WO2021219576A1

WO2021219576A1 - Multiparticulate dosage form containing eva copolymer and additional excipient

Info

Publication number: WO2021219576A1
Application number: PCT/EP2021/060878
Authority: WO
Inventors: Peter PERSICH; Ulrike Bertram; Klaus WENING
Original assignee: Grünenthal GmbH
Priority date: 2020-04-27
Filing date: 2021-04-26
Publication date: 2021-11-04

Abstract

The invention relates to an oral pharmaceutical dosage form comprising a multitude of particles, wherein the particles comprise a pharmacologically active ingredient at a content within the range of from 5.0 to 65 wt.-%, (b) an EVA copolymer at a content within the range of from 25 to 85 wt.-%, and (c) an additional excipient at a content within the range of from 8.0 to 30 wt.-%, in each case relative to the total weight of the particles. The pharmacologically active ingredient is embedded in a prolonged release matrix comprising the EVA copolymer and the additional excipient. The pharmaceutical dosage form preferably provides resistance against solvent extraction, resistance against grinding, and resistance against alcoholic dose-dumping.

Description

Multiparticulate dosage form containing EVA copolymer and additional excipient

FIELD OF THE INVENTION

[0001] The invention relates to an oral pharmaceutical dosage form comprising a multitude of particles, wherein the particles comprise a pharmacologically active ingredient at a content within the range of from 5.0 to 65 wt.-%, (b) an EVA copolymer at a content within the range of from 25 to 85 wt.-%, and (c) an additional excipient at a content within the range of from 8.0 to 30 wt.-%, in each case relative to the total weight of the particles. The pharmacologically active ingredient is embedded in a prolonged release matrix comprising the EVA copolymer and the additional excipient. The pharmaceutical dosage form preferably provides resistance against solvent extraction, resistance against grinding, and resistance against alcoholic dose-dumping.

BACKGROUND OF THE INVENTION

[0002] A large number of pharmacologically active substances have a potential for being abused or misused, i.e. they can be used to produce effects which are not consistent with their intended use. Thus, e.g. opioids which exhibit an excellent efficacy in controlling severe to extremely severe pain are frequently abused to induce euphoric states similar to being intoxicated. In particular, active substances which have a psychotropic effect are abused accordingly.

[0003] To enable abuse, the corresponding pharmaceutical dosage forms, such as pharmaceutical dosage forms or capsules are crashed, for example ground by the abuser, the active substance is extracted from the thus obtained powder using a preferably aqueous liquid and after being optionally filtered through cotton wool or cellulose wadding, the resultant solution is administered parenterally, in particular intravenously. This type of dosage results in an even faster diffusion of the active substance compared to the oral abuse, with the result desired by the abuser, namely the kick. This kick or these intoxication-like, euphoric states are also reached if the powdered pharmaceutical dosage form is administered nasally, i.e. is sniffed.

[0004] Various concepts for the avoidance of drag abuse have been developed.

[0005] It has been proposed to incorporate in pharmaceutical dosage forms aversive agents and/or antagonists in a manner so that they only produce their aversive and/or antagonizing effects when the pharmaceutical dosage forms are tampered with. However, the presence of such aversive agents is principally not desirable and there is a need to provide sufficient tamper-resistance without relying on aversive agents and/or antagonists.

[0006] Another concept to prevent abuse relies on the mechanical properties of the pharmaceutical dosage forms, particularly an increased breaking strength (resistance to crashing). The major advantage of such pharmaceutical dosage forms is that comminuting, particularly pulverization, by conventional means, such as grinding in a mortar or fracturing by means of a hammer, is impossible or at least substantially impeded. Thus, the pulverization, necessary for abuse, of the pharmaceutical dosage forms by the means usually available to a potential abuser is prevented or at least complicated. Such pharmaceutical dosage forms are useful for avoiding drug abuse of the pharmacologically active ingredient contained therein, as they may not be powdered by conventional means and thus, cannot be administered in powdered form, e.g. nasally. The mechanical properties, particularly the high breaking strength of these pharmaceutical dosage forms renders them tamper-resistant. In the context of such tamper-resistant pharmaceutical dosage forms it can be referred to, e.g., WO 2005/016313, WO 2005/ 016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, WO 2006/082099, and WO 2009/092601.

[0007] These dosage forms are typically based upon polyethylene oxides having comparatively high molecular weights. These polyethylene oxides are water soluble such that the release mechanism involves erosion of the dosage forms over time but is not or not exclusively diffusion controlled. It would be desirable to provide dosage forms providing a release mechanism that is essentially diffusion controlled.

[0008] Besides tampering of pharmaceutical dosage forms in order to abuse the drugs contained therein, the potential impact of concomitant intake of ethanol on the in vivo release of drugs from modified release oral formulations (dose-dumping) has recently become an increasing concern. Controlled or modified release formulations typically contain a higher amount of the pharmacologically active ingredient relative to its immediate release counterpart. If the controlled release portion of the formulation is easily defeated, the end result is a potential increase in exposure to the active drug and possible safety concerns. In order to improve safety and circumvent intentional tampering (e.g. dissolving a controlled release pharmaceutical dosage form in ethanol to extract the drug), a reduction in the dissolution of the modified release fractions of such formulations, in ethanol, may be of benefit. Accordingly, the need exists to develop new formulations having reduced potential for dose dumping in alcohol.

[0009] Further, various controlled release dosage forms provide prolonged release of the pharmacologically active ingredient contained therein based upon the concept of matrix retardation. In such dosage forms, the pharmacologically active ingredient is contained in a prolonged release matrix of suitable excipients, in many instances polymers. The polymers avoid immediate release of the pharmacologically active ingredient all at once, but retain the pharmacologically active ingredient to a certain extent thereby providing prolonged release over time, e.g. 12 hours or 24 hours. The release mechanism, however, greatly depends upon the chemical nature of the polymers and their individual interaction with the release medium. The release mechanism from hydrophilic matrices, i.e. from prolonged release matrices comprising water soluble polymers, typically involves various simultaneous processes such as (i) swelling of the dosage form by diffusion of release medium into the dosage form, (ii) dissolution of the pharmacologically active ingredient into the release medium, and (iii) erosion of the dosage form by ongoing dissolution of the water soluble polymers. The more complex the release mechanism, the more difficult is it to predict the behavior of a given system e.g. based upon mathematical models. For example, it is desirable that the release speed can be specified through the pellet size based upon comparatively simple considerations. There is therefore a demand for pharmaceutical dosage forms that provide prolonged release of a pharmacologically active ingredient wherein only a single release mechanism is involved or at least where one of the simultaneously ongoing release mechanism is so dominant that parallel processes can be neglected. Ethylene vinylacetate (EVA) copolymers are useful for the manufacture of prolonged release matrices where the release mechanism is predominantly diffusion controlled.

[0010] WO 03/070191 A1 discloses a transdermal-delivery device which is said to be tamper-resistant and comprises an opioid, or a pharmaceutically acceptable salt thereof, and an acyl opioid antagonist, or a pharmaceutically acceptable salt thereof.

[0011] B. Sreenivasa Rao el al, Indian J. Pharm. Sci. 65, 2003, 496-502 disclose a method of preparation of sintered matrix tablets of rifampicin with EVA copolymer for controlling the release rate. However, these references are fully silent on the possibility of preparing tamper-resistant pharmaceutical dosage forms from EVA (EVA) polymers.

[0012] WO 2009/051819 discloses implants for delivery of therapeutic agents such as opioids, and the manufacture and uses of such implants.

[0013] A. Almeida et al., Eur. J. Pharm. Biopharm. 77, 2011, 297-305 disclose ethylene vinylacetate as matrix for oral sustained release dosage forms which contain metoprolol tartrate as the pharmacologically active ingredient and are produced via hot-melt extrusion.

[0014] A. Almeida et al., Eur. J. Pharm. Biopharm. 82, 2012, 526-533 discloses sustained release of metoprolol tartrate from hot-melt extruded matrices based on ethylene vinylacetate and polyethylene oxide.

[0015] WO 2015/004245 discloses a tamper-resistant, oral pharmaceutical dosage form comprising a pharmacologically active ingredient having psychotropic action and an EVA polymer which provides resistance against solvent extraction, resistance against grinding, and resistance against dose-dumping in aqueous ethanol. Melt extrusion preferably provides a melt-extruded strand that is preferably cut into monoliths, which are then optionally compressed and formed. In the examples, the extruded strands were cooled in ambient air and were manually cut yielding pellets. Manual cutting e.g. with a knife, however, is not viable for production on commercial scales.

[0016] There is a demand for tamper-resistant and dose-dumping resistant, oral pharmaceutical dosage forms containing a pharmacologically active ingredient having psychotropic action which have advantages compared to the pharmaceutical dosage forms of the prior art. There is also a demand for improved processes for the manufacture pharmaceutical dosage forms.

[0017] The properties of these pharmaceutical dosage forms of the prior art, however, are not satisfactory in every respect and there is a demand for improved pharmaceutical dosage forms.

[0018] It is an object of the invention to provide pharmaceutical dosage forms having advantages compared to the pharmaceutical dosage forms of the prior art. The pharmaceutical dosage forms should allow for high drug loads and should provide reliable and steady release profdes, preferably not based upon release coatings. The pharmaceutical dosage forms should provide resistance against alcoholic dose dumping and preferably other forms of tamper resistance, e.g. resistance against extraction in hot water. Various in vitro release profiles should be adjustable in a reliable and predictable manner for a broad variety of different pharmacologically active ingredients.

[0019] This object has been achieved by the subject-matter of the patent claims.

[0020] It has been surprisingly found that matrix pellets based on EVA (ethylene-vinylacetate copolymer) are suitable for the preparation of solid oral dosage forms providing reliable matrix controlled drug release of a large variety of different pharmacologically active ingredients. EVA based matrix pellets are resistant against mechanical manipulation and extraction for parenteral abuse. With respect to pharmacologically active ingredients that are at risk of being abused through non-oral routes of administration, tamper resistance of EVA based matrix pellets is superior compared to tamper resistance of conventional dosage forms that are based upon high molecular weight polyethylene oxides.

[0021] Further, it has been surprisingly found that EVA based pellets allow for high drug loads (40 wt.-% and even more) without compromising prolonged release properties and tamper resistance in terms of resistance against solvent extraction.

[0022] Furthermore, it has been surprisingly found that product properties can be tailored in a predictable manner by adjusting the relative content of vinylacetate (VA) in EVA, adjusting the molecular weight of EVA, and employing additional excipients.

[0023] In particular, it has been surprisingly found that when increasing the VA content, in vitro dissolution rates under physiological conditions pass a minimum, and at late timepoints (e.g. after 10 hours), dissolution rates become relatively faster. Further, when increasing the VA content, resistance against extraction in hot water can be steadily improved and a more steady dissolution profile can be achieved, whereas the product becomes more prone to alcoholic dose dumping. Thus, resistance against solvent extraction in hot water on the one hand and resistance against alcoholic dose dumping on the other hand may require balanced VA contents, as these properties depend upon VA content in opposite directions. These properties do not essentially depend upon the pharmacologically active ingredient.

[0024] Further, it has been surprisingly found that with the decreasing molecular weight of EVA, in vitro release is generally slowed down and the in vitro release profile is more steady without compromising resistance against alcoholic dose dumping.

[0025] Moreover, it has been surprisingly found that particularly advantageous pharmaceutical dosage forms can be provided when the content of the pharmacologically active ingredient is comparatively high and when the EVA copolymer has a comparatively low vinylacetate content along with a comparatively low molecular weight (i.e. comparatively high melt flow index (MFI)). Such dosage forms according to the invention provide an advantageous compromise of release properties and resistance against alcoholic dose dumping. [0026] Furthermore, it has been surprisingly found that product properties can be altered or modulated by means of low amounts of additional excipients. While e.g. HPMC-AS, alginate or carboxymethyl starch allow for retarding release at high drug loads, conventional gelling agents such as xanthan, croscarmellose sodium and alginate are advantageous with respect to resistance against alcoholic dose dumping.

[0027] Further, the automated cutting of small pellets from the strand exiting the extruder is actually one of the biggest challenges that was also solved by the present invention. In conventional processes for the manufacture of EVA pellets by hot-melt extrusion, the cutting is either performed completely manually e.g. with a knife and this obviously is not useful for production on commercial scale. The alternative of extruding the material into a liquid with immediate cooling is not viable either (e.g. underwater pelletizing where aqueous liquids are conventionally used), especially when the material contains a pharmacologically active ingredient which can be released into the liquid. According to the present invention, it has been surprisingly found that cutting the extruded strand can advantageously be achieved by means of a micropelletizer without using a cooling liquid.

[0028] The present invention provides a matrix retardation technology that is useful for a broad variety of different oral dosage forms. The release mechanism does not rely upon coatings and is essentially diffusion controlled. The technology allows for steady retardation at high drug load and provides protection against intentional or accidental alcoholic dose dumping.

[0029] A first aspect of the invention relates to an oral pharmaceutical dosage form comprising a multitude of particles, wherein the particles comprise

(a) a pharmacologically active ingredient; wherein the weight content of the pharmacologically active ingredient is within the range of from 5.0 to 65 wt.-%, relative to the total weight of the particles;

(b) an EVA copolymer having

(i) a vinylacetate content within the range of from 10 to 50 wt.-%, relative to the total weight of the EVA copolymer; and

(ii) a melt flow index at 190°C/2.16 kg measured according to ASTM D 1238 within the range of from 2 to 500 g/10 min; wherein the weight content of the EVA copolymer is within the range of from 25 to 85 wt.-%, relative to the total weight of the particles; and

(c) an additional excipient; wherein the weight content of the additional excipient is within the range of from 8.0 to 30 wt. -%, relative to the total weight of the particles; wherein the pharmacologically active ingredient, preferably the total content of the pharmacologically active ingredient that is contained in the pharmaceutical dosage form, is embedded in a prolonged release matrix comprising the EVA copolymer and the additional excipient; and preferably wherein the pharmaceutical dosage form under in vitro conditions has released

- after 30 minutes not more than 75 wt.-%;

- after 360 minutes at least 35 wt.-%; and after 720 minutes at least 60 wt.-% of the pharmacologically active ingredient that was originally contained in the pharmaceutical dosage form.

[0030] The pharmaceutical dosage form according to the invention is for oral administration.

[0031] In a preferred embodiment, the pharmaceutical dosage form according to the invention is adapted for administration once daily. In another preferred embodiment, the pharmaceutical dosage form according to the invention is adapted for administration twice daily. In still another preferred embodiment, the pharmaceutical dosage form according to the invention is adapted for administration thrice daily. In yet another preferred embodiment, the pharmaceutical dosage form according to the invention is adapted for administration more frequently than thrice daily, for example 4 times daily, 5 times daily, 6 times daily, 7 times daily or 8 times daily.

[0032] For the purpose of the specification, "twice daily" means equal or nearly equal time intervals, i.e., about every 12 hours, or different time intervals, e.g., 8 and 16 hours or 10 and 14 hours, between the individual administrations. For the purpose of the specification, "thrice daily" means equal or nearly equal time intervals, i.e., about every 8 hours, or different time intervals, e.g., 6, 6 and 12 hours; or 7, 7 and 10 hours, between the individual administrations.

[0033] The subjects to which the pharmaceutical dosage forms according to the invention can be administered are not particularly limited. Preferably, the subjects are animals, more preferably human beings.

[0034] The pharmaceutical dosage form according to the invention comprises a multitude of particles.

[0035] For the purpose of specification, the term "particle" refers to a discrete mass of material that is solid, e.g. at 20°C or at room temperature or ambient temperature. Preferably a particle is solid at 20 ^°C. Preferably, the particles are monoliths. Preferably, the pharmacologically active ingredient, the EVA copolymer, the additional excipient and optionally further excipient/ s) are intimately homogeneously distributed in the particles so that the particles do not contain any segments where either pharmacologically active ingredient is present in the absence of EVA copolymer and additional excipient, or where EVA copolymer is present in the absence of pharmacologically active ingredient and additional excipient, or where additional excipient is present in the absence of either pharmacologically active ingredient or EVA copolymer.

[0036] The pharmaceutical dosage form is multiparticulate. The pharmaceutical dosage form according to the invention comprises a multitude i.e. plurality of particles containing pharmacologically active ingredient, EVA copolymer, additional excipient and optionally further excipient(s) (drug-containing particles) and may optionally further comprise particles not containing any pharmacologically active ingredient (drug-free particles).

[0037] Preferably, the pharmaceutical dosage form preferably comprises at least 2, more preferably at least 4, still more preferably at least 6, yet more preferably at least 8, even more preferably at least 10, most preferably at least 15 and in particular at least 20 or at least 100 or at least 1000 drug-containing particles. [0038] The particles of the pharmaceutical dosage form according to the invention (e.g. pellets or cutrods) preferably comprise the prolonged release matrix and at least a portion of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical dosage form. Preferably, the particles comprise the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical dosage form.

[0039] When the pharmaceutical dosage form according to the invention can be regarded as a MUPS formulation which preferably comprises drug-containing particles and an outer matrix material, the outer matrix material is not a constituent of the prolonged release matrix.

[0040] The pharmacologically active ingredient is embedded in a prolonged release matrix comprising the EVA copolymer and the additional excipient. Preferably, the pharmacologically active ingredient is dispersed in the prolonged release matrix. The prolonged release matrix comprises the EVA copolymer, the additional excipient and optionally further excipient(s).

[0041] Preferably, the pharmaceutical dosage form provides prolonged release of the pharmacologically active ingredient. Particularly preferably, the prolonged release matrix comprising the EVA copolymer provides prolonged release of the pharmacologically active ingredient embedded therein.

[0042] In a preferred embodiment, the additional excipient exerts an influence on the release profile of the pharmacologically active ingredient under physiological in vitro conditions. According to this embodiment, a pharmaceutical dosage form according to the invention comprising a pharmacologically active ingredient, an EVA copolymer and an additional excipient preferably exhibits an increased release rate of the pharmacologically active ingredient compared to a pharmaceutical dosage form comprising the same types and amounts of the pharmacologically active ingredient and the EVA copolymer but not containing the additional excipient.

[0043] In a preferred embodiment, the additional excipient exerts an influence on the release profde of the pharmacologically active ingredient in alcoholic medium. According to this embodiment, a pharmaceutical dosage form according to the invention comprising a pharmacologically active ingredient, an EVA copolymer and an additional excipient preferably exhibits a decreased release rate of the pharmacologically active ingredient in alcoholic medium compared to a pharmaceutical dosage form comprising the same types and amounts of the pharmacologically active ingredient and the EVA copolymer but not containing the additional excipient.

[0044] For the purpose of specification "prolonged release" preferably means that the rate of release of pharmacologically active ingredient from the formulation after administration has been reduced over time, in order to maintain therapeutic activity, to reduce toxic effects, or for some other therapeutic purpose such as reducing the dosing frequency.

[0045] Preferably, the pharmaceutical dosage form according to the invention under physiological in vitro conditions has released after 30 minutes not more than 75 wt.-%; after 360 minutes at least 35 wt.-%; and - after 720 minutes at least 60 wt.-% of the pharmacologically active ingredient that was originally contained in the pharmaceutical dosage form.

[0046] Preferably, under physiological in vitro conditions the pharmaceutical dosage form according to the invention has released after 30 minutes 0.1 to 75%, after 240 minutes 0.5 to 95%, after 480 minutes 1.0 to 100% and after 720 minutes 2.5 to 100% of the pharmacologically active ingredient (A). Further preferred release profiles Ri to Rg are summarized in the table here below [all data in wt. -% of released pharmacologically active ingredient] :

[0047] Suitable physiological in vitro conditions are known to the skilled artisan. In this regard it can be referred to, e.g., the Eur. Ph. Preferably, the release profile is measured under the following conditions: Paddle apparatus equipped without sinker, 50 rpm, 37±5 °C, 900 mL simulated intestinal fluid pH 6.8 (phosphate buffer) or pH 4.5. In a preferred embodiment, the rotational speed of the paddle is increased to 75 rpm.

[0048] The multitude of particles of the pharmaceutical dosage form according to the invention comprise a pharmacologically active ingredient.

[0049] The pharmacologically active ingredient is not particularly limited.

[0050] In a preferred embodiment, the pharmaceutical dosage form contains only a single pharmacologically active ingredient. In another preferred embodiment, the pharmaceutical dosage form contains a combination of two or more pharmacologically active ingredients.

[0051] In preferred embodiments, the pharmacologically active ingredient has psychotropic action. For the purpose of definition, a pharmacologically active ingredient having psychotropic action is preferably meant to refer to any pharmacologically active ingredient which crosses the blood-brain barrier and acts primarily upon the central nervous system where it affects brain function, resulting in alterations in perception, mood, consciousness, cognition, and behavior.

[0052] Preferably, the pharmaceutical dosage form according to the invention comprises a pharmacologically active ingredient having potential for abuse and/or potential for dose dumping in ethanol. Pharmacologically active ingredients with potential for being abused typically have psychotropic action and are known to the person skilled in the art and comprise e.g. tranquillizers, stimulants, barbiturates, narcotics, opioids or opioid derivatives. Pharmacologically active ingredients having potential for dose dumping in ethanol do not need to have psychotropic action and also are known to the person skilled in the art. [0053] Preferably, the pharmacologically active ingredient is selected from the group consisting of opiates, opioids, stimulants, tranquilizers, other narcotics and anesthetics. Preferably, the pharmacologically active ingredient is selected from the group consisting of ethers; halogenated hydrocarbons; pain barbiturates; and barbiturates in combination with other drugs; opioid anesthetics; or any other general anesthetics.

[0054] In a particularly preferred embodiment, the pharmacologically active ingredient is an opioid or a physiologically acceptable salt thereof. According to the ATC index, opioids are divided into natural opium alkaloids, phenylpiperidine derivatives, diphenylpropylamine derivatives, benzomorphan derivatives, oripavine derivatives, morphinan derivatives and others.

[0055] The following opiates, opioids, tranquillizers, anesthetics or other narcotics are substances with a psychotropic action, i.e. have a potential of abuse, and hence are preferably contained in the pharmaceutical dosage form and the particles, respectively: alfentanil, allobarbital, allylprodine, alphaprodine, alprazolam, amfepramone, amphetamine, amphetaminil, amobarbital, anileridine, apocodeine, axomadol, barbital, bemidone, benzylmorphine, bezitramide, bromazepam, brotizolam, buprenorphine, butobarbital, butorphanol, camazepam, carfentanil, cathine/D-norpseudoephedrine, cebranopadol, chlordiazepoxide, clobazam clofedanol, clonazepam, clonitazene, clorazepate, clotiazepam, cloxazolam, cocaine, codeine, cyclobarbital, cyclorphan, cyprenorphine, delorazepam, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, diazepam, dihydrocodeine, dihydromorphine, dihydromorphone, dimenoxadol, dimephetamol, dimethylthiambutene, dioxaphetyl- butyrate, dipipanone, dronabinol, eptazocine, estazolam, ethoheptazine, ethylmethylthiambutene, ethyl loflazepate, ethylmorphine, etonitazene, etorphine, faxeladol, fencamfamine, fenethylline, fenpipramide, fenpro- porex, fentanyl, fludiazepam, flunitrazepam, flurazepam, halazepam, haloxazolam, heroin, hydrocodone, hydro- morphone, hydroxypethidine, isomethadone, hydroxymethylmorphinan, ketamine, (.S') -ketamine ketazolam, ke- tobemidone, levacetylmethadol (LAAM), levomethadone, levorphanol, levophenacylmorphane, levoxemacin, lisdexamfetamine dimesylate, lofentanil, loprazolam, lorazepam, lormetazepam, mazindol, medazepam, mefenorex, meperidine, meprobamate, metapon, meptazinol, metazocine, methylmorphine, metamphetamine, methadone, methaqualone, 3-methylfentanyl, 4-methylfentanyl, methylphenidate, methylphenobarbital, methyprylon, metopon, midazolam, modafinil, morphine, myrophine, nabilone, nalbuphene, nalorphine, narceine, nicomorphine, nimetazepam, nitrazepam, nordazepam, norlevorphanol, normethadone, normorphine, nor- pipanone, opium, oxazepam, oxazolam, oxycodone, oxymorphone, Papaver somniferum, papaveretum, pemoline, pentazocine, pentobarbital, pethidine, phenadoxone, phenomorphane, phenazocine, phenoperidine, piminodine, pholcodeine, phenmetrazine, phenobarbital, phentermine, pinazepam, pipradrol, piritramide, prazepam, profadol, proheptazine, promedol, properidine, propoxyphene, remifentanil, secbutabarbital, secobarbital, sufentanil, tapen- tadol, temazepam, tetrazepam, tilidine (cis and trans), tramadol, triazolam, and vinylbital, and corresponding ste- reoisomeric compounds, in each case the corresponding derivatives thereof, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemates and the physiologically acceptable derivatives thereof, e.g. ethers, esters or amides, and in each case the physiologically acceptable compounds thereof, in particular the acid or base addition salts thereof and solvates, e.g. hydrochlorides. [0056] In a preferred embodiment, the pharmacologically active ingredient is an opioid, preferably selected from the group consisting of tramadol, tapentadol, oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, and the physiologically acceptable salts thereof.

[0057] In another preferred embodiment, the pharmacologically active ingredient is a stimulant, preferably selected from the group consisting of amphetamine, dex-amphetamine (dextroamphetamine), dex -methylphenidate, atomoxetine, caffeine, ephedrine, phenylpropanolamine, phenylephrine, fencamphamin, fenozolone, fenetylline, methylenedioxymethamphetamine (MDMA), methylenedioxypyrovalerone (MDPV), prolintane, lisdexamfet- amine, mephedrone, methamphetamine, methylphenidate, modafinil, nicotine, pemoline, phenylpropanolamine, propylhexedrine, dimethylamylamine, and pseudoephedrine.

[0058] In a particularly preferred embodiment, the pharmacologically active ingredient is amphetamine or a physiologically acceptable salt thereof, preferably amphetamine sulfate and/or amphetamine aspartate, such as amphetamine aspartate monohydrate. In another particularly preferred embodiment, the pharmacologically active ingredient is dextroamphetamine or a physiologically acceptable salt thereof, preferably dextroamphetamine sac- charate or dextroamphetamine sulfate. In still another particularly preferred embodiment, the pharmacologically active ingredient is lisdexamfetamin or a physiologically acceptable salt thereof. In another preferred embodiment, the pharmacologically active ingredient is amphetamine sulfate and the pharmaceutical dosage form does not contain any other salt of amphetamine. In yet another particularly preferred embodiment, the pharmacologically active ingredient is methylphenidate or a physiologically acceptable salt thereof. In even another particularly preferred embodiment, the pharmacologically active ingredient is dexmethylphenidate or a physiologically acceptable salt thereof.

[0059] In preferred embodiments, the pharmaceutical dosage form according to the invention contains a pharmacologically active ingredient selected from the group consisting of

(i) agents for the treatment and prevention of diseases of the alimentary system and metabolism [A] ; in particular stomatological preparations [A01], agents for the treatment and prevention of acid-related disorders [A02], agents for the treatment and prevention of functional gastrointestinal tract disorders [A03], serotonin 5HT3 antagonists [A04AA], antihistamine preparations [A04AB], agents for bile and liver therapy [A05], laxatives [A06], intestinal antiinfectives [A07A], intestinal adsorbents [A07B], electrolytes with carbohydrates [A07C], intestinal antiinflammatory agents [A07E], microbial antidiarrhoeals [A07F], digestives including enzymes [A09], drags used in diabetes [A10], vitamins [A11], minerals [A12], anabolic agents for systemic applications [A14] and appetite stimulants [A15];

(ii) agents for the treatment and prevention of diseases of the blood and the blood forming organs [B] ; in particular antithrombotic agents [B01], antihaemorrhagics [B02], antianaemic preparations [B03] and other haematological agents [B06];

(iii) agents for the treatment and prevention of diseases of the cardiovascular system [C] ; in particular agents for cardiac therapy [C01], antihypertensives [C02], diuretics [C03], peripheral vasodilatators [C04], vaso- protectives [C05], antihypotensives [C06A], □-adrenoceptor antagonists [C07], calcium channel blockers [C08], agents acting on the renin-angiotensin system [C09] and lipid reducing agents [CIO]; (iv) dermatologicals [D] ; in particular antifungals for systemic use [DO IB], antipsoriatics for systemic use [D05B], antiacne preparations for systemic use [D10B];

(v) agents for the treatment and prevention of diseases of the genitourinary system and sex hormones [G]; in particular gynaecological antiinfectives and antiseptics [G01], oxytocics [G02A], sympathomimetic labour repressants [G02CA], prolactin inhibitors [G02CB], hormonal contraceptives for systemic use [G03] and urologicals [G04];

(vi) systemic hormone preparations excluding sex hormones and insulins [H]; in particular pituitary and hypothalamic hormones and analogue [HOI], corticosteroids for systemic use [H02], thyroid preparations [H03], pancreatic hormones [H04], and agents for regulating calcium homeostatis [H05];

(vii) antiinfectives for systemic use [J]; in particular antibiotics for systemic use [J01], antimycotics for systemic use [J02], antimycobacterials [J04], antivirals for systemic use [J05], immune sera and immunoglobulins [J06], and vaccines [J07]);

(viii) antineoplastic and immunomodulating agents [L] (in particular antineoplastistic agents [L01], agents for endocrine therapy [L02], immuno stimulants [L03] and immunosuppressive agents [L04] ;

(ix) agents for the treatment and prevention of diseases of the musculo-skeletal system [M]; in particular antiinflammatory and antirheumatic agents [M01], peripherally acting muscle relaxants [M03A], directly acting muscle relaxants [M03C], antigout preparations [M04] and agents for the treatment of bone diseases [M05];

(x) agents for the treatment and prevention of diseases of the nervous system [N]; in particular salicylic acid the derivatives thereof [N02BA], pyrazolones [N02BB], anilides [N02BE], ergot alkaloids [N02CA], corticosteroid derivatives [N02CB], selective serotonin-5HTl agonists [N02CC], hydantoin derivatives [N03AB], oxazolidine derivatives [N03AC], succinimide derivatives [N03AD], carboxamide derivatives [N03AF], fatty acid derivatives [N03AG], antiparkinson drags [N04]), antipsychotics [N05A], antidepressants [N06A], antidementia drugs [N06D], parasympathomimetics [N07A] and antivertigo preparations [N07C];

(xi) antiparasitic products, insecticides and repellents [P]; in particular antiprotozoals [P01], anthelmintics [P02] and ectoparasiticides, including scabicides, insecticides and repellents [P03];

(xii) agents for the treatment and prevention of diseases of the respiratory system [R]; in particular nasal preparations [R01], throat preparations [R02], drags for obstructive airways diseases [R03], expectorants, excluding combinations with cough suppressants [R05C] and antihistamines for systemic use [R06];

(xiii) agents for the treatment and prevention of diseases of the sensory organs [S] ; in particular otologicals [S02] ; and

(xiv) general diet products [V06] and therapeutic radiopharmaceuticals [V10]; wherein the abbreviations stated in square brackets here correspond to the ATC Index, as used by the WHO for classifying pharmaceutical substances (preferred version: 2019). [0060] The pharmacologically active ingredient may be present in form of a physiologically acceptable salt, e.g. physiologically acceptable acid addition salt.

[0061] Physiologically acceptable acid addition salts comprise the acid addition salt forms which can conveniently be obtained by treating the base form of the active ingredient with appropriate organic and inorganic acids. Active ingredients containing an acidic proton may be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. The term addition salt also comprises the hydrates and solvent addition forms which the active ingredients are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

[0062] The content of the pharmacologically active ingredient in the pharmaceutical dosage form and in the particles, respectively, can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially pharmaceutical dosage formability) and patient compliance.

[0063] The pharmacologically active ingredient is present in the pharmaceutical dosage form in a therapeutically effective amount. The amount that constitutes a therapeutically effective amount varies according to the active ingredients being used, the condition being treated, the severity of said condition, the patient being treated, and the frequency of administration.

[0064] The dose of the pharmacologically active ingredient in the pharmaceutical dosage form is not limited. The dose of the pharmacologically active ingredient which is adapted for administration depends upon its potency, efficacy and efficiency and preferably is in the range of 0.1 mg to 500 mg, more preferably in the range of 1.0 mg to 400 mg, even more preferably in the range of 5.0 mg to 300 mg, and most preferably in the range of 10 mg to 250 mg. In a preferred embodiment, the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical dosage form is within the range of from 0.01 to 200 mg, more preferably 0.1 to 190 mg, still more preferably 1.0 to 180 mg, yet more preferably 1.5 to 160 mg, most preferably 2.0 to 100 mg and in particular 2.5 to 80 mg.

[0065] The weight content of the pharmacologically active ingredient contained in the multitude of particles of the pharmaceutical dosage form according to the invention is within the range of from 5.0 to 65 wt.-%, relative to the total weight of the particles.

[0066] Preferably, the weight content of the pharmacologically active ingredient is at least 10 wt.-%, or at least 20 wt. -%, or at least 25 wt.-%, or at least 30 wt.-%, or at least 35 wt.-%, or at least 40 wt.-%, in each case relative to the total weight of the particles.

[0067] Preferably, the weight content of the pharmacologically active ingredient is at most 45 wt.-%, or at most 40 wt. -%, or at most 35 wt.-%, or at most 30 wt.-%, or at most 25 wt.-%, or at most 20 wt.-%, or at most 15 wt- %, in each case relative to the total weight of the particles. [0068] In a preferred embodiment, the weight content of the pharmacologically active ingredient is within the range of 15±10 wt.-%, relative to the total weight of the particles (embodiment Al). In another preferred embodiment, the weight content of the pharmacologically active ingredient is within the range of 35±20 wt.-%, preferably 35±15 wt. -%, more preferably 35±10 wt.-%, in each case relative to the total weight of the particles (embodiment A2). In still another preferred embodiment, the weight content of the pharmacologically active ingredient is within the range of 55±10, relative to the total weight of the particles (embodiment A3).

[0069] The multitude of particles of the pharmaceutical dosage form according to the invention comprise an EVA copolymer (EVA copolymer).

[0070] The EVA copolymer is preferably homogeneously distributed in the particles according to the invention that contain the pharmacologically active ingredient, the additional excipient and optionally further excipient(s).

[0071] Ethylene-vinylacetate copolymers that are suitable for use in the pharmaceutical dosage forms according to the invention are commercially available, e.g. from Celanese, for example Ateva^® 1081, Ateva^® 1070, Ateva^® 1075A, Ateva^® 1221, Ateva^® 11231, Ateva^® 1241, Ateva^® 1615, Ateva^® 1641, Ateva^® 1608, Ateva^® 1609, Ateva^® 1811, Ateva^® 1813, Ateva^® 1820, Ateva^® 1821 A, Ateva^® 1850A, Ateva^® 1880A, Ateva^® 1941, Ateva^® 2005 A, Ateva^® 2030, Ateva^® 2020, Ateva^® 2604 A, Ateva^® 2810A, Ateva^® 2861A, Ateva^® 9020, Ateva^® 2820A, Ateva^® 2821 A, Ateva^® 9021 A, Ateva^® 2825 A, Ateva^® 2830A, Ateva^® 2842A, Ateva^® 2842AC, Ateva^® 2850A, Ateva^® 9030, Ateva^® 3325A, Ateva^® 3325AC, Ateva^® 4030AC, VitalDose^® EVA; and from DuPont, for example, Elvax^® 40W, Elvax^® 220W, Elvax^® 265, Elvax^® 40L-03, Elvax^® 660, Elvax^® 150, Elvax^® 150W, Elvax^® 210W, Elvax^® 240W, Elvax^® 250, Elvax^® 260, Elvax^® 350, Elvax^® 360, Elvax^® 410, Elvax^® 420, Elvax^® 440, Elvax^® 450, Elvax^® 460, Elvax^® 470, Elvax^® 550, Elvax^® 560, Elvax^® 650Q, Elvax^® 670, Elvax^® 750, Elvax^® 760, Elvax^® 760Q, Elvax^® 770. Preferred polymers are Elvax^® 40W, Elvax^® 220 W, Elvax^® 265, Elvax^® 40L-03 and Elvax^® 660. For details concerning the properties of these products, it can be referred to e.g. the product specification.

[0072] The vinylacetate content of the EVA copolymer contained in the multitude of particles of the pharmaceutical dosage form according to the invention is within the range of from 10 to 50 wt.-%, relative to the total weight of the EVA copolymer.

[0073] Preferably, the EVA copolymer has a vinylacetate content of at least 10 wt.-%, or at least 15 wt.-%, or at least 20 wt.-%, or at least 25 wt.-%, or at least 30 wt.-%, or at least 35 wt.-%, or at least 40 wt.-%, in each case relative to the total weight of the EVA copolymer.

[0074] Preferably, the EVA copolymer has a vinylacetate content of at most 45 wt.-%, or at most 40 wt.-%, or at most 35 wt. -%, or at most 30 wt.-%, or at most 25 wt.-%, or at most 20 wt.-%, or at most 15 wt.-%, in each case relative to the total weight of the EVA copolymer.

[0075] In a preferred embodiment, the EVA copolymer has a vinylacetate content within the range of 20±10 wt- %, relative to the total weight of the EVA copolymer (embodiment B 1). In another preferred embodiment, the EVA copolymer has a vinylacetate content within the range of 30±20 wt.-%, preferably 30±15 wt.-%, more preferably 30±10 wt.-%, in each case relative to the total weight of the EVA copolymer (embodiment B2). In still another preferred embodiment, the EVA copolymer has a vinylacetate content within the range of 40±20 wt.-%, relative to the total weight of the EVA copolymer (embodiment B3).

[0076] Preferred sub-combinations of embodiments A1 to A3 and B1 to B3 are: A1B1, A1B2, A1B3, A2B1, A2B2, A2B3, A3B1, A3B2, and A3B3.

[0077] In preferred embodiments, the EVA copolymer has a vinylacetate content

(i) of at most 22 wt.-%, or at most 20 wt.-%, or at most 18 wt.-%, or at most 16 wt.-%;

(ii) within the range of 28±5 wt.-%, or 28±3 wt.-%; or

(iii) of at least 34 wt.-%, or at least 36 wt.-%, or at least 38 wt.-%, or at least 40 wt.-%; in each case relative to the total weight of the EVA copolymer

[0078] It has been surprisingly found that on the one hand, when (i) the vinylacetate content is comparatively low, the material can be easier processed, whereas on the other hand, when (iii) the vinylacetate content is comparatively high, the release profile is more steady and uniform (i.e. burst effects are avoided); as a good compromise, when the vinylacetate content is (ii) intermediate, the advantages and disadvantages with respect to processability and release performance are well balanced.

[0079] The melt flow index at 190°C/2.16 kg measured according to ASTM D1238 of the EVA copolymer contained in the multitude of particles of the pharmaceutical dosage form according to the invention is within the range of from 2 to 500 g/10 min.

[0080] Preferably, the EVA copolymer has a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 of at least 5 g/10 min, or at least 10 g/10 min, or at least 25 g/10 min, or at least 50 g/10 min, or at least 100 g/10 min, or at least 150 g/10 min, or at least 200 g/10 min, or at least 250 g/10 min, or at least 300 g/10 min, or at least 350 g/10 min, or at least 400 g/10 min.

[0081] Preferably, the EVA copolymer has a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 of at most 450 g/10 min, or at most 400 g/10 min, or at most 350 g/10 min, or at most 300 g/10 min, or at most 250 g/10 min, or at most 200 g/10 min, or at most 150 g/10 min, or at most 100 g/10 min, or at most 50 g/10 min, or at most 25 g/10 min, or at most 10 g/10 min.

[0082] In a preferred embodiment, the EVA copolymer has a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 within the range of 100±90 g/10 min, preferably 100±50 g/10 min (embodiment Cl). In another preferred embodiment, the EVA copolymer has a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 within the range of 200±190 g/10 min, preferably 200±100 g/10 min, more preferably 200±50 g/10 min (embodiment C2). In still another preferred embodiment, the EVA copolymer has a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 within the range of 300±190 g/10 min, preferably 300±100 g/10 min, more preferably 300±50 g/10 min (embodiment C3). In yet another preferred embodiment, the EVA copolymer has a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 within the range of 400±90 g/10 min, preferably 400±50 g/10 min (embodiment C4).

[0083] Preferred sub-combinations of embodiments A1 to A3 and Cl to C4 are: AlCl, A1C2, A1C3, A1C4, A2C1, A2C2, A2C3, A2C4, A3C1, A3C2, A3C3, and A3C4. Preferred sub-combinations of embodiments B 1 to B3 and Cl to C4 are: B1C1, B1C2, B1C3, B1C4, B2C1, B2C2, B2C3, B2C4, B3C1, B3C2, B3C3, and B3C4.

[0084] Preferably, the EVA copolymer preferably has a melting point in the range of 40 to 100°C, determined via differential scanning calorimetry (DSC) in accordance with ASTM D3418. In preferred embodiments, the EVA copolymer has a melting point of 40±10 °C, 47±10 °C, 52±10 °C, 58±10 °C, 65±10 °C, 70±10 °C, 80±10 °C, 90±10 °C or 96±10 °C, more preferably 40±5 °C, 47±5 °C, 52±5 °C, 58±5 °C, 65±5 °C, 70±5 °C, 80±5 °C, 90±5 °C or 96±5 °C, determined via differential scanning calorimetry (DSC) in accordance with ASTM D3418.

Preferably, the EVA copolymer preferably has a freezing point in the range of 20 to 80°C, determined via DSC in accordance with ASTM D3418. In preferred embodiments, the EVA copolymer has a freezing point of 20±10 °C, 27±10 °C, 30±10 °C, 35±10 °C, 40±10 °C, 49±10 °C, 60±10 °C, 70±10 °C or 74±10 °C, more preferably 20±5 °C, 27±5 °C, 30±5 °C, 35±5 °C, 40±5 °C, 49±5 °C, 60±5 °C, 70±5 °C or 74± °C, determined via DSC in accordance with ASTM D3418.

[0085] The EVA copolymer may comprise a single EVA copolymer having a particular melt flow rate, or a mixture (blend) of different EVA copolymers, such as two, three, four or five EVA copolymers, e.g., EVA copolymers of the same chemical nature (e.g. same vinylacetate content) but different melt flow rates, EVA copolymers of different chemical nature but same melt flow rates, or EVA copolymers of different chemical nature as well as different melt flow rates.

[0086] The weight content of the EVA copolymer contained in the multitude of particles of the pharmaceutical dosage form according to the invention is within the range of from 25 to 85 wt.-%, relative to the total weight of the particles.

[0087] Preferably, the weight content of the EVA copolymer is at least 45 wt.-%, or at least 50 wt.-%, or at least 55 wt. -%, or at least 60 wt.-%, or at least 65 wt.-%, or at least 70 wt.-%, or at least 75 wt.-%, in each case relative to the total weight of the particles.

[0088] Preferably, the weight content of the EVA copolymer is at most 80 wt.-%, or at most 75 wt.-%, or at most 70 wt. -%, or at most 65 wt.-%, or at most 60 wt.-%, or at most 55 wt.-%, or at most 50 wt.-%, in each case relative to the total weight of the particles.

[0089] In a preferred embodiment, the weight content of the EVA copolymer is within the range of from 35±10 wt. -%, relative to the total weight of the particles (embodiment Dl). In another preferred embodiment, the weight content of the EVA copolymer is within the range of from 45±20 wt.-%, preferably 45±15 wt.-%, more preferably 45±10 wt. -%, in each case relative to the total weight of the particles (embodiment D2). In still another preferred embodiment, the weight content of the EVA copolymer is within the range of from 55±20 wt.-%, preferably 55±15 wt. -%, more preferably 55±10 wt.-%, in each case relative to the total weight of the particles (embodiment D3). In yet another preferred embodiment, the weight content of the EVA copolymer is within the range of from 65±20 wt. -%, preferably 65±15 wt.-%, more preferably 65±10 wt.-%, in each case relative to the total weight of the particles (embodiment D4). In another preferred embodiment, the weight content of the EVA copolymer is within the range of from 75±10 wt.-%, relative to the total weight of the particles (embodiment D5).

[0090] Preferred sub-combinations of embodiments A1 to A3 and D1 to D5 are: AlCl, A1C2, A1C3, A1C4, A1C5, A2C1, A2C2, A2C3, A2C4, A2C5, A3C1, A3C2, A3C3, A3C4, and A3C5. Preferred sub-combinations of embodiments B1 to B3 and D1 to D5 are: B1C1, B1C2, B1C3, B1C4, B1C5, B2C1, B2C2, B2C3, B2C4, B2C5, B3C1, B3C2, B3C3, B3C4, and B3C5. Preferred sub-combinations of embodiments Cl to C4 and D1 to D5 are: C1D1, C1D2, C1D3, C1D4, C1D5, C2D1, C2D2, C2D3, C2D4, C2D5, C3D1, C3D2, C3D3, C3D4, C3D5, C4D1, C4D2, C4D3, C4D4, and C4D5.

[0091] Preferred sub-combinations of embodiments B 1 to B3, Cl to C4, and D1 to D5 are: B1C1D1, B1C2D1, B1C3D1, B1C4D1, B2C1D1, B2C2D1, B2C3D1, B2C4D1, B3C1D1, B3C2D1, B3C3D1, B3C4D1; B1C1D2,

B1C2D2, B1C3D2, B1C4D2, B2C1D2, B2C2D2, B2C3D2, B2C4D2, B3C1D2, B3C2D2, B3C3D2, B3C4D2;

B1C1D3, B1C2D3, B1C3D3, B1C4D3, B2C1D3, B2C2D3, B2C3D3, B2C4D3, B3C1D3, B3C2D3, B3C3D3,

B3C4D3; B1C1D4, B1C2D4, B1C3D4, B1C4D4, B2C1D4, B2C2D4, B2C3D4, B2C4D4, B3C1D4, B3C2D4,

B3C3D4, B3C4D4; B1C1D5, B1C2D5, B1C3D5, B1C4D5, B2C1D5, B2C2D5, B2C3D5, B2C4D5, B3C1D5,

B3C2D5, B3C3D5, and B3C4D5.

[0092] Preferably, the relative weight ratio of the EVA copolymer to the pharmacologically active ingredient is within the range of 20:1 to 1:20, more preferably 15:1 to 1:15, still more preferably 10:1 to 1:10, yet more preferably 7: 1 to 1:7, most preferably 5 : 1 to 1:5, and in particular 3 : 1 to 1:1.

[0093] The multitude of particles of the pharmaceutical dosage form according to the invention comprise an additional excipient.

[0094] For the purpose of the specification, the additional excipient is a single distinct ingredient of the particles that are contained in the pharmaceutical dosage form. Thus, for the purpose of the specification, any definition of weight or percentage by weight relates to this single distinct ingredient. It is the weight content of this single distinct ingredient (additional excipient) that must be within the range of from 8.0 to 30 wt.-%, relative to the total weight of the particles

[0095] For the purpose of the specification, a single distinct ingredient may encompass a multitude of species, e.g. a multitude of polymer molecules composed of the same monomer units but having different molecular weight and optionally also having different relative quantitative content of comonomers. Thus, for example, HPMC-AS having an average molecular weight of 50,000 g/mol may be regarded as a single distinct ingredient, although the individual polymer molecules will have varying molecular weight. However, excipients having a different chemical composition, e.g. polymers composed of different monomer units, are not to be regarded as single distinct ingredient. Thus, for example, carboxymethylcellulose and crosslinked carboxymethylcellulose are not to be regarded as single distinct ingredient.

[0096] The additional excipient does not need to be the only additional ingredient contained in the particles besides the EVA copolymer and the pharmacologically active ingredient. However, for the purpose of the specification, any potentially further contained ingredient is referred to as "further excipient(s)". Thus, any definition of weight or percentage by weight relating to said additional excipient does not encompass the quantity of said optionally present further excipient(s).

[0097] In a preferred embodiment, the additional excipient is a polymer, preferably an ionic polymer, more preferably an ionic polymer, still more preferably an anionic polymer, yet more preferably an anionic polymer, most preferably an anionic polysaccharide (embodiment El).

[0098] In another preferred embodiment, the additional excipient is a hydrocolloid [i.e. a colloidal substance with an affinity for water], preferably a hydrocolloid selected from the group consisting of agars, alginates, propylene glycol alginates (PGA), carrageenans, pectins, native starches, modified starches, furcellarans, larch gums, guar gums, locust bean gums, tara gums, tamarind seed gums, konjac gums, acacia gums, gums arabic, tragacanth, karaya gums, ghatti gums, xanthans, gellans, pullulans, dextrans, curdlans, scleroglucans, cellulose derivatives, and the physiologically acceptable salts thereof (embodiment E2); preferred cellulose derivatives include cellulose esters and cellulose ethers, preferably methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylme- thylcellulose, hydroxypropylmethylcellulose acetate succinate (HPMC-AS) and the physiologically acceptable salts thereof, hydroxypropylmethylcellulose phthalate (HPMC-P) and the physiologically acceptable salts thereof, carboxymethylcellulose and the physiologically acceptable salts thereof, crosslinked carboxymethylcellulose and the physiologically acceptable salts thereof.

[0099] In still another preferred embodiment, the additional excipient is selected from the group consisting of alginates, carboxymethyl starch, carboxymethyl cellulose, crosslinked carboxymethyl cellulose, hydroxypropylmethylcellulose acetate succinate, xanthans, polyacrylates, copolymers of acrylic acid, and the physiologically acceptable salts thereof (embodiment E3).

[0100] In yet another preferred embodiment, the additional excipient is a non-ionic polymer, preferably selected from the group consisting of hydroxypropylmethylcellulose, starch, polyvinylpyrrolidone, polyvinylacetate/ pol- yvinyl-pyrrolidone copolymers, and polyvinyl alcohol/polyethylene glycol graft copolymers (embodiment E4).

[0101] In particularly preferred embodiments, the additional excipient is selected from the group consisting of hydroxypropylmethylcellulose acetate succinates, alginates, carboxymethyl starches and the physiologically acceptable salts thereof, croscarmelloses and the physiologically acceptable salts thereof, and xanthans.

[0102] Preferred sub-combinations of embodiments A1 to A3 and El to E4 are: A1E1, A1E2, A1E3, A1E4, A2E1, A2E2, A2E3, A2E4, A3E1, A3E2, A3E3, and A3E4. Preferred sub-combinations of embodiments B1 to B3 and El to E4 are: B1E1, B1E2, B1E3, B1E4, B2E1, B2E2, B2E3, B2E4, B3E1, B3E2, B3E3, and B3E4. Preferred sub-combinations of embodiments Cl to C4 and El to E4 are: C1E1, C1E2, C1E3, C1E4, C2E1, C2E2, C2E3, C2E4, C3E1, C3E2, C3E3, C3E4, C4E1, C4E2, C4E3, and C4E4. Preferred sub-combinations of embodiments D1 to D5 and El to E4 are: D1E1, D1E2, D1E3, D1E4, D2E1, D2E2, D2E3, D2E4, D3E1, D3E2, D3E3, D3E4, D4E1, D4E2, D4E3, D4E4, D5E1, D5E2, D5E3, and D5E4.

[0103] In a preferred embodiment, the additional excipient is a hydroxypropylmethylcellulose acetate succinate (HPMC-AS). With various contents of acetyl and succinoyl groups in the polymer, there are several types of HPMC-AS, which dissolve at different pH levels. Type L HPMC-AS represents polymer with high ratio of succinoyl substitution to acetyl substitution (S/A ratio), while type H with a low S/A ratio and type M with a medium S/A ratio. With a high S/A ratio, type L HPMC-AS dissolves at a lower pH (>5.5), compared with pH > 6.0 for type M and pH > 6.8 for type H. Preferably, the HPMC-AS according to the invention is selected from type L, M, and H.

[0104] In another preferred embodiment, the additional excipient is an alginate. Preferably, the alginate is selected from the group consisting of alginic acid, sodium alginate, ammonium alginate, potassium alginate, calcium alginate, magnesium alginate, and propylene glycol alginate.

[0105] In still another preferred embodiment, the additional ingredient is a carboxymethyl starch (starch glyco- late) or a physiologically acceptable salt thereof (e.g. sodium starch glycolate).

[0106] In yet another preferred embodiment, the additional ingredient is a croscarmellose or a physiologically acceptable salt thereof (e.g. croscarmellose sodium).

[0107] In another preferred embodiment, the additional ingredient is a xanthan.

[0108] The weight content of the additional excipient contained in the multitude of particles of the pharmaceutical dosage form according to the invention is within the range of from 8.0 to 30 wt.-%, relative to the total weight of the particles.

[0109] Preferably, the weight content of the additional excipient is at least 9.0 wt.-%, or at least 10 wt.-%, or at least 11 wt.-%, or at least 12 wt.-%, or at least 13 wt.-%, or at least 14 wt.-%, or at least 15 wt.-%, or at least 16 wt. -%, or at least 17 wt.-%, or at least 18 wt.-%, or at least 19 wt.-%, or at least 20 wt.-%, in each case relative to the total weight of the particles within the range of from 8.0 to 30 wt.-%.

[0110] Preferably, the weight content of the additional excipient is at most 25 wt.-%, or at most 24 wt.-%, or at most 23 wt. -%, or at most 22 wt.-%, or at most 21 wt.-%, or at most 20 wt.-%, or at most 19 wt.-%, or at most 18 wt. -%, or at most 17 wt.-%, or at most 16 wt.-%, or at most 15 wt.-%, or at most 14 wt.-%, or at most 13 wt.-%, or at most 12 wt.-%, or at most 11 wt.-%, or at most 10 wt.-%, in each case relative to the total weight of the particles. [0111] In a preferred embodiment, the weight content of the additional excipient is within the range of from 12±4 wt. -%, preferably 12±3 wt.-%, in each case relative to the total weight of the particles (embodiment FI). In another preferred embodiment, the weight content of the additional excipient is within the range of from 18±4 wt.-%, preferably 18±3 wt.-%, in each case relative to the total weight of the particles (embodiment F2).

[0112] Preferred sub-combinations of embodiments A1 to A3 andFl to F2 are: A1F1, A1F2, A2F1, A2F2, A3F1, and A3F2. Preferred sub-combinations of embodiments B1 to B3 and FI to F2 are: B1F1, B1F2, B2F1, B2F2, B3F1, and B3F2. Preferred sub-combinations of embodiments Cl to C4 and FI to F2 are: C1F1, C1F2, C2F1, C2F2, C3F1, C3F2, C4F1, and C4F2. Preferred sub-combinations of embodiments D1 to D5 and FI to F2 are: D1F1, D1F2, D2F1, D2F2, D3F1, D3F2, D4F1, D4F2, D5F1, and D5F2. Preferred sub-combinations of embodiments El to E4 and FI to F2 are: E1F1, E1F2, E2F1, E2F2, E3F1, E3F2, E4F1, and E4F2.

[0113] Preferably, the relative weight ratio of the additional excipient to the pharmacologically active ingredient is within the range of 20:1 to 1:20, more preferably 10:l to 1:15, still more preferably 7:1 to 1:10, yet more preferably 5:1 to 1:7, most preferably 1:1 to 1:5, and in particular 1:2 to 1:5.

[0114] The pharmaceutical dosage form according to the invention and/or the particles which contain the pharmacologically active ingredient may contain further excipient(s) conventionally contained in pharmaceutical dosage forms in conventional amounts, such as antioxidants, preservatives, lubricants, plasticizer, fillers, binders, and the like.

[0115] The skilled person will readily be able to determine appropriate further excipient(s) as well as the quantities of each of these further excipient(s). Specific examples of pharmaceutically acceptable carriers and excipients are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986).

[0116] Preferably, the pharmaceutical dosage form according to the invention and/or the particles which contain the pharmacologically active ingredient comprise an antioxidant. Suitable antioxidants include ascorbic acid, bu- tylated hydro xyanisole (BHA), butylated hydro xytoluene (BHT), salts of ascorbic acid, monothioglycerol, phosphorous acid, vitamin C, vitamin E and the derivatives thereof, coniferyl benzoate, nordihydroguajaretic acid, gallus acid esters, sodium bisulfite, particularly preferably butylhydroxytoluene or butylhydroxyanisole and a- tocopherol. The antioxidant is preferably present in quantities of 0.01 wt.-% to 10 wt.-%, more preferably of 0.03 wt.-% to 5 wt. -%, most preferably of 0.05 wt.-% to 2.5 wt.-%, based on the total weight of the pharmaceutical dosage form and the particles, respectively.

[0117] Preferably, the pharmaceutical dosage form according to the invention and/or the particles which contain the pharmacologically active ingredient comprise an acid, preferably citric acid. The amount of acid is preferably in the range of 0.01 wt.-% to about 20 wt.-%, more preferably in the range of 0.02 wt.-% to about 10 wt.-%, and still more preferably in the range of 0.05 wt.-% to about 5 wt.-%, and most preferably in the range of 0.1 wt.-% to about 1.0 wt. -%, based on the total weight of the pharmaceutical dosage form and the particles, respectively. [0118] Preferably, the pharmaceutical dosage form according to the invention and/or the particles which contain the pharmacologically active ingredient comprise an lubricant. Especially preferred lubricants are selected from

- magnesium stearate and stearic acid;

- polyoxyethylene glycerol fatty acid esters, such as mixtures of mono-, di- and triesters of glycerol and di- and monoesters of macrogols having molecular weights within the range of from 200 to 4000 g/mol, e.g., macro- golglycerolcaprylocaprate, macrogolglycerollaurate, macrogolglycerolococoate, macrogolglycerollinoleate, macrogol-20-glycerolmonostearate, macrogol-6-glycerolcaprylocaprate, macrogolglycerololeate; macrogol- glycerolstearate, macrogolglycerolhydroxystearate, and macrogolglycerolrizinoleate;

- polyglycolyzed glycerides, such as the one known and commercially available under the trade name "Labra- sol";

- fatty alcohols that may be linear or branched, such as cetylalcohol, stearylalcohol, cetylstearyl alcohol, 2-oc- tyldodecane-l-ol and 2-hexyldecane-l-ol; and

- polyethylene glycols having a molecular weight between 10.000 and 60.000 g/mol.

[0119] Preferably, the amount of the lubricant ranges from 0.01 wt.-% to about 10 wt.-%, more preferably in the range of 0.05 wt.-%to about 7.5 wt.-%, most preferably in the range of 0.1 wt.-%to about 5 wt.-%, and in particular in the range of 0.1 wt.-% to about 1 wt.-%, based on the total weight of the pharmaceutical dosage form and the particles, respectively.

[0120] Preferably, the pharmaceutical dosage form according to the invention and/or the particles which contain the pharmacologically active ingredient comprise a plasticizer. The plasticizer improves the processability of the EVA copolymer, additional excipient and optionally prefers further excipient(s), respectively. A preferred plasticizer is polyalkylene glycol, like polyethylene glycol, triacetin, fatty acids, fatty acid esters, waxes and/or micro- crystalline waxes. Particularly preferred plasticizers are polyethylene glycols, such as PEG 6000.

[0121] Preferably, the content of the plasticizer is within the range of from 0.5 to 30 wt.-%, more preferably 1.0 to 25 wt. -%, still more preferably 2.5 wt.-% to 22.5 wt.-%, yet more preferably 5.0 wt.-% to 20 wt.-%, most preferably 6 to 20 wt.-% and in particular 7 wt.-% to 17.5 wt.-%, based on the total weight of the pharmaceutical dosage form and the particles, respectively. Plasticizers can sometimes act as a lubricant, and lubricants can sometimes act as a plasticizer.

[0122] Preferably, the pharmaceutical dosage form according to the invention is tamper-resistant.

[0123] Preferably, the pharmaceutical dosage form according to the invention provides resistance against solvent extraction, resistance against grinding, and/or resistance against dose-dumping in aqueous ethanol. Preferably, the prolonged release matrix of the pharmaceutical dosage form according to the invention not only provides prolonged release of the pharmacologically active ingredient, but additionally provides tamper resistance, i.e. resistance against solvent extraction, resistance against grinding, and resistance against dose-dumping in aqueous ethanol. [0124] As used herein, the term "tamper resistant" refers to pharmaceutical dosage forms that are resistant to conversion into a form suitable for misuse or abuse by conventional means, particular for nasal and/or intravenous administration.

[0125] Preferably, the particles which contain the pharmacologically active ingredient exhibit mechanical properties such that they cannot be pulverized by conventional means any further. As the particles are of macroscopic size and contain the pharmacologically active ingredient, they cannot be administered nasally thereby rendering the pharmaceutical dosage form tamper resistant. Further, when trying to disrupt the pharmaceutical dosage forms by means of a hammer or mortar, the particles preferably tend to adhere to one another thereby forming aggregates and agglomerates, respectively, which are larger in size than the untreated particles.

[0126] The pharmaceutical dosage form according to the invention preferably exhibits resistance against solvent extraction. Preferably, the prolonged release matrix provides the pharmaceutical dosage form according to the invention with resistance against solvent extraction.

[0127] Preferably, when trying to tamper the pharmaceutical dosage form in order to prepare a formulation suitable for abuse by intravenous administration, the liquid part of the formulation that can be separated from the remainder by means of a syringe at room temperature is as less as possible, preferably it contains not more than 75 or 45 or 40 wt.-%, more preferably not more than 35 wt.-%, still more preferably not more than 30 wt.-%, yet more preferably not more than 25 wt.-%, even more preferably not more than 20 wt.-%, most preferably not more than 15 wt.-% and in particular not more than 10 wt.-% of the originally contained pharmacologically active ingredient.

[0128] Preferably, this property is tested by (i) dispensing a pharmaceutical dosage form that is either intact or has been manually comminuted by means of two spoons in 5 mL of solvent, either purified water or aqueous ethanol (40 vol.%), (ii) allowing the dispersion to stand for 10 min at room temperature, (iii) drawing up the hot liquid into a syringe (needle 21G equipped with a cigarette filter), and (iv) determining the amount of the pharmacologically active ingredient contained in the liquid within the syringe.

[0129] The pharmaceutical dosage form according to the invention preferably exhibits resistance against grinding. Preferably, the prolonged release matrix provides the pharmaceutical dosage form according to the invention with resistance against grinding.

[0130] Preferably, at least a fraction of the particles of the pharmaceutical dosage form according to the invention have a breaking strength of at least 300 N.

[0131] Preferably, the mechanical properties, particularly the breaking strength, substantially relies on the presence and spatial distribution of the EVA copolymer, although its mere presence does typically not suffice in order to achieve said properties. The advantageous mechanical properties may not automatically be achieved by simply processing pharmacologically active ingredient, EVA copolymer, additional excipient, and optionally further ex- cipient(s) by means of conventional methods for the preparation of pharmaceutical dosage forms. In fact, usually suitable apparatuses must be selected for the preparation and critical processing parameters must be adjusted, particularly pressure/force, temperature and time. Thus, even if conventional apparatuses are used, the process protocols usually must be adapted in order to meet the required criteria.

[0132] In general, the desired properties may be obtained only if, during preparation of the pharmaceutical dosage form, suitable components in suitable amounts are exposed to a sufficient pressure at a sufficient temperature for a sufficient period of time. Thus, regardless of the apparatus used, the process protocols must be adapted in order to meet the required criteria. Therefore, the breaking strength is separable from the composition.

[0133] The particles according to the invention which contain the pharmacologically active ingredient preferably have a breaking strength of at least 300 N, at least 400 N, or at least 500 N, preferably at least 600 N, more preferably at least 700 N, still more preferably at least 800 N, yet more preferably at least 1000 N, most preferably at least 1250 N and in particular at least 1500 N.

[0134] The "breaking strength" (resistance to crushing) of a particle is known to the skilled person. In this regard it can be referred to, e.g., W.A. Ritschel, Die Tablette, 2. Auflage, Editio Cantor Verlag Aulendorf, 2002; H Liebermann et ak, Pharmaceutical dosage forms: Pharmaceutical dosage forms, Vol. 2, Informa Healthcare; 2 edition, 1990; and Encyclopedia of Pharmaceutical Technology, Informa Healthcare; 1 edition.

[0135] For the purpose of specification, the breaking strength is preferably defined as the amount of force that is necessary in order to fracture a particle (= breaking force). Therefore, for the purpose of specification, a particle does preferably not exhibit the desired breaking strength when it breaks, i.e., is fractured into at least two independent parts that are separated from one another. In another preferred embodiment, however, the particle is regarded as being broken if the force decreases by 25% (threshold value) of the highest force measured during the measurement (see below).

[0136] The particles according to the invention are preferably distinguished from conventional particles in that due to their breaking strength, they cannot be pulverized by the application of force with conventional means, such as for example a pestle and mortar, a hammer, a mallet or other usual means for pulverization, in particular devices developed for this purpose (pharmaceutical dosage form crushers). In this regard "pulverization" means cmmbling into small particles. Avoidance of pulverization virtually rules out oral or parenteral, in particular intravenous or nasal abuse. Conventional particles typically have a breaking strength well below 200 N.

[0137] The breaking strength of conventional round pharmaceutical dosage forms/particles may be estimated according to the following empirical formula: Breaking Strength [inN] = 10 x Diameter of pharmaceutical dosage form/particle [in mm]. Thus, according to said empirical formula, a round particle having a breaking strength of at least 300 N would require a diameter of at least 30 mm. Such a particle, however, could not be swallowed, let alone a pharmaceutical dosage form containing a plurality of such particles. The above empirical formula preferably does not apply to the particles, according to the invention, which are not conventional but rather special. [0138] Further, the actual mean chewing force is about 220 N (cf, e.g., P.A. Proeschel et al, J Dent Res, 2002, 81(7), 464-468). This means that conventional particles having a breaking strength well below 200 N may be cmshed upon spontaneous chewing, whereas the particles according to the invention may preferably not.

[0139] Still further, when applying a gravitational acceleration of about 9.81 m/s², 300 N correspond to a gravitational force of more than 30 kg, i.e. the particle according to the invention can preferably withstand a weight of more than 30 kg without being pulverized.

[0140] Methods for measuring the breaking strength are known to the skilled artisan. Suitable devices are commercially available.

[0141] For example, the breaking strength (resistance to crushing) can be measured in accordance with the Eur. Ph. 5.0, 2.9.8 or 6.0, 2.09.08 "Resistance to Crushing of Pharmaceutical dosage forms". The particles may be subjected to the same or similar breaking strength test as the pharmaceutical dosage form. The test is intended to determine, under defined conditions, the resistance to crushing of pharmaceutical dosage forms and individual particles, respectively, measured by the force needed to disrupt them by crushing. The apparatus consists of 2 jaws facing each other, one of which moves towards the other. The flat surfaces of the jaws are perpendicular to the direction of movement. The crushing surfaces of the jaws are flat and larger than the zone of contact with the pharmaceutical dosage form and individual particle, respectively. The apparatus is calibrated using a system with a precision of 1 Newton. The particle is placed between the jaws, taking into account, where applicable, the shape, the break-mark and the inscription; for each measurement the particle is oriented in the same way with respect to the direction of application of the force (and the direction of extension in which the breaking strength is to be measured). The measurement is carried out on 10 particles taking care that all fragments have been removed before each determination. The result is expressed as the mean, minimum and maximum values of the forces measured, all expressed in Newton.

[0142] Alternatively, the breaking strength (resistance to crushing) can be measured in accordance with WO 2008/107149, which can be regarded as a modification of the method described in the Eur. Ph. The apparatus used for the measurement is preferably a "Zwick Z 2.5" materials tester, F_max = 2.5 kN with a maximum draw of 1150 mm, which should be set up with one column and one spindle, a clearance behind of 100 mm and a test speed adjustable between 0.1 and 800 mm min together with testControl software. Measurement is performed using a pressure piston with screw-in inserts and a cylinder (diameter 10 mm), a force transducer, F_max. 1 kN, diameter = 8 mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with manufacturer's test certificate M according to DIN 55350-18 (Zwick gross force F_max = 1.45 kN) (all apparatus from Zwick GmbH & Co. KG, Ulm, Germany) with Order No BTC-FR 2.5 TH. D09 for the tester, Order No BTC-LC 0050N. P01 for the force transducer, Order No BO 70000 S06 for the centring device.

[0143] In a preferred embodiment, the particle is regarded as being broken if it is fractured into at least two separate pieces. [0144] The particles according to the invention preferably exhibit mechanical strength over a wide temperature range, in addition to the breaking strength (resistance to crushing) optionally also sufficient hardness, impact resistance, impact elasticity, tensile strength and/or modulus of elasticity, optionally also at low temperatures (e.g. below -24 °C, below -40 °C or possibly even in liquid nitrogen), for it to be virtually impossible to pulverize by spontaneous chewing, grinding in a mortar, pounding, etc. Thus, preferably, the comparatively high breaking strength of the particles according to the invention is maintained even at low or very low temperatures, e.g., when the pharmaceutical dosage form is initially chilled to increase its brittleness, for example to temperatures below - 25°C, below -40 °C or even in liquid nitrogen.

[0145] The particle according to the invention is preferably characterized by a certain degree of breaking strength. This does not mean that it must also exhibit a certain degree of hardness. Hardness and breaking strength are different physical properties. Therefore, the tamper resistance of the pharmaceutical dosage form does not necessarily depend on the hardness of the pharmaceutical dosage form and particle, respectively. For instance, due to its breaking strength, impact strength, elasticity modulus and tensile strength, respectively, the particles can preferably be deformed, e.g. plastically, when exerting an external force, for example using a hammer, but cannot be pulverized, i.e., crumbled into a high number of fragments. In other words, the particle according to the invention are characterized by a certain degree of breaking strength, but not necessarily also by a certain degree of form stability.

[0146] Therefore, in the meaning of the specification, a particle that is deformed when being exposed to a force in a particular direction of extension but that does not break (plastic deformation or plastic flow) is preferably to be regarded as having the desired breaking strength in said direction of extension.

[0147] Preferred particles are those having a suitable tensile strength as determined by a test method currently accepted in the art. Further preferred particles are those having a Young’s Modulus as determined by a test method of the art. Still further preferred pharmaceutical dosages form and particles, respectively, are those having an acceptable elongation at break.

[0148] The pharmaceutical dosage form according to the invention preferably exhibits resistance against dosedumping in aqueous ethanol. Preferably, the prolonged release matrix provides the pharmaceutical dosage form according to the invention with resistance against dose-dumping in aqueous ethanol.

[0149] The pharmaceutical dosage form or the separate particles can be tested in vitro using ethanol / simulated gastric fluid of 0%, 20% and 40% to evaluate alcohol extractability . Testing is preferably performed using standard procedures, e.g. USP Apparatus 1 (basket) or USP Apparatus 2 (paddle) at e.g. 50 rpm or 75 rpm in e.g. 500 mL of media at 37°C, using a Perkin Elmer UV/VIS Spectrometer Lambda 20, UV at an appropriate wavelength for detection of the pharmacologically active ingredient present therein. Sample time points preferably include 0.5 and 1 hour.

[0150] Preferably, when comparing the in vitro release profile at 37°C in simulated gastric fluid with the in vitro release profile in ethanol / simulated gastric fluid (40 vol.-%) at 37°C, the in vitro release in ethanol / simulated gastric fluid (40 vol.-%) is preferably not substantially accelerated compared to the in vitro release in simulated gastric fluid. Preferably, in this regard "substantially" means that at any given time point the in vitro release in ethanol / simulated gastric fluid (40 vol.-%) relatively deviates from the in vitro release in simulated gastric fluid by not more than +25%, more preferably not more than +20%, still more preferably not more than +15%, yet more preferably not more than +10%, even more preferably not more than +7.5%, most preferably not more than +5.0% and in particular not more than +2.5%.

[0151] A substantial relative acceleration of the in vitro release in ethanol / simulated gastric fluid (40 vol.-%) compared to the in vitro release in simulated gastric fluid is to be prevented according to the invention. However, a substantial relative deceleration of the in vitro release in ethanol / simulated gastric fluid (40 vol.-%) compared to the in vitro release in simulated gastric fluid, e.g., a relative deviation by -25% or more, may be possible and can even be desirable.

[0152] Preferably, the particles that are contained in the pharmaceutical dosage form according to the invention are pellets, preferably extruded pellets.

[0153] In a preferred embodiment, the particles that are contained in the pharmaceutical dosage form according to the invention have an extension in any direction of at least 2.0 mm, more preferably at least 2.2 mm, still more preferably at least 2.5 mm, yet more preferably at least 2.8 mm, even more preferably at least 3.0 mm, most preferably at least 3.2 mm, and in particular at least 3.5 mm or 4.0 mm. Preferably, the individual drug-containing particles have an extension in any direction of more than 2.0 mm.

[0154] In another preferred embodiment, the particles that are contained in the pharmaceutical dosage form according to the invention have an extension in any direction of not more than 2.0 mm, more preferably not more than 1.9 mm, still more preferably not more than 1.8 mm, yet more preferably not more than 1.7 mm, even more preferably not more than 1.6 mm, most preferably not more than 1.5 mm, and in particular not more than 1.4 mm or 1.3 mm. Preferably, the individual drug-containing particles have an extension in any direction of less than 2.0 mm.

[0155] The particles are preferably of macroscopic size, typically the average diameter is within the range of from 100 pm to 2000 pm, preferably 200 pm to 1500 pm, more preferably 300 pm to 1500 pm, still more preferably 400 pm to 1500 pm, most preferably 500 pm to 1500 pm, and in particular 600 pm to 1500 pm. Preferably, the particles in the pharmaceutical dosage form have an average particle size of at least 50 pm, more preferably at least 100 pm, still more preferably at least 150 pm or at least 200 pm, yet more preferably at least 250 pm or at least 300 pm, most preferably at least 400 pm or at least 500 pm, and in particular at least 550 pm or at least 600 pm. Preferably, the particles in the pharmaceutical dosage form have an average particle size of at least 700 pm, more preferably at least 800 pm, most preferably at least 900 pm and in particular at least 1000 pm.

[0156] The shape of the particles is not particularly limited. As the particles are preferably manufactured by hot- melt extrusion, preferred particles present in the pharmaceutical dosage forms according to the invention are generally cylindrical in shape. The diameter of such particles is therefore the diameter of their circular cross section. The cylindrical shape is caused by the extrusion process according to which the diameter of the circular cross section is a function of the extrusion die and the length of the cylinders is a function of the cutting length according to which the extruded strand of material is cut into pieces of preferably more or less predetermined length.

[0157] Typically, the aspect ratio is regarded as an important measure of the spherical shape. The aspect ratio is defined as the ratio of the maximal diameter (d_max) and its orthogonal Feret-diameter. For aspherical particles, the aspect ratio has values above 1. The smaller the value the more spherical is the particle. In a preferred embodiment, the aspect ratio of the particles is at most 1.40, more preferably at most 1.35, still more preferably at most 1.30, yet more preferably at most 1.25, even more preferably at most 1.20, most preferably at most 1.15 and in particular at most 1.10. In another preferred embodiment, the aspect ratio of the particles is at least 1.10, more preferably at least 1.15, still more preferably at least 1.20, yet more preferably at least 1.25, even more preferably at least 1.30, most preferably at least 1.35 and in particular at least 1.40.

[0158] Preferred particles have an average length and average diameter of about 1000 pm or less. When the particles are manufactured by extmsion technology, the "length" of particles is the dimension of the particles that is parallel to the direction of extmsion. The "diameter" of particles is the largest dimension that is perpendicular to the direction of extmsion.

[0159] Particularly preferred particles have an average diameter of less than about 2000 pm, more preferably less than about 1000 or 800 pm, still more preferably of less than about 650 pm. Especially preferred particles have an average diameter of less than 700 pm, particularly less than 600 pm, still more particularly less than 500 pm, e.g. less than 400 pm. Particularly preferred particles have an average diameter in the range of 200-1500 pm, more preferably 400-800 pm, still more preferably 450-700 pm, yet more preferably 500-650 pm, e.g. about 500- 600 pm. Further preferred particles have an average diameter of between about 300 pm and about 400 pm, of between about 400 pm and 500 pm, or of between about 500 pm and 600 pm, or of between 600 pm and 700 pm or of between 700 pm and 800 pm.

[0160] In a preferred embodiment, particles that are present in the pharmaceutical dosage forms according to the invention have an average length in the range of 500 to 5000 pm, more preferably 750 to 4600 pm, still more preferably 1000 to 4200 pm, yet more preferably 1250 to 3800 pm, even more preferably 1500 to 3400 pm, most preferably 1750 to 3200 pm and in particular 2000 to 3000 pm. According to this embodiment, particles that are present in the pharmaceutical dosage forms according to the invention preferably have an average length of less than about 4000 pm, more preferably less than about 3000 pm, still more preferably less than about 2000 pm, e.g. a length of about 1800 pm, about 1600 pm about 1400 pm, about 1200 pm or about 1000 pm.

[0161] In another preferred embodiment, particles that are present in the pharmaceutical dosage forms according to the invention have an average length in the range of 200 to 1000 pm, more preferably 400 to 800 pm, still more preferably 450 to 700 pm, yet more preferably 500 to 650 pm, e.g. about 500 to 600 pm. According to this embodiment, particles that are present in the pharmaceutical dosage forms according to the invention preferably have an average length of less than about 1000 pm, more preferably less than about 800 pm, still more preferably less than about 650 pm, e.g. a length of about 800 pm, about 700 pm about 600 pm, about 500 pm, about 400 pm or about 300 mih. Especially preferred particles have an average length of less than 700 pm, particularly less than 650 pm, still more particularly less than 550 pm, e.g. less than 450 pm.

[0162] The minimum average length of the particles is determined by the cutting step and may be, e.g. 4.0 mm, 3.0 mm, 2.0 mm, 2.5 mm, 2.0 mm, 1.5 mm, 1.0 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm or 0.2 mm.

[0163] The size of particles may be determined by any conventional procedure known in the art, e.g. laser light scattering, sieve analysis, light microscopy or image analysis.

[0164] Preferably, the plurality of particles that is contained in the pharmaceutical dosage form according to the invention has an arithmetic average weight, in the following referred to as "aaw", wherein at least 70%, more preferably at least 75%, still more preferably at least 80%, yet more preferably at least 85%, most preferably at least 90% and in particular at least 95% of the individual particles contained in said plurality of particles has an individual weight within the range of aaw±30%, more preferably aaw±25%, still more preferably aaw±20%, yet more preferably aaw±15%, most preferably aaw±10%, and in particular aaw±5%. For example, if the pharmaceutical dosage form according to the invention contains a plurality of 100 particles and aaw of said plurality of particles is 1.00 mg, at least 75 individual particles (i.e. 75%) have an individual weight within the range of from 0.70 to 1.30 mg (1.00 mg ±30%).

[0165] In a preferred embodiment, the particles each have a weight of less than 20 mg, more preferably less than 18 mg, still more preferably less than 16 mg, yet more preferably less than 14 mg, even more preferably less than 12 mg or less than 10 mg, most preferably less than 8 mg, and in particular less than 6 or 4 mg. According to this embodiment, all individual particles each preferably have a weight of from 1 to 19 mg, more preferably 1.5 to 15 mg, still more preferably 2.0 to 12 mg, yet more preferably 2.2 to 10 mg, even more preferably 2.5 to 8 mg, most preferably 2.8 to 6 mg and in particular 3 to 5 mg.

[0166] In another preferred embodiment, the particles, more preferably the drug-containing particles, each have a weight of 20 mg or more. According to this embodiment, all individual particles preferably each have a weight of at least 30 mg, more preferably at least 40 mg, still more preferably at least 50 mg, most preferably at least 60 mg and in particular at least 100 mg. Preferably, all individual particles each have a weight of from 20 to 1000 mg, more preferably 30 to 800 mg, still more preferably 40 to 600 mg, yet more preferably 50 to 400 mg, even more preferably 60 to 200 mg, most preferably 70 to 150 mg and in particular 80 to 120 mg. According to this embodiment, the particles according to the invention preferably each have an extension in any given direction of at least 2.0 mm or 3.0 mm and have a weight of at least 20 mg.

[0167] Preferably, the particles are not film coated.

[0168] In another preferred embodiment, the particles are film coated. The particles according to the invention can optionally be provided, partially or completely, with a conventional coating. The particles are preferably film coated with conventional film coating compositions. Suitable coating materials are commercially available, e.g. under the trademarks Opadry^® and Eudragit^®.

[0169] Preferably, the multitude of particles contained in the pharmaceutical dosage form according to the invention are thermoformed, more preferably hot-melt extruded. Thermoforming preferably means that in the course of the manufacture of the particles the mixture comprising the EVA copolymer, the pharmacologically active ingredient, the additional excipients and optionally further excipient(s) is heated to a temperature above ambient temperature, preferably at least 60 °C or at least 80 °C, and compressed, preferably at pressures of at least 1 bar or at least 2 bar, more preferably at least 10 bar or at least 30 bar. The compression force may be exerted prior to, during or subsequent to the application of heat.

[0170] The particles that contain the pharmacologically active ingredient are preferably thermoformed, preferably by melt-extrusion, although also other methods of thermoforming may be useful, such as press-molding at elevated temperature or heating of compacts that were manufactured by conventional compression in a first step and then heated above the softening temperature of the EVA copolymer in a second step to form break resistant, hardened compacts. In this regard, thermoforming preferably means the forming or molding of a mass after, before or during the application of heat. Preferably, thermoforming is performed by hot-melt extrusion.

[0171] Preferably, the particles according to the invention can be regarded as "extruded pellets". The term “extruded pellets” has structural implications which are understood by persons skilled in the art. A person skilled in the art knows that pelletized pharmaceutical dosage forms can be prepared by a number of techniques, including:

- drug layering on nonpareil sugar or microcrystalline cellulose beads,

- spray drying,

- spray congealing,

- rotogranulation,

- hot-melt extrusion,

- spheronization of low melting materials, or

- extrusion-spheronization of a wet mass.

[0172] Accordingly, "extruded pellets" can be obtained either by hot-melt extrusion or by extrusion-spheronization. "Extruded pellets" can be distinguished from other types of pellets because they are structurally different. For example, chug layering on nonpareils yields multilayered pellets having a core, whereas extrusion typically yields a monolithic mass comprising a homogeneous mixture of all ingredients. Similarly, spray drying and spray congealing typically yield spheres, whereas extmsion typically yields cylindrical extrudates which can be subsequently spheronized.

[0173] The structural differences between “extruded pellets” and “agglomerated pellets” are significant because they may affect the release of active substances from the pellets and consequently result in different pharmacological profiles. Therefore, a person skilled in the pharmaceutical formulation art would not consider “extruded pellets” to be equivalent to “agglomerated pellets”. [0174] Another aspect of the invention relates to a process for the production of a pharmaceutical dosage form according to the invention as described above comprising the steps of

(i) mixing a pharmacologically active ingredient, an EVA copolymer, an additional excipient and optionally further excipient(s); and

(ii) thermoforming the mixture obtained in step (i), wherein said mixture is simultaneously or before or after the application of heat subjected to pressure.

[0175] Preferably, the multitude of particles contained in the pharmaceutical dosage form according to the invention are hot-melt extruded.

[0176] The particles according to the invention may be produced by different processes, the particularly preferred of which are explained in greater detail below. Several suitable processes have already been described in the prior art. In this regard it can be referred to, e.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, and WO 2006/082099.

[0177] In general, the process for the production of the particles according to the invention preferably comprises the following steps:

(a) mixing all ingredients;

(b) optionally pre-forming the mixture obtained from step (a), preferably by applying heat and/or force to the mixture obtained from step (a), the quantity of heat supplied preferably not being sufficient to heat the EVA copolymer up to its softening point;

(c) hardening the mixture by applying heat and force, it being possible to supply the heat during and/or before the application of force and the quantity of heat supplied being sufficient to heat the EVA copolymer at least up to its softening point; and thereafter allowing the material to cool and removing the force

(d) optionally singulating the hardened mixture;

(e) optionally shaping the particles; and

(f) optionally providing a film coating.

[0178] Heat may be supplied directly, e.g. by contact or by means of hot gas such as hot air, or with the assistance of ultrasound; or is indirectly supplied by friction and/or shear. Force may be applied and or the particles may be shaped for example with the assistance of a suitable extruder, particularly by means of a screw extruder equipped with one or two screws (single-screw-extruder and twin-screw-extruder, respectively) or by means of a planetary gear extruder.

[0179] The final shape of the particles may either be provided during the hardening of the mixture by applying heat and force (step (c)) or in a subsequent step (step (e)). In both cases, the mixture of all components is preferably in the plastified state, i.e. preferably, shaping is performed at a temperature at least above the softening point of the EVA copolymer. However, extrusion at lower temperatures, e.g. ambient temperature, is also possible and may be preferred. Shaping can be performed, e.g., by means of a pharmaceutical dosage forming press comprising die and punches of appropriate shape.

[0180] The ingredients may be mixed in a mixer known to the person skilled in the art. The mixer may, for example, be a roll mixer, shaking mixer, shear mixer or compulsory mixer. The, preferably molten, mixture which has been heated in the extruder at least up to the softening point of the EVA copolymer is extruded from the extruder through a die with at least one bore. The process according to the invention requires the use of suitable extruders, preferably screw extruders. Screw extruders which are equipped with two screws (twin-screw-extruders) are particularly preferred.

[0181] In a preferred embodiment, extrusion is performed in the absence of water, i.e., no water is added. However, traces of water (e.g., caused by atmospheric humidity) may be present. The extruded strand is preferably water-free, which preferably means that the water content of the extruded strand is preferably at most 10 wt.-%, or at most 7.5 wt.-%, or at most 5.0 wt.-%, or at most 4.0 wt.-%, or at most 3.0 wt.-%, or at most 2.0 wt.-%, more preferably at most 1.7 wt.-%, still more preferably at most 1.5 wt.-%, yet more preferably at most 1.3 wt.-%, even more preferably at most 1.0 wt.-%, most preferably at most 0.7 wt.-%, and in particular at most 0.5 wt.-%.

[0182] The extruder preferably comprises at least two temperature zones, with heating of the mixture at least up to the softening point of the EVA copolymer, proceeding in the first zone, which is downstream from a feed zone and optionally mixing zone. The throughput of the mixture is preferably from 1.0 kg to 15 kg/hour. In a preferred embodiment, the throughput is from 0.2 kg/hour to 3.5 kg/hour. In another preferred embodiment, the throughput is from 4 to 15 kg/hour.

[0183] In a preferred embodiment, the die head pressure is within the range of from 0.5 to 200 bar. The die head pressure can be adjusted inter alia by die geometry, temperature profile, extrusion speed, number of bores in the dies, screw configuration, first feeding steps in the extruder, and the like.

[0184] The die geometry or the geometry of the bores is freely selectable. The die or the bores may accordingly exhibit a flat (film), round, oblong or oval cross-section, wherein the round cross-section preferably has a diameter of 0.1 mm to 2 mm for extruded particles and a larger diameter for extruded monolithic pharmaceutical dosage forms. Preferably, the die or the bores have a round cross-section. The casing of the extruder used according to the invention may be heated or cooled. The corresponding temperature control, i.e. heating or cooling, is so arranged that the mixture to be extruded exhibits at least an average temperature (product temperature) corresponding to the softening temperature of the EVA copolymer and does not rise above a temperature at which the pharmacologically active ingredient to be processed may be damaged. Preferably, the temperature of the mixture to be extruded is adjusted to below 180 °C, preferably below 150 °C, but at least to the softening temperature of the EVA copolymer. Typical extrusion temperatures are 120 °C and 150 °C.

[0185] In a preferred embodiment, the extruder torque is within the range of from 30 to 95%. Extruder torque can be adjusted inter alia by die geometry, temperature profile, extrusion speed, number of bores in the dies, screw configuration, first feeding steps in the extruder, and the like. [0186] After extrusion of the molten mixture and optional cooling of the extruded strand or extmded strands, the extrudates are preferably singulated. This singulation may preferably be performed by cutting up the extrudates by means of revolving or rotating knives, wires, blades or with the assistance of laser cutters.

[0187] In a particularly preferred embodiment, singulation is performed by means of a micropelletizer. The automated cutting of small pellets from the strand exiting the extruder is actually one of the biggest challenges that was also solved by the present invention. It has been surprisingly found that cutting the extmded strand can advantageously be achieved by means of a micropelletizer without using a cooling liquid, e.g. without underwater pelletizing where aqueous liquids are conventionally used. In micro pelletizing, the hot melt is preferably cut by centrically aligned knives directly after discharge from the die. Subsequently, it is preferably air-cooled e.g. through pneumatic conveyance. This process is bound to certain product parameters. Depending on the product, spherical pellets can be produced. Common diameters are 0.8 to 1 mm, but in some cases a diameter of 0.5 mm can be achieved. Micropelletizers are commercially available, e.g. from Leistritz Extrusionstechnik GmbH.

[0188] Preferably, intermediate or final storage of the optionally singulated extrudate or the final shape of the particle according to the invention is performed under oxygen-free atmosphere which may be achieved, e.g., by means of oxygen-scavengers.

[0189] The application of force in the extruder onto the at least plasticized mixture is adjusted by controlling the rotational speed of the conveying device in the extruder and the geometry thereof and by dimensioning the outlet orifice in such a manner that the pressure necessary for extruding the plasticized mixture is built up in the extruder, preferably immediately prior to extrusion. The extrusion parameters which, for each particular composition, are necessary to give rise to a pharmaceutical dosage form with desired mechanical properties, may be established by simple preliminary testing. For example but not limiting, extrusion may be performed by means of a twin-screw- extruder type ZSE 18 or ZSE 27 (Leistritz, Niimberg, Germany) or Thermo Scientific* Pharma 16 HME, screw diameters of 16, 18 or 27 mm. Screws having eccentric or blunt ends may be used. A heatable die with a round bore or with a multitude of bores each having a diameter of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0 or 6.0 mm may be used. The extmsion parameters may be adjusted e.g. to the following values: rotational speed of the screws: 120 Upm; delivery rate 0.5 kg/h for Pharma 16, 2 kg/h for a ZSE 18 or 8 kg/h for a ZSE 27; product temperature: in front of die 100 to 125°C and behind die 125 to 135°C; and jacket temperature: 110 °C.

[0190] Preferably, extmsion is performed by means of twin-screw-extruders or planetary-gear-extruders, twin- screw extruders (co-rotating or contra-rotating) being particularly preferred.

[0191] The process for the preparation of the particle according to the invention is preferably performed continuously. Preferably, the process involves the extmsion of a homogeneous mixture of all components. It is particularly advantageous if the thus obtained intermediate, e.g. the strand obtained by extmsion, exhibits uniform properties. Particularly desirable are uniform density, uniform distribution of the pharmacologically active ingredient, uniform mechanical properties, uniform porosity, uniform appearance of the surface, etc. Only under these circumstances the uniformity of the pharmacological properties, such as the stability of the release profile, may be ensured and the amount of rejects can be kept low.

[0192] The multitude of particles containing the pharmacologically active ingredient are contained in the pharmaceutical dosage form according to the invention. As used herein, the term "pharmaceutical dosage form" refers to a pharmaceutical entity that is comprised of a pharmacologically active ingredient and which is actually administered to, or taken by, a patient. It may be compressed or molded in its manufacture, and it may be of almost any size, shape, weight, and color.

[0193] The pharmaceutical dosage form is preferably solid or semisolid.

[0194] Examples of pharmaceutical dosage forms according to the invention include, but are not limited to, tablets, capsules, pills, granules, pellets, sachets and effervescent, powders, and the like. In an embodiment of the present invention, the composition is formulated in a capsule. In accordance with this embodiment, the pharmaceutical dosage form comprises a hard or soft gelatin capsule. Most pharmaceutical dosage forms are intended to be swallowed whole and accordingly, the pharmaceutical dosage forms according to the invention are designed for oral administration.

[0195] Preferably, the content of the particles in the pharmaceutical dosage forms according to the invention is at most 95 wt.-%, more preferably at most 90 wt.-%, still more preferably at most 85 wt.-%, yet more preferably at most 80 wt.-%, most preferably at most 75 wt.-% and in particular at most 70 wt.-%, based on the total weight of the pharmaceutical dosage forms.

[0196] Preferably, the content of the particles in the pharmaceutical dosage forms according to the invention is at least 10 wt.-%, at least 15 wt.-%, at least 20 wt.-% or at least 25 wt.-%; more preferably at least 30 wt.-%, at least 35 wt.-%, at least 40 wt.-% or at least 45 wt.-%; most preferably at least 50 wt.-%, at least 55 wt.-%, at least 60 wt.-% or at least 65 wt.-%; and in particular at least 70 wt.-%, at least 75 wt.-%, at least 80 wt.-% or at least 85 wt.-%; based on the total weight of the pharmaceutical dosage form.

[0197] The pharmaceutical dosage form according to the invention has preferably a total weight in the range of 0.01 to 1.5 g, more preferably in the range of 0.05 to 1.2 g, still more preferably in the range of 0.1 g to 1.0 g, yet more preferably in the range of 0.2 g to 0.9 g, and most preferably in the range of 0.3 g to 0.8 g.

[0198] In a preferred embodiment, the pharmaceutical dosage form according to the invention is a round pharmaceutical dosage form. In another preferred embodiment, the pharmaceutical dosage form according to the invention is an oblong pharmaceutical dosage form.

[0199] The pharmaceutical dosage form according to the invention may optionally comprise a coating, e.g. a cosmetic coating. The coating is preferably applied after formation of the pharmaceutical dosage form. The coating may be applied prior to or after the curing process. The pharmaceutical dosage forms according to the invention are preferably film coated with conventional fdm coating compositions. Suitable coating materials are commercially available, e.g. under the trademarks Opadry^® and Eudragit^®. The coating can be resistant to gastric juices and dissolve as a function of the pH value of the release environment. The coating can also be applied e.g. to improve the aesthetic impression and/or the taste of the pharmaceutical dosage forms and the ease with which they can be swallowed. Coating the pharmaceutical dosage forms according to the invention can also serve other purposes, e.g. improving stability and shelf-life.

[0200] The particles may be e.g. loosely contained in a capsule.

[0201] In a preferred embodiment, the pharmaceutical dosage form according to the invention is monolithic. In this regard, monolithic preferably means that the pharmaceutical dosage form is formed or composed of material without joints or seams or consists of or constitutes a single unit.

[0202] In a preferred embodiment, the pharmaceutical dosage forms according to the invention comprise particles as a discontinuous phase, i.e. the particles form a discontinuous phase in an outer matrix material which in turn preferably forms a continuous phase. In this regard, discontinuous means that not each and every particle is in intimate contact with another particle but that the particles are at least partially separated from one another by the outer matrix material in which the particles are embedded. In other words, the particles preferably do not form a single coherent mass within the pharmaceutical dosage forms according to the invention.

[0203] In another preferred embodiment, the pharmaceutical dosage form according to the invention is not monolithic. Preferably, the pharmaceutical dosage form according to the invention is multiparticulate, i.e. comprises a multitude of particles. An advantage of multiparticulate pharmaceutical dosage forms is that the particles may be mixed in different amounts to thereby produce pharmaceutical dosage forms of different strengths.

[0204] In a preferred embodiment, the pharmaceutical dosage form according to the invention can be regarded as a MUPS formulation (multiple unit pellet system). Preferably, the pharmaceutical dosage form according to the invention contains all ingredients in a dense compact unit which in comparison to capsules has a comparatively high density. Under these circumstances, the pharmaceutical dosage forms according to the invention preferably comprise subunits having different morphology and properties, namely drug-containing particles and an outer matrix material, wherein the particles form a discontinuous phase within the outer matrix material. The constituents of the outer matrix material are preferably different from the constituents of the chug-containing particles. Preferably, the outer matrix material neither contains a pharmacologically active ingredient having psychotropic action nor an EVA copolymer.

[0205] The particles typically have mechanical properties that differ from the mechanical properties of the outer matrix material. Preferably, the particles have a higher mechanical strength than the outer matrix material. The particles can preferably be visualized by conventional means such as solid state nuclear magnetic resonance spectroscopy, raster electron microscopy, terahertz spectroscopy and the like.

[0206] From a macroscopic perspective, the outer matrix material preferably forms a continuous phase in which the particles are embedded as discontinuous phase. Preferably, the outer matrix material is a homogenous coherent mass, preferably a homogeneous mixture of solid constituents, in which the particles are embedded thereby spatially separating the particles from one another. While it is possible that the surfaces of particles are in contact or at least in very close proximity with one another, the plurality of particles preferably cannot be regarded as a single continuous coherent mass within the pharmaceutical dosage form. In other words, the pharmaceutical dosage form according to the invention preferably comprises the particles as volume element(s) of a first type in which the pharmacologically active ingredient, the EVA copolymer, the additional excipient and the optionally present further excipient(s) are contained, and the outer matrix material as volume element of a second type differing from the material that forms the particles, preferably containing neither pharmacologically active ingredient nor EVA copolymer.

[0207] The relative weight ratio of particles to outer matrix material is not particularly limited. Preferably, said relative weight ratio is within the range of 1: 1.00±0.75, more preferably 1 : 1.00±0.50, still more preferably 1 : 1.00±0.40, yet more preferably 1 : 1.00±0.30, most preferably 1 : 1.00±0.20, and in particular 1 : 1.00±0.10.

[0208] Preferably, the content of the outer matrix material is at least 2.5 wt.-%, at least 5 wt.-%, at least 7.5 wt- % or at least 10 wt.-%; at least 12.5 wt.-%, at least 15 wt.-%, at least 17.5 wt.-% or at least 20 wt.-%; at least 22.5 wt. -%, at least 25 wt.-%, at least 27.5 wt.-% or at least 30 wt.-%; at least 32.5 wt.-%, at least 35 wt.-%, at least

37.5 wt.-% or at least 40 wt.-%; more preferably at least 42.5 wt.-%, at least 45 wt.-%, at least 47.5 wt.-% or at least 50 wt.-%; still more preferably at least 52.5 wt.-%, at least 55 wt.-%, at least 57.5 wt.-% or at least 60 wt.-%; yet more preferably at least 62.5 wt.-%, at least 65 wt.-%, at least 67.5 wt.-% or at least 60 wt.-%; most preferably at least 72.5 wt.-%, at least 75 wt.-%, at least 77.5 wt.-% or at least 70 wt.-%; and in particular at least 82.5 wt- %, at least 85 wt.-%, at least 87.5 wt.-% or at least 90 wt.-%; based on the total weight of the pharmaceutical dosage form.

[0209] Preferably, the content of the outer matrix material is at most 90 wt.-%, at most 87.5 wt.-%, at most 85 wt. -%, or at most 82.5 wt.-%; more preferably at most 80 wt.-%, at most 77.5 wt.-%, at most 75 wt.-% or at most

72.5 wt.-%; still more preferably at most 70 wt.-%, at most 67.5 wt.-%, at most 65 wt.-% or at most 62.5 wt.-%; yet more preferably at most 60 wt.-%, at most 57.5 wt.-%, at most 55 wt.-% or at most 52.5 wt.-%; most preferably at most 50 wt.-%, at most 47.5 wt.-%, at most 45 wt.-% or at most 42.5 wt.-%; and in particular at most 40 wt.-%, at most 37.5 wt.-%, or at most 35 wt.-%; based on the total weight of the pharmaceutical dosage form.

[0210] Preferably, the outer matrix material is a mixture, preferably a homogeneous mixture of at least two different constituents, more preferably of at least three different constituents. In a preferred embodiment, all constituents of the outer matrix material are homogeneously distributed in the continuous phase that is formed by the outer matrix material.

[0211] Preferably, the outer matrix material is also provided in particulate form, i.e. in the course of the manufacture of the pharmaceutical dosage forms according to the invention, the constituents of the outer matrix material are preferably processed into particles, subsequently mixed with the particles that contain the pharmacologically active ingredient and the EVA copolymer, and then compressed into the pharmaceutical dosage forms. [0212] The outer matrix material preferably does not contain any pharmacologically active ingredient.

[0213] Preferably, the outer matrix material comprises a filler or a binder. As many fillers can be regarded as binders and vice versa, for the purpose of specification "filler/binder" refers to any excipient that is suitable as filler, binder or both. Thus, the outer matrix material preferably comprises a filler/binder. Preferred fillers (=filler/binders) are selected from the group consisting of silicium dioxide (e.g. Aerosil^®), microcrystalline cellulose (e.g. Avicel^®, Elcema^®, Emocel^®, ExCel^®, Vitacell^®); cellulose ether (e.g. Natrosol^®, Klucel^®, Methocel^®, Blanose^®, Pharmacoat^®, Viscontran^®); mannitol; dextrines; dextrose; calciumhydrogen phosphate (e.g. Emcom- press^®); maltodextrine (e.g. Emdex^®); lactose (e.g. Fast-Flow Lactose^®; Ludiprcss" Pharmaceutical dosage formtose^®, Zeparox^®); polyvinylpyrrolidone (PVP) (e.g. Kollidone^®, Polyplasdone^®, Polydone^®); saccharose (e.g. Nu-Tab^®, Sugar Tab^®); magnesium salts (e.g. MgCCh, MgO, MgSiOi): starches and pretreated starches (e.g. Prejel^®, Primotab^® ET, Starch^® 1500). Preferred binders are selected from the group consisting of alginates; chi- tosanes; and any of the fdlers mentioned above (= fillers/binders). Some fillers/binders may also serve other purposes. It is known, for example, that silicium dioxide exhibits excellent function as a glidant. Thus, preferably, the outer matrix material comprises a glidant such as silicium dioxide. Preferably, the filler/binder is contained in the outer matrix material but not in the drug-containing particles of the pharmaceutical dosage form according to the invention.

[0214] Preferably, the outer matrix material comprises a diluent or lubricant, preferably selected from the group consisting of calcium stearate; magnesium stearate; glycerol monobehenate (e.g. Compritol^®); Myvatex^®; Preci- rol^®; Precirol^® Ato5; sodium stearylfumarate (e.g. Pruv^®); and talcum. Magnesium stearate is particularly preferred. Preferably, the content of the lubricant in the outer matrix material is at most 10.0 wt.-%, more preferably at most 7.5 wt.-%, still more preferably at most 5.0 wt.-%, yet more preferably at most 2.0 wt.-%, even more preferably at most 1.0 wt.-%, and most preferably at most 0.5 wt.-%, based on the total weight of the outer matrix material and based on the total weight of pharmaceutical dosage form. In particularly preferred embodiment, the outer matrix material comprises a combination of filler/binder and lubricant.

[0215] The outer matrix material of the pharmaceutical dosage forms according to the invention may additionally contain other excipients that are conventional in the art, e.g. diluents, binders, granulating aids, colorants, flavor additives, glidants, wet-regulating agents and disintegrants. The skilled person will readily be able to determine appropriate quantities of each of these excipients.

[0216] The pharmaceutical dosage forms according to the invention may be prepared by any conventional method. Preferably, however, the pharmaceutical dosage forms are prepared by compression. Thus, particles as hereinbefore defined are preferably mixed, e.g. blended and/or granulated (e.g. wet granulated), with outer matrix material and the resulting mix (e.g. blend or granulate) is then compressed, preferably in molds, to form pharmaceutical dosage forms. It is also envisaged that the particles herein described may be incorporated into a matrix using other processes, such as by melt granulation (e.g. using fatty alcohols and/or water-soluble waxes and/or water-insoluble waxes) or high shear granulation, followed by compression. [0217] The pharmaceutical dosage forms according to the invention may be used in medicine. The disease or disorder to be prevented or treated depends upon the nature and dose of the pharmacologically active ingredient.

[0218] A further aspect of the invention relates to the use of a pharmaceutical dosage form as described above for providing prolonged release of the pharmacologically active ingredient contained therein.

[0219] A further aspect of the invention relates to the use of a pharmaceutical dosage form as described above for avoiding or hindering the abuse of the pharmacologically active ingredient contained therein.

[0220] A further aspect of the invention relates to the use of a pharmaceutical dosage form as described above for avoiding or hindering the unintentional overdose of the pharmacologically active ingredient contained therein. In this regard, the invention also relates to the use of a pharmaceutical dosage form as described above for the prophylaxis and/or the treatment of a disorder, thereby preventing an overdose of the pharmacologically active ingredient, particularly due to comminution of the pharmaceutical dosage form by mechanical action.

[0221] Preferred embodiments of the invention are summarizes as clauses 1 to 40 hereinafter: 1: An oral pharmaceutical dosage form comprising a multitude of particles, wherein the particles comprise (a) a pharmacologically active ingredient; wherein the weight content of the pharmacologically active ingredient is within the range of from 5.0 to 65 wt.-%, relative to the total weight of the particles; (b) an EVA copolymer having (i) a vinylacetate content within the range of from 10 to 50 wt.-%, relative to the total weight of the EVA copolymer; and (ii) a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 within the range of from 2 to 500 g/10 min; and wherein the weight content of the EVA copolymer is within the range of from 25 to 85 wt.-%, relative to the total weight of the particles; and (c) an additional excipient; wherein the weight content of the additional excipient is within the range of from 8.0 to 30 wt.-%, relative to the total weight of the particles; and wherein the pharmacologically active ingredient is embedded in a prolonged release matrix comprising the EVA copolymer and the additional excipient. 2: The pharmaceutical dosage form according to clause 1, which under physiological in vitro conditions has released - after 30 minutes not more than 75 wt.-%; - after 360 minutes at least 35 wt.-%; and - after 720 minutes at least 60 wt.-% of the pharmacologically active ingredient that was originally contained in the pharmaceutical dosage form. 3: The pharmaceutical dosage form according to clause 1 or 2, wherein the weight content of the pharmacologically active ingredient is at least 10 wt.-%, or at least 20 wt.-%, or at least 25 wt.-%, or at least 30 wt. -%, or at least 35 wt.-%, or at least 40 wt.-%, in each case relative to the total weight of the particles. 4: The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the pharmacologically active ingredient is at most 45 wt.-%, or at most 40 wt.-%, or at most 35 wt.-%, or at most 30 wt.-%, or at most 25 wt.-%, or at most 20 wt.-%, or at most 15 wt.-%, in each case relative to the total weight of the particles. 5: The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the pharmacologically active ingredient is within the range of 15±10 wt,-%, relative to the total weight of the particles. 6: The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the pharmacologically active ingredient is within the range of 35±20 wt.-%, preferably 35±15 wt.-%, more preferably 35±10 wt.-%, in each case relative to the total weight of the particles. 7: The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the pharmacologically active ingredient is within the range of 55±10, relative to the total weight of the particles. 8: The pharmaceutical dosage form according to any of the preceding clauses, wherein the EVA copolymer has a vinylacetate content of at least 10 wt. -%, or at least 15 wt.-%, or at least 20 wt.-%, or at least 25 wt.-%, or at least 30 wt.-%, or at least 35 wt.-%, or at least 40 wt.-%, in each case relative to the total weight of the EVA copolymer. 9: The pharmaceutical dosage form according to any of the preceding clauses, wherein the EVA copolymer has a vinylacetate content of at most 45 wt. -%, or at most 40 wt.-%, or at most 35 wt.-%, or at most 30 wt.-%, or at most 25 wt.-%, or at most 20 wt- %, or at most 15 wt.-%, in each case relative to the total weight of the EVA copolymer. 10: The pharmaceutical dosage form according to any of the preceding clauses, wherein the EVA copolymer has a vinylacetate content within the range of 20±10 wt.-%, relative to the total weight of the EVA copolymer; or wherein the EVA copolymer has a vinylacetate content (i) of at most 22 wt.-%, or at most 20 wt.-%, or at most 18 wt.-%, or at most 16 wt- %; (ii) within the range of 28±5 wt.-%, or 28±3 wt.-%; or (iii) of at least 34 wt.-%, or at least 36 wt.-%, or at least 38 wt. -%, or at least 40 wt.-%; in each case relative to the total weight of the EVA copolymer. 11 : The pharmaceutical dosage form according to any of the preceding clauses, wherein the EVA copolymer has a vinylacetate content within the range of 30±20 wt.-%, preferably 30±15 wt.-%, more preferably 30±10 wt.-%, in each case relative to the total weight of the EVA copolymer. 12: The pharmaceutical dosage form according to any of the preceding clauses, wherein the EVA copolymer has a vinylacetate content within the range of 40±20 wt.-%, relative to the total weight of the EVA copolymer. 13: The pharmaceutical dosage form according to any of the preceding clauses, wherein the EVA copolymer has a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 of at least 5 g/10 min, or at least 10 g/10 min, or at least 25 g/10 min, or at least 50 g/10 min, or at least 100 g/10 min, or at least 150 g/10 min, or at least 200 g/10 min, or at least 250 g/10 min, or at least 300 g/10 min, or at least 350 g/10 min, or at least 400 g/10 min. 14: The pharmaceutical dosage form according to any of the preceding clauses, wherein the EVA copolymer has a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 of at most 450 g/10 min, or at most 400 g/10 min, or at most 350 g/10 min, or at most 300 g/10 min, or at most 250 g/10 min, or at most 200 g/10 min, or at most 150 g/10 min, or at most 100 g/10 min, or at most 50 g/10 min, or at most 25 g/10 min, or at most 10 g/10 min. 15: The pharmaceutical dosage form according to any of the preceding clauses, wherein the EVA copolymer has a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 within the range of 100±90 g/10 min, preferably 100±50 g/10 min. 16: The pharmaceutical dosage form according to any of the preceding clauses, wherein the EVA copolymer has a melt flow index at 190°C/2.16 kg measured according to ASTM D 1238 within the range of 200±190 g/10 min, preferably 200±100 g/10 min, more preferably 200±50 g/10 min. 17: The pharmaceutical dosage form according to any of the preceding clauses, wherein the EVA copolymer has a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 within the range of 300±190 g/10 min, preferably 300±100 g/10 min, more preferably 300±50 g/10 min. 18: The pharmaceutical dosage form according to any of the preceding clauses, wherein the EVA copolymer has a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 within the range of 400±90 g/10 min, preferably 400±50 g/10 min. 19: The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the EVA copolymer is at least 45 wt.-%, or at least 50 wt.-%, or at least 55 wt.-%, or at least 60 wt.-%, or at least 65 wt.-%, or at least 70 wt.-%, or at least 75 wt.-%, in each case relative to the total weight of the particles. 20: The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the EVA copolymer is at most 80 wt.-%, or at most 75 wt.-%, or at most 70 wt.-%, or at most 65 wt. -%, or at most 60 wt.-%, or at most 55 wt.-%, or at most 50 wt.-%, in each case relative to the total weight of the particles. 21 : The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the EVA copolymer is within the range of from 35±10 wt.-%, relative to the total weight of the particles. 22: The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the EVA copolymer is within the range of from 45±20 wt.-%, preferably 45±15 wt.-%, more preferably 45±10 wt.-%, in each case relative to the total weight of the particles. 23 : The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the EVA copolymer is within the range of from 55±20 wt- %, preferably 55±15 wt.-%, more preferably 55±10 wt.-%, in each case relative to the total weight of the particles. 24: The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the EVA copolymer is within the range of from 65±20 wt.-%, preferably 65±15 wt.-%, more preferably 65±10 wt.-%, in each case relative to the total weight of the particles. 25: The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the EVA copolymer is within the range of from 75±10 wt- %, relative to the total weight of the particles. 26: The pharmaceutical dosage form according to any of the preceding clauses, wherein the additional excipient is a polymer, preferably an ionic polymer, more preferably an ionic polymer, still more preferably an anionic polymer, yet more preferably an anionic polymer, most preferably an anionic polysaccharide. 27: The pharmaceutical dosage form according to any of the preceding clauses, wherein the additional excipient is a hydrocolloid, preferably a hydrocolloid selected from the group consisting of agars, alginates, propylene glycol alginates (PGA), carrageenans, pectins, native starches, modified starches, furcellarans, larch gums, guar gums, locust bean gums, tara gums, tamarind seed gums, konjac gums, acacia gums, gums arabic, tragacanth, karaya gums, ghatti gums, xanthans, gellans, pullulans, dextrans, curdlans, scleroglucans, cellulose derivatives, and the physiologically acceptable salts thereof. 28: The pharmaceutical dosage form according to any of the preceding clauses, wherein the additional excipient is selected from the group consisting of alginates, car- boxymethyl starch, carboxymethyl cellulose, crosslinked carboxymethyl cellulose, hydro xypropylmethyl cellulose acetate succinate, xanthans, polyacrylates, copolymers of acrylic acid, and the physiologically acceptable salts thereof. 29: The pharmaceutical dosage form according to any of the preceding clauses, wherein the additional excipient is a non-ionic polymer, preferably selected from the group consisting of hydroxy-propylmethyl cellulose, starch, polyvinylpyrrolidone, polyvinylacetate/ polyvinylpyrrolidone copolymers, and polyvinyl alcohol/polyethylene glycol graft copolymers. 30: The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the additional excipient is at least 9.0 wt.-%, or at least 10 wt.-%, or at least 11 wt- %, or at least 12 wt.-%, or at least 13 wt.-%, or at least 14 wt.-%, or at least 15 wt.-%, or at least 16 wt.-%, or at least 17 wt.-%, or at least 18 wt.-%, or at least 19 wt.-%, or at least 20 wt.-%, in each case relative to the total weight of the particles within the range of from 8.0 to 30 wt.-%. 31 : The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the additional excipient is at most 25 wt.-%, or at most 24 wt. -%, or at most 23 wt.-%, or at most 22 wt.-%, or at most 21 wt.-%, or at most 20 wt.-%, or at most 19 wt. -%, or at most 18 wt.-%, or at most 17 wt.-%, or at most 16 wt.-%, or at most 15 wt.-%, or at most 14 wt.-%, or at most 13 wt.-%, or at most 12 wt.-%, or at most 11 wt.-%, or at most 10 wt.-%, in each case relative to the total weight of the particles. 32: The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the additional excipient is within the range of from 12±4 wt.-%, preferably 12±3 wt. -%, in each case relative to the total weight of the particles. 33: The pharmaceutical dosage form according to any of the preceding clauses, wherein the weight content of the additional excipient is within the range of from 18±4 wt.-%, preferably 18±3 wt.-%, in each case relative to the total weight of the particles. 34: The pharmaceutical dosage form according to any of the preceding clauses, which is tamper-resistant. 35: The pharmaceutical dosage form according to any of the preceding clauses, which provides resistance against solvent extraction, resistance against grinding, and/or resistance against dose-dumping in aqueous ethanol. 36: The pharmaceutical dosage form according to any of the preceding clauses, wherein at least a fraction of the particles have a breaking strength of at least 300 N. 37: The pharmaceutical dosage form according to any of the preceding clauses, wherein the particles are pellets. 38: The pharmaceutical dosage form according to any of the preceding clauses, wherein the particles have an extension in any direction of at least 2.0 mm. 39: The pharmaceutical dosage form according to any of the preceding clauses, wherein the particles are hot-melt extruded. 40: A process for the production of a pharmaceutical dosage form according to any of the preceding clauses comprising the steps of (i) mixing a pharmacologically active ingredient, an EVA (EVA) polymer, an additional excipient and optionally further excipients; and (ii) thermoforming the mixture obtained in step (i), wherein said mixture is simultaneously or before or after the application of heat subjected to pressure.

EXAMPLES

[0222] The following examples illustrate the invention but are not to be construed as limiting its scope. Two different types of particles were manufactured that significantly differed in size, pellets and cutrods. Pellets were manufactured by hot-melt extrusion through dies having a diameter of 0.8 mm, whereas cutrods were hot-melt extruded through dies having a diameter of 5.5 mm. The average weight of a single representative cutrod was above 100 mg, whereas the average weight of a single average pellet was below 5 mg.

[0223] General procedure for pellet manufacture: Mixtures of the pharmacologically active ingredient, EVA and excipients were produced by weighing the ingredients (batch size 250.0 - 1000.0 g), sieving (Mesh size 2.0 mm), blending in a Bohle LM 40 MC 20, followed by extrusion using a Leistritz ZSE 18 melt extruder type MICRO 18 GL-40D Pharma (screw rotation speed 100 rpm). The extruded strands were cut yielding pellets of about 1 mm in size by means of a Micropelletizer (26 holes, die hole diameter: 0.8 mm, two rotating knifes).

[0224] General procedure for cutrod manufacture: Mixtures of the pharmacologically active ingredient, EVA and excipients were produced by weighing the ingredients (batch size 1000.0 g), sieving (Mesh size 1.0 mm), blending in a Bohle LM 40 MC 20, followed by extrusion using a Leistritz Micro 18 HME or a Leistritz Micro 27 lab extruder (screw rotation speed 90-100 rpm, die diameter 5.5 mm, melt pressure 16-47 bar). The extruded strands were cooled in ambient air and were manually cut with a hot knife into cutrods.

[0225] The pellets and cutrods, respectively, were subjected to different tests in order to assess the tamper-resistance with respect to the pharmacologically active ingredient contained in the pellets and cutrods, respectively.

[0226] General procedure for measuring in vitro dissolution under physiological conditions ("Disso") - drug release after administration in the prescribed manner: Dissolution of the pharmacologically active ingredients from the pellets and cutrods was measured by means of USP Apparatus 1 (basket) or USP Apparatus 2 (paddle) at e.g. 50 rpm or 75 rpm in e.g. 500 mL of media at pH 6.8 at 37°C

[0227] General procedure for measuring dissolution in aqueous ethanol - resistance against alcoholic dose dumping: Dissolution is determined in vitro under essentially the same conditions as for in vitro dissolution under physiological conditions, but the release medium is replaced by the corresponding volume of aqueous ethanol (40% ethanol v/v). Resistance against alcoholic dose dumping (ADD) is expressed in numerical values in terms of the ratio of the dissolved percentage in 40% ethanol after 60 minutes to the dissolved percentage under physiological conditions after 60 minutes. Thus, value for the ratio of significantly more than 1 means that the formulation is prone to alcoholic dose dumping, whereas a value for the ratio of about 1 means that the formulation does not show alcoholic dose dumping. A value for the ratio below 1 means that the formulation even provides additional resistance against alcoholic dose dumping.

[0228] General procedure for determining resistance against extraction in hot water - resistance against intra venous abuse ("IV Test"): Prior to extraction, cutrods were physically manipulated in a laboratory mill. In contrast to cutrods, pellets were used intact, i.e. pellets were not physically manipulated in a laboratory mill prior to extraction. While coffee grinders are a typical tool for tablets to prepare for abuse (e.g. for intranasal abuse), EVA pellets cannot be reduced in size by means of a coffee grinder.

[0229] A sample was stirred for 5 minutes in 5 mL or 10 mL of water at 90°C, filtered and the dissolved quantity of the pharmacologically active ingredient was subsequently determined by HPLC. Results are expressed as average values (n=2) in wt.-% relative to the total amount of the pharmacologically active ingredient that was originally contained in the sample (abuse deterrent formulation, ADF).

Example 1 - EVA cutrods - effect of VA content:

[0230] Different commercially available EVA products having different contents of vinylacetate (VA) were tested (12 wt.-%, 28 wt.-%, 40 wt.-%). In addition, intermediate VA contents amounting to 17.8 wt.-%, 20 wt.-% and 32.3 wt.-% were adjusted by blending appropriate amounts of the above commercially available materials.

[0231] Cutrods were manufactured by hot-melt extrusion from mixtures containing the following ingredients at the following contents:

¹ EVA (12 wt.-% VA), melt flow index 3 g/10 min (190°C/2.16 kg, ASTM D 1238)

² EVA (28 wt.-% VA), melt flow index 150 g/10 min (125°C/0.325 kg, ASTM D 1238)

³ EVA (40 wt.-% VA), melt flow index 55 g/10 min (190°C/2.16 kg, ASTM D1238)

[0232] In vitro dissolution under physiological conditions after 240 min and resistance against extraction in hot water were analyzed. The results are shown in Figures 1 A to C. [0233] As demonstrated, in vitro dissolution under physiological conditions and extractability in hot water are both a function of the VA content. At comparatively low VA contents of from about 12 wt.-% to about 28 wt.-%, release of Tramadol from the cutrods under both conditions is increased when the VA content is decreased. EVA having a VA content of 28 wt.-% provides slower release of Tramadol under in vitro conditions and allows extraction of lower amounts of Tramadol in hot water than EVA having a VA content of 20 wt.-%. When further increasing the VA content to 32.3 wt.-%, the trend with respect to extractability continues, i.e. extraction in hot water becomes even more difficult. Interestingly, however, in vitro dissolution is not further slowed down but becomes faster again. Under the given experimental conditions, the amount of Tramadol that is released under in vitro conditions after 240 minutes from the formulation containing EVA having a VA content of 17.8 wt.-% essentially corresponds to the amount that is released from the formulation containing EVA having a VA content of 32.3 wt- % (see Figure IB). At higher VA contents, both trends continue. When the VA content is increased from 32.3 wt- % to 40 wt. -%, extraction in hot water becomes even more difficult but in vitro dissolution is accelerated.

[0234] In vitro dissolution under physiological conditions after 240 min ("Diss.") and resistance against extraction in hot water ("ADF") were analyzed; the results are also displayed in the above table. Furthermore, the resistance against processability through a syringe filter was qualified ("resistance syringe", +++: good resistance, - - poor resistance).

[0235] Summing up, it has been surprisingly found that resistance against solvent extraction can be steadily improved by increasing the relative VA content in EVA. At the same time, when increasing the VA content from about 12 wt.-% to about 40 wt.-%, in vitro dissolution rate under physiological conditions passes a minimum.

Example 2 - EVA pellets - effect of additional excipient:

[0236] Different commercially available additional excipients were tested (sodium starch glycolate, Kollidon^® 90F, mannitol, xanthan, Carbopol^®, HPMC, croscarmellose sodium, alginate, Starch 1500^®, Kollidon^® SR, Kol- licoat^® IR).

[0237] Pellets were manufactured by hot-melt extrusion from mixtures containing the following ingredients at the following contents:

14.3 wt.-% Tramadol HC1,

63.7 wt.-% EVA (40 wt.-% VA),

20 wt.-% additional excipient, and 2.0 wt.-% Aerosil^®.

[0238] In vitro dissolution under physiological conditions, resistance against alcoholic dose dumping and resistance against extraction in hot water were analyzed.

[0239] The results of in vitro dissolution under physiological conditions are shown in Figure 2, where the order of the excipients in the legend corresponds to the order of the curves in the array of curves. As demonstrated, in vitro dissolution profiles can easily be modulated by selecting proper additional excipients. Typical gelling agents provide release profdes that are particularly relevant for oral delivery where administration once daily or twice daily is typically desirable.

[0240] The results of in vitro dissolution under physiological conditions after 360 minutes ("Disso."), resistance against alcoholic dose dumping ("ADD"), and resistance against extraction in hot water ("ADF") are compiled in the table here below:

[0241] As demonstrated, anionic polymers such as Carbopol^®, sodium carboxymethyl cellulose (NaCMC), alginate and carboxymethyl starch (sodium starch glycolate) in combination with EVA under the tested conditions provide the best resistance against alcoholic dose dumping.

[0242] Resistance against extraction in hot water ("ADF") does not dramatically vary, whereas the best results are achieved by mannitol and Kollidon^® 90F. However, the respective formulations provide very slow in vitro dissolution under physiological conditions (only about 25 wt.-% after 360 minutes); for many oral dosage forms it is desirable to reach after 360 minutes in vitro dissolution under physiological conditions of at least 40 wt.-%, preferably within the range of from about 60 wt.-% to about 85 wt.-%.

Example 3 - EVA pellets - various VA contents and various additional excipients:

[0243] Different commercially available additional excipients (sodium starch glycolate, xanthan, Carbopol^®, HPMC, croscarmellose sodium, alginate, Kollicoat^® IR) were each combined with three different commercially available EVA products having different contents of vinylacetate (12 wt.-%, 28 wt.-%, 40 wt.-%).

[0244] Pellets were manufactured by hot-melt extrusion from mixtures containing the following ingredients at the following contents:

14.3 wt.-% Tramadol HC1,

63.7 wt.-% EVA (12 wt.-% VA, 28 wt.-% VA or 40 wt.-% VA),

20 wt.-% additional excipient, and 2.0 wt.-% Aerosil^®. [0245] In vitro dissolution values under physiological conditions after 600 minutes ("Disso.") and the ratio of the dissolved amount of Tramadol after 180 minutes to the dissolved amount of Tramadol after 15 minutes ("Burst") are compiled in the table here below:

[0246] With regard to the "burst" release it is noted that a low value indicates a burst release as large portion of the pharmacologically active ingredient is released already after 15 min. So this is the opposite of the desired steady (i.e. prolonged) release rate (which is indicated by a higher "burst" ratio).

[0247] As demonstrated, at late timepoints (e.g. after 10 hours), EVA (12 wt.-% VA) has a slower dissolution rate than EVA (28 wt.-% VA) and EVA (40 wt.-% VA). Further, the higher the VA content, the more steady dissolution rates can be achieved (= no burst release).

[0248] The in vitro dissolution profdes under physiological conditions are displayed as Figures 7A through G and Figures 8A through G.

[0249] The formulations containing xanthan were also tested for resistance against alcoholic dose dumping and the results are compiled in the table here below:

[0250] As demonstrated, the higher the content of vinylacetate, the more the product is prone to alcoholic dose dumping.

Example 4 - EVA pellets - effect of drug load:

[0251] EVA Pellets containing different amounts of Tramadol HC1 were tested (20.0 wt.-%, 28.57 wt.-%, and 40.0 wt.-%). Pellets were manufactured by hot-melt extrusion from mixtures containing the following ingredients at the following contents:

[0252] The results of in vitro dissolution after 360 minutes ("Disso."), resistance against alcoholic dose dumping ("ADD"), and resistance against extraction in hot water ("ADF") are also compiled in the above table. The results of in vitro dissolution under physiological conditions are additionally shown in Figure 3.

[0253] As demonstrated, increasing the dmg load also increases dissolution rate without compromising resistance against alcoholic dose dumping or resistance against extraction in hot water.

Example 5 - EVA pellets - various VA contents and various additional excipients at high drug load:

[0254] Different commercially available additional excipients (HPMC-AS, alginate, carboxymethyl starch, xanthan, HPMC, carbopol, croscarmellose sodium) were each combined with two different commercially available EVA products having different contents of vinylacetate (28 wt.-%, 40 wt.-%).

[0255] Pellets were manufactured by hot-melt extrusion from mixtures containing the following ingredients at the following contents:

40.0 wt.-% Tramadol HC1,

48.0 wt.-% EVA (28 wt.-% VA or 40 wt.-% VA),

10.0 wt.-% additional excipient, and 2.0 wt.-% Aerosil^®.

[0256] While the formulations containing xanthan, HPMC, Carbopol, and croscarmellose sodium released Tramadol too quickly, good results were achieved with HPMC-AS, alginate, and sodium starch glycolate. The results for resistance against alcoholic dose dumping ("ADD"), resistance against extraction in hot water ("ADF"), and the ratio of the dissolved amount of Tramadol after 180 minutes to the dissolved amount of Tramadol after 15 minutes ("Burst") are compiled in the table here below:

[0257] As demonstrated, essentially the same trends are also observed for higher dmg loads: The higher the VA content, the more steady dissolution rates can be achieved (= no burst release). The higher the VA content, the more the product is prone to ADD.

Example 6 - EVA pellets - effect of nature of pharmacologically active ingredient: [0258] Different pharmacologically active ingredients having different physicochemical properties were tested (Etoricoxib, Metamizol Sodium, Naproxen, Paracetamol, Pregabalin). Pregabalin showed ~50% degradation.

[0259] Pellets were manufactured by hot-melt extrusion from mixtures containing the following ingredients at the following contents:

40.0 wt.-% pharmacologically active ingredient,

48.0 wt.-% EVA (12 wt.-%, 28 wt.-% VA or 40 wt.-% VA),

10.0 wt.-% carboxymethyl starch, and 2.0 wt.-% Aerosil^®.

[0260] The results for chemical stability ("Assay"), in vitro dissolution under physiological conditions after 600 minutes ("Disso."), resistance against alcoholic dose dumping ("ADD"), and the ratio of the dissolved amount of pharmacologically active ingredient after 180 minutes to the dissolved amount of pharmacologically active ingredient after 15 minutes ("Burst") are compiled in the table here below:

[0261] The in vitro dissolution profiles under physiological conditions are also shown in Figure 4A-D.

[0262] As demonstrated, essentially the same trend as for Tramadol also observed for other pharmacologically active ingredients: Release from EVA having a VA content of 28 wt.-% and 40 wt.-% is faster than from EVA having a VA content of 12 wt.-%. The higher the VA content, the more steady dissolution rates can be achieved (= no burst release). The higher the VA content, the more the product is prone to alcoholic dose dumping.

[0263] Pellets were manufactured by hot-melt extrusion from mixtures containing the following ingredients at the following contents:

40.0 wt.-% Oxycodone HC1,

48.0 wt.-% EVA (28 wt.-% VA or 40 wt.-% VA),

10.0 wt.-% HPMC-AS, and 2.0 wt.-% Aerosil^®.

[0264] The results for in vitro dissolution under physiological conditions after 600 minutes ("Disso."), resistance against alcoholic dose dumping ("ADD"), and the ratio of the dissolved amount of pharmacologically active ingredient after 180 minutes to the dissolved amount of pharmacologically active ingredient after 15 minutes ("Burst") are compiled in the table here below:

[0265] The in vitro dissolution profile under physiological conditions is also shown in Figure 5.

[0266] As demonstrated, essentially the same trend as for Tramadol was also observed for Oxycodone: The higher the VA content, the more steady dissolution rates can be achieved (= no burst release). The higher the VA content, the more the product is prone to alcoholic dose dumping.

Example 7 - EVA pellets - effect of molecular weight of EVA (in terms of melt flow index):

[0267] Different commercially available EVA products were tested having a content of vinylacetate of 28 wt.-% and having different molecular weights, expressed in terms of melt flow indices (MFI, 190°C/2.16 kg) (Ateva^® 2810A: 6 g/10 min, Ateva^® 2820A: 25 g/10 min, Ateva^® 2825A: 43 g/10 min, Ateva^® 2830A: 150 g/10 min, Ateva^® 2842A: 400 g/10 min).

[0268] Pellets were manufactured by hot-melt extrusion from mixtures containing the following ingredients at the following contents:

40.0 wt.-% Tapentadol HC1,

48.0 wt.-% EVA (28 wt.-% VA),

10.0 wt.-% HPMC-AS or Kollidon^® 90F, and 2.0 wt.-% Aerosil^®.

[0269] The in vitro dissolution profiles under physiological conditions are compiled in the table here below and shown in Figures 6 A and 6B:

[0270] The results for resistance against alcoholic dose dumping ("ADD"), and the ratio of the dissolved amount of pharmacologically active ingredient after 180 minutes to the dissolved amount of pharmacologically active ingredient after 15 minutes ("Burst") are also compiled in the above table.

[0271] Figure 6C shows a comparison of the amount of Tapentadol release after 120 minutes for the different EVA grades and the different additional excipients.

[0272] As demonstrated, with increasing melt flow index, i.e. with decreasing molecular weight, in vitro release is generally slowed down, with an increasing trend in the middle region of the time scale. Further, with increasing melt flow index, i.e. with decreasing molecular weight, the in vitro release profile is more steady (= less burst) and there is very little effect on alcoholic dose dumping resistance.

Claims

Patent claims:

1. An oral pharmaceutical dosage form comprising a multitude of particles, wherein the particles comprise

(b) an EVA copolymer having

(ii) a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 within the range of from 2 to 500 g/10 min; and wherein the weight content of the EVA copolymer is within the range of from 25 to 85 wt.-%, relative to the total weight of the particles; and

(c) an additional excipient; wherein the weight content of the additional excipient is within the range of from 8.0 to 30 wt.-%, relative to the total weight of the particles; and wherein the pharmacologically active ingredient is embedded in a prolonged release matrix comprising the EVA copolymer and the additional excipient.

2. The pharmaceutical dosage form according to claim 1, wherein the weight content of the pharmacologically active ingredient is at least 35 wt.-%, or at least 40 wt.-%, in each case relative to the total weight of the particles.

3. The pharmaceutical dosage form according to claim 1 or 2, which under physiological in vitro conditions has released

- after 30 minutes not more than 75 wt.-%;

- after 360 minutes at least 35 wt.-%; and

- after 720 minutes at least 60 wt.-% of the pharmacologically active ingredient that was originally contained in the pharmaceutical dosage form.

4. The pharmaceutical dosage form according to any of the preceding claims, wherein the EVA copolymer has a vinylacetate content

(ii) within the range of 28±5 wt.-%, or 28±3 wt.-%; or

(iii) of at least 34 wt.-%, or at least 36 wt.-%, or at least 38 wt.-%, or at least 40 wt.-%; in each case relative to the total weight of the EVA copolymer.

5. The pharmaceutical dosage form according to any of the preceding claims, wherein the EVA copolymer has a melt flow index at 190°C/2.16 kg measured according to ASTM D1238 of at least 100 g/10 min, or at least 150 g/10 min, or at least 200 g/10 min, or at least 250 g/10 min, or at least 300 g/10 min, or at least 350 g/10 min, or at least 400 g/10 min.

6. The pharmaceutical dosage form according to any of the preceding claims, wherein the weight content of the EVA copolymer is within the range of from 45±20 wt.-%, preferably 45±15 wt.-%, more preferably 45±10 wt. -%, in each case relative to the total weight of the particles.

7. The pharmaceutical dosage form according to any of the preceding claims, wherein the weight content of the EVA copolymer is within the range of from 55±20 wt.-%, preferably 55±15 wt.-%, more preferably 55±10 wt. -%, in each case relative to the total weight of the particles.

8. The pharmaceutical dosage form according to any of the preceding claims, wherein the weight content of the EVA copolymer is within the range of from 65±20 wt.-%, preferably 65±15 wt.-%, more preferably 65±10 wt. -%, in each case relative to the total weight of the particles.

9. The pharmaceutical dosage form according to any of the preceding claims, wherein the additional excipient is a polymer, preferably an ionic polymer, more preferably an ionic polymer, still more preferably an anionic polymer, yet more preferably an anionic polymer, most preferably an anionic polysaccharide.

10. The pharmaceutical dosage form according to any of the preceding claims, wherein the additional excipient is a hydrocolloid, preferably a hydrocolloid selected from the group consisting of agars, alginates, propylene glycol alginates (PGA), carrageenans, pectins, native starches, modified starches, furcellarans, larch gums, guar gums, locust bean gums, tara gums, tamarind seed gums, konjac gums, acacia gums, gums arabic, tragacanth, karaya gums, ghatti gums, xanthans, gellans, pullulans, dextrans, curdlans, scleroglu- cans, cellulose derivatives, and the physiologically acceptable salts thereof.

11. The pharmaceutical dosage form according to any of the preceding claims, wherein the additional excipient is selected from the group consisting of alginates, carboxymethyl starch, carboxymethyl cellulose, cross- linked carboxymethyl cellulose, hydroxypropylmethylcellulose acetate succinate, xanthans, polyacrylates, copolymers of acrylic acid, and the physiologically acceptable salts thereof.

12. The pharmaceutical dosage form according to any of the preceding claims, wherein the additional excipient is selected from the group consisting of hydroxypropylmethylcellulose acetate succinates, alginates, carboxymethyl starches and the physiologically acceptable salts thereof, croscarmelloses and the physiologically acceptable salts thereof, and xanthans.

13. The pharmaceutical dosage form according to any of the preceding claims, wherein the weight content of the additional excipient is within the range of from 12±4 wt.-%, preferably 12±3 wt.-%, in each case relative to the total weight of the particles.

14. The pharmaceutical dosage form according to any of the preceding claims, wherein the weight content of the additional excipient is within the range of from 18±4 wt.-%, preferably 18±3 wt.-%, in each case relative to the total weight of the particles.

15. The pharmaceutical dosage form according to any of the preceding claims, wherein the particles are pellets, preferably extruded pellets.