Self-controlled release of active pharmaceutical ingredients

Abstract

To provide methods and compositions that deter drug abuse and minimize or reduce the potential for physical or psychological dependency.SOLUTION: Provided is an abuse deterrent pharmaceutical composition comprising: 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 being present in an amount sufficient to suppress the peak plasma concentration (Cmax) of the pharmaceutically active ingredient when the composition is ingested in excess of a dose suitable for providing a therapeutic effect.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED PRIOR APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 61 / 731,901, filed Nov. 30, 2012, and entitled "METHOD AND COMPOSITION FOR SELF-CONTROLLED RELEASE OF ACTIVE PHARMACEUTICAL INGREDIENTS," the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Classes of drugs that exhibit opium or morphine-like properties are termed opioids or opioid agonists. As agonists, certain drugs are characterized by their interaction 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 presumed to be involved in the regulation of pain perception; movement, mood, and behavior; and neuroendocrinological functions. Three classical opioid receptor types have been extensively studied: mu (μ), delta (δ), and kappa (κ). Each of these three receptors exhibits a unique anatomical distribution in the brain, spinal cord, and periphery. Most clinically available 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 high enough doses, which can lead to altered pharmacological effects. This is especially true when opioid doses are gradually increased to exceed tolerance.

[0003] The potential for the development of tolerance, physical and / or physiological dependence (i.e., addiction) with repeated use of opioids is an inherent feature of most drugs that contain opioid analgesics. The potential for habit formation is one of the primary 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 with legitimate pain to other individuals (non-patients) for recreational purposes.

[0004] Drug abusers and / or addicts typically obtain solid dosage forms intended for oral administration containing one or more opioid analgesics and may crush, shear, grind, chew, dissolve and / or heat, extract, or otherwise tamper with or destroy the dosage unit so that most or even all of the active drug can be administered by 1) injection, 2) inhalation, and / or 3) oral ingestion in amounts that exceed typical therapeutic doses for such drugs.

[0005] There are three basic patterns of behavior that lead to opioid abuse. The first involves an individual who initiates the use of an opioid drug in a legitimate medical treatment context and receives their initial supply of drugs by prescription from a properly licensed health care provider. Through cunning, such an individual may eventually begin to seek prescriptions for a supply of drugs far in excess of their legitimate medical need from multiple health care providers and / or illicit sources that are diversions from pharmacies and / or other legitimate drug distribution channels. The second pattern of abuse begins with the experimental or "recreational" drug user who has no legitimate medical indication for the abuse-prone drug and seeks a "high." The third pattern of abuse involves a user who initiates use in one of the ways described above and eventually switches to an orally administered drug obtained from an organized, legitimate addiction treatment program.

[0006] There are various routes of administration that abusers can commonly use to abuse opioid-containing drug preparations. There are several methods of abuse of oral solid drugs. The most common methods include 1) parenteral (e.g., intravenous injection), 2) intranasal (e.g., snorting), and 3) repeated oral ingestion of excessive amounts, e.g., oral administration of tablets or capsules. One mode of abuse of oral solid drugs involves the extraction of the opioid component from the dosage form by first mixing the dosage form with a suitable solvent (e.g., water) and then extracting the opioid component from the mixture for use as a solution suitable for subsequent intravenous injection of the opioid to obtain a "high".

[0007] Attempts have been made to reduce the abuse potential of orally administered drugs, and such attempts have generally focused on including in the oral dosage form an antagonist that is orally inactive, but which will dissolve the drug and substantially block the effect of the drug if it were to be administered parenterally. Summary of the Invention

[0008] Despite all attempts, misuse and abuse of pharmaceuticals continues to increase. There is clearly 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 for drugs susceptible 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 one embodiment of the present invention, the abuse-deterrent pharmaceutical composition comprises an active pharmaceutical ingredient; an acid-soluble ingredient; and a buffering ingredient. In one embodiment, the acid-soluble ingredient and the buffering ingredient inhibit the release of the active pharmaceutical ingredient when the composition is ingested in excess of the intended dose.

[0010] In certain embodiments, the pharmaceutical active ingredient is a drug susceptible to abuse, hi certain embodiments, the pharmaceutical active ingredient is a drug with a narrow therapeutic index. In certain embodiments, the acid-soluble component may 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 about 1% to about 40% by weight of the pharmaceutical composition.

[0011] In certain embodiments, the pharma- ceutical active ingredient is contained within a matrix of acid-soluble components. In certain embodiments, the buffering component may include calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or combinations thereof. The buffering component may be present in an amount of about 45% to about 95% by weight.

[0012] The present invention may be more fully understood by examining the following drawings which illustrate certain features of the invention. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 shows the effect of calcium carbonate on the pH of the dissolution medium over time. [Diagram 2] FIG. 2 shows the effect of dissolution media on the release of active ingredient from calcium carbonate granules. [Diagram 3] FIG. 3 shows the release of active ingredients from cationic copolymer granules. [Figure 4] FIG. 4 shows the change in pH of the dissolution medium when multiple tablets are added. [Diagram 5] FIG. 5 shows a comparison of in vitro active ingredient release from single and multiple tablet administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] With reference to the drawings, features that are the same throughout the drawings are designated with the same numerals. In some embodiments, the formulations of the present invention are designed to block or prevent the effects caused by intentional or unintentional overdosing of drug products. Under normal administration conditions, the formulations of the present invention can allow for full and / or bioequivalent oral delivery of the desired drug dose. However, if an excessive dose is taken, either intentionally or unintentionally, the formulations of the present invention can act to delay or block the release and subsequent absorption of the excess dose. Thus, in the case of intentional overdosing, where a drug abuser takes an excessive dose of the abused drug to experience a euphoric effect, the effect will be greatly reduced with the formulations of the present invention compared to a dose where the excess abused drug is freely released. In this way, the formulations of the present invention can act as a deterrent to the abuse of the formulations of the present invention for the purpose of obtaining a euphoric effect. However, a patient who uses 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 with one or more components that control the release and / or absorption of the active pharmaceutical ingredient. In certain embodiments, the pharmaceutical formulations can be designed to have pH-modifying 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 stomach environment based on whether the pharmaceutical composition is taken in an adequate dose or in an overdose. 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 pharmaceutical ingredient by containing or releasing the active pharmaceutical ingredient depending on the pH of the stomach environment. The pH-dependent solubility characteristics can be provided by including one or more acid-soluble components in the pharmaceutical composition.

[0016] component Active Pharmaceutical Ingredients Any drug, therapeutically acceptable drug salt, drug derivative, drug analog, drug homolog, or polymorph can be used in the present invention.Drugs suitable for use in the present invention can be found in Physician's Desk Reference, 59th Edition, the contents of which are incorporated herein by reference.In one embodiment, the drug is an orally administered drug.

[0017] In certain embodiments, drugs that are easily abused are used.Drugs that are easily abused in general include psychoactive drugs and analgesics, including but not limited to opioids, opiates, stimulants, tranquilizers, sedatives, anxiolytics, narcotics, and drugs that can cause physiological and / or physical dependency.In one embodiment, the drugs used 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 split isomers of drugs described herein, and / or their salts.

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

[0019] In another embodiment, drugs for use in the present invention that may be susceptible to abuse include one or more of the following: dextromethorphan (3-Methoxy-17-methy-9a,13a,14a-morphinan hydrobromidemonohydrate), 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), (±)-alpha-methylphenethylamine (amphetamine), 2-(alpha-methylphenethyl-amino)propionanilide (alfentanil), )-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 (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 (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 (Kassin / 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 (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, cyprenorphine, 7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepine Pin-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, dimephetamol [sic-Tr. Ed.], dimethylthiambutene, dioxaphetyl butyrate 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 (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 (flunitrazepam), 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)propionanilide (fentanyl), 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), morphinone, 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), 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-phenethylamine] 5-ethyl-1-methyl-5-phenylbarbituric acid (methylphenobarbital), 3,3-diethyl-5-methyl-2,4-piperidinedione (methyprilon), metopon, 8- Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-α][1,4]benzodiazepine (midazolam), 2-(benzhydrylsulfinyl)acetamide (modafinil), 4,5α-epoxy-17-methyl-7-morphine-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 (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, Papaver somniferum somniferum (opium), 7-chloro-3 -Hydroxy-5-phenyl-1H-1,4-benzodiazepin-2-(3H)-one (oxazepam), (cis-trans)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(5H)-one (oxazolam), 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone (oxycodone), oxymorphone, and plants belonging to the species Papaversomniferum (including the subspecies setigerum) and plant parts (papaversomniferum), papaveretum, 2-imino-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, falco pholcodeine, 3-methyl-2-phenylmorpholine (phenmetrazine) , 5-ethyl-5-phenylbarbituric acid (phenobarbital), α,α-dimethylphenethylamine (phentermine), 7-chloro-5-phenyl-1-(2-propynyl)-1H-1, 4-Benzodiazepin-2(3H)-one (pinazepam), α-(2-piperidyl)benzhydryl alcohol (pipradol), 1'-(3-cyano-3,3-diphenylpropyl)[1,4'-bipiperidine]-4'-carboxamide (piritramide), 7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzhydryl alcohol (pipradol), Zodiazepine-2(3H)-one (prazepam), profadol, proheptazine, promedol, properidine, propoxy Phen, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl-{3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]propanoate} (remifentanil), 5-sec-butyl-5-ethylbarbituric acid (secbutabarbital), 5-allyl-5-( 1-Methylbutyl)barbituric acid (secobarbital), N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide (sufentanil), 7-chloro-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepin-2-(3H)-one (temazepam), 7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one (tetrazepam), ethyl-(2-dimethylamino-1-phenyl-3-cyclohexane-1-carbo xylate) (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), (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 of which may, if desired, be the corresponding stereoisomeric compounds and also the corresponding derivatives, in particular esters or ethers, and all of which are physiologically compatible compounds, in particular salts and solvates.

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

[0021] With respect to the analgesic agent in the unit dosage form, such agents may be present in a pharma- ceutically acceptable amount; standard doses of such agents are generally known in the art, and are disclosed, for example, in United States Pharmacopeia and National Formulary (USP 36-NF 31). Rockville, MD: United States Pharmacopeia Convention; 2013, the entire contents of which are incorporated herein by reference. In some embodiments, such agents may be present in an amount of about 5, 25, 50, 75, 100, 125, 150, 175, or 200 mg. In some embodiments, the agents may be present in an amount of about 5 to about 500 mg, or about 5 to about 200 mg. In some embodiments, the dosage form contains an amount of agent suitable for providing a therapeutic effect.

[0022] In certain embodiments, the active pharmaceutical ingredient may include a drug with a narrow therapeutic index, including, but not limited to, aminophylline, carbamazepine, clindamycin, clonidine, digoxin, disopyramide, dyphylline, guanthidine, isoetharine mesylate, isoproterenol, Levothyroxine, lithium carbonate, metaproterenol, minoxidil, oxytriphylline, phenytoin, pasosin, primidone, procaine amide, quinidine gluconate, theophylline, valproic acid, sodium valproate, and warfarin sodium. For drugs with narrow therapeutic doses in unit dosage form, such drugs may be present in pharma- ceutically acceptable amounts; the standard doses of such drugs are generally known in the art, and are disclosed, for example, in United States Pharmacopeia and National Formulary (USP 36-NF 31). Rockville, MD: United States Pharmacopeia Convention; 2013, the entire contents of which are incorporated herein by reference. In some 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 of about 0.01 to about 1000 mg, or about 0.05 to about 500 mg. In certain embodiments, the dosage form contains an amount of drug suitable to provide a therapeutic effect.

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

[0024] In some embodiments, the acid-soluble component is included in the pharmaceutical composition in the form of a particle 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 some embodiments, the active ingredient is sequestered in the acid-soluble component. The acid-soluble component is capable of influencing the release of the active pharmaceutical ingredient according to the pH of the environment, which is raised or maintained by the buffer and / or antacid component depending on the amount of pharmaceutical composition ingested: when the pharmaceutical composition is ingested in an appropriate dosage, the pH buffer component is not present in an amount that alters or sufficiently raises the gastrointestinal pH, and the acid-soluble component dissolves and the active pharmaceutical ingredient is released; when the pharmaceutical composition is ingested in an excessive amount, the pH buffer component is present in an amount that raises the gastrointestinal pH, and thus prevents the acid-soluble component from dissolving and releasing the active pharmaceutical ingredient.

[0025] In certain embodiments, the acid soluble component is 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. weight%; 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, di- and tribasic calcium phosphate, and magnesium hydroxide.

[0027] Buffering and / or antacid components In some embodiments, the pharmaceutical composition of the present invention comprises one or more buffering and / or antacid components. Such components can cause an increase in gastric pH when the pharmaceutical composition is ingested in an appropriate amount. In some embodiments, such components can cause a rapid and sustained increase in gastric pH to a pH greater than about 4 when the pharmaceutical composition is ingested in an appropriate amount.

[0028] In some embodiments, the buffering and / or antacid component may be included in an amount such that, when the pharmaceutical composition is taken in an appropriate therapeutic amount, the gastric pH is not affected, but the gastric pH can be increased if the pharmaceutical composition is taken in an excessive amount. In some embodiments, the buffering and / or antacid component is included in the pharmaceutical composition in an amount of about 45% to about 95% by weight; about 50% to about 90% by weight; about 55% to about 85% by weight; about 60% to about 80% by weight; about 65% to about 75% by weight; about 45% by weight; about 50% by weight; about 55% by weight; about 60% by weight; about 65% by weight; about 70% by weight; about 75% by weight; about 80% by weight; about 85% by weight; about 90% by weight; or about 95% by weight.

[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, glyceryl phosphate ... Magnesium glycinate, magnesium hydroxide, magnesium oxide, potassium bicarbonate, sodium bicarbonate, sodium potassium tartrate, tribasic sodium phosphate, and tricalcium phosphate.

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

[0031] Additional Ingredients The present invention may also include other ingredients as desired 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 pharma- ceutically acceptable fillers / diluents. In one embodiment, Avicel PH (microcrystalline cellulose) is the filler used in the formulation. Avicel PH has a particle size ranging from 20 to about 200 μm, preferably about 100 μm. The density may be 1.512 to 1.668 g / cm 3 Avicel PH should have a molecular weight of about 36000. The effectiveness of Avicel PH is optimal when present in an amount of about 10 to 65 percent by weight of the formulation on a solids basis. Typical fillers may be present in an amount of 10 to 65 percent by weight of the total composition on a dry weight basis. 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.

[0033] In certain embodiments of the invention, the filler, which may be present at about 10 to 65 weight percent on a dry weight basis, functions as a binder that not only imparts binding properties to the materials in the formulation, but also can increase the bulk weight of the directly compressible formulation (discussed below) to obtain a formulation weight that is acceptable for direct compression. In certain embodiments, the additional filler does not need to provide the same level of binding properties as the selected binder, but can contribute to the homogeneity of the formulation and inhibit separation from the formulation after it has been blended. Additionally, preferred fillers do not adversely affect the flow properties of the composition or the dissolution profile of the formed tablets.

[0034] In one embodiment, the present invention may include one or more pharma- ceutically acceptable disintegrants. Such disintegrants are known to those skilled 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, starch (e.g., Starch 22) having a particle size of about 400 microns and a density of about 1.22 g / mL, and starch (e.g., Starch 23) having a particle size of about 400 microns and a density of about 1.22 g / mL. Disintegrants that may be included include Crospovidone®, which has a particle size of about 37 to about 73.7 microns, and croscarmellose sodium (Ac-Di-Sol), which has a density of about 0.529 g / mL. The disintegrant selected should contribute to the compressibility, flowability, and homogeneity of the formulation. Additionally, the disintegrant can minimize segregation and provide an immediate release profile to the formulation. In certain embodiments, the disintegrant(s) are present in an amount of about 2 to about 25 weight percent on a solids basis of the directly compressible formulation. Additionally, an antacid added to the formulation can aid in the disintegration of the tablet when it is introduced into a low pH environment due to the effervescence of the antacid component, thus potentially reducing the need for additional disintegrants.

[0035] In one embodiment, the present invention provides a method for the preparation of a silicone-based silicone gel, including but not limited to colloidal silicon dioxide. The formulation may include one or more pharma- ceutically acceptable glidants that do not include glycerol, glycerol, or other soluble glycerols. In one embodiment, colloidal silicon dioxide (Cab-O-Sil®) having a density of about 0.029 to about 0.040 g / mL may be used to improve the flow properties of the formulation. Such glidants may 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 is understood that while colloidal silicon dioxide is one particular glidant, other known or hereafter developed glidants having similar properties may be used, so long as they are compatible with the other excipients and active ingredients in the formulation and do not significantly affect the flow, homogeneity, and compressibility of the formulation.

[0036] In one embodiment, the present invention may include one or more pharma- ceutically acceptable lubricants, including, but not limited to, magnesium stearate. In one embodiment, the 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 magnesium stearate can contribute to reducing friction between the die wall and the pharmaceutical composition of the present invention during compression, which can facilitate tablet ejection, thus facilitating processing. In some embodiments, the lubricant prevents adhesion to the punch and die, and / or aids in the flow of the powder in the hopper and / or into the die. In an embodiment of the present invention, magnesium stearate having a particle size of about 5 to about 50 microns and a density of about 0.1 to about 1.1 g / mL is used in the pharmaceutical composition. In certain embodiments, the lubricant should comprise about 0.1 to about 2 weight percent of the formulation on a solids basis. A suitable lubricant is stable and does not polymerize within the formulation after mixing. Other lubricants known in the art or hereafter developed which exhibit acceptable or equivalent properties include stearic acid, hydrogenated oils, sodium stearyl fumarate, polyethylene glycol, and Lubritab®.

[0037] In certain embodiments, the most important criterion in the selection of an excipient is that it achieves good content uniformity and releases the active ingredient as desired. The excipient should have very good binding properties and homogeneity, as well as good compressibility, cohesiveness, and flowability in the mixed form, to minimize powder segregation in the hopper during compression.

[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 and subsequent absorption of an overdose of the active pharmaceutical ingredient. In certain embodiments, the pharmaceutical formulations can be designed to have pH-modifying 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 stomach environment based on whether the pharmaceutical composition is taken in an appropriate dose or in an overdose. 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 pharmaceutical 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, the pharmaceutical composition can be formulated such that, when the composition is taken in an appropriate amount, the pH modifying characteristics are minimally affected (i.e., the pH of the stomach environment is not substantially modified or is maintained at a desired level) and the pH dependent solubility characteristics are maximally affected (i.e., the active pharmaceutical ingredient is released), thereby allowing the release and / or absorption of the active ingredient. However, if the pharmaceutical composition is taken in excess, If so, in one embodiment, the composition is formulated such that the pH modifying characteristics are maximally affected (i.e., the pH of the gastric environment is raised) and the pH-dependent solubility characteristics are minimally affected (i.e., acid-soluble components are insoluble and therefore do not dissolve), thereby preventing 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 the acid-soluble ingredient(s) by any suitable process (i.e., dry or wet granulation, hot melt extrusion, etc.) so that a particulate matrix is ​​formed in particulate form. The release of the drug from this matrix can then be controlled by the surrounding pH environment proximate to the matrix when the pharmaceutical composition is ingested. In a low pH environment (i.e., pH 1-4), the matrix can be prone to dissolve and release the drug quickly; however, in a higher pH environment (i.e., pH > 4), the matrix is ​​prone to become insoluble and drug release is likely to be retarded and incomplete, thereby resulting in reduced levels of drug being absorbed.

[0041] In one embodiment, in a single unit dose, the required amount of acid soluble drug matrix is ​​further mixed with a sufficient amount of buffer and / or antacid component(s) such that when the single unit dose is ingested, the buffer and / or antacid component(s) neutralizes the gastric pH to a point where the gastric pH is maintained within the range of pH 1 to 4. The acid soluble drug matrix / antacid / buffer blend may be formed into an oral solid dosage form such as, but not limited to, a tablet or capsule.

[0042] As a result, pharmaceutical compositions can be formulated with pH modifying and pH dependent solubility characteristics such that when a single dose is ingested under normal administration conditions (i.e., one or two tablets), the buffering / antacid component(s) neutralize a portion of the gastric acid, but the gastric acid remains in the pH range of 1 to 4. Under such conditions, the acid soluble drug matrix is ​​soluble in the acidic gastric environment and the drug is rapidly released in the stomach and available for absorption into the bloodstream.

[0043] Under conditions where an overdose is ingested, either intentionally or unintentionally (i.e., 3 or more tablets), the amount of buffer and / or antacid component(s) from the overdose may now be sufficient to cause a rapid and sustained increase in gastric pH (>pH 4). Thus, the acid-soluble drug matrix may be less soluble in the higher pH gastric environment, and release of the drug from the matrix may be inhibited. In certain embodiments, inhibition of drug from the acid-soluble matrix is ​​further aided by gastrointestinal transit, which may move the acid-soluble matrix particles to the intestine and lower gastrointestinal tract, which have a biologically controlled high pH environment (i.e., pH 5.5-8). The overall inhibition of drug release from the overdose results in a pharmacokinetic profile with an increased Tmax and a decreased Cmax, compared to the same oral dose that releases drug at normal gastric pH (i.e., pH 1-4).

[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 made from the pharmaceutical compositions of the present invention. The dosage form may be any shape, including regular or irregular shapes, according to the needs of the artisan.

[0045] The compressed tablets containing the pharmaceutical composition of the present invention may be direct or indirect compressed tablets. In one embodiment, the dosage forms of the present invention may be made by wet granulation and dry granulation (e.g., slugging or roller compaction). The method of formulation and type of excipients are selected to impart the desired physical properties to the tablet formulation that allow for rapid compression of the tablet. After compression, the tablets must possess several additional attributes such as appearance, hardness, disintegrability, 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 tablet. It is understood that the adjustment of such parameters is within the general understanding of those skilled in the art. Suitable fillers and excipients are described in more detail above.

[0047] Manufacturing of dosage forms of the present invention may involve direct compression, as well as wet and dry granulation methods including slugging and roller compaction. In certain embodiments, one or more components may be sequestered, as described in US Patent Application Publication No. 2012 / 0202839, the entire contents of which are incorporated herein by reference.

[0048] Immediate release and controlled drug release formulations may be produced using the present invention. Controlled release formulations include delayed release, bi-modal and tri-modal release, sustained release and and sustained 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 mean effectively 40.5% to 49.5%.

[0050] As used herein, the term "bioequivalence" refers to the C max , T maxor the area under the curve "AUC" is understood to mean that one or more of the

[0051] Certain aspects of the present invention will be better understood when illustrated by the following examples, which are intended to be illustrative and not limiting. Example 1 Two dissolution vessels were prepared: one vessel contained 25 milliequivalents of HCl and a single commercial 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 FIG. 1. In the case of a single tablet, the tablet reacted completely in about 30 minutes, and dissolution of a single tablet showed no change in pH. However, introduction of five tablets resulted in a relatively rapid increase in pH to above pH 4.5 in 10 minutes, and after 90 minutes, a significant amount of undissolved solid was found in the vessel. Thus, while low levels of calcium carbonate (500 mg) were able to dissolve completely with little effect on pH, excessive amounts of calcium carbonate caused a rapid pH increase creating a high pH environment in which 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 faced in designing a self-controlling dosage form is to provide 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 taken. Calcium carbonate was evaluated in both direct blend matrix tablets and dry granulated tablets containing alprazolam, where the granules were added to control drug release. The calcium carbonate in the granules, and the calcium carbonate outside the granules, was responsible for the pH change. Both techniques resulted in a slower release of alprazolam in the single tablets at high pH (approximately pH 6) compared to low pH (pH 1), although in this case the release gap was not as high as desired (Figure 2). However, the results suggest that the pH It is shown that granules can be used to control drug release depending on the environment. Granules may be composed of the drug present with a functional component that inhibits erosion or disintegration at elevated pH, so that a slower and / or incomplete release of the drug is observed. The extragranular portion of the tablet may contain primarily pH control agents that need to be released quickly to initiate the reaction.

[0053] Example 3 Eudragit® EPO (EPO) is a dimethylaminoethyl methacrylate EPO is a cationic copolymer based on methacrylate, butyl methacrylate, and methyl methacrylate. According to technical literature, this polymer is soluble in acid up to pH 5; above pH 5 it swells without dissolving. Dry granulation containing 5% alprazolam in EPO polymer was made and size fractions of -16 mesh and +20 mesh (16 / 20) and -20 mesh and +30 mesh (20 / 30) were collected. Dissolution for these granule size fractions was performed both at low pH (pH 1.5), where EPO is soluble, and at high pH (pH 6), where EPO is less soluble. The results are shown in Figure 3. At low pH, rapid and complete release of alprazolam occurs within 15 minutes, regardless of particle size. However, at high pH, ​​release of alprazolam is very delayed and incomplete for both size fractions, although the smaller fraction is slightly higher. Note that this dissolution simulation represents fixed pH conditions at the extreme pHs possible when the tablet is taken as directed (pH 1) and in excess (pH 6). The next example explores a pH modifying system that does not affect the pH when taken as directed, but rapidly increases the pH when taken in excess.

[0054] Example 4 Subsequent testing using calcium carbonate as the primary pH modifier resulted in a relatively rapid release of alprazolam (60%) from the 5% alprazolam / EPO granules in 15 minutes. The pH change to pH 5 in 10 minutes seen above for calcium carbonate (FIG. 1) may be recognized as fast, assuming that the release of alprazolam is also rapid and complete in 15 minutes, but in alprazolam / EPO granules, calcium carbonate may not affect the pH change quickly enough. Previous experiments have shown that sodium bicarbonate has a more rapid pH effect, raising the acid medium from pH 1 to pH 6 in less than 2 minutes. Thus, sodium bicarbonate was added to the prototype formulation primarily to control the rapid pH rise, and calcium carbonate for more sustained control of the elevated pH. Representative formulations of the present invention are shown in the table below.

[0055] [Table 1]

[0056] Dynamic studies were performed in which the prototype formulation was made into tablets, pH modifiers were included in the tablets, and dynamically reacted in 0.55N HCl medium (pH 1.6). Multiple tablet doses, both with and without self-regulation, and single doses with self-regulation were tested and compared. Dissolution medium pH and drug release were monitored. As shown in Figure 4, a rapid increase in pH was observed in the prototype multiple tablets, with the increase to pH 6 occurring in less than 2 minutes. Thus, the rapid increase in pH can be affected by a pH modifier contained in the tablet.

[0057] Furthermore, as shown in FIG. 5, the single tablet releases alprazolam in 15 minutes, indicating that the immediate release profile of the single tablet is not affected by the on-board self-regulation system. However, the multiple tablets with self-regulation show that approximately a single dose is released in 15 minutes, with the excess alprazolam being released delayed over approximately 2 hours. In comparison, the multiple tablets without self-regulation show that the entire alprazolam dose (approximately 9 mg) is released in approximately 15 minutes, while at the same time point, the multiple tablets with self-regulation only release 20% of the alprazolam. Clearly, the prototype self-regulating alprazolam tablet shows that it releases a single dose of alprazolam as intended, but the multiple tablets show suppression of the release of the excess dose compared to the excess dose without self-regulation.

[0058] Those skilled in the art will appreciate that numerous changes and / or modifications may be made to the invention as illustrated in the specific embodiments 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. [1] An abuse-deterrent pharmaceutical composition comprising: a. a pharmacologic active ingredient; b. an acid-soluble ingredient; and c. a buffering ingredient, wherein the acid-soluble ingredient and the buffering ingredient inhibit release of the pharmacologic active ingredient when the composition is ingested in excess of an intended dose. [2] The composition described in [1], wherein the pharmacologic active ingredient comprises a drug that is susceptible to abuse. [3] The composition of [1], wherein the pharma- ceutical active ingredient comprises a drug having a narrow therapeutic index. [4] The composition of [1], wherein the acid-soluble ingredient comprises calcium carbonate, a cationic copolymer, or a combination thereof. [5] The composition of [1], wherein the acid-soluble component comprises a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. [6] The composition described in [1], wherein the medicamentously active ingredient is contained in a matrix of the acid-soluble ingredient. [7] The composition described in [1], wherein the acid-soluble component is present in an amount of about 1% by weight to about 40% by weight of the pharmaceutical composition. [8] The composition of [1], wherein the buffer component comprises calcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodium phosphate, or a combination thereof. [9] The composition described in [1], wherein the buffer 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 to reach peak plasma concentration (C) of the pharmacologic active ingredient (T) 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 to reach peak plasma concentration (C) of the pharmacoactive ingredient (T) 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 inhibit release of the medicament active ingredient at a pH below 4 but is present in an amount sufficient to inhibit release of the medicament active ingredient at a pH above 4, and the medicament active ingredient is a psychoactive drug or an analgesic. Abuse-deterrent pharmaceutical compositions.

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