WO2011066980A2

WO2011066980A2 - Oral dosage forms with reduced potential for drug abuse

Info

Publication number: WO2011066980A2
Application number: PCT/EP2010/007340
Authority: WO
Inventors: Lars Holger Hermann
Original assignee: Lars Holger Hermann
Priority date: 2009-12-04
Filing date: 2010-12-03
Publication date: 2011-06-09
Also published as: WO2011066980A3

Abstract

The invention is directed to an oral dosage form with reduced potential for drug abuse comprising (a) at least one amine-containing pharmaceutically active compound or salt or solvate thereof, (b) at least one weak organic acid or salt thereof, which forms an insoluble precipitate with component (a) in an aqueous environment at a pH of at least 5, and (c) at least one basifying agent in an appropriate amount to achieve a pH of at least 5 in the environment of the oral dosage form when being dissolved, wherein at least one portion of the oral dosage form is formulated for immediate release and components (b) and (c) are predominantly contained in this portion, and wherein another portion of the oral dosage form is formulated for extended release and contains at least the majority of component (a).

Description

Oral dosage forms with reduced potential for drug abuse

The present invention relates to oral dosage forms with reduced potential for drug abuse.

BACKGROUND OF THE INVENTION

Many therapeutic agents are highly effective for improving quality of life but, because of their abuse potential, attract drug abusers. For example, opioids are excellent analgesic agents that can control severe and/or chronic pain, such as cancer pain and post-operative pain, but are also subject to abuse by drug users. The abuse of therapeutic agents is, thus, a serious and growing problem throughout the world. There are three main routes that drug abusers use for administering the drug substances: parenteral, oral, and inhalation. The parenteral route requires the drug substance to be in solution such that it can be injected intravenously with a syringe. For solid dosage forms this requires some type of extraction and concentration procedure to render the drug substance suitable for injection. Inhalation of a solid drug substance through the nose is commonly called "snorting". For solid dosage form drugs this requires only that the dosage form be crushed into a powder, or emptied from a capsule. Breathing in vapors is frequently known as "huffing". Both snorting and huffing result in the rapid absorption of the drug substance through the mucosa of the respiratory system.

The intensity of the drug-induced high depends on the rate of entry of the drug into the blood. Increasing the rate of entry increases the intensity of the drug-induced high. Consequently, injection of the drug directly into the blood gives the most rapid rate of entry, and the most intense drug-induced high. For other routes of administration the route of entry into the blood is by absorption through mucosal membranes.

The potential for abuse is increased by the use of extended release formulations because they typically contain more than the immediate release single dose of active ingredient. Circumventing the extended release mechanism delivers the full dose immediately. For example, by crushing an extended release tablet that uses a gelling matrix or coating to control the release rate separates the gelling matrix from the active ingredient or disrupts the coating, such that when the crushed formulation is inhaled through the nose the gelling matrix cannot exert the extended release effect or such that the active ingredient is released rapidly instead of over an extended period, respectively. Similarly it is sometimes possible to circumvent the extended release effect by chewing the dosage form. Such formulations are also susceptible to abuse by illicit extraction.

Extended release formulations present a greater hazard to abusers than immediate release formulations because they generally contain larger dosages of the active ingredient. However, immediate release dosage forms are also susceptible to abuse by methods similar to those for the extended release formulations.

In the art there exist different strategies to provide dosage forms or pharmaceutical formulations with reduced potential for drug abuse. One way is to provide dosage forms or pharmaceutical formulations that contain additional component(s), such as: antagonists or inhibitors of the drug, aversive or adverse-effect agents, e.g. irritants, bitter agents, dyes, emetics, viscosity enhancing agents, agents decreasing the solubility of the drug, by e.g. complexation or (irreversible) precipitation.

In particular, WO 2006/133733 discloses oral solid dosage forms containing one or several active principle(s) having analgesic properties which prevent the intentional or unintentional misuse of the dosage form through the liquid extraction of the active principle(s) with commonly available solvents (water, alcohol and other types of drinkable solvents). The oral solid dosage forms of WO 2006/133733 contain at least one salt of at least one analgesic active principle (such as an opioid) and an anti-misuse system comprising at least one quenching agent, wherein the quenching agent is suitable to induce complexation of the analgesic active principle salt when the analgesic active principle salt is improperly extracted, notably by a drug abuser, in vitro in solution from the oral solid dosage form. The concept is to include within a solid oral dosage form a quenching agent, namely a salt, wherein this salt comprises an ion which has a polarity opposite to that of the analgesic active principle in solution. In particular, the quenching agent(s) comprise a salt selected from the group comprising (a) organic anionic salts, (b) anionic polymers, (c) monovalent or polyvalent salts, (d) saponified fatty acids, (e) polyamino acids, proteins or peptides and (e) mixtures of the above. WO 2006/133733 discloses that the quenching agent forms a complex which is poorly soluble in water at any physiological pH from the stomach to the colon. Furthermore, the quenching agents used are innocuous to the regular user and are pharmacologically inert, approved by the Pharmacopoeia and health authorities in charge of market approval of drugs.

Furthermore, DE 22 17 132 (= US 3,885,027) discloses pharmaceutical formulations which contain agents decreasing the solubility of the drug, by e.g. complexation or (irreversible) precipitation. The solid compositions are suitable for the oral treatment of narcotic addiction and are dispersible for dissolution in an acidic medium before ingestion. It is disclosed to incorporate in a drug formulation for oral administration a component which will induce precipitation of a major portion of the therapeutic agent if the composition is dissolved in water and the solutio is then concentrated, while at the same time permitting full dissolution in orange juice or comparable acidic media which do not permit of injection. Essentially, the reduced solubility may be attained either by a composition which produces a pH of about 7.5 to 10 directly upon dispersion in water, or by a composition which upon initial dispersion produces a pH of at least 6 which then increases to pH 7.5 or more upon concentration; or by a component which will form a salt with the therapeutic agent which is soluble at an acidic pH but has markedly reduced solubility at a substantially neutral or alkaline pH.

In particular, the compositions of DE 22 17 132 comprise (a) an effective amount of an amine-containing therapeutic agent for the maintenance therapy treatment of narcotic drug addiction, the hydrochloride salt form of which is soluble in water but essentially insoluble in alkaline solution (such as methadone or its acidic salts); (b) a precipitating agent selected from the class consisting of (i) an ingestible solid alkalinizing agent in an amount which provides an alkaline pH of at least 7.5 when dissolved in water either directly, or indirectly upon heating or concentration of the solution, (ii) an ingestible alkaloid precipitating substance selected from the group consisting of tannic acid and picrolonic acid in an amount active as a precipitant in non-acidic conditions, and (iii) combinations of (i) and (ii). In particular, tablet compositions are disclosed which contain methadone hydrochloride as therapeutic agent (a) and tannic acid as precipitating agent (b). Furthermore, US 2003/0170181 discloses a method for treating a patient with a methylphenidate-responsive condition that is at a risk of abusing or becoming addicted to methylphenidate (MPH). The patient is first evaluated for an elevated risk of drug abuse or addiction through psychological evaluations and then treated with a MPH product that includes an emesis-inducing agent that is inert when ingested orally and only produces emesis when snorted or taken intravenously or a topical analgesic that is inert when ingested orally and only produces irritation when snorted or taken intravenously. US 2003/0170181 furthermore discloses that in order to maximize the effect of the oral MPH, the drug may be administered in a once-daily pulsatile release dosage form comprised of an immediate release dosage unit and a delayed release dosage unit, each said dosage unit containing MPH and at least one of said dosage units containing the additional emesis-inducing agent. This mode of administration of MPH has the advantage of increasing the efficacy of the orally administered MPH by ensuring that effective dosages of d-MPH are released into the patient's system throughout a set time interval. Under the pulsatile release delivery system, a first dose of MPH is released substantially immediately from the immediate release dosage unit, followed by a time interval during which substantially no drug is released from the dosage form, and after which time interval a second dose of MPH is released from the delayed release dosage unit. The active agents in the individual tablets may be in the form of a pharmaceutically acceptable salt, wherein suitable acids for preparing acid addition salts may be weak acids, including organic acids.

US 2004/0234608 discloses pharmaceutical compositions for use in a dosage form for oral administration which expand upon contact with gastric fluid and promote retention of the dosage form in the patient's stomach for a prolonged period of time. The compositions comprise a non-hydrated hydrogel, a superdisintegrant and tannic acid, preferably in amounts, exclusive of any other excipients that may be present, of from about 20 wt-% to about 70 wt- % hydrogel, from about 10 wt- % to about 75 wt- % superdisintegrant and from about 2 wt-% to about 12 wt- % tannic acid. The forms are adapted for immediate or controlled release of the active ingredient. The dosage forms may be used advantageously in the treatment of Parkinson's disease with levodopa and hyperactivity and attention deficit disorder with methylphenidate .

US 2005/0232987 discloses pharmaceutical dosage forms which contain a morphine derivative with antitussive activity such as, e.g., codeine, dihydrocodeine, hydrocodone and/or a pharmaceutically acceptable salt thereof in combination with at least one additional active ingredient, such as an antihistamine. The dosage forms release the morphine derivative and the at least one additional active ingredient at rates which provide pharmaceutically suitable plasma concentrations thereof over similar or different periods of time. Thereby, multi- layered tables with a first layer as an immediate release layer and a second layer as a controlled release layer are, for example, described as dosage forms, which can furthermore contain excipients. As an example of an excipient, in particular a lubricant, stearic acid is mentioned.

There is a need in the art for a pharmaceutical dosage form that will greatly reduce the potential for drug abuse by the known routes of abuse and improves existing abuse-deterrent pharmaceutical compositions.

SUMMARY OF THE INVENTION

According to the present invention this object is solved by providing an oral dosage form with reduced potential for drug abuse.

An "oral dosage form with reduced potential for drug abuse" refers to an oral dosage form which is designed and formulated in order to prevent or inhibit abuse, misuse or tampering of the oral dosage form, in particular by crushing to make it injectable, inhalable and/or sniffable.

Said oral dosage form comprises at least one component (a), at least one component (b), and at least one component (c).

Component (a) is at least one amine-containing pharmaceutically active compound or salt or solvate thereof.

Component (b) is at least one weak organic acid or salt thereof which forms an insoluble precipitate with component (a) in an aqueous environment at a pH of at least 5. Component (c) is at least one basifying agent in an appropriate amount to achieve a pH of at least 5 in the environment of the oral dosage form when being dissolved.

Furthermore, at least one portion of the oral dosage form is formulated for immediate release and components (b) and (c) are predominantly contained in this portion, and wherein another portion of the oral dosage form is formulated for extended release and contains at least the majority of the amine-containing pharmaceutically active compound, i.e. component (a).

The term "predominantly", in the context of this application, means from about 80 to about 100 wt-%, preferably about 90 wt-%, most preferably 100 wt-%. The term "majority", in the context of this application, means at least more than about 50 wt-%, usually more than about 60 wt-%, preferably more than about 70 wt-%.

Therefore, the proportion of components (b) and (c) contained in the portion for immediate release in relation to the total content of those components in the composition is between 80 to about 100 wt-%, preferably about 90 wt-%, most preferably 100 wt-% whereas the proportion of those components in the portion for extended release is between 20 to 0 wt-%, preferably about 10 wt-%, most preferably 0 wt-%.

Moreover, the portion for extended release contains at least more than about 50 wt-%, usually between 60 wt-% and 100%, preferably between 70 wt-% and 100 wt-% of the total content of component (a) in the composition.

Preferably, the immediate release portion of the oral dosage form additionally contains a smaller amount of component (a), i.e. the amine-containing pharmaceutically active compound or salt or solvate thereof, wherein "smaller amount" means less than about 50 wt- % in the composition.

Therefore, the content of component (a) in the portion for immediate release is less than about 50 wt-%, preferably between 40 wt-% and 0 wt-%, more preferably between 30 wt-% and 0 wt-% of the total content of component (a) in the composition.

Preferably, component (a) is formulated to be released in the intestine. Also, preferably, component (b) is formulated to be released in the stomach and small intestine.

In a further preferred embodiment, component (b) is present in an amount sufficient to precipitate, upon dissolution/disintegration of the oral dosage form in aqueous media, at least the majority of component (a), wherein "majority", in this context, has the same meaning as hereinabove.

Further, the mole ratio of component (a) to component (b) is in the range from 0.5:1.0 to 2.0:1.0.

Component (a) is preferably selected from the compounds as listed in Table 1 or salts or solvates thereof, most preferably from the group consisting of methylphenidate, morphine, tramadol, modafinil, and morphine derivatives, namely hydromorphone, codeine, dihydrocodeine, oxycodone, hydrocodone, noscapine, D,L-methadone, leveacetylmethadole, naltrexon, and naloxon and salts and solvates thereof.

Component (b) is preferably selected from the acids as listed in Table 2 or salts thereof, most preferably from the group consisting of tannic acid and pamoic acid and salts thereof.

Therefore, the presently most preferred combinations of components (a) and (b) are: oxycodone or a salt (such as oxycodone hydrochloride) or solvate thereof as component (a) and tannic acid or pamoic acid or salts thereof as component (b); methylphenidate or a salt of solvate thereof as component (a) and tannic acid or pamoic acid or salts thereof as component (b); morphine or a salt (such as morphine sulfate or morphine hydrochloride) or solvate thereof as component (a) and tannic acid or pamoic acid or salts thereof as component (b); hydromorphone or tramadol or a salt or solvate thereof as component (a) and tannic acid or pamoic acid of salts thereof as component (b); and modafinil or a salt or solvate thereof as component (a) and tannic acid or pamoic acid or salts thereof as component (b).

Component (c) is preferably selected from the group consisting of carbonates, phosphates, citrates, silicates, sulfates, hydroxides and oxides. Preferably, the dosage form is a bi- or multilayered tablet having one or more layers for immediate release and one or more layers for extended release.

More preferably, the one ore more layers for extended release are provided with a protective layer or coating.

Additionally, one or more colouring and/or flavouring agents are added.

Alternatively, the extended release portion may be embedded in the immediate release portion.

According to the present invention the object is furthermore solved by using the oral dosage forms according to the invention for preventing or inhibiting abuse, misuse or tampering of the oral dosage form.

DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

Before the present invention is described in more detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. For the purpose of the present invention, all references cited herein are incorporated by reference in their entireties.

Dosage forms with reduced potential for drug abuse

As outlined above, the present invention provides oral dosage forms with a reduced potential for drug abuse which utilize precipitation of the active compound with a weak organic acid in the presence of a basifying agent. An oral dosage form with reduced potential for drug abuse according to the present invention comprises at least one component (a), at least one component (b), and at least one component (c), and, optionally, one or more pharmaceutically acceptable excipients.

Component (a): amine -containing pharmaceutically active compound

Component (a) is a pharmaceutically active or drug compound or a pharmaceutically acceptable salt or solvate thereof.

The oral dosage forms of the invention comprise one or more (such as two, three or more) component(s) (a), i.e. one or more amine-containing pharmaceutically active compound(s).

Compound (a) is a compound that forms an insoluble precipitate (salt or complex) with component (b) in an aqueous environment at a pH of at least 5.

Component (a) is preferably a psychostimulating substance, a strong analgetic or a psychotropic drug. Component (a) is furthermore preferably a centrally active drug, centrally active agent or pharmacologically active agent in the CNS.

"Psychostimulating substances" is meant to refer to substances that, when taken in or administered into the body, affect mental processes, e.g. cognition or affect. This term and its equivalent, "psychotropic drug", are the most neutral and descriptive term for the whole class of substances, licit and illicit, of interest to drug policy. "Psychostimulating" does not necessarily imply dependence-producing, and in common parlance, the term is often left unstated, as in "drug use" or "substance abuse".

The terms "centrally active drug", "centrally active agent", and "pharmacologically active agent in the CNS" are used interchangeably herein to refer to a chemical compound that induces a desired pharmacological, physiological effect in the central nervous system. The terms also encompass pharmaceutically acceptable derivatives of those active agents specifically mentioned herein, including, but not limited to, salts, solvates, hydrates, complexes with one or more molecules, prodrugs, active metabolites, analogs, and the like. When the terms "active agent", "pharmacologically active agent" and "drug" are used, or when a particular drug, such as oxycodone, is identified, it is to be understood as including the active agent per se as well as pharmaceutically acceptable salts, solvates, hydrates, complexes with one or more molecules, prodrugs, active metabolites, and analogs.

Examples of preferred drugs, i.e. component (a), include, but are not limited to:

1 -phenylcyclohexylamine, 1 -piperidinocyclohexanecarbonitrile, alfentanil, alphacetylmethadol, alphaprodine, alprazolam, amobarbital, amphetamine, Amytriptylin, anileridine, apomorphine, Aprazolam, aprobarbital, Azelastin, barbital, barbituric acid derivative, bemidone, benzoylecgonine, benzphetamine, Benzatropin, betacetylmethadol, betaprodine, bezitramide, Biperiden, Bornaprin, bromazepam, buprenorphine, butabarbital, butalbital, butorphanol, Butyrophenone, camazepam, cathine, Cetirizin, chloral, chlordiazepoxide, Chlorphenoxamin, Citalopram, clobazam, Clomipramin, clonazepam, Clobutinol, Clozapin, clorazepate, clotiazepam, cloxazolam, cocaine, codeine, Coffein, chlorphentermine, delorazepam, Desipramin, dexfenfluramine, Dextroamphetamin, Dextromethorphan, dextromoramide, dextropropoxyphen, Dexchlorpheniramin, dezocine, diazepam, Diacetylmorphin, Dibenzepin, diethylpropion, difenoxin, dihydrocodeine, dihydromorphine, Dimetinden, dioxaphentyl butyrate, dipanone, diphenoxylate, Diphenhydramin, diprenorphine, Diphenylbutylpiperidine, Doxepin, Doxylamin, ecgonine, enadoline, Ephedrin, eptazocine, estazolam, ethoheptazine, ethyl loflazepate, ethylmo hine, etorphine, femproponex, fencamfamin, fenfluramine, fentanyl, Fenetyllin, fludiazepam, flunitrazepam, Fluoxetin, flurazepam, Fluvoxamin, glutethimide, halazepam, haloxazolam, hexylgon, hydrocodone, hydromorphone, Hydroxyzin, isomethadone, hydrocodone, Imipramin, ketamine, ketazolam, ketobemidone, Ketotifen, levanone, levoalphacetylmethadol, levomethadone, levomethadyl acetate, levomethorphan, levorphanol, lofentanil, Lofepramin, loperamide, loprazolam, lorazepam, Loratidin, lormetazepam, lysergic acid, lysergic acid amide, mazindol, medazepam, mefenorex, meperidine, meptazinol, metazocine, methadone, methamphetamine, methohexital, methotrimeprazine, methyldihydromorphinone, methylphenidate, methylphenobarbital, MetixenTiaprid, metopon, morphine, nabilone, nalbuphine, nalbupine, nalorphine, Naloxon, Naltrexon, narceine, Nefazodon, nefopam, nicomorphine, nimetazepam, nitrazepam, nordiazepam, Noscapin, normethadone, normorphine, Nortriptylin, Olanzapin, oxazepam, oxazolam, oxycodone, oxymorphone, Oxitriptan, pentazocine, pentobarbital, Pentoxyverin, phenadoxone, phenazocine, phencyclidine, phendimetrazine, Pheniramin, phenmetrazine, Phenobarbital, Phenothiazine, Phenothiazin-Analoge, pheneridine, Phenylephrin, pimnodine, Pipazetat, Piritramid, Procyclidin, prodilidine, Promethazin, properidine, propoxyphene, Quetiapin, racemethorphan, racemorphan, racemoramide, remifentanil, Risperidon, Reboxetin, secobarbital, Sertalin, sufentanil, Sulpirid, talbutal, thebaine, Theophyllin, thiamylal, thiopental, Tilidin, tramadol, Trazodon, Trihexphenidyl, trimeperidine, Trimipramin, Venlafaxin, vinbarbital, Viloxazin, Zaleplon, Ziprasid, Zolpidem, Zotepin and Zopliclon.

(wherein active substance names as international non-proprietary name (ΓΝΝ) are shown in italic).

In addition to the compounds above, the following scheduled drugs may be incorporated into the composition as component (a): allobarbitone, alprazolam, amylobarbitone, aprobarbital, barbital, barbitone, benzphetamine, brallobarbital, bromazepam, brotizolam, buspirone, butalbital, butobarbitone, buto hanol, camazepam, captodiame, carbromal, carfentanil, carpipramine, cathine, chloral, chloral betaine, chloral hydrate, chloralose, chiordiazepoxide, chlorhexadol, chlormethiazole edisylate, chlormezanone, cinolazepam, clobazam, potassium clorazepate, clotiazepam, cloxazolam, cyclobarbitone, delorazepam, dexfenfluramine, diazepam, diethylpropion, difebarbamate, difenoxin, enciprazine, estazolam, ethyl loflazepate, etizolam, febarbamate, fencamfamin, fenfluramine, fenproporex, fluanisone, fludiazepam, flunitraam, flunitrazepam, flurazepam, flutoprazepam, gepirone, glutethimide, halazepam, haloxazolam, hexobarbitone, ibomal, ipsapirone, ketazolam, loprazolam mesylate, lorazepam, lonnetazepam, mazindol, mebutamate, medazepam, mefenorex, mephobarbital, meprobamate, metaclazepam, methaqualone, methohexital, methylpentynol, methylphenobarbital, midazolam, milazolam, morphine, nimetazepam, nitrazepam, nordiazepam, oxazepam, oxazolam, paraldehyde, pemoline, pentabarbitone, pentazocine, pentobarbital, phencyclidine, phenobarbital, phendimetrazine, phenmetrazine, phenprobamate, phentermine, phenyacetone, pinazepam, pipradol, prazepam, proxibarbal, quazepam, quinalbaritone, secobarbital, secbutobarbitone, sibutramine, temazepam, tetrazepam, triazolam, triclofos, zalepan, zaleplon, zolazepam, Zolpidem, and zopiclone. Certain compounds described herein may exist in particular geometric or stereoisomeric forms. The invention disclosed herein contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, compounds of different spacial conformations, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.

The pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000, p. 704, the disclosure of which is hereby incorporated by reference.

Preferred examples of component (a) are shown in Table 1. Component (a) is preferably selected from the group consisting of methylphenidate, morphine, tramadol, modafinil, hydromorphone, codeine, dihydrocodeine, oxycodone, hydrocodone, noscapine, D,L-methadone, leveacetylmethadole, naltrexon, and naloxon, and salts and solvates thereof.

Component (a) is most preferably selected from the group consisting of methylphenidate, morphine, oxycodone, and modafinil.

Component (a) is comprised in the dosage form in a therapeutic concentration or amount, which depends on the respective application. Preferably, the content of component (a) in the composition is between 2 wt-% and 40 wt-%, preferably between 5 wt-% and 10 wt-%.

The term "therapeutic concentration" or "therapeutic amount", as used herein, means the concentration of the pharmaceutically active ingredient or drug that is obtained by the administration of the recommended doses using the prescribed method of administration.

Importantly, the desired pharmacological effect of component (a) is not impaired by component(s) (b) and/or component(s) (c) when the dosage form is intact / not misused.

Component (b): weak organic acid

Component (b) is at least one weak organic acid or salt thereof.

The term "weak" (organic) acid refers to an (organic) acid that dissociates incompletely and does not release all of its hydrogens in a solution, i.e. does not completely donate all of its protons. A "weak" (organic) acid has a higher pKa compared to strong acids, which release all of their hydrogens when dissolved in water.

The oral dosage forms of the invention comprise one or more (such as two, three or more) component(s) (b), i.e. one or more weak organic acid(s).

Component (b) is preferably selected from - aromatic carboxylic acids and polyphenols, and

- sulfonic acids, or salts thereof.

Preferred aromatic carboxylic acids and polyphenols are selected from pamoic acid (also called embonic acid), 1 -hydroxy 2-naphthoic acid, rosmarinic acid, cinnamic acid, salicylic acid, furan-2-carboxylic acid, gallic acid, tannic acid, catechines (e.g. epigallo catechine gallate) or salts thereof.

Preferred sulfonic acids are selected from benzene sulfonic acid, p-chloro benzene sulfonic acid, dihydroxy benzene sulfonic acid, p- toluol sulfonic acid or salts thereof.

Preferred further acids are orotic acid, 4-O-P-D-galacto pyranosyl D-gluconic acid, undecylene acid, methyl diethylene triamine penta acetic acid, trans-4 butyl cyclohexyl carboxylic acid, 3-cyclopentyl propionic acid or salts thereof.

A more detailed list of appropriate organic acids can be seen from Table 2. Component (b) may preferably be tannic acid or pamoic acid.

The term "tannic acid" or "tannin" as used herein refers to tannic acid (Acidum tannicum) which is a commercial form of tannin. Tannic acid or tannin is a polyphenol. Due to its phenol groups tannic acid has a weak acidity (pK_a around 10). Tannic acid or tannin is a mixture of related compounds which are (glucose) esters of gallic acid with different isomers. It is a yellow to light brown amorphous powder which is highly soluble in water; one gram dissolves in about 0.35 ml of water. Tannic acid or tannin are commercially available, such as Tannin EMPROVE^® Ph. Eur., USP (Merck).

The term„pamoic acid", also called„embonic acid", refers to a naphthoic acid derivative. It can be prepared by the reaction of 2-hydroxy-3-naphthoic acid with formaldehyde. The presence of multiple hydroxylic groups enables significant hydrogen bonding to occur.

Pamoic acid or pamoate are also commercially available.

Preferably, component(s) (b) is (are) comprised in an amount sufficient to precipitate or complex, upon dissolution of the oral dosage form in aqueous media, at least the majority of component (a).

Preferably, the content of component(s) (b) in the composition is between 10 wt-% and 30 wt- %, preferably between 12.5 wt-% and 17.5 wt-%.

Weak organic acids have been used in pharmaceutical compositions and formulations for other purposes, such as: for preparing acid addition salts of the pharmaceutically active agent(s) or drug(s) (see, for example, US 2003/0170181);

- as component or matrix of an expanding composition, as described for tannic acid in US 2004/0234608 wherein pharmaceutical compositions for use in a dosage form for oral administration are described which expand upon contact with gastric fluid and promote retention of the dosage form in the patient's stomach for a prolonged period of time;

as a lubricant or excipient (as described in e.g. US 2005/0232987 for stearic acid).

In contrast thereto, weak organic acids which are used as component(s) (b) according to this invention are utilized to interact with component (a) in case of an attempted abuse and form an insoluble precipitate with component (a) in an aqueous environment at a pH of at least 5, as it is explained in further detail in this specification. Component (c): basifying agent

Component (c) is at least one basifying agent in an appropriate amount to achieve or provide a pH of at least 5 in the environment of the oral dosage form when being dissolved.

Preferably, the content of component (c) in the composition is between 2 wt-% and 12 wt-%, preferably between 3.5 wt-% and 5.5 wt-%.

The term "basifying agent" refers to the effect the component has on the precipitation reaction or its effect on the pH value of the environment of the oral dosage form when being dissolved, respectively. The addition of the basifying agent results in an increase of the pH value which allows the precipitation reaction to occur or which facilitates/improves the precipitation reaction.

The oral dosage forms of the invention comprise one or more (such as two, three or more) component(s) (c), i.e. one or more basifying agent(s).

Component (c) is preferably selected from the group consisting of carbonates, phosphates, citrates, silicates, sulfates, hydroxides and oxides.

Preferred examples are trimagnesium citrate, sodium carbonate, sodium hydrogen carbonate, magnesium hydroxide, magnesium oxide, sodium sulphate, and disodium hydrogen phosphate.

Ratios of the components in the formulation

Preferably, the mole ratio of component (a) to component (b) in the composition is in the range from 0.5:1.0 to 2.0:1.0.

Preferably, in the oral dosage forms of the invention component (b) is comprised in an amount sufficient to completely or almost completely complex or precipitate component (a) in solution, meaning that per 1 mol of component (a) 2.0 to 0.5 mol of component (b) should be comprised, depending on the valances of the components. Reduction of drug abuse

In case of (attempted) abuse or misuse of the oral dosage form of the invention, component(s) (b) is (are) able to induce irreversible complexation or precipitation of component(s) (a), they form an insoluble salt or precipitate or complex. Presence of component (c) is necessary to provide a pH of at least 5 in the environment of the oral dosage form when being dissolved in order to allow or facilitate the precipiation reaction.

The term "insoluble salt or precipitate" refers to a salt or precipitate of the amine-containing pharmaceutically active compound and the weak organic cyclic acid that is insoluble or almost not soluble in an aqueous solution and a pH of at least 5.

The term "attempted abuse" or "abuse" or "misuse" or "tampering" of the oral dosage form of the present invention refers to the known abuse, misuse and tampering methods, such as in vitro liquid extraction of the addictive drug from the formulation which comprises

- solvent extraction,

- mixing and solubilizing with an aqueous or aqueoua-alcoholic liquid, preferably from 0.5 to about 10 ml of the aqueous or aquoues-alcoholic liquid and/or

- dissolution in water, in vitro mechanical extraction of the addictive drug from the formulation or compromising the physical integrity of the composition (such that the resulting material is exposed to an aqueous liquid or medium) - mechanically treating the formulation, such as tablets, microparticles or beads, wherein mechanically treating comprises crushing, grinding, chopping with a blade,

- optionally, followed by mixing and solubilizing the mechanically treated formulation with an aqueous liquid or medium (such as water), preferably from 0.5 to about 10 ml of the aqueous liquid

Preferably, the oral dosage form comprises component(s) (b) in an amount sufficient to precipitate, upon dissolution/disintegration of the oral dosage form in water or dilute acid, at least the majority of component (a), wherein majority, in this context, has the same meaning as herein-above.

Thereby, component (a) is rendered useless for administering parenterally, orally, and by inhalation.

Release characteristics or profiles

At least one portion of the oral dosage form is formulated for immediate release and another portion of the oral dosage form is formulated for extended release.

Component (b) and (c) are predominantly contained in the at least one portion of the oral dosage form that is formulated for immediate release or fast release, wherein "predominantly", in the context of this application, has the same meaning as hereinabove.

The portion of the oral dosage form that is formulated for extended release contains at least the majority of the amine-containing pharmaceutically active compound, i.e. component (a), wherein "majority", in the context of this application, has the same meaning as hereinabove.

When describing dosage forms the term "immediate release" or "fast release" as used herein means a dosage form from which the active ingredient is dissolved as quickly as possible after administration or solution in a solvent. In the pharmaceutical arts the immediate or fast release dosage forms are also referred to as conventional dosage forms.

Furthermore, by "immediate release" dosage form is meant the release by a dosage form of the major part of the active principle dose in a short time, for instance, 70 wt-% of the active principle are released in 1 hour, preferably in 30 min., at any pH between 1.4 and about 8.5, during an in vitro dissolution test (wherein major part, in this context, has the same meaning as hereinabove.

When describing dosage forms, the term "extended release" or "modified release" as used herein means a dosage form whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms. The modified release dosage forms of the present invention include dosage forms commonly known in the art as delayed, sustained, extended, prolonged and controlled.

Furthermore, by "extended release" or "modified release" dosage form is meant any dosage form wherein the major part of the active principle is released at a lower rate than in an immediate release dosage form, (wherein major part, in this context, means more than about 50 wt-%, usually more than about 60 wt-%, preferably more than about 70 wt-%).

The release characteristics of the oral dosage forms of the present invention work as follows:

In case of the intended use:

When the oral dosage form is administered and used according to its intended medical use or according to the prescription, than an interaction of component (a) and component (b) in the body is avoided, because component (a) and component (b) will preferably not be released with the same rate at the same time and, thus, importantly, not in an amount sufficient to cause substantial precipitation/complexation of the pharmaceutically active compound ("drug"). Instead component (b) will be released first such that at the time the drug release reaches a therapeutic concentration/amount in vivo in the body, component (b) is already (almost) exhausted. The term "an amount sufficient to cause substantial precipitation/complexation of the pharmaceutically active compound ("drug")" means an amount that causes precipitation/complexation of more than about 50 wt-%, usually more than about 60 wt-%, preferably more than about 70 wt-% of the pharmaceutically active compound or drug.

Preferably, component (b) will be released and (almost) exhausted in a period of about 2 hours and/or in the period from oral uptake/administration until the end of residence in the stomach. The release of component (a) in substantial amounts (reaching a therapeutic amount) starts delayed, in the intestine.

In case of (attempted) abuse:

When the oral dosage form is not administered and used according to its intended medical use or according to the prescription, i.e. when its being tampered with, than the extended release formulation of component (a) will be destroyed or is not functional anymore, such that component (a) and component (b) as well as component (c) will all be released and, thus, present in an amount sufficient to cause substantial precipitation/complexation of the drug.

Preferably, compound (b) is formulated to be released in the stomach.

Thus, compound (b) is preferably formulated to be (immediately or fast) released at a neutral or acidic pH, wherein a neutral pH refers to a pH value of about 7, such as the pH value of water, an acidic pH refers to a pH value below 4, preferably to a pH value in the range of about 1 to about 4.

Thus, compound (b) is released in the pH value of the stomach. Preferably, component (a) is formulated to be released in the intestine.

Thus, compound (a) is preferably formulated to be released at a basic pH, wherein a basic pH refers to a pH value above 7, preferably to a pH value in the range of about 7 to about 8, preferably the pH value of the intestine. Thus, compound (a) is released in the pH value of the intestine.

Preferably, component (c) is incorporated in the immediate release portion.

In one preferred embodiment of the present application, the immediate release portion of the oral dosage form additionally contains a smaller amount of the amine-containing pharmaceutically active compound, i.e. component (a), wherein "smaller amount", in this context has the same meaning as hereinabove.

In this embodiment, the release of component (a) will be in a bimodal manner causing an initial release and an extended / retarded release of component (a).

Formulation forms

Preferably, the dosage form according to the present invention is a two- or multilayer (e.g. tri- layer) tablet having one or more layers for immediate release and one or more layers for extended release.

In a preferred embodiment, the one ore more layers for extended release are provided with a coating, e.g. an enteric coating.

For examples, see Figures 8 and 9.

Preferably, one or more colouring agents are added in order to achieve an uniform colour of all layers. Suitable colouring agents are known in the art. Also, one or more flavouring agents may be added.

In a preferred embodiment, the extended release portion is embedded in the immediate release portion.

Further components Optionally, the pharmaceutical compositions of the present invention furthermore comprise one or more pharmaceutically acceptable excipients, as commonly used such as binders, glidants, disintegrating agents, etc.

The following examples and drawings illustrate the different aspects of the present invention without, however, limiting the same thereto.

Use of the oral dosage forms for preventing or inhibiting abuse, misuse or tampering thereof

As outlined above, the present invention also provides the use of the oral dosage forms according to the invention for preventing or inhibiting abuse, misuse or tampering of the oral dosage form.

Thereby, the oral dosage forms are as defined and described herein.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. 'HNMR spectrum of MPH.

The signals at 1.5 ppm (6 H atoma) were later used to determine the mixture ratio of MPH and tannin.

Figure 2. 'HNMR spectrum of a mixture of 34.0 mg tannin and 36.6 mg MPH.

The signals at 5.5, 6.0 und 6.5 ppm are from tannins, the signal cluster at 1.5 ppm are from MPH. From the ratios of these signals to each other, the weight ratios of tannin and MPH can be determined. The sample contained 0.93 g tannin per 1 g MPH (which corresponds to 48 wt-% tannin).

Figure 3. 'HNMR spectrum of the precipitate in de-DMSO/D₂0.

The weight ratio can be determined (according to the reference measurement, see Figure 2) from the integrals of the signal clusters (the integral of the MPH signal cluster was set at 100): The sample contained 3.6 g tannin per gram MPH (78 wt-% tannin).

Figure 4. 13, C NMR spectrum of MPH in d₆-DMSO.

DMSO signal at 40 ppm.

Figure 5. 13 C, NMR spectrum of citric acid in d -DMSO.

Figure 6. 13 C NMR spectrum of the precipitate in d^-DMSO.

The characteristic signals of MPH can be seen (even though with slightly different chemical shifts). In addition to that, lots of signals can be seen in the aromatic area (100 - 150 ppm) and several ester signals (about 165 ppm) of the tannins. Signals of citrate can not be seen (compare to reference spectrum of citric acid, Figure 5).

Thus, the precipitate contains only a mixture of tannin and MPH (with a content of about 78 wt-% tannin), but no citric acid (or citrate).

Figure 7. Precipitation of MPH from solutions.

This figure shows the precipitation of different concentrations of MPH with different concentrations of tannin and the basifying agent (in this case, disodium hydrogen phosphate

(Na₂HP0₄).

Figure 8. Design ofbilayered tablets. first layer: IR portion (IR = immediate release) second layer: Matrix (ER portion, ER = extended release)

Figure 9. Design of core tablets. left: the outer portion or coat contains component (b) (tannin), a minor amount of component (a) (MPH) and component (c) (Na C0₃), the inner portion or core contains the majority of component (a) (MPH); right: the outer portion or coat contains component (b) (tannin), a minor amount of component (a) (MPH) and component (c) (Na₂C0₃), the inner portion or core contains the majority of component (a) (MPH), between coat and core is a retard coating or membrane.

EXAMPLES

"%" in this application means "wt-%", unless indicated otherwise. Example 1 Precipitation of methylphenidate with tannin

Tannin precipitates or complexes methylphenidate (MPH). The precipitate can be determined and evaluated by using NMR, as can be seen in Figures 1-6.

NMR showed that MPH was contained in the precipitate and that 3.56 tannine complex 1 g MPH (see Figures 3 and 6). Thus, the ratio of MPH and tannin in the precipitate was about 1 to 4.

Furthermore, the precipitation reaction is pH dependent. The addition of a basifying agent, such as tri magnesium citrate, increased the pH to above 4 (such as 4.35). The magnesium citrate is not contained in the precipitate (see Figure 6).

The best precipitation efficiencies were achieved when mixing 40 mg MPH with 100 mg tannin and 20 mg Na₂HP0₄. (see Figure 7).

Example 2 Precipitation of morphine hydrochloride with tannin

Morphine hydrochloride precipitates with tannin when the pH is adjusted (to at least pH 5), in presence of a basifying agent (in this case Na₂C0₃). Morphine HC1 Tannin Na₂C0₃ + 5 ml H₂0 pH

[mg] [mg] [mg]

200 200 43 precipitation 6.62

30 100 20 precipitation 7.47

30 100 — NO precipitation 3.35

30 ~ 19 precipitation 9.62

Example 3 Precipitation of oxycodone with tannin

Oxycodone hydrochloride precipitates with tannin when the pH is adjusted (to at least pH 5), in presence of a basifying agent (in this case Na₂C0₃).

Oxycodone HC1 Tannin Na₂C0₃ + 5 ml H₂0 pH

[mg] [mg] [∞g]

80.5 149.8 40.2 precipitation 8.11

40.4 100.1 19.1 precipitation 7.72

40.3 100.1 — NO precipitation 3.24

3039.8 — 19.7 precipitation 9.92

20 52.0 10.0 precipitation 7.87

10.4 53.2 4.6 precipitation 6.88

5.4 53.0 4.5 precipitation 6.86

80 ~ ~ NO precipitation 4.70 Example 4 Formulation of a bi-layered tablet

Ratio IR:ER = 1 :1

Example 5 Formulation of a bi-layered tablet

Ratio IR:ER = 1 :1

The ratio between the immediate release and extended release layer in Examples 4 and 5_may vary according to the dosage and the active ingredient. It would usually range from 50 to 75 wt-% for the immediate release layer and from 50 to 25 wt-% for the extended release layer. However, the invention is not restricted to those ratios and may be higher or lower for the immediate release layer and extended release layer, respectively. Example 6 Study of a formulation with methylphenidate in pigs

Animal studies have been conducted on pigs (n=5) measuring the plasma levels of methylphenidate after the ingestion of the formulation according to Example 4. The animals received a dosage of 20 mg methylphenidate once in the morning at 9.00 a.m.. Serum drawings were performed hourly for 24 hours. The tablet was applied orally by mouth of the animals with the use of a protective garment to ensure the swallowing of the pill. The experiment was performed in full appliance of any ethical standard and under the guidance of the relevant ethical committee. The results (average plasma levels over time) can be seen from Fig. 10. The results show a rapid increase and a slow decrease over 12 hours under in vivo conditions. Animal studies in pigs are seen as highly indicative for administration of the respective formulations to humans because of the similarity of gastrointestinal absorption processes.

The features disclosed in the foregoing description, in the claims and/or in the accompanying drawings may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof.

Table 1 Preferred examples of component (a)

Drug Trade name Structure, formula Drug class

central stimulating agents

Methylphenidate

Dextroamphetam ine

Methamphetamine Captagon (D)

Dextroamphetamine Fenetyllin

Coffein

Theophylline

Pemoline

Fenetyllin

Modafinil

o o Modafinil morphine and morphine MST Continus

derivates etc.

Tossamin

Morphine

Morphine derivatives:

Hydromorphone

Codeine, Dihydrocodeine

Oxycodone

Hydrocodone

Noscapine

D,L-Methadone

Leveacetylmethadole

Naltrexon

Naloxon

benzodiazepines

e.g. Lorazepame Temesta Diazepame, Aprazolame

Chlordiazepoxide

Prazepame, Oxazepame

Dipotassium clorazepate,

Clonazepame, Bromazepame,

Temazepame

Names of active substance names as international non-proprietary name (INN) are shown in italic.

Table 2 Preferred examples of component (b)

Claims

1. An oral dosage form with reduced potential for drug abuse comprising

(a) at least one amine-containing pharmaceutically active compound or salt or solvate thereof,

(b) at least one weak organic acid or salt thereof, which forms an insoluble precipitate with component (a) in an aqueous environment at a pH of at least 5, and

(c) at least one basifying agent in an appropriate amount to achieve a pH of at least 5 in the environment of the oral dosage form when being dissolved, wherein at least one portion of the oral dosage form is formulated for immediate release and components (b) and (c) are predominantly contained in this portion, and wherein another portion of the oral dosage form is formulated for extended release and contains at least the majority of component (a).

2. The dosage form according to claim 1, wherein the immediate release portion of the oral dosage form additionally contains a smaller amount of component (a).

3. The dosage form according to any one of claims 1 or 2, wherein component (a) is formulated to be released in the intestine.

4. The dosage form according to any of claims 1 to 3, wherein component (b) is formulated to be released in the stomach and small intestine.

5. The dosage form according to any of the preceding claims, wherein component (b) is present in an amount sufficient to precipitate, upon dissolution/disintegration of the oral dosage form in aqueous media, at least the majority of component (a).

6. The dosage form according to claim 5, wherein the mole ratio of component (a) to component (b) is in the range from 0.5: 1.0 to 2.0: 1.0.

7. The dosage form according to any of the preceding claims, wherein component (a) is selected from the compounds as listed in Table 1 or salts or solvates thereof.

8. The dosage form according to claim 7, wherein component (a) is preferably selected from the group consisting of methylphenidate, morphine, tramadol, modafinil, hydromorphone, codeine, dihydrocodeine, oxycodone, hydrocodone, noscapine, D,L- methadone, leveacetylmethadole, naltrexon, and naloxon, and salts and solvates thereof.

9. The dosage form according to claim 8, wherein component (a) is most preferably selected from the group consisting of methylphenidate, morphine, oxycodone, and modafinil.

10. The dosage form according to any of the preceding claims, wherein component (b) is selected from the acids as listed in Table 2 or salts thereof.

11. The dosage form according to claim 10, wherein component (b) is selected from the group consisting of tannic acid and pamoic acid and salts thereof.

12. The dosage form according to any of the preceding claims, wherein component (c) is selected from the group consisting of carbonates, phosphates, citrates, silicates, sulfates, hydroxides and oxides.

13. The dosage form according to any of the preceding claims, wherein the dosage form is a bi- or multilayered tablet having one or more layers for immediate release and one or more layers for extended release.

14. The dosage form according to claim 13, wherein the one ore more layers for extended release are provided with a protective layer or coating.

15. The dosage form according to claims 13 or 14, wherein one or more colouring and/or flavouring agents are added.

16. The dosage form according to any of claims 1 to 12, wherein the extended release portion is embedded in the immediate release portion.