The pH-dependent solubility characteristics can be provided by including one or more pH-soluble components in the pharmaceutical composition.

[0039] In certain embodiments, for the pharmaceutical composition, when the composition is taken in an appropriate amount, the influence by the pH-modifying characteristics is minimal (i.e., the pH of the gastric environment is not substantially modified or is maintained at the desired level), and the influence by the pH-dependent solubility characteristics is maximal (i.e., the active pharmaceutical ingredient is released), so that the release and / or absorption of the active ingredient can be enabled. However, when the pharmaceutical composition is taken in excess When this occurs, in certain embodiments, the composition is formulated such that the effect due to the pH-modifying feature is maximized (i.e., the pH of the gastric environment is increased), and the effect due to the pH-dependent solubility feature is minimized (i.e., the acid-soluble component is insoluble and thus does not dissolve), thereby preventing the release and / or absorption of the active ingredient.

[0040] In certain embodiments, the pharmaceutical composition can be made by intimately mixing the active pharmaceutical ingredient with one or more acid-soluble components by any suitable process (i.e., dry or wet granulation, hot melt extrusion, etc.) such that the particulate matrix is formed in particulate form. The release of the drug from this matrix can, in this case, be controlled by the surrounding pH environment in proximity to the matrix when the pharmaceutical composition is ingested. In a low pH environment (i.e., pH 1 - 4), the matrix can dissolve and become prone to rapidly releasing the drug; in a higher pH environment (i.e., pH > 4), the matrix is likely to become insoluble, the release of the drug is suppressed and is likely to be incomplete, thereby reducing the level of the drug absorbed.

[0041] In certain embodiments, in a single unit dose, an amount of one or more buffering and / or antacid components sufficient to neutralize the gastric pH up to the point where the gastric pH is maintained within the range of pH 1 - 4 when the single unit dose is ingested is further mixed with the required amount of the acid-soluble drug matrix. The blend of the acid-soluble drug matrix / antacid / buffer can be formed into an oral solid dosage form such as, but not limited to, tablets or capsules.

[0042] As a result, when a single dose is ingested under normal dosing conditions (i.e., one or two tablets), the (one or more) buffering / antacid components neutralize a portion of the gastric acid, but the gastric acid has the characteristics of modifying the pH and pH-dependent solubility so as to maintain the range of pH 1 to 4. A pharmaceutical composition can be formulated. Under such conditions, the acid-soluble drug matrix is soluble in the acidic gastric environment, and the drug can be rapidly released in the stomach and absorbed into the bloodstream.

[0043] Under conditions where an excessive dose is ingested, either intentionally or not (i.e., three or more tablets), the amount of the (one or more) buffering and / or antacid components from the excessive ingestion may here be sufficient to cause a rapid and sustained increase in gastric pH (>pH 4). Thus, the acid-soluble drug matrix may have reduced solubility in a higher pH gastric environment, and the release of the drug from the matrix can be suppressed. In certain embodiments, the suppression of the drug from the acid-soluble matrix is further assisted by gastrointestinal transit that can move the acid-soluble matrix particles to the intestinal tract and lower gastrointestinal tract having a biologically controlled high pH environment (i.e., pH 5.5 to 8). As a result of the overall suppression of drug release from the excessive ingestion, a pharmacokinetic profile with an increase in Tmax and a decrease in Cmax is obtained as compared to the same oral dose that releases the drug at normal gastric pH (i.e., pH 1 to 4).

[0044] 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 manufactured from the pharmaceutical composition of the present invention. The dosage form may be in any shape, including regular or irregular shapes, depending on the needs of those skilled in the art.

[0045] The compressed tablets containing the pharmaceutical composition of the present invention may be direct compression tablets or indirect compression tablets. In one embodiment, the dosage form of the present invention may be prepared by wet granulation and dry granulation (e.g., slug method or roller compression). The method of formulation and the type of excipients are selected such that the desired physical properties enabling rapid compression of the tablets are imparted to the tablet formulation. The tablets after compression need to have several additional attributes such as appearance, hardness, disintegration ability, and an acceptable dissolution profile.

[0046] The selection of fillers and other excipients typically depends on the chemical and physical properties of the drug, the behavior of the mixture during processing, and the properties of the final tablets. Adjustment of such parameters is understood to be within the general understanding of those skilled in the relevant art. Suitable fillers and excipients are described in more detail above.

[0047] The manufacture of the dosage form of the present invention may include direct compression and wet and dry granulation methods including the slug method and roller compression. In certain embodiments, one or more components may be isolated as described in U.S. Patent Application Publication No. 2012 / 0202839, the entire contents of which are incorporated herein by reference.

[0048] Using the present invention, immediate release and controlled drug release formulations may be manufactured. Examples of controlled release formulations may include delayed release, bi-modal and tri-modal release, sustained release and extended release oral solid dosage formulations.

[0049] As used herein, the term "about" is understood to mean ± 10% of the referenced value. For example, "about 45%" is understood to effectively mean from 40.5% to 49.5%.

[0050] As used herein, the term "bioequivalence" refers to the C max , T max、or that one or more of the area under the concentration curve "AUC" is understood to mean within 75% to 120% of the same marker for the reference drug.

[0051] Certain aspects of the present invention will be better understood when shown by the following examples, which are intended to illustrate and not to limit. Example 1 Two dissolution vessels were prepared: one vessel contained 25 milliequivalents of HCl and a single commercially available calcium carbonate antacid tablet (Tums®), and the other vessel contained 25 milliequivalents of HCl and five calcium carbonate antacid tablets. The pH of each vessel was monitored, and the results are shown in Figure 1. In the case of the single tablet, the tablet completely reacted in about 30 minutes, and the dissolution of the single tablet showed no change in pH. However, the introduction of five tablets resulted in a relatively rapid increase in pH to above 4.5 within 10 minutes, and after 90 minutes, a significant amount of undissolved solid was seen in the vessel. Thus, a low level (500 mg) of calcium carbonate was completely soluble with little effect on pH, but in the case of an excess amount of calcium carbonate, a rapid pH increase occurred creating a high pH environment where calcium carbonate was found to have low solubility. Calcium carbonate demonstrated its ability as a pH modifier and pH-dependent solubility.

[0052] Example 2 The challenge in the design of self-regulated dosage forms is to effect control at elevated pH (i.e., slower or incomplete release) without compromising the desired rapid release rate associated with immediate release tablets when a single dose is administered. Calcium carbonate was evaluated in both direct blend matrix tablets and dry granulation tablets containing alprazolam, where the granules were used to control drug release It contained calcium carbonate, and the calcium carbonate outside the granules was for causing pH changes. In both methods, slower release of alprazolam was obtained in single tablets at high pH (approximately pH 6) compared to low pH (pH 1), but in this case, the release interval was not as high as desired (Figure 2). However, from this result, it is shown that granules can be used for controlling drug release according to the pH environment. The granules may be composed of a drug present together with a functional component that inhibits erosion or disintegration at elevated pH so that slower and / or incomplete release of the drug is seen. The outer granule portion of the tablet may mainly contain a pH control agent that needs to be rapidly released and react.

[0053] Example 3 Eudragit® E PO (EPO) is a cationic copolymer based on dimethylaminoethyl methacrylate rate, butyl methacrylate, and methyl methacrylate. According to the technical literature, this polymer is soluble in acids up to pH 5; above pH 5, it swells without dissolving. Dry granules containing 5% alprazolam in the EPO polymer were prepared, and size fractions of -16 mesh and +20 mesh (16 / 20) as well as -20 mesh and +30 mesh (20 / 30) were recovered. Dissolution for these granule size fractions was carried out at both low pH (pH 1.5) where EPO is soluble and high pH (pH 6) where the solubility of EPO is low. The results are shown in Figure 3. At low pH, rapid and complete release of alprazolam occurs within 15 minutes regardless of the particle size. However, at high pH, for both size fractions, the release of alprazolam is very delayed and incomplete, but the smaller fraction is slightly higher. It should be noted that this dissolution simulation represents fixed pH conditions at the possible extreme pHs when the tablet is taken as directed (pH 1) and excessively (pH 6). The following example examines a pH modification system that does not affect the pH during normal intake as directed but rapidly raises the pH during over - ingestion.

[0054] Example 4 The test using calcium carbonate as the main pH modifier was continued, and as a result, alprazolam was released relatively rapidly in 15 minutes from 5% alprazolam / EPO granules (60%). The pH change up to pH 5 in 10 minutes seen above for calcium carbonate (Figure 1) is rapid for the release of alprazolam and can be recognized as fast assuming it is completed in 15 minutes, but in the alprazolam / EPO granules, calcium carbonate may not affect the pH change quickly enough. In previous experiments, sodium bicarbonate has been shown to have a more rapid pH effect, raising the acidic medium from pH 1 to pH 6 in less than 2 minutes. Therefore, sodium bicarbonate was added to the prototype formulation mainly to control the rapid pH rise, and calcium carbonate was added for more sustained control of the elevated pH. Representative formulations of the present invention are shown in the following table.

[0055] [Table 1]

[0056] The prototype formulation was made into tablets, the pH modifier was contained in the tablets, and a dynamic test was carried out in which it was reacted dynamically in a 0.55N HCl medium (about pH 1.6). Multiple tablet doses with and without self-control, as well as a single dose with self-control, were tested and compared. The dissolution medium pH and drug release were monitored. As shown in Figure 4, in the prototype multiple tablets, a rapid rise in pH was observed, and the rise to pH 6 occurred in less than 2 minutes. Therefore, the rapid rise in pH can be affected by the pH modifier contained in the tablets.

[0057] Furthermore, as shown in Figure 5, the single tablet releases alprazolam in 15 minutes, indicating that the immediate release characteristics of the single tablet are not affected by the incorporated self-control system. However, the multiple tablets with self-control show that approximately a single dose is released in 15 minutes, and the excess alprazolam is released in a delayed manner over approximately 2 hours. For comparison, the multiple tablets without self-control show that all alprazolam doses (approximately 9 mg) are released in approximately 15 minutes, while at the same time point, the multiple tablets with self-control release only 20% of the alprazolam. Clearly, the prototype self-control alprazolam tablets showed that they release a single dose of alprazolam as intended, but the multiple tablets showed suppression of the release of the excess dose compared to the non-self-controlled excess dose.

[0058] Those skilled in the art will understand that numerous changes and / or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit and scope of the invention as broadly described. Further, each and every reference cited above is hereby incorporated by reference into this specification as if fully set forth herein. [1] A misuse-deterrent pharmaceutical composition comprising a. a pharmaceutically active ingredient, b. an acid-soluble component, and c. a buffering component, wherein the acid-soluble component and the buffering component suppress the release of the pharmaceutically active ingredient when the composition is ingested in excess of the intended dose. [2] The composition according to [1], wherein the pharmaceutically active ingredient comprises a drug that is prone to misuse. [3] The composition according to [1], wherein the pharmaceutically active ingredient comprises a drug having a narrow therapeutic index. [4] The composition according to [1], wherein the acid-soluble component comprises calcium carbonate, a cationic copolymer, or a combination thereof. [5] The composition according to [1], wherein the acid-soluble component comprises a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. [6] The composition according to [1], wherein the pharmaceutically active ingredient is contained in the matrix of the acid-soluble component. [7] The composition according to [1], wherein the acid-soluble component is present in an amount of about 1% to about 40% by weight of the pharmaceutical composition. [8] The composition according to [1], wherein the buffering component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. [9] The composition according to [1], wherein the buffering component is present in an amount of about 45% to about 95% by weight.

Claims

1. a. a pharmaceutical active ingredient; b. an acid-soluble component comprising a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate; and c. buffering component, 1. An abuse-deterrent pharmaceutical composition comprising: wherein the buffering component is present in an amount sufficient to suppress the peak plasma concentration (Cmax) of the pharmacoactive ingredient when the composition is taken in excess of a dose suitable to provide a therapeutic effect, and the pharmacoactive ingredient is a psychoactive drug or an analgesic. Abuse-deterrent pharmaceutical compositions.

2. 10. The composition of claim 1, wherein the buffer component is present in an amount sufficient to inhibit release of the pharmacologic active ingredient when the composition is ingested in excess of a dose suitable to provide a therapeutic effect.

3. 2. The composition of claim 1, wherein the buffer component is present in an amount sufficient to increase the time (T) to reach a peak plasma concentration (C) of the pharmacoactive ingredient when the composition is taken in excess of a dose suitable to provide a therapeutic effect.

4. 10. The composition of claim 1, wherein the buffering component is present in an amount sufficient to raise gastric pH to greater than 4 when the composition is ingested in excess of a dose suitable to provide a therapeutic effect.

5. 2. The composition of claim 1, wherein when the composition is ingested in excess of a dose suitable for providing a therapeutic effect, release of the medicament active ingredient is inhibited as compared to when an equivalent amount of the medicament active ingredient but no buffer ingredient is ingested.

6. 10. The composition of claim 1, wherein when the composition is ingested in a dose greater than that suitable for providing a therapeutic effect, release of the pharmacologic active ingredient is inhibited as compared to ingestion of the composition in a dose of the pharmacologic active ingredient suitable for providing a therapeutic effect.

7. a. a pharmaceutical active ingredient; b. an acid-soluble component comprising a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate; and c. buffering component, 1. An abuse-deterrent pharmaceutical composition comprising: wherein the buffering component is present in an amount sufficient to inhibit release of the pharmacologic active ingredient when the composition is ingested in excess of a dose suitable to provide a therapeutic effect, and the pharmacologic active ingredient is a psychoactive drug or an analgesic. Abuse-deterrent pharmaceutical compositions.

8. 8. The composition of claim 7, wherein the buffer component is present in an amount sufficient to suppress peak plasma concentrations (Cmax) of the pharmacoactive ingredient when the composition is taken in excess of a dose suitable to provide a therapeutic effect.

9. 8. The composition of claim 7, wherein the buffer component is present in an amount sufficient to increase the time (T) to reach a peak plasma concentration (C) of the pharmacoactive ingredient when the composition is taken in excess of a dose suitable to provide a therapeutic effect.

10. 8. The composition of claim 7, wherein the buffering component is present in an amount sufficient to raise gastric pH to greater than 4 when the composition is ingested in excess of a dose suitable to provide a therapeutic effect.

11. 8. The composition of claim 7, wherein when the composition is ingested in excess of a dose suitable for providing a therapeutic effect, release of the medicament active ingredient is inhibited as compared to when an equivalent amount of the medicament active ingredient and no buffer ingredient is ingested.

12. 8. The composition of claim 7, wherein when the composition is ingested in excess of a dose suitable to provide a therapeutic effect, release of the pharmacologic active ingredient is inhibited as compared to ingestion of the composition at a dose of the pharmacologic active ingredient suitable to provide a therapeutic effect.

13. a. a pharmaceutical active ingredient; b. an acid-soluble component comprising a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate; and c. buffering component, 1. An abuse-deterrent pharmaceutical composition comprising: wherein the buffer component does not substantially inhibit release of the medicament active ingredient at a pH below about 4, but is present in an amount sufficient to inhibit release of the medicament active ingredient at a pH above about 4, and the medicament active ingredient is a psychoactive drug or an analgesic. Abuse-deterrent pharmaceutical compositions.

14. 14. The composition of claim 13, wherein when an amount of the composition comprising the pharmacologic active ingredient in an amount greater than a therapeutic dose is exposed to a pH greater than 4, release of the pharmacologic active ingredient is inhibited.

15. 14. The composition of claim 13, wherein when an amount of the composition comprising the pharma- ceutical active ingredient at or below a therapeutic dose is exposed to a pH greater than 4, release of the pharma- ceutical active ingredient is not substantially inhibited.

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