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US 2017007 1862A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0071862 A1 WENING et al. (43) Pub. Date: Mar. 16, 2017

(54) PROTECTING ORAL OVERDOSE WITH Publication Classification ABUSE DETERRENT IMMEDIATE RELEASE (51) Int. Cl. FORMULATIONS A69/20 (2006.01) A6II 3/167 (2006.01) (71) Applicant: GRÜNENTHAL GMBH, Aachen (DE) A63/37 (2006.01) (72) Inventors: KLAUS WENING, Koln (DE): A63L/485 (2006.01) Sebastian Schwier, Aachen (DE); (52) U.S. Cl. Ulrike Bertram, Aachen (DE) CPC ...... A61K 9/2022 (2013.01); A61K 31/485 (2013.01); A61K 31/167 (2013.01); A61 K (73) Assignee: GRUNENTHAL GMBH, Aachen (DE) 31/137 (2013.01) (57) ABSTRACT (21) Appl. No.: 15/260,643 The invention relates to a pharmaceutical dosage form which is particularly useful for the prevention of an over (22) Filed: Sep. 9, 2016 dose of the pharmacologically active ingredient contained therein after accidental or intentional simultaneous admin (30) Foreign Application Priority Data istration of a plurality of the dosage forms containing an overall Supratherapeutic dose of the pharmacologically Sep. 10, 2015 (EP) ...... 15184634 active ingredient. Patent Application Publication Mar. 16, 2017. Sheet 1 of 16 US 2017/0071862 A1 Ø · ???????-3x=?ö--

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x & 2 & 222222222 222222222222 222222 s.r.

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Patent Application Publication Mar. 16, 2017. Sheet 8 of 16 US 2017/0071862 A1

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FIG 10A

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FIG 10C

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FIG. 16A

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PROTECTING ORAL OVERDOSE WITH WO 2005/016314, WO 2005/063214, WO 2005/102286, ABUSE DETERRENT IMMEDIATE RELEASE WO 2006/002883, WO 2006/002884, WO 2006/002886, FORMULATIONS WO 2006/082097, WO 2006/082099, WO 2008/107149, 0001. This application claims priority of European patent WO 2009/092601, WO 2011/009603, WO 2011/009602, application no. 15 184634.2 that was filed on Sep. 10, 2015. WO 2009/135680, WO 2011/095314, WO 2012/028317, 0002 The invention relates to a pharmaceutical dosage WO 2012/028318, WO 2012/028319, WO 2011/009604, form which is particularly useful for the prevention of an WO 2013/017242, WO 2013/017234, WO 2013/050539, overdose of the pharmacologically active ingredient con WO 2013/127830, WO 2013/072395, WO 2013/127831, tained therein after accidental or intentional simultaneous WO 2013/156453, WO 2013/167735, WO 2015/004245, administration of a plurality of the dosage forms containing WO 2014/191396, and WO 2014/191397. an overall Supratherapeutic dose of the pharmacologically 0007 Still another concept to prevent abuse relies on the active ingredient. presence of auxiliary Substances that increase the Viscosity 0003) A large number of drugs have a potential for being of the resultant composition when the dosage forms are abused or misused, i.e. they can be used to produce effects tampered with, e.g. when they are subjected to liquids in which are not consistent with their intended use. Examples order to prepare formulations for parenteral administration, of commonly abused drugs include psychoactive drugs, e.g. intravenous injection. Said auxiliary Substances increase anxiolytics, sedative hypnotics, stimulants, depressants, and the viscosity of the resultant compositions to Such an extent such as narcotic analgesics, among others. In that the liquids cannot be drawn-up in Syringes. While it may particular, drugs which have a psychotropic effect, e.g. be possible to extract the drug from the dosage form at least , derivatives, barbiturates, amphetamines, to a certain extent, the extract is not useful for Subsequent , and other drugs, are abused to induce euphoric abuse. states similar to being intoxicated, and can cause psycho logical or physical dependence. 0008 WO 2015/103379 A1 discloses abuse-resistant, 0004 Some common techniques for intentionally abus immediate-release liquid pharmaceutical compositions com ing a drug begin with an abuser obtaining a solid dosage prising a mixture of an effective amount at least one phar form such as an orally administered tablet or capsule, and maceutically active agent Susceptible to abuse, an organic crushing the Solid dosage form into a powder. The powder vehicle, a surfactant, a co-solvent, and optionally a viscos may be administered by an abuser by nasal insufflation (i.e., ity-building polymer; wherein said organic vehicle, Surfac "snorting) to introduce the drug to the abuser's bloodstream tant, and co-solvent co-elute with the pharmaceutically intranasally. Alternately, the crushed dosage form may be active agent when exposed to a solvent, and wherein the combined with a solvent that is capable of dissolving the Viscosity-building polymer is present in an amount that drug, and the solvent with the dissolved drug may be slows the release of the pharmaceutically active agent if injected directly into an abuser's bloodstream. This type of multiple unit doses of the composition are administered. The administration results in an even faster diffusion of the drug compositions shall reduce the likelihood of improper admin compared to the oral abuse, with the result desired by the istration of drugs that are susceptible to abuse. The compo abuser, namely the kick. sitions contain abuse deterrent agents that cause discomfort 0005 Various concepts for the avoidance of drug abuse to the user when administered in an improper manner and have been developed. It has been proposed to incorporate in make the extraction of an active ingredient more difficult. dosage forms aversive agents and/or antagonists in a manner 0009. Alternatively, with immediate release oral dosage so that they only produce their aversive and/or antagonizing forms, an abuser might simply ingest multiple units (e.g., effects when the dosage forms are tampered with. However, tablets) of the dosage form together, e.g., simultaneously. the presence of Such aversive agents, e.g. bitter Substances, Each one of the multiple dosage form units—immediately irritants, colorants, emetics, and the like is principally not releases an amount of drug to produce a short-term concen desirable and there is a need to provide sufficient tamper tration spike of the drug in the user's bloodstream and a resistance without relying on aversive agents and/or antago desired “high’ in the user. nists. 0006 Another concept to prevent abuse relies on the (0010 WO 2008/107149 discloses a multiparticulate mechanical properties of the pharmaceutical dosage forms, pharmaceutical form with impeded abuse including at least particularly an increased breaking strength (resistance to one active ingredient with the potential for abuse (A), at crushing). The mechanical properties, particularly the high least one synthetic or natural polymer (C), optionally at least breaking strength of these pharmaceutical dosage forms one natural, semi-synthetic, or synthetic wax (D), at least renders them tamper-resistant. The major advantage of Such one disintegrant (E), and optionally one or more additional pharmaceutical dosage forms is that comminuting, particu physiologically tolerable excipients (B), wherein the indi larly pulverization, by conventional means, such as grinding vidual particles of the pharmaceutical form have a breaking in a mortar or fracturing by means of a hammer, is impos strength of at least 500 N and an active ingredient release of sible or at least substantially impeded. Thus, the pulveriza at least 75% after 45 minutes, measured according to Pharm. tion, necessary for abuse of the dosage forms, by the means Eur. in the paddle mixer with a sinker in a 600 ml aqueous that are usually available to a potential abuser is prevented buffer solution with a pH value of 1.2 at 37° C. and 75 or at least complicated. Such pharmaceutical dosage forms revolutions per minute. are useful for avoiding drug abuse of the drug contained O011 WO 2013/017242 and WO 2013/017234 relate to a therein, as they may not be powdered by conventional means tamper-resistant tablet comprising a matrix material in an and thus, cannot be administered in powdered form, e.g. amount of more than one third of the total weight of the nasally. In the context of such break resistant pharmaceutical tablet, and a plurality of particulates in an amount of less dosage forms it can be referred to, e.g., WO 2005/016313, than two thirds of the total weight of the tablet; wherein said US 2017/007 1862 A1 Mar. 16, 2017

particulates comprise a pharmacologically active compound simultaneous administration of a plurality of the dosage and a polyalkylene oxide; and form a discontinuous phase forms containing an overall Supratherapeutic dose of the within the matrix material. pharmacologically active ingredient a. 0012 US 2015 0118300 A1 discloses oral dosage forms (0019 Preferably, the overdose that is to be prevented is that contain abuse-deterrent features and that contain core the result of an accidental or intentional simultaneous oral shell polymers that include an active pharmaceutical ingre administration of a plurality of not-manipulated dosage dient, with particular examples including immediate release forms, i.e. the plurality of dosage forms is preferably intact dosage forms that contain a drug that is commonly suscep and with respect to an individual dosage form present in tible to abuse. prescribed form. Preferably, the only deviation from the 0013 US 2015 0118302 A1 and US 2015 0118303 A1 prescribed mode of administration and prescribed route of disclose immediate release oral dosage forms that contain administration is the number of the administered dosage abuse-deterrent features. In particular, the disclosed dosage forms, namely a plurality of the dosage forms containing an forms provide deterrence of abuse by ingestion of multiple overall Supratherapeutic dose of the pharmacologically individual doses. In addition, the disclosed dosage forms active ingredient a. provide protection from overdose in the event of accidental 0020. It has been surprisingly found that the dosage or intentional ingestion of multiple individual doses. The forms according to the invention provide deterrence against dosage forms have a relatively complex construction of a) abuse by multi-tablet dosing (multi-dosage-form-dosing). core-shell particles comprising: a core; an active pharma More specifically, in vitro testing of dosage forms was ceutical layer Surrounding the core; at least one layer Sur performed by conducting dissolution testing of one or more rounding the active pharmaceutical layer, the at least one dosage forms (tablets) in various volumes of 0.1N HCL layer comprising a pH-sensitive film comprising pH-sensi maintained at 37° C. using a 25 rpm and 50 rpm paddle tive polymer that is insoluble in water at a pH greater than speed. At 25 rpm the amount (percentage per tablet) of 5 and is soluble in water at a pH below 5; and b) a matrix pharmacologically active ingredient a () and pharma comprising a disintegrant and a gelling polymer. cologically active ingredient b (acetaminophen) released in 0014. The properties of conventional tamper-resistant the media is reduced with an increase in the number of dosage forms are not satisfactory in every respect. The tablets, whereas at 50 rpm this effect was less pronounced or requirements for tamper-resistant dosage forms that nowa could not be observed. The mixing conditions at 25 rpm are days need to be satisfied are complex and sometimes are still not comparable with the conditions in the gastrointes difficult to be combined and arranged with one another. tinal tract under in vivo conditions (J. L. Baxter et al., Int J While a certain measure may improve tamper-resistance in Pharm 292 (2005) 17-28; M. Koziolek et al., Eur J Pharm a certain aspect, the same measure may deteriorate tamper Sci 57 (2014) 250-256). Under in vivo conditions in the resistance in another aspect or otherwise may have a detri stomach pharmaceutical dosage forms are not subject to mental effect on the properties of the dosage forms. rotational movement but to compression forces. The data 0015. Although the pharmaceutical industry has identi Suggest that the dosage forms according to the invention are fied a variety of abuse deterrent features useful with oral effective to prevent increased levels of drug uptake in an dosage forms, there is continuing need to improve and individual who would accidentally or intentionally ingest identify new abuse deterrent features to inhibit or prevent abuse or overdosing of active pharmaceutical ingredients. multiple tablets, preventing or reducing the risk of an 0016. It is an object of the invention to provide pharma intentional or unintentional overdose of the drug. ceutical dosage forms having advantages compared to the 0021 Accordingly, the dosage forms according to the pharmaceutical dosage forms of the prior art. The pharma invention provide a method of preventing a short-term ceutical dosage forms should be particularly useful for concentration spike of the drug in the bloodstream of a avoiding or preventing of an overdose of the pharmacologi patient who is prescribed the drug, or in the bloodstream of cally active ingredient contained therein after accidental or an abuser who consumes the drug for recreational purposes, intentional simultaneous administration of a plurality of the in the event that a patient or the abuser intentionally or dosage forms containing an overall Supratherapeutic dose of unintentionally consumes a Supratherapeutic dose of the the pharmacologically active ingredient. drug. In addition, dosage forms as described herein provide 0017. This object has been achieved by the subject-matter a method whereby a drug overdose may be prevented in the of the patent claims. event that a patient intentionally or unintentionally con 0018. A first aspect of the invention relates to a pharma Sumes a Supratherapeutic dose of the drug. By "suprathera ceutical dosage form comprising a pharmacologically active peutic' is meant a dose that exceeds what would normally be ingredient a and a polymer matrix which comprises a prescribed for therapy, for example a dose in excess of four, polyalkylene oxide having an average molecular weight of five, six, seven, eight, nine, ten, eleven or twelve individual at least 200,000 g/mol; preferably of at least 500,000 g/mol; dose units (e.g., tablets, capsules, etc.). wherein preferably a single dosage form provides under 0022. Thus, the dosage formas according to the invention physiological conditions fast release, more preferably imme are useful for the prevention of an overdose of the pharma diate release of the pharmacologically active ingredient a: cologically active ingredient a after accidental or intentional and simultaneous preferably oral administration of a plurality of wherein at least a portion of the pharmacologically active the dosage forms containing an overall Supratherapeutic ingredient a is contained in one or more particles A which dose of the pharmacologically active ingredient a. comprise the polymer matrix in which the pharmacologi 0023. Unexpectedly, the advantages of the dosage form cally active ingredient a is embedded; according to the invention do not only affect the pharma for use in the prevention of an overdose of the pharmaco cologically active ingredient a that is embedded in the logically active ingredient a after accidental or intentional polyalkylene oxide in particle(s) A, but also the optionally US 2017/007 1862 A1 Mar. 16, 2017 present pharmacologically active ingredient b that may be concerning dosage, release profile, tamper-resistance, present elsewhere in the dosage form. patient compliance, ease of manufacture and the like. The 0024. It has been surprisingly found that these advantages dosage forms according to the invention can be prepared can be achieved by dosage forms that additionally are crush from a variety of components that are separately prepared. resistant, i.e. have an increased breaking strength, at least Specific selection of specific components from said variety with respect to particle(s) A comprising the pharmacologi of components allows for tailoring dosage forms satisfying cally active ingredient a. a large variety of different requirements. For example, it is 0025. Some tamper-resistant dosage forms of the prior art possible to make available a variety of three different types have also been used to avoid an overdose of the drug of particle(s) A that differ e.g. in their content of pharma contained therein. Said overdose, however, is not the result cologically active compound a. When manufacturing phar of a simultaneous administration of a plurality of the dosage maceutical dosage forms according to the invention having forms containing an overall Supratherapeutic dose of the a predetermined total dosage of pharmacologically active drug (multi-tablet dosing), but the result of an acceleration ingredient a, one may select different combinations of par of the release profile and/or the result of the change of the ticles A, A and A in order to achieve said total dosage of route of administration. When accelerating the release pro pharmacologically active ingredient a. For example, par file, e.g. by pulverizing a dosage form, and/or extracting a ticles A may contain a dosage of 0.25 mg, particles A may drug therefrom and administering the extract, the dose of the contain a dosage of 1.50 mg, and particles A may contain drug that was originally contained in the dosage form is a dosage of 3.50 mg. Such that a total dosage of e.g. 5.00 mg absorbed by the organism in a faster manner thereby leading pharmacologically active ingredient a can be achieved by to a transient increase of the plasma level. Once a certain 0029 20 particles A: plasma level has been exceeded, an euphoric state can be 0030) 2 particles A in combination with 3 particles A: achieved and this is usually desired by potential abusers. No 0031) 1 particle A in combination with 1 particle A: plurality of dosage forms is needed in order to achieve Such O overdose, as a single dosage form already contains a Sufi 0.032 6 particles A in combination with 1 particle A. cient dose of the drug that—once absorbed in a sufficiently 0033. Another advantage of the concept underlying the fast manner reaches excessive plasma levels. This type of dosage forms according to the invention is that nearly every overdose, i.e. this excessive plasma level, is conventionally combination may be either filled into capsules or may be prevented by providing dosage forms having an increased compressed into tablets. This flexibility has particular breaking strength such that they cannot be easily pulverized. advantages when providing tamper-resistant products that Therefore, the type of overdose that is to be conventionally need to satisfy the confidence requirements with respect to prevented substantially differs from the type of overdose that the marketing authorization for the initial non-tamper-resis is to be prevented according to the invention. tant product. Thus, the present invention makes available at 0026. The dosage forms according to the invention can be a high degree of flexibility tamper-resistant counterparts to preferably formulated to provide an immediate release pro existent non-tamper-resistant products. If in initial tests the file of the pharmacologically active ingredient a as well as confidence intervals are not met, the present invention of the optionally present pharmacologically active ingredi provides easy and predictable measures for slightly altering ent b, and can also be prepared to include effective or the properties of the dosage form in order to meet the advantageous abuse deterrent features that are effective to confidence requirements. deter abuse of the same (e.g., one that is commonly suscep tible to abuse) that exhibits the immediate release profile. 0034 FIG. 1 illustrates the preferred behavior of the Thus, the dosage forms according to the invention combine particle(s) contained in the dosage form according to the immediate release with broad abuse resistance for multiple invention when being Subjected to a breaking strength test, abuse modalities including multi-tablet dosing. The dosage in particular their deformability. forms according to the invention can provide an immediate 0035 FIG. 2 illustrates the behavior of conventional release profile, and can at the same time include abuse particle(s) when being Subjected to a breaking strength test. deterrent features that provide general abuse deterrence or 0036 FIGS. 3 and 4 show the release profiles of exem abuse resistance. plified dosage according to the invention that comprise two 0027. The dosage forms can also be more specifically pharmacologically active ingredients, namely characterized as resistant to certain common methods of and acetaminophen. abuse, Such as 1) abuse by injection, 2) abuse by nasal 0037 FIG. 3 shows the in vitro release profiles of exem insufflation, and 3) abuse by multi-tablet dosing by oral plified dosage forms with respect to the release of hydro consumption, meaning simultaneous oral ingestion of mul codone (pharmacologically active ingredienta) when testing tiple or excessive quantities of orally administered dosage a single dosage form, a multitude of 5 dosage forms and a forms such as tablets or capsules. The third mode of abuse, multitude of 10 dosage forms expressed in mg of hydroco multi-tablet dosing, is particularly common with immediate done release per tablet. release dosage forms and is particularly difficult to defend 0038 FIG. 4 shows the in vitro release profiles of exem against by design of a dosage form structure or by formu plified dosage forms with respect to the release of acet lation. Accordingly, that the dosage forms according to the aminophen (pharmacologically active ingredient b) when invention can be effective to prevent or deter abuse (or even testing a single dosage form, a multitude of 5 dosage forms accidental overdose) by the mode of multi-tablet dosing is a and a multitude of 10 dosage forms expressed in mg of particularly useful feature of the dosage forms according to hydrocodone release per tablet. the invention. 0039 FIGS. 5 and 6 illustrate preferred embodiments of 0028. The concept underlying the dosage forms accord pharmaceutical dosage forms according to the invention that ing to the invention provides a high degree in flexibility comprise two pharmacologically active ingredients a and b. US 2017/007 1862 A1 Mar. 16, 2017

0040 FIG. 5 illustrates preferred embodiments of phar practices and processes. The objective in Such deterrence maceutical dosage forms according to the invention. FIG. includes both making abuse practices significantly more 5A illustrates a capsule comprising a multitude of particles difficult to carry out, and making any product resulting from A (1) and pharmacologically active ingredient b that is an attempt to carry out Such abuse practices on the dosage contained outside the particles A in an outer matrix material, forms significantly less desirable, less profitable, and less here shown in form of granules (2). Particles A (1) may abusable to the potential abuser. additionally comprise a portion b of pharmacologically 0055 Preferably, the dosage form according to the inven active ingredient b and/or a coating comprising a portion be tion is a capsule or a tablet. of pharmacologically active ingredient b. The capsule 0056. In a preferred embodiment, when the dosage form according to FIG. 5B additionally comprises a portion be of is a capsule, it is preferably a sprinkle capsule or a multitude pharmacologically active ingredient b contained in particles of sprinkle capsules. The capsule may comprise the particles B (3), whereas the capsule according to FIG.5C additionally and all excipients in form of a loose filling, i.e. an homo comprises a portion be of pharmacologically active ingre geneous mixture, or in form of layers (layered capsule dient b in form of a powder (4); thus, according to this filling). embodiment, the outer matrix material comprises granules 0057. In another preferred embodiment, when the dosage (2) as well as powder (4). form is a tablet, the tablet may comprise the particle(s) A in 0041 FIG. 6 illustrates the corresponding preferred an outer matrix material with homogeneous distribution or embodiments of FIG. 5 where the dosage form is provided in form of a mantle tablet. as a tablet comprising an outer matrix material (5) in which 0058. The dosage from comprises particle(s) of a first particles A (1), the optionally present granules (2), the type, referred to as “particles(s) A' and optionally additional optionally present particles B (3) and/or the optionally particle(s) of a second type, referred to as “particle(s) B'. present powder are embedded. It is also possible that said The particle(s) A, the optionally present particle(s) B, and/or outer matrix material (5) consists of granules (2), and the the dosage form as such may be film-coated. optionally present particles B (3) and/or the optionally 0059. The dosage form according to the invention com present powder. prises one or more particles A and optionally, additionally 0042 FIG. 7 schematically illustrates the TIMagc system one or more particles B. In the following, it is referred to that was used in Examples 2 and 3 (Inventive vs. Compara “particles(s) A' and “particle(s) B in order to express that tive). the number of particles in each case may be independently 0043 FIG. 8 illustrates a comparison of the fasted state one or more. When it is referred to “particle(s), the respec experiments according to Example 2 for hydrocodone. tive embodiment independently applies to both, to particle 0044 FIG. 9 illustrates a comparison of the fed state (S) A and to optionally present particle(s) B. experiments according to Example 2 for hydrocodone. 0060. The dosage form according to the invention may be 004.5 FIGS. 10A, 10B and 10C illustrate a comparison of compressed or molded in its manufacture, and it may be of fasted versus fed state experiments for hydrocodone accord almost any size, shape, weight, and color. Most dosage ing to Example 2. forms are intended to be swallowed as a whole and accord 0046 FIG. 11 illustrates a comparison of the fasted state ingly, preferred dosage forms according to the invention are experiments according to Example 2 for acetaminophen. designed for oral administration. However, alternatively 0047 FIG. 12 illustrates a comparison of the fed state dosage forms may be dissolved in the mouth, chewed, or experiments according to Example 2 for acetaminophen. dissolved or dispersed in liquid or meal before Swallowing, 0048 FIGS. 13A, 13B and 13C illustrate a comparison of and some may be placed in a body cavity. Thus, the dosage fasted versus fed State experiments for acetaminophen form according to the invention may alternatively be according to Example 2. adapted for buccal, lingual, rectal or vaginal administration. 0049 FIG. 14 illustrates a comparison of fasted state Implants are also possible. experiments for amphetamine (capsules and tablets) accord 0061. In a preferred embodiment, the dosage form ing to Example 3. according to the invention preferably can be regarded as a 0050 FIG. 15 illustrates a comparison offed state experi MUPS formulation (multiple unit pellet system). In a pre ments for amphetamine (capsules and tablets) according to ferred embodiment, the dosage form according to the inven Example 3. tion is monolithic. In another preferred embodiment, the 0051 FIGS. 16A, 16B and 16C illustrate a comparison of dosage form according to the invention is not monolithic. In fasted versus fed State experiments for amphetamine (cap this regard, monolithic preferably means that the dosage Sules and tablets) according to Example 3. form is formed or composed of material without joints or 0052 FIG. 17 illustrates a comparison of fasted state seams or consists of or constitutes a single unit. experiments for amphetamine (pellets) according to 0062. In a preferred embodiment, the dosage form Example 3. according to the invention contains all ingredients in a dense 0053 As used herein, the term “pharmaceutical dosage compact unit which in comparison to capsules has a com form' or “dosage form” refers to a pharmaceutical entity paratively high density. In another preferred embodiment, comprising a pharmacologically active ingredient a which is the dosage form according to the invention contains all actually administered to, or taken by, a patient, preferably ingredients in a capsule which in comparison to dense orally. compact unit has a comparatively low density. 0054 As used herein, expressions such as “tamper resis 0063. An advantage of the dosage forms according to the tant”, “abuse deterrent”, “preventing”, “avoiding”, “deter invention is that upon manufacture the particle(s) A may be ring or “inhibiting associated with the abuse and overdose mixed with excipients in different amounts to thereby pro of drugs, relate to features of the dosage forms that provide duce dosage forms of different strengths. Another advantage significant physical and chemical impediments to these of the dosage forms according to the invention is that upon US 2017/007 1862 A1 Mar. 16, 2017 manufacture the different particle(s) A, i.e. particles A logically active ingredient a, optionally besides pharmaco having a different constitution, may be mixed with one logically active ingredient b. In another preferred embodi another to thereby produce dosage forms of different prop ment, the particle(s) A and the dosage form, respectively, erties, e.g. different release rates, different pharmacologi contain a combination of two or more pharmacologically cally active ingredients a, and the like. active ingredient a, optionally besides pharmacologically 0064. The dosage form according to the invention has active ingredient b. preferably a total weight in the range of 0.01 to 1.5 g. more 0074 Preferably, pharmacologically active ingredient a preferably in the range of 0.05 to 1.2g, still more preferably is an active ingredient with potential for being abused. in the range of 0.1 g to 1.0 g, yet more preferably in the range Active ingredients with potential for being abused are of 0.2 g to 0.9 g, and most preferably in the range of 0.3 g known to the person skilled in the art and comprise e.g. to 0.8 g. tranquilizers, stimulants, barbiturates, narcotics, opioids or 0065. In a preferred embodiment, the dosage form opioid derivatives. according to the invention is not film coated. 0075 Preferably, the pharmacologically active ingredient 0066. In another preferred embodiment, the dosage form a exhibits psychotropic action, i.e. has a psychotropic effect. according to the invention is provided, partially or com 0076 Preferably, the pharmacologically active ingredient pletely, with a conventional coating. The dosage forms a is selected from the group consisting of , opioids, according to the invention are preferably film coated with stimulants, tranquilizers, and other narcotics. conventional film coating compositions. Suitable coating 0077. In a preferred embodiment, the pharmacologically materials are commercially available, e.g. under the trade active ingredienta is an opioid. According to the ATC index, marks Opadry(R, Opaglos(R) and Eudragit(R). opioids are divided into natural alkaloids, phenylpi 0067. The coating can be resistant to gastric juices and peridine derivatives, diphenylpropylamine derivatives, ben dissolve as a function of the pH value of the release Zomorphan derivatives, derivatives, morphinan environment. By means of this coating, it is possible to derivatives and others. ensure that the dosage form according to the invention 0078. In another preferred embodiment, the pharmaco passes through the stomach undissolved and the active logically active ingredient a is a stimulant. Stimulants are compound is only released in the intestines. The coating psychoactive drugs that induce temporary improvements in which is resistant to gastric juices preferably dissolves at a either mental or physical functions or both. Examples of pH value of between 5 and 7.5. these kinds of effects may include enhanced wakefulness, 0068. The subjects to which the dosage forms according locomotion, and alertness. Preferred stimulants are phenyl to the invention can be administered are not particularly ethylamine derivatives. According to the ATC index, stimu limited. Preferably, the subjects are animals, more prefer lants are contained in different classes and groups, e.g. ably human beings. psychoanaleptics, especially psychoStimulants, agents used 0069. The tamper-resistant dosage form according to the for ADHD and nootropics, particularly centrally acting invention comprises particle(s) A which comprise the phar sympathomimetics; and e.g. nasal preparations, especially macologically active ingredient a. Preferably, the particle(s) nasal decongestants for systemic use, particularly sympath A contain the total amount of pharmacologically active omimetics. ingredient a that is contained in the dosage form according 007.9 The following opiates, opioids, stimulants, tran to the invention, i.e. the dosage form according to the quilizers or other narcotics are Substances with a psycho invention preferably does not contain pharmacologically tropic action, i.e. have a potential of abuse, and hence are active ingredient a outside particle(s) A. preferably contained in the dosage form and the particle(s) 0070 The particle(s) A contain at least a pharmacologi A, respectively: , allobarbital, allylprodine, alp cally active ingredient a and a polymer matrix that prefer haprodine, alprazolam, amfepramone, amphetamine, ably comprises a polyalkylene oxide. Preferably, however, amphetaminil, amobarbital, anilleridine, apocodeine, axom the particle(s) A contain additional pharmaceutical excipi adol, barbital, bemidone, , , bro ents such as disintegrants, antioxidants and plasticizers. mazepam, brotizolam, , butobarbital, butor 0071. The pharmacologically active ingredient a is phanol, camazepam, , cathine/D- embedded, preferably dispersed in a polymer matrix pref norpseudoephedrine, , chlordiazepoxide, erably comprising a polyalkylene oxide. Preferably, the clobazam clofedanol, clonazepam, clonitaZene, cloraZepate, pharmacologically active ingredient a and the polyalkylene clotiazepam, cloxazolam, , , cyclobarbital, oxide are homogeneously distributed in the core of particle , , delorazepam, , (s) A. Thus, the pharmacologically active ingredient a and dex-amphetamine, , , the polyalkylene oxide are preferably homogeneously , diampromide, diamorphone, diazepam, dihydro admixed with one another. Thus, the particle(s) Aaccording codeine, , dihydromorphone, dimenox to the invention are preferably not multilayered, but are adol, dimephetamol, dimethylthiambutene, dioxaphetylbu preferably composed of a homogeneous core comprising the tyrate, , dronabinol, , estaZolam, pharmacologically active ingredient a and the polyalkylene , ethylmethylthiambutene, ethyl loflazepate, oxide, which homogenous core may optionally be coated , etonitaZene, , faxeladol, fencam with a film coating material that neither is pH sensitive nor famine, fenethylline, fenpipramide, fenproporex, . contains the pharmacologically active ingredient a or the fludiazepam, flunitrazepam, flurazepam, halazepam, halox polyalkylene oxide. aZolam, , hydrocodone, , hydroxy 0072 The pharmacologically active ingredient a is not , , hydroxymethylmorphinan, keta particularly limited. Zolam, , (LAAM), 0073. In a preferred embodiment, the particle(s) A and the levomethadone, , levophenacylmorphane, dosage form, respectively, contain only a single pharmaco levoXemacin, lisdexamfetamine dimeSylate, , US 2017/007 1862 A1 Mar. 16, 2017 loprazolam, lorazepam, lormetazepam, mazindol, medaze hydromorphone, morphine, , , cebrano pam, mefenorex, meperidine, meprobamate, metapon, padol and the physiologically acceptable salts thereof. , , methylmorphine, metamphet I0082 In another preferred embodiment, the pharmaco amine, , methaqualone, 3-methylfentanyl. logically active ingredient a is a stimulant selected from the 4-methylfentanyl, methylphenidate, methylphenobarbital, group consisting of amphetamine, dex-amphetamine, dex methyprylon, , midazolam, modafinil, morphine, methylphenidate, atomoxetine, caffeine, ephedrine, phenyl myrophine, , nalbuphene, , narceline, propanolamine, phenylephrine, fencamphamin, fenozolone, , nimetazepam, nitrazepam, nordazepam, nor fenetyline, methylenedioxymethamphetamine (MDMA), levorphanol, normethadone, normorphine, , methylenedioxypyrovalerone (MDPV), prolintane, lisdex opium, oxazepam, oxazolam, oxyco done, , amfetamine, mephedrone, methamphetamine, methylpheni , papaveretum, pemoline, , date, modafinil, nicotine, pemoline, phenylpropanolamine, pentobarbital, pethidine, , phenomorphane, propylhexedrine, dimethylamylamine, and pseudoephed , , , pholcodeine, phenmetrazine, phenobarbital, phentermine, pinazepam, 1. pipradrol, , prazepam, , , I0083. The pharmacologically active ingredient a may be promedol, properidine, propoxyphene, pseudoephedrine, present in form of a physiologically acceptable salt, e.g. , secbutabarbital, secobarbital, , physiologically acceptable acid addition salt. tapentadol, temazepam, tetrazepam, (cis and trans), I0084 Physiologically acceptable acid addition salts com tramadol, triazolam, vinylbital, N-(1-methyl-2-piperidino prise the acid addition salt forms which can conveniently be ethyl)-N-(2-pyridyl)propionamide, (1R,2R)-3-(3-dimethyl obtained by treating the base form of the active ingredient amino-1-ethyl-2-methyl-propyl)phenol, (1R,2R,4S)-2-(dim with appropriate organic and inorganic acids. Active ingre ethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m- dients containing an acidic proton may be converted into methoxyphenyl)cyclo-hexanol, (1R,2R)-3-(2- their non-toxic metal or amine addition salt forms by treat dimethylaminomethyl-cyclohexyl)phenol, (1S,2S)-3-(3- ment with appropriate organic and inorganic bases. The term dimethylamino-1-ethyl-2-methyl-propyl)phenol. (2R,3R)- addition salt also comprises the hydrates and solvent addi 1-dimethyl amino-3(3-methoxyphenyl)-2-methyl-pentan-3- tion forms which the active ingredients are able to form. ol, (1RS,3RS,6RS)-6-dimethyl amino methyl-1-(3- Examples of Such forms are e.g. hydrates, alcoholates and methoxyphenyl)-cyclohexane-1,3-diol, preferably as the like. racemate, 3-(2-dimethyl amino methyl-1-hydroxy-cyclo hexyl)phenyl 2-(4-isobutyl-phenyl)propionate, 3-(2-dim I0085. The pharmacologically active ingredient a is pres ethyl amino methyl-1-hydroxy-cyclohexyl)phenyl 2-(6- ent in the dosage form in a therapeutically effective amount. methoxy-naphthalen-2-yl)propionate, 3-(2- The amount that constitutes a therapeutically effective dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(4- amount varies according to the active ingredients being isobutyl-phenyl)propionate, 3-(2-dimethylaminomethyl used, the condition being treated, the severity of said con cyclohex-1-enyl)-phenyl 2-(6-methoxy-naphthalen-2-yl) dition, the patient being treated, and the frequency of propionate, (RR-SS)-2-acetoxy-4-trifluoromethyl-benzoic administration. acid 3-(2-dimethyl amino methyl-1-hydroxy-cyclohexyl)- I0086. The content of the pharmacologically active ingre phenyl ester, (RR-SS)-2-hydroxy-4-trifluoromethyl-benzoic dient a in the dosage form is not limited. The dose of the acid 3-(2-dimethyl amino methyl-1-hydroxy-cyclohexyl)- pharmacologically active ingredient a which is adapted for phenyl ester, (RR-SS)-4-chloro-2-hydroxy-benzoic acid administration preferably is in the range of 0.1 mg to 500 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl mg, more preferably in the range of 1.0 mg to 400 mg, even ester, (RR-SS)-2-hydroxy-4-methyl-benzoic acid 3-(2-dim more preferably in the range of 5.0 mg to 300 mg, and most ethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, preferably in the range of 10 mg to 250 mg. In a preferred (RR-SS)-2-hydroxy-4-methoxy-benzoic acid 3-(2-dimethyl embodiment, the total amount of the pharmacologically aminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR active ingredient a that is contained in the dosage form is SS)-2-hydroxy-5-nitro-benzoic acid 3-(2-dimethylaminom within the range of from 0.01 to 200 mg, more preferably 0.1 ethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2',4'- to 190 mg, still more preferably 1.0 to 180 mg, yet more difluoro-3-hydroxy-biphenyl-4-carboxylic acid 3-(2- preferably 1.5 to 160 mg, most preferably 2.0 to 100 mg and dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, in particular 2.5 to 80 mg. and corresponding Stereoisomeric compounds, in each case I0087. The skilled person may readily determine an appro the corresponding derivatives thereof, physiologically priate amount of pharmacologically active ingredient a to acceptable enantiomers, Stereoisomers, diastereomers and include in a dosage form. For instance, in the case of racemates and the physiologically acceptable derivatives analgesics, the total amount of pharmacologically active thereof, e.g. ethers, esters or amides, and in each case the ingredient a present in the dosage form is that sufficient to physiologically acceptable compounds thereof, in particular provide analgesia. The total amount of pharmacologically the acid or base addition salts thereof and Solvates, e.g. active ingredient a administered to a patient in a dose will hydrochlorides. vary depending on numerous factors including the nature of 0080. In a preferred embodiment, the pharmacologically the pharmacologically active ingredient a, the weight of the active ingredient a is selected from the group consisting of patient, the severity of the pain, the nature of other thera DPI-125, M6G (CE-04-410), ADL-5859, CR-665, NRP290 peutic agents being administered etc. and sebacoyl dinalbuphine ester. I0088. In a particularly preferred embodiment, the phar 0081. In a preferred embodiment, the pharmacologically macologically active ingredient a is tapentadol, preferably active ingredient a is an opioid selected from the group its HCl salt, and the dosage form is adapted for administra consisting of , hydrocodone, oxymorphone, tion once daily, twice daily, thrice daily or more frequently. US 2017/007 1862 A1 Mar. 16, 2017

In this embodiment, pharmacologically active ingredienta is preferably at most 50 wt.-%, based on the total weight of the preferably contained in the dosage form in an amount of dosage form and/or based on the total weight of the particle from 25 to 100 mg. (s) A. 0089. In a particularly preferred embodiment, the phar 0096. In another preferred embodiment, the content of macologically active ingredient a is oxymorphone, prefer the pharmacologically active ingredient a is at most 20 ably its HCl salt, and the dosage form is adapted for wt.-%, more preferably at most 17.5 wt.-%, still more administration once daily, twice daily, thrice daily or more preferably at most 15 wt.-%, yet more preferably at most frequently. In this embodiment, the pharmacologically 12.5 wt.-%, most preferably at most 10 wt.-%, based on the active ingredient a is preferably contained in the dosage total weight of the dosage form and/or based on the total form in an amount of from 5 to 40 mg. In another particu weight of the particle(s) A. larly preferred embodiment, the pharmacologically active 0097. Preferably, the content of the pharmacologically ingredient a is oxymorphone, preferably its HCl salt, and the active ingredient a is within the range of from 0.01 to 80 dosage form is adapted for administration once daily. In this wt.-%, more preferably 0.1 to 50 wt.-%, still more preferably embodiment, the pharmacologically active ingredient a is 1 to 25 wt.-%, based on the total weight of the dosage form preferably contained in the dosage form in an amount of and/or based on the total weight of the particle(s) A. from 10 to 80 mg. 0098. The particle(s) A present in the dosage forms 0090. In another particularly preferred embodiment, the according to the invention preferably comprise 1 to 75 wt.-% pharmacologically active ingredient a is oxycodone, prefer of pharmacologically active ingredient a, more preferably 2 ably its HCl salt, and the dosage form is adapted for to 70 wt.-% of pharmacologically active ingredient a, still administration once daily, twice daily, thrice daily or more more preferably 3 to 65 wt.-% of pharmacologically active frequently. In this embodiment, the pharmacologically ingredient a, based on the total weight of the dosage form active ingredient a is preferably contained in the dosage and/or based on the total weight of the particle(s) A. form in an amount of from 5 to 80 mg. Oxycodone, 0099. A skilled person knows how to determine pharma preferably its HCl salt, is preferably combined with acet cokinetic parameters Such as ta. T. C., AUC and aminophen as optionally present pharmacologically active bioavailability. For the purposes of the description, the ingredient b. pharmacokinetic parameters, which may be determined 0091. In still another particularly preferred embodiment, from the blood plasma concentrations of 3-(2-dimethylam the pharmacologically active ingredient a is hydromor inomethylcyclohexyl)phenol, are defined as follows: phone, preferably its HCl, and the dosage form is adapted for administration once daily, twice daily, thrice daily or more C. maximum measured plasma concentration of the active ingredient frequently. In this embodiment, the pharmacologically after single administration (Eaverage peak plasma level) active ingredient a is preferably contained in the dosage t interval of time from administration of the active ingredient until form in an amount of from 2 to 52 mg. In another particu C, is reached larly preferred embodiment, the pharmacologically active AUC total area of the plasma concentration time curve including the ingredient a is hydromorphone, preferably its HCl, and the Subarea from the final measured value extrapolated to infinity dosage form is adapted for administration once daily, twice t12 half-life daily, thrice daily or more frequently. In this embodiment, the pharmacologically active ingredient a is preferably con 0100. The above parameters are in each case stated as tained in the dosage form in an amount of from 4 to 104 mg. mean values of the individual values for all investigated 0092. In yet another particularly preferred embodiment, patients/test Subjects. the pharmacologically active ingredient a is hydrocodone, 0101 A person skilled in the art knows how the pharma preferably its bitartrate salt, and the dosage form is adapted cokinetic parameters of the active ingredient may be calcu for administration once daily, twice daily, thrice daily or lated from the measured concentrations of the active ingre more frequently. In this embodiment, the pharmacologically dient in the blood plasma. In this connection, reference may active ingredient a is preferably contained in the dosage be made, for example, to Willi Cawello (ed.) Parameters for form in an amount of from 2.5 to 10 mg. Hydrocodone, Compartment-free Pharmacokinetics, Shaker Verlag Aachen preferably its bitartrate salt, is preferably combined with (1999). acetaminophen as optionally present pharmacologically 0102. In a preferred embodiment, the pharmacologically active ingredient b. active ingredient a is tapentadol or a physiologically accept able salt thereof, e.g. the hydrochloride. Preferably, the 0093 Preferably, the content of the pharmacologically dosage form according to the invention provides a mean active ingredient a is at least 0.5 wt.-%, based on the total absolute bioavailability of tapentadol of at least 22%, more weight of the dosage form and/or based on the total weight preferably at least 24%, still more preferably at least 26%, of the particle(s) A. yet more preferably at least 28%, most preferably at least 0094 Preferably, the content of the pharmacologically 30%, and in particular at least 32%. T. of tapentadol is active ingredient a is at least 2.5 wt.-%, more preferably at preferably within the range of 1.25+1.20 h, more preferably least 3.0 wt.-%, still more preferably at least 3.5 wt.-%, yet 1.25+1.00 h, still more preferably 1.25+0.80 h, yet more more preferably at least 4.0 wt.-%, most preferably at least preferably 1.25+0.60h, most preferably 1.25+0.40 h, and in 4.5 wt.-%, based on the total weight of the dosage form particular 1.25+0.20 h. t of tapentadol is preferably within and/or based on the total weight of the particle(s) A. the range of 4.0+2.8 h, more preferably 4.0+2.4 h, still more 0095. In a preferred embodiment, the content of the preferably 4.0+2.0 h, yet more preferably 4.0-1.6 h, most pharmacologically active ingredient a is at most 70 wt.-%, preferably 4.0-1.2 h, and in particular 4.0+0.8 h. Preferably, more preferably at most 65 wt.-%, still more preferably at when normalized to a dose of 100 mg tapentadol, C of most 60 wt.-%, yet more preferably at most 55 wt.-%, most tapentadol is preferably within the range of 90-85 ng/mL, US 2017/007 1862 A1 Mar. 16, 2017 more preferably 90+75 ng/mL, still more preferably 90+65 0106. In still another preferred embodiment, the pharma ng/mL, yet more preferably 90+55 ng/mL, most preferably cologically active ingredient a is amphetamine or a physi 90+45 ng/mL, and in particular 90+35 ng/mL; and/or AUC ologically acceptable salt thereof. T of amphetamine is of tapentadol is preferably within the range of 420+400 preferably within the range of 1.7+1.2 h, more preferably ng/mLh, more preferably 420+350 ng/mLh, still more 1.7+1.0 h, still more preferably 1.7+0.8 h, yet more prefer preferably 420+300 ng/mLh, yet more preferably 420+250 ably 1.7+0.6 h, most preferably 1.7+0.4 h, and in particular ng/mLh, most preferably 420+200 ng/mL h, and in particu 1.7.0.2 h. lar 420+150 ng/mL. h. 0107. In still another preferred embodiment, the pharma cologically active ingredient a is dex-amphetamine or a 0103) In another preferred embodiment, the pharmaco logically active ingredient a is oxycodone or a physiologi physiologically acceptable salt thereof, e.g. the Sulfate. T cally acceptable salt thereof, e.g. the hydrochloride. Prefer of dex-amphetamine is preferably within the range of ably, the dosage form according to the invention provides a 3.0+2.9 h, more preferably 3.0+2.5 h, still more preferably mean absolute bioavailability of oxycodone of at least 40%, 3.0+2.1 h, yet more preferably 3.0+1.7 h, most preferably more preferably at least 45%, still more preferably at least 3.0+1.3 h., and in particular 3.0+0.9 h. t of dex-amphet 50%, yet more preferably at least 55%, most preferably at amine is preferably within the range of 10+6.0 h, more least 60%, and in particular at least 70%. T. of oxycodone preferably 10+5.0h, still more preferably 10+4.0h, yet more is preferably within the range of 2.6+2.5 h, more preferably preferably 10+3.0 h, most preferably 10+2.0 h, and in 2.6+2.0 h, still more preferably 2.6+ 1.8 h, yet more prefer particular 10+1.0 h. ably 2.6+0.1.6 h, most preferably 2.6+1.4h, and in particular 0108. In a preferred embodiment, the pharmaceutical 2.6t1.2 h. t of oxycodone is preferably within the range of dosage form additionally contains a second pharmacologi 3.8+3.5 h, more preferably 3.8+3.0 h, still more preferably cally active ingredient (pharmacologically active ingredient 3.8-2.5 h, yet more preferably 3.8+2.0 h, most preferably b). 3.8+1.5 h, and in particular 3.8+1.0 h. Preferably, when 0109 The optionally present pharmacologically active normalized to a dose of 30 mg oxycodone, C of oxyco ingredient b is not particularly limited. The optionally pres done is preferably within the range of 40+35 ng/mL, more ent pharmacologically active ingredient b differs from the preferably 40+30 ng/mL, still more preferably 40+25 pharmacologically active ingredient a. ng/mL, yet more preferably 40+20 ng/mL, most preferably 0110. In a preferred embodiment, the optionally present 40+15 ng/mL, and in particular 40+10 ng/mL, and/or AUC pharmacologically active ingredient b exhibits no psycho of oxycodone is preferably within the range of 270+250 tropic action. ng/mLh, more preferably 270-200 ng/mLh, still more 0111. In another preferred embodiment, the optionally preferably 270+150 ng/mLh, yet more preferably 270+100 present pharmacologically active ingredient b is selected ng/mLh, most preferably 270-75 ng/mL h, and in particular from ATC classes M01A, MO1C, NO2B and NO2C 270+50 ng/mL. h. according to the WHO. 0112. In a particularly preferred embodiment, 0104. In still another preferred embodiment, the pharma 0113 (i) the pharmacologically active ingredient a has cologically active ingredient a is hydrocodone or a physi a psychotropic effect; and/or ologically acceptable salt thereof, e.g. the bitartrate. T of 0114 (ii) the optionally present pharmacologically hydrocodone is preferably within the range of 1.3-1.2 h, active ingredient b is selected from ATC classes more preferably 1.3+1.0 h, still more preferably 1.3+0.8 h, M01A), M01C, NO2B and NO2C) according to the yet more preferably 1.3+0.6 h, most preferably 1.3+0.4 h. WHO. and in particular 1.3-0.2 h. t of hydrocodone is preferably 0115 Preferably, the optionally present pharmacologi within the range of 3.8+3.5 h, more preferably 3.8-3.0 h. cally active ingredient b is selected from the group consist still more preferably 3.8-2.5 h, yet more preferably 3.8+2.0 ing of acetylsalicylic acid, , choline Salicylate, h, most preferably 3.8-1.5 h, and in particular 3.8+1.0 h. , , , , 0105. In yet another preferred embodiment, the pharma morpholine salicylate, , , , cologically active ingredient a is morphine or a physiologi potassium salicylate, guacetisal, , imida cally acceptable salt thereof, e.g. the sulfate. Preferably, the Zole salicylate, , sodium, amino dosage form according to the invention provides a mean phenaZone, , , acetaminophen absolute bioavailability of morphine of at least 15%, more (), , , , rimaZo preferably at least 20%, still more preferably at least 25%, lium, , , , , , yet more preferably at least 30%, most preferably at least , , , dihydroergot 35%, and in particular at least 40%. T. of morphine is amine, ergotamine, methysergide, lisuride, flumedroxone, preferably within the range of 0.625+0.60h, more preferably Sumatriptan, naratriptan, Zolmitriptan, rizatriptan, almotrip 0.625+0.50 h, still more preferably 0.625+0.40 h, yet more tan, eletriptan, froVatriptan, pizotifen, , ipra preferably 0.625+0.30h, most preferably 0.625+0.20 h, and Zochrome, dimetotiazine, oxetorone, , in particular 0.625+0.15 h. Preferably, when normalized to , , , , a dose of 30 mg morphine Sulfate, C of morphine is indomethacin, , , , , preferably within the range of 25+20 ng/mL, more prefer , , , , , ably 25+15 ng/mL, still more preferably 25+10 ng/mL, yet , , , , more preferably 25+5 ng/mL, and/or AUC of morphine is , , , , , preferably within the range of 50+45 ng/mLh, more pref , , , , , erably 50+40 ng/mLh, still more preferably 50+35 ng/mLh, , , , , , yet more preferably 50+30 ng/mLh, most preferably 50+25 , , , , oxapro ng/mLh, and in particular 50+20 ng/mLh. Zin, , , , , US 2017/007 1862 A1 Mar. 16, 2017 , , , tolfenamic erably contained in the particle(s) B or the dosage form in an acid, , , , rofe amount of from 100 to 600 mg, more preferably 150 to 550 coxib, , , , , nabu mg, still more preferably 200 to 500 mg, most preferably metone, , , , benzy 250 to 450 mg and in particular 275 to 400 mg. damine, glucosaminoglycan polysulfate, produaZone, I0123. In another particularly preferred embodiment, the orgotein, , , , , optionally present pharmacologically active ingredient b is , , , oxycinchophen, ibuprofen. In this embodiment, the ibuprofen is preferably Sodium aurothiomalate, sodium aurotiosulfate, auranofin, contained in the particle(s) B or the dosage form in an aurothioglucose, aurotioprol, penicillamine, bucillamine, amount of from 100 to 600 mg, more preferably 150 to 550 their physiologically acceptable salts, as well as mixtures mg, still more preferably 200 to 500 mg, most preferably thereof. 250 to 450 mg and in particular 275 to 400 mg. 0116. In a preferred embodiment, the optionally present (0.124 Preferred combinations A' to A of the pharma pharmacologically active ingredient b is acetaminophen or cologically active ingredient a and the optionally present ibuprofen, more preferably acetaminophen. pharmacologically active ingredient b are summarized in the 0117. In a particularly preferred embodiment, the phar table here below, wherein the pharmacologically active macologically active ingredienta is hydrocodone or a physi ingredient a as well as the optionally present pharmacologi ologically acceptable salt thereof and the optionally present cally active ingredient beach also refer to the physiologi pharmacologically active ingredient b is acetaminophen. cally acceptable salts thereof, particularly to the hydrochlo 0118. The optionally present pharmacologically active rides orbitartrates: ingredient b is present in the dosage form in a therapeutically effective amount. In general, the amount that constitutes a therapeutically effective amount varies according to the 8. b pharmacologically active ingredients being used, the condi Al Oxycodone ibuprofen tion being treated, the severity of said condition, the patient A2 Oxymorphone ibuprofen being treated, and whether the dosage form or the segment A3 hydrocodone ibuprofen in which the pharmacologically active ingredient is con A4 hydromorphone ibuprofen As morphine ibuprofen tained is designed for an immediate or retarded release. A6 apentadol ibuprofen 0119 The total amount of the optionally present pharma A7 tramadol ibuprofen cologically active ingredient b in the dosage form is not A8 buprenorphine ibuprofen limited. The total amount of the optionally present pharma A9 pseudoephedrine ibuprofen A10 Oxycodone acetaminophen cologically active ingredient b which is adapted for admin All Oxymorphone acetaminophen istration preferably is in the range of 0.1 mg to 2,000 mg or AI2 hydrocodone acetaminophen 0.1 mg to 1,000 mg or 0.1 mg to 500 mg, more preferably A13 hydromorphone acetaminophen in the range of 1.0 mg to 400 mg, even more preferably in A14 morphine acetaminophen A15 apentadol acetaminophen the range of 5.0 mg to 300 mg, and most preferably in the A16 tramadol acetaminophen range of 10 mg to 250 mg. In a preferred embodiment, the A17 buprenorphine acetaminophen total amount of the optionally present pharmacologically A18 pseudoephedrine acetaminophen active ingredient b which is contained in the dosage form is A19 Oxycodone diclofenac A20 Oxymorphone diclofenac within the range of from 10 to 1,000 mg, more preferably 50 A21 hydrocodone diclofenac to 900 mg, still more preferably 100 to 800 mg, yet more A22 hydromorphone diclofenac preferably 200 to 600 mg, most preferably 250 to 500 mg A23 morphine diclofenac and in particular 300 to 400 mg. In another preferred A24 apentadol diclofenac A25 tramadol diclofenac embodiment, the total amount of the optionally present A26 buprenorphine diclofenac pharmacologically active ingredient b which is contained in A27 pseudoephedrine diclofenac the dosage form is within the range of from 10 to 500 mg. A28 Oxycodone acetylsalicylic acid more preferably 12 to 450 mg, still more preferably 14 to A29 Oxymorphone acetylsalicylic acid A30 hydrocodone acetylsalicylic acid 400 mg, yet more preferably 16 to 375 mg, most preferably A31 hydromorphone acetylsalicylic acid 18 to 350 mg and in particular 20 to 325 mg. A32 morphine acetylsalicylic acid 0120. The total content of the optionally present pharma A33 apentadol acetylsalicylic acid cologically active ingredient b preferably ranges from about A34 tramadol acetylsalicylic acid A35 buprenorphine acetylsalicylic acid 0.01 wt.-% to about 95 wt.-%, more preferably from about A36 pseudoephedrine acetylsalicylic acid 0.1 wt.-% to about 80 wt.-%, even more preferably from about 1.0 wt.-% to about 50 wt.-%, yet more preferably from about 1.5 wt.-% to about 30 wt.-%, and most preferably from 0.125. In a preferred embodiment, the relative weight about 2.0 wt.-% to 20 wt.-%, based on the total weight of the ratio of the total content of the pharmacologically active dosage form. ingredient a to the total content of the optionally present 0121 Preferably, the total content of the optionally pres pharmacologically active ingredient b ab is within the ent pharmacologically active ingredient b is within the range range of (8+1): 1, more preferably (7+1):1, still more pref of from 0.01 to 80 wt.-%, more preferably 0.1 to 50 wt.-%, erably (6+1): 1, yet more preferably (5+1):1, even more still more preferably 1 to 25 wt.-%, based on the total weight preferably (4+1):1, most preferably (3+1):1 and in particular of the dosage form. (2+1):1. 0122. In a particularly preferred embodiment, the option I0126. In still another preferred embodiment, the relative ally present pharmacologically active ingredient b is acet weight ratio of the total content of the optionally present aminophen. In this embodiment, the acetaminophen is pref pharmacologically active ingredient b to the total content of US 2017/007 1862 A1 Mar. 16, 2017 the pharmacologically active ingredient a bia is within the I0132 Preferably, the dosage form according to the inven range of (8+1): 1, more preferably (7+1):1, still more pref tion provides an in vitro release profile of the pharmaco erably (6+1): 1, yet more preferably (5+1):1, even more preferably (4+1):1, most preferably (3-1):1 and in particular logically active ingredient a such that after 30 min under in (2+1):1. Preferably, the relative weight ratio of the total vitro conditions at 37° C. in 900 mL 0.1 M HCl at 25 rpm content of the optionally present pharmacologically active in accordance with Ph. Eur. ingredient b to the total content of the pharmacologically active ingredient a bia is within the range of from 10:1 to 0.133 (i) a single dosage form has released X mg of the 150:1, more preferably 10:1 to 50:1, or 30:1 to 140:1. pharmacologically active ingredient a originally con 0127. The dosage form according to the invention pref tained in the dosage form; and erably provides fast release, more preferably immediate 0.134 (ii) a multitude of n dosage forms has released Y release under in vitro conditions of the pharmacologically mg of the pharmacologically active ingredienta originally active ingredient a, and independently of the optionally contained in the a multitude of n dosage forms; present pharmacologically active ingredient b in accordance with Ph. Eur. wherein Y/n is not more than 50% of X, preferably not more 0128. The term “immediate release' as applied to dosage than 45% of X, still more preferably not more than 40% of forms is understood by persons skilled in the art which has X, yet more preferably not more than 35% of X, most structural implications for the respective dosage forms. The preferably not more than 30% of X; and wherein n is an term is defined, for example, in the current issue of the US integer of from 2 to 10, preferably 5 or 10, more preferably Pharmacopoeia (USP), General Chapter 1092, “THE DIS 10. SOLUTION PROCEDURE: DEVELOPMENT AND VALIDATION', heading “STUDY DESIGN”, “Time 0.135 For example, when a single dosage form has Points. For immediate-release dosage forms, the duration released after 30 minutes 4.65 mg of pharmacologically of the procedure is typically 30 to 60 minutes; in most cases, a single time point specification is adequate for Pharmaco active ingredient a, X is 4.65. Under these circumstances, a peia purposes. Industrial and regulatory concepts of product multitude of 10 dosage forms (n=10) must not release more comparability and performance may require additional time than a total of 23.25 mg of the pharmacologically active points, which may also be required for product registration ingredient a. or approval. A sufficient number of time points should be selected to adequately characterize the ascending and pla 0.136 Preferably, when the dosage form according to the teau phases of the dissolution curve. According to the invention comprises the optionally present pharmacologi Biopharmaceutics Classification System referred to in sev cally active ingredient b, the dosage form provides an in eral FDA Guidances, highly soluble, highly permeable drugs vitro release profile of the pharmacologically active ingre formulated with rapidly dissolving products need not be dient b such that after 30 min under in vitro conditions at 37° Subjected to a profile comparison if they can be shown to C. in 900 mL 0.1 M HCl at 25 rpm in accordance with Ph. release 85% or more of the active drug substance within 15 Eur. minutes. For these types of products a one-point test will suffice. However, most products do not fall into this cat 0.137 (i) a single dosage form has released V mg of the egory. Dissolution profiles of immediate-release products pharmacologically active ingredient b originally con typically show a gradual increase reaching 85% to 100% at tained in the dosage form; and 30 to 45 minutes. Thus, dissolution time points in the range of 15, 20, 30, 45, and 60 minutes are usual for most 0.138 (ii) a multitude of n dosage forms has released W immediate-release products. mg of the pharmacologically active ingredient b originally 0129. Preferably, the dosage form according to the inven contained in the a multitude of n dosage forms; tion provides an in vitro release profile of the pharmaco wherein W/n is not more than 50% of V, preferably not more logically active ingredient a such that after 30 min under in than 45% of V, still more preferably not more than 40% of vitro conditions at 37° C. in 900 mL 0.1 M HCl at 25 rpm V, yet more preferably not more than 35% of V, most in accordance with Ph. Eur. preferably not more than 30% of V; and wherein n is an 0130 (i) a single dosage form has released at least 30 integer of from 2 to 10, preferably 5 or 10, more preferably wt.-%, or at least 31 wt.-%, or at least 32 wt.-%, or at least 33 wt.-%, or at least 34 wt.-%, or at least 35 wt.-%, or at 10. least 36 wt.-%, or at least 37 wt.-%, or at least 38 wt.-%, 0.139 Suitable in vitro conditions are known to the skilled or at least 39 wt.-%, or at least 40 wt.-%, of the pharma artisan. In this regard it can be referred to, e.g., the Eur, Ph. cologically active ingredient a originally contained in the dosage form; and/or Preferably, the release profile is measured under the follow 0131 (ii) a multitude of ten dosage forms has released ing conditions: Paddle apparatus equipped without sinker, not more than 25 wt.-%, or not more than 24 wt.-%, or not 25 rpm, 37+5° C., 900 mL 0.1 NHC1. more than 23 wt.-%, or not more than 22 wt.-%, or not 0140. Further preferred release profiles B to B' that more than 21 wt.-%, or not more than 20 wt.-%, or not independently apply to the release of pharmacologically more than 19 wt.-%, or not more than 18 wt.-%, or not more than 17 wt.-%, or not more than 16 wt.-%, or not active ingredienta and optionally present pharmacologically more than 15 wt.-%, of the overall content of the phar active ingredient b are summarized in the table here below macologically active ingredient a originally contained in all data in wt.-% of released pharmacologically active the multitude often dosage forms. ingredient a?b: US 2017/007 1862 A1 Mar. 16, 2017 11

time Bl B2 B3 B4 B5 B6 B7 BS B10 10 min e3O e35 e40 e45 eSO 6O >70 e8O e80 20 min eSO eSS e60 e65 efC) efs e80 e85 e.95 30 min eSS e60 e65 efC) efs e85 e90 e.95 e.95 40 min e60 e65 efC) e8O e85 e90 e95 e95 e.95 50 min e65 ef) e8O e85 e88 e92 e95 e95 e.95 60 min efS e80 e85 e.90 e.92 >94 e95 e95 e.95

0141. In a preferred embodiment, the dosage form particles A. Preferably, the dosage form comprises not more according to the invention is adapted for administration once than 500, or not more than 400, or not more than 300, or not daily. In another preferred embodiment, the dosage form more than 200 particles A. according to the invention is adapted for administration 0149 Preferably, when the dosage form contains more twice daily. In still another preferred embodiment, the than a single particle A, the individual particles A may be of dosage form according to the invention is adapted for the same or of different size, shape and/or composition. administration thrice daily. In yet another preferred embodi 0150. In a preferred embodiment, all particles Aare made ment, the dosage form according to the invention is adapted from the same mixture of ingredients and/or are substan for administration more frequently than thrice daily, for tially of the same size, shape, weight and composition. example 4 times daily, 5 times daily, 6 times daily, 7 times 0151. In another preferred embodiment, particles A can daily or 8 times daily. be divided into at least 2 or at least 3 different types, e.g. 0142 Preferably, the dosage form according to the inven particles A, particles A, and optionally particles A, that tion has under in vitro conditions a disintegration time differ from one another in at least one property, preferably measured in accordance with Ph. Eur, of at most 10 minutes, being selected from the group consisting of size, shape, more preferably at most 8 minutes, or at most 6 minutes, or weight, composition, release profile, breaking strength and at most 5 minutes, more preferably at most 4 minutes, still resistance against Solvent extraction. more preferably at most 3 minutes, yet more preferably at 0152 The content of the particle(s) is not particularly most 2.5 minutes, most preferably at most 2 minutes and in limited and preferably amounts to a total content within the particular at most 1.5 minutes. range of from 10 wt.-% to 80 wt.-%, based on the total 0143. The dosage form according to the invention com weight of the dosage form. Preferably, the content of the prises one or more particle(s) A, typically a multitude of particle(s) A in the dosage forms according to the invention particles A. The particle(s) A comprise a pharmacologically is at most 99 wt.-%, or at most 98 wt.-%, or at most 96 active ingredient a, which is embedded in a polymer matrix wt.-%, or at most 94 wt.-%, more preferably at most 92 that preferably comprises a polyalkylene oxide and prefer wt.-%, or at most 90 wt.-%, or at most 88 wt.-%, or at most ably further excipients. 86 wt.-%, still more preferably at most 84 wt.-%, or at most 82 wt.-%, or at most 80 wt.-%, or at most 78 wt.-%, yet more 0144. For the purpose of the specification, the term preferably at most 76 wt.-%, or at most 74 wt.-%, or at most “particle' refers to a discrete mass of material that is solid, 72 wt.-%, or at most 70 wt.-%, most preferably at most 65 e.g. at 20°C. or at room temperature or ambient temperature. wt.-%, or at most 60 wt.-%, or at most 55 wt.-%, or at most Preferably a particle is solid at 20° C. Preferably, the 50 wt.-%, and in particular at most 45 wt.-%, or at most 40 individual particle(s) A are monoliths. The multitude of wt.-%, or at most 35 wt.-%, or at most 30 wt.-%, based on particles A, however, is not monolithic, but multiparticulate. the total weight of the dosage form. Preferably, the pharmacologically active ingredienta and the 0153. Preferably, the content of the particle(s) A in the constituents of the polymer matrix are intimately homoge dosage forms according to the invention is at least 2.5 wt.-%, neously distributed in the particle(s) A so that the particle(s) at least 3.0 wt.-%, at least 3.5 wt.-% or at least 4.0 wt.-%; A do not contain any segments where either pharmacologi more preferably at least 4.5 wt.-%, at least 5.0 wt.-%, at least cally active ingredient a is present in the absence of polymer 5.5 wt.-% or at least 6.0 wt.-%; still more preferably at least matrix or where polymer matrix is present in the absence of 6.5 wt.-%, at least 7.0 wt.-%, at least 7.5 wt.-% or at least 8.0 pharmacologically active ingredient a. wt.-%; yet more preferably at least 8.5 wt.-%, at least 9.0 0145. It is principally possible that the dosage form wt.-%, at least 9.5 wt.-% or at least 10 wt.-%; even more according to the invention comprises a single particle A. preferably at least 11 wt.-%, at least 12 wt.-%, at least 13 0146 In another preferred embodiment, the dosage form wt.-% or at least 14 wt.-%: most preferably at least 15 wt.-%, according to the invention comprises a plurality of particles at least 17.5 wt.-%, at least 20 wt.-% or at least 22.5 wt.-%; A, more preferably a multitude of particles A. and in particular at least 25 wt.-%, at least 27.5 wt.-%, at least 30 wt.-% or at least 35 wt.-%; based on the total weight 0147 In a preferred embodiment, the dosage form com of the dosage form. prises at least 2, or at least 3, or at least 4, or at least 5 0154) In a preferred embodiment, the dosage form particles A. Preferably, the dosage form comprises not more according to the invention comprises one or more particle(s) than 10, or not more than 9, or not more than 8, or not more A comprising a pharmacologically active ingredient a as than 7 particles A. well as one or more particle(s) B comprising an optionally 0148. In another preferred embodiment, the particles A present pharmacologically active ingredient b. As besides amount to a total number within the range of from 20 to 600. the different pharmacologically active ingredient a and b, More preferably, the dosage form comprises at least 30, or respectively, the particle(s) A and the particle(s) B have at least 60, or at least 90, or at least 120, or at least 150 preferably, but independently of one another corresponding US 2017/007 1862 A1 Mar. 16, 2017

composition and properties, in the following it is referred to um, most preferably at least 400 um or at least 500 um, and “particle(s) meaning that these preferred embodiments in particular at least 550 um or at least 600 um. independently apply to particle(s) Aas well as to optionally 0.161 Preferred particle(s) have an average length and present particle(s) B. average diameter of 1000 um or less. When the particle(s) 0155. When the particle(s) are film coated, the polymer are manufactured by extrusion technology, the “length of matrix is preferably homogeneously distributed in the core particle(s) is the dimension of the particle(s) that is parallel of the dosage form, i.e. the film coating preferably does not to the direction of extrusion. The “diameter of particle(s) is contain polymer matrix. Nonetheless, the film coating as the largest dimension that is perpendicular to the direction of Such may of course contain one or more polymers, which extrusion. however, preferably differ from the constituents of the 0162 Particularly preferred particle(s) have an average polymer matrix contained in the core. diameter of less than 1000 um, more preferably less than 800 0156 When the particle(s) are film coated, the pharma um, still more preferably of less than 650 um. Especially cologically active ingredient afb is preferably homoge preferred particle(s) have an average diameter of less than neously distributed in the core of the dosage form, i.e. the 700 um, particularly less than 600 um, still more particularly film coating preferably does not contain pharmacologically less than 500 um, e.g. less than 400 um. Particularly pre active ingredient afb. ferred particle(s) have an average diameter in the range 200 0157. The shape of the particle(s) is not particularly to 1000 um, more preferably 400 to 800 um, still more limited. As the particle(s) are preferably manufactured by preferably 450 to 700 um, yet more preferably 500 to 650 hot-melt extrusion, preferred particle(s) present in the dos um, e.g. 500 to 600 um. Further preferred particle(s) have an age forms according to the invention are generally cylindri average diameter of between 300 um and 400 um, of cal in shape. The diameter of such particle(s) is therefore the between 400 um and 500 um, or of between 500 um and 600 diameter of their circular cross section. The cylindrical um, or of between 600 um and 700 um or of between 700 shape is caused by the extrusion process according to which um and 800 um. the diameter of the circular cross section is a function of the 0163 Preferred particle(s) that are present in the dosage extrusion die and the length of the cylinders is a function of forms according to the invention have an average length of the cutting length according to which the extruded strand of less than 1000 um, preferably an average length of less than material is cut into pieces of preferably more or less prede 800 um, still more preferably an average length of less than termined length. 650 um, e.g. a length of 800 um, 700 um 600 um, 500 um, 0158. The suitability of cylindrical, i.e. a spherical par 400 um or 300 um. Especially preferred particle(s) have an ticle(s) for the manufacture of the dosage forms according to average length of less than 700 um, particularly less than the invention is unexpected. Typically, the aspect ratio is 650 um, still more particularly less than 550 um, e.g. less regarded as an important measure of the spherical shape. than 450 lum. Particularly preferred particle(s) therefore The aspect ratio is defined as the ratio of the maximal have an average length in the range 200-1000 um, more diameter (d) and its orthogonal Feret-diameter. For preferably 400-800 um, still more preferably 450-700 um, aspherical particle(s), the aspect ratio has values above 1. yet more preferably 500-650 um, e.g. 500-600 um. The The smaller the value the more spherical is the particle(s). minimum average length of the microparticle(s) is deter Aspect ratios below 1.1 are typically considered satisfactory, mined by the cutting step and may be, e.g. 500 um, 400 um, aspect ratios above 1.2, however, are typically considered 300 um or 200 um. not suitable for the manufacture of conventional dosage 0164. In a preferred embodiment, the particle(s) have (i) forms. The inventors have surprisingly found that when an average diameter of 1000+300 um, more preferably manufacturing the dosage forms according to the invention, 1000+250 um, still more preferably 1000+200 um, yet more even particle(s) having aspect ratios above 1.2 can be preferably 1000+150 um, most preferably 1000+100 um, processed without difficulties and that it is not necessary to and in particular 1000+50 um; and/or (ii) an average length provide spherical particle(s). In a preferred embodiment, the of 1000+300 um, more preferably 1000+250 um, still more aspect ratio of the particle(s) is at most 1.40, more preferably preferably 1000+200 um, yet more preferably 1000+150 at most 1.35, still more preferably at most 1.30, yet more um, most preferably 1000+100 um, and in particular preferably at most 1.25, even more preferably at most 1.20, 1000+50 um. most preferably at most 1.15 and in particular at most 1.10. 0.165. The size of particle(s) may be determined by any In another preferred embodiment, the aspect ratio of the conventional procedure known in the art, e.g. laser light particle(s) is at least 1.10, more preferably at least 1.15, still scattering, sieve analysis, light microscopy or image analy more preferably at least 1.20, yet more preferably at least sis. 1.25, even more preferably at least 1.30, most preferably at 0166 Preferably, the individual particle(s) have a weight least 1.35 and in particular at least 1.40. within the range of from 0.1 mg to 5.0 mg. 0159. The particle(s) are of macroscopic size, typically 0167. In preferred embodiments, the individual particle the average diameter is within the range of from 100 um to (s) preferably have a weight within the range of 1.0+0.9 mg, 1500 um, preferably 200 um to 1500 um, more preferably or 1.0+0.8 mg, or 1.0+0.7 mg, or 1.0+0.6 mg, or 1.0+0.5 mg. 300 um to 1500 um, still more preferably 400 um to 1500 or 1.0+0.4 mg. or 1.0+0.3 mg; or 1.5-0.9 mg, or 1.5+0.8 mg, um, most preferably 500 um to 1500 um, and in particular or 1.5-0.7 mg, or 1.5+0.6 mg, or 1.5-0.5 mg, or 1.5+0.4 mg. 600 um to 1500 um. or 1.5-0.3 mg; or 2.0+0.9 mg, or 2.0+0.8 mg, or 2.0+0.7 mg, 0160 The particle(s) in the dosage forms according to the or 2.0+0.6 mg, or 2.0+0.5 mg, or 2.0+0.4 mg. or 2.0+0.3 mg: invention are of macroscopic size, i.e. typically have an or 2.5+0.9 mg, or 2.5+0.8 mg, or 2.5-0.7 mg, or 2.5+0.6 mg, average particle(s) size of at least 50 um, more preferably at or 2.5+0.5 mg. or 2.5+0.4 mg. or 2.5-0.3 mg; or 3.0+0.9 mg, least 100 um, still more preferably at least 150 um or at least or 3.0+0.8 mg, or 3.0+0.7 mg, or 3.0+0.6 mg, or 3.0+0.5 mg. 200 um, yet more preferably at least 250 um or at least 300 or 3.0+0.4 mg. or 3.0+0.3 mg. US 2017/007 1862 A1 Mar. 16, 2017

0168 Preferably, the particle(s) A have a total weight (0175 Preferably, the polyalkylene oxide is selected from over all particles A within the range of from 10 mg to 500 polymethylene oxide, polyethylene oxide and polypropyl mg. In preferred embodiments, the total weight of the ene oxide, or copolymers thereof. Polyethylene oxide is particle(s) A is within the range of 180+170 mg. or 180+150 preferred. mg, or 180+130 mg. or 180+110 mg. or 180+90 mg. or 0176 Preferably, the polyalkylene oxide has a weight 180+70 mg. or 180+50 mg. or 180+30 mg. average molecular weight of at least 200,000 g/mol, more preferably at least 500,000 g/mol. In a preferred embodi 0169 Preferably, the particle(s) that are contained in the ment, the polyalkylene oxide has a weight average molecu dosage form according to the invention have an arithmetic lar weight (M) or viscosity average molecular weight (M) average weight, in the following referred to as “aaw’. of at least 750,000 g/mol, preferably at least 1,000,000 wherein at least 70%, more preferably at least 75%, still g/mol or at least 2,500,000 g/mol, more preferably in the more preferably at least 80%, yet more preferably at least range of 1,000,000 g/mol to 15,000,000 g/mol, and most 85%, most preferably at least 90% and in particular at least preferably in the range of 5,000,000 g/mol to 10,000,000 95% of the individual particle(s) contained in said one or g/mol. Suitable methods to determine M and M, are more particle(s) has an individual weight within the range of known to a person skilled in the art. M, is preferably aaw-30%, more preferably aaw-25%, still more preferably determined by rheological measurements, whereas M. can aaw-20%, yet more preferably aawit 15%, most preferably be determined by gel permeation chromatography (GPC). aawit 10%, and in particular aaw-5%. For example, if the 0177 Polyalkylene oxide may comprise a single poly dosage form according to the invention contains a plurality alkylene oxide having a particular average molecular of 100 particles and aaw of said plurality of particles is 1.00 weight, or a mixture (blend) of different polymers, such as mg, at least 75 individual particles (i.e. 75%) have an two, three, four or five polymers, e.g., polymers of the same individual weight within the range of from 0.70 to 1.30 mg chemical nature but different average molecular weight, (1.00 mgi-30%). polymers of different chemical nature but same average 0170 In a preferred embodiment, the particle(s) are not molecular weight, or polymers of different chemical nature film coated. In another preferred embodiment, the particle(s) as well as different molecular weight. are film coated. 0.178 For the purpose of the specification, a polyalkylene glycol has a molecular weight of up to 20,000 g/mol whereas 0171 The particle(s) according to the invention can a polyalkylene oxide has a molecular weight of more than optionally be provided, partially or completely, with a 20,000 g/mol. In a preferred embodiment, the weight aver conventional coating. The particle(s) according to the inven age over all molecular weights of all polyalkylene oxides tion are preferably film coated with conventional film coat that are contained in the dosage form is at least 200,000 ing compositions. Suitable coating materials are commer g/mol. Thus, polyalkylene glycols, if any, are preferably not cially available, e.g. under the trademarks Opadry(R) and taken into consideration when determining the weight aver Eudragit(R). age molecular weight of polyalkylene oxide. 0172. When the particle(s) are film coated, the content of 0179 The polyalkylene oxide may be combined with one the dried film coating is preferably at most 5 wt.-%, more or more different polymers selected from the group consist preferably at most 4 wt.-%, still more preferably at most 3.5 ing of polyalkylene oxide, preferably polymethylene oxide, wt.-%, yet more preferably at most 3 wt.-%, most preferably polyethylene oxide, polypropylene oxide; polyethylene, at most 2.5 wt.-%, and in particular at most 2 wt.-%, based polypropylene, polyvinyl chloride, polycarbonate, polysty on the total weight of the particle(s). In a particularly rene, polyvinylpyrrolidone, poly(alk)acrylate, poly(hydroxy preferred embodiment, the weight increase based on the total fatty acids). Such as for example poly(3-hydroxybutyrate weight of the dosage form and/or based on the total weight co-3-hydroxyvalerate) (BiopolR), poly(hydroxyvaleric of the particle(s) (uncoated Starting material) is within the acid); polycaprolactone, polyvinyl , polyesteramide, range of from 3.0 to 4.7 wt.-%, more preferably 3.1 to 4.6 polyethylene Succinate, polylactone, polyglycolide, polyure wt.-%, still more preferably 3.2 to 4.5 wt.-%, yet more thane, polyamide, polylactide, polyacetal (for example poly preferably 3.3 to 4.4 wt.-%, most preferably 3.4 to 4.3 saccharides optionally with modified side chains), polylac wt.-%, and in particular 3.5 to 4.2 wt.-%. tide/glycolide, polylactone, polyglycolide, polyorthoester, polyanhydride, block polymers of polyethylene glycol and 0173. In a preferred embodiment of the invention, the polybutylene terephthalate (Polyactive(R), polyanhydride film coating of the particle(s) A contains the total amount of (Polifeprosan), copolymers thereof, block-copolymers the optionally present pharmacologically active ingredient b thereof (e.g., PoloxamerR), and mixtures of at least two of or a portion be thereof. the stated polymers, or other polymers with the above 0.174. The tamper-resistant dosage form according to the characteristics. invention comprises one or more particle(s) A which com 0180 Preferably, the molecular weight dispersity M/M, prise a polymer matrix, wherein the polymer matrix prefer of polyalkylene oxide is within the range of 2.5+2.0, more ably comprises a polyalkylene oxide, preferably at a content preferably 2.5-1.5, still more preferably 2.5-1.0, yet more of at least 25 wt.-%, based on the total weight of the dosage preferably 2.5+0.8, most preferably 2.5+0.6, and in particu form and/or based on the total weight of the particle(s) A. lar 2.5-0.4. The optionally present particle(s) B may also, independently 0181. The polyalkylene oxide preferably has a viscosity of the particle(s) A, comprise a polymer matrix, wherein the at 25° C. of 30 to 17,600 cB, more preferably 55 to 17,600 polymer matrix preferably comprises a polyalkylene oxide, cP still more preferably 600 to 17,600 cB and most prefer preferably at a content of at least 25 wt.-%, based on the total ably 4,500 to 17,600 cp measured in a 5 wt.-% aqueous weight of the dosage form and/or based on the total weight solution using a model RVF Brookfield viscosimeter of the particle(s) B. (spindle no. 2/rotational speed 2 rpm); of 400 to 4,000 cp. US 2017/007 1862 A1 Mar. 16, 2017

more preferably 400 to 800 cp or 2,000 to 4,000 cF. 1:1, still more preferably 15:1 to 5:1, yet more preferably measured on a 2 wt.-% aqueous solution using the stated 14:1 to 6:1, most preferably 13:1 to 7:1, and in particular viscosimeter (spindle no. 1 or 3/rotational speed 10 rpm); or 12:1 to 8:1. of 1,650 to 10,000 cB, more preferably 1,650 to 5,500 cB. 0186 Preferably, the total content of the polyalkylene 5,500 to 7,500 cP or 7,500 to 10,000 cP, measured on a 1 oxide in the pharmaceutical dosage form according to the wt.-% aqueous Solution using the stated viscosimeter invention amounts to at least 25 mg, or at least 30 mg. or at (spindle no. 2/rotational speed 2 rpm). least 35 mg, or at least 40 mg. or at least 45 mg; more 0182 Polyethylene oxide that is suitable for use in the preferably at least 50 mg. or at least 55 mg, or at least 60 mg. dosage forms according to the invention is commercially or at least 65 mg, or at least 70 mg. or at least 75 mg; still available from Dow. For example, Polyox WSR N-12K, more preferably at least 80 mg. or at least 85 mg. or at least Polyox N-60K, Polyox WSR 301 NF or Polyox WSR 90 mg. or at least 95 mg; and most preferably at least 100 303NF may be used in the dosage forms according to the ng. invention. For details concerning the properties of these 0187. The dosage form according to the invention is products, it can be referred to e.g. the product specification. preferably tamper-resistant. 0183 Preferably, the content of the polyalkylene oxide is 0188 As used herein, the term “tamper-resistant” refers within the range of from 25 to 80 wt.-%, more preferably 25 to dosage forms that are preferably resistant to conversion to 75 wt.-%, still more preferably 25 to 70 wt.-%, yet more into a form Suitable for misuse or abuse, particular for nasal preferably 25 to 65 wt.-%, most preferably 30 to 65 wt.-% and/or intravenous administration, by conventional means and in particular 35 to 65 wt.-%, based on the total weight Such as grinding in a mortar or crushing by means of a of the dosage form and/or based on the total weight of the hammer. In this regard, the dosage forms as such may be particle(s). In a preferred embodiment, the content of the crushable by conventional means. However, the particle(s) polyalkylene oxide is at least 30 wt.-%, more preferably at A contained in the dosage forms according to the invention least 35 wt.-%, still more preferably at least 40 wt.-%, yet preferably exhibit mechanical properties such that they more preferably at least 45 wt.-% and in particular at least cannot be pulverized by conventional means any further. 50 wt.-%, based on the total weight of the dosage form The same may independently apply to the optionally present and/or based on the total weight of the particle(s). particle(s) B. As the particle(s) A are of macroscopic size 0184. In a preferred embodiment, the overall content of and contain the pharmacologically active ingredient a, and polyalkylene oxide is within the range of 35+8 wt.-%, more as the optionally present particle(s) B may independently be preferably 35+6 wt.%, most preferably 35+4 wt.%, and in of macroscopic size and contain the optionally present particular 35+2 wt.-%, based on the total weight of the pharmacologically active ingredient b, they cannot be dosage form and/or based on the total weight of the particle administered nasally thereby rendering the dosage forms (s). In another preferred embodiment, the overall content of tamper-resistant. polyalkylene oxide is within the range of 40+12 wt.-%, more 0189 Preferably, the particle(s) A have a breaking preferably 40+10 wt.-%, most preferably 40+7 wt.-%, and in strength of at least 300 N. Preferably, the overall dosage particular 40+3 wt.-%, based on the total weight of the form as such does not have a breaking strength of at least dosage form and/or based on the total weight of the particle 300N, i.e. typically the breaking strength of the dosage form (s). In still another preferred embodiment, the overall con as such, e.g. of the tablet or capsule, is below 300 N. tent of polyalkylene oxide is within the range of 45+16 wt.-%, more preferably 45+12 wt.-%, most preferably 45+8 0190. When the dosage form additionally contains par wt.-%, and in particular 45+4 wt.-%, based on the total ticle(s) B, these particle(s) B may also have a breaking weight of the dosage form and/or based on the total weight strength of at least 300 N. However, though being less of the particle(s). In yet another preferred embodiment, the preferred, the invention also includes embodiments where overall content of polyalkylene oxide is within the range of optionally present particle(s) B do not have a breaking 50+20 wt.-%, more preferably 50+15 wt.-%, most prefer strength of at least 300 N. ably 50+10 wt.-%, and in particular 50+5 wt.-%, based on 0191 Preferably, the particle(s) are tamper-resistant as the total weight of the dosage form and/or based on the total Such so that they also provide tamper-resistance after they weight of the particle(s). In a further preferred embodiment, have been separated from the remaining constituents of the the overall content of polyalkylene oxide is within the range dosage form. Thus, preferably the particle(s) as such contain of 55+20 wt.-%, more preferably 55+15 wt.-%, most pref all ingredients that are necessary to render them tamper erably 55+10 wt.-%, and in particular 55+5 wt.-%, based on resistant. the total weight of the dosage form and/or based on the total 0.192 Preferably, when trying to tamper the dosage form weight of the particle(s). In still a further a preferred in order to prepare a formulation suitable for abuse by embodiment, the overall content of polyalkylene oxide is intravenous administration, the liquid part of the formulation within the range of 60+20 wt.-%, more preferably 60+15 that can be separated from the remainder by means of a wt.-%, most preferably 60+10 wt.-%, and in particular 60+5 Syringe is as less as possible, preferably it contains not more wt.-%. In a still further a preferred embodiment, the overall than 20 wt.-%, more preferably not more than 15 wt.-%, still content of polyalkylene oxide is within the range of 65+20 more preferably not more than 10 wt.-%, and most prefer wt.-%, more preferably 65+15 wt.-%, and most preferably ably not more than 5 wt.-% of the originally contained 65+10 wt.-%, and in particular 65+5 wt.-%, based on the pharmacologically active ingredient a. total weight of the dosage form and/or based on the total 0193 The same may apply to optionally present pharma weight of the particle(s). cologically active ingredient b. However, in a preferred 0185. Preferably, the relative weight ratio of the poly embodiment pharmacologically active ingredient a is more alkylene oxide to the pharmacologically active ingredient a prone to abuse than optionally present pharmacologically is within the range of 30:1 to 1:10, more preferably 20:1 to active ingredient b. US 2017/007 1862 A1 Mar. 16, 2017

0194 Preferably, this property is tested by (i) dispensing 0207. In order to verify whether a particle(s) exhibits a a dosage form that is either intact or has been manually particular breaking strength of e.g. 300 N or 500 N it is comminuted by means of two spoons in 5 ml of purified typically not necessary to Subject said particle(s) to forces water, (ii) heating the liquid up to its boiling point, (iii) much higher than 300 N and 500 N. respectively. Thus, the boiling the liquid in a covered vessel for 5 min without the breaking strength test can usually be terminated once the addition of further purified water, (iv) drawing up the hot force corresponding to the desired breaking strength has liquid into a Syringe (needle 21G equipped with a cigarette been slightly exceeded, e.g. at forces of e.g. 330 N and 550 filter), (v) determining the amount of the pharmacologically N, respectively. active ingredienta and/orb contained in the liquid within the 0208. The “breaking strength' (resistance to crushing) of Syringe. a dosage form and of a particle(s) is known to the skilled 0.195. Further, when trying to disrupt the dosage forms by person. In this regard it can be referred to, e.g., W. A. means of a hammer or mortar, the particle(s) preferably tend Ritschel, Die Tablette, 2. Auflage, Editio Cantor Verlag to adhere to one another thereby forming aggregates and Aulendorf, 2002; H Liebermann et al., Dosage forms: Dos agglomerates, respectively, which are larger in size than the age forms, Vol. 2, Informa Healthcare; 2 edition, 1990; and untreated particle(s). Encyclopedia of Pharmaceutical Technology, Informa 0196. Preferably, tamper-resistance is achieved based on Healthcare; 1 edition. the mechanical properties of the particle(s) so that commi 0209 For the purpose of the specification, the breaking nution is avoided or at least Substantially impeded. Accord strength is preferably defined as the amount of force that is ing to the invention, the term comminution means the necessary in order to fracture the particle(s) (breaking pulverization of the particle(s) using conventional means force). Therefore, for the purpose of the specification a usually available to an abuser, for example a pestle and particle does preferably not exhibit the desired breaking mortar, a hammer, a mallet or other conventional means for strength when it breaks, i.e., is fractured into at least two pulverizing under the action of force. Thus, tamper-resis independent parts that are separated from one another. tance preferably means that pulverization of the particle(s) using conventional means is avoided or at least Substantially 0210. In another preferred embodiment, however, the impeded. particle is regarded as being broken if the force decreases by 0.197 Preferably, the mechanical properties of the par 50% (threshold value) of the highest force measured during ticle(s) according to the invention, particularly their break the measurement (see below). ing strength and deformability, Substantially rely on the 0211. The particle(s) according to the invention are dis presence and spatial distribution of a polymer matrix, pref tinguished from conventional particles that can be contained erably comprising polyalkylene oxide, although its mere in dosage forms in that, due to their breaking strength, they presence does typically not suffice in order to achieve said cannot be pulverized by the application of force with con properties. The advantageous mechanical properties of the ventional means, such as for example a pestle and mortar, a particle(s) according to the invention may not automatically hammer, a mallet or other usual means for pulverization, in be achieved by simply processing pharmacologically active particular devices developed for this purpose (tablet crush ingredient a?b, the components of the polymer matrix Such ers). In this regard “pulverization” means crumbling into as polyalkylene oxide, and optionally further excipients by small particles. Avoidance of pulverization virtually rules means of conventional methods for the preparation of dos out oral or parenteral, in particular intravenous or nasal age forms. In fact, usually Suitable apparatuses must be abuse. selected for the preparation and critical processing param 0212 Conventional particles typically have a breaking eters must be adjusted, particularly pressure/force, tempera strength well below 200 N. ture and time. Thus, even if conventional apparatuses are 0213. The breaking strength of conventional round dos used, the process protocols usually must be adapted in order age forms/particle may be estimated according to the fol to meet the required criteria. lowing empirical formula: Breaking Strength in N=10x 0198 In general, the particle(s) exhibiting the desired Diameter Of The Dosage form/Particle in mm. Thus, properties may be obtained only if, during preparation of the according to said empirical formula, a round dosage form/ particle(s), particle having a breaking strength of at least 300 N would 0199 suitable components require a diameter of at least 30 mm. Such a particles, 0200 in suitable amounts however, could not be Swallowed, let alone a dosage form 0201 are exposed to containing a plurality of Such particles. The above empirical 0202) a sufficient pressure formula preferably does not apply to the particle(s) accord 0203 at a sufficient temperature ing to the invention, which are not conventional but rather 0204 for a sufficient period of time. special. 0205 Thus, regardless of the apparatus used, the process 0214. Further, the actual mean chewing force is 220 N protocols must be adapted in order to meet the required (cf., e.g., P. A. Proeschel et al., J Dent Res, 2002, 81 (7), criteria. Therefore, the breaking strength and deformability 464-468). This means that conventional particles having a of the particle(s) is separable from the composition. breaking strength well below 200 N may be crushed upon 0206. The particle(s) contained in the dosage form spontaneous chewing, whereas the particle(s) according to according to the invention preferably have a breaking the invention may preferably not. strength of at least 300 N, at least 400 N, or at least 500 N. 0215 Still further, when applying a gravitational accel preferably at least 600 N., more preferably at least 700 N. eration of 9.81 m/s, 300 N correspond to a gravitational still more preferably at least 800 N, yet more preferably at force of more than 30 kg, i.e. the particle(s) according to the least 1000 N., most preferably at least 1250 N and in invention can preferably withstand a weight of more than 30 particular at least 1500 N. kg without being pulverized. US 2017/007 1862 A1 Mar. 16, 2017

0216 Methods for measuring the breaking strength of a for example. Measurement is performed using a pressure dosage form are known to the skilled artisan. Suitable piston with screw-in inserts and a cylinder (diameter 10 devices are commercially available. mm), a force transducer, F. 1 kN, diameter-8 mm, class 0217 For example, the breaking strength (resistance to 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with crushing) can be measured in accordance with the Eur, Ph. manufacturer's test certificate Maccording to DIN 55350-18 5.0, 2.9.8 or 6.0, 2.09.08 “Resistance to Crushing of Dosage (Zwick gross force F-1.45 kN) (all apparatus from forms'. The test is intended to determine, under defined Zwick GmbH & Co. KG, Ulm, Germany) with Order No conditions, the resistance to crushing of dosage forms and of BTC-FR 2.5 TH. D09 for the tester, Order No BTC-LC the particle(s), respectively, measured by the force needed to 005ON. PO1 for the force transducer, Order No BO 70000 disrupt them by crushing. The apparatus consists of 2 jaws S06 for the centring device. facing each other, one of which moves towards the other. 0220. When using the testControl software (testXpert The flat surfaces of the jaws are perpendicular to the V10.11), the following exemplified settings and parameters direction of movement. The crushing Surfaces of the jaws have revealed to be useful: LE-position: clamping length are flat and larger than the Zone of contact with the dosage 150 mm. LE-speed: 500 mm/min, clamping length after form and a single particle, respectively. The apparatus is pre-travel: 195 mm, pre-travel speed: 500 mm/min, no calibrated using a system with a precision of 1 Newton. The pre-force control pre-force: pre-force 1N, pre-force speed dosage form and particle, respectively, is placed between the 10 mm/min-sample data: no sample form, measuring jaws, taking into account, where applicable, the shape, the length traverse distance 10 mm, no input required prior to break-mark and the inscription; for each measurement the testing testing/end of test; test speed: position-controlled dosage form and particle, respectively, is oriented in the 10 mm/min, delay speed shift: 1, force shut down threshold same way with respect to the direction of application of the 50% F, no force threshold for break-tests, no max length force (and the direction of extension in which the breaking variation, upper force limit: 600N-expansion compensa strength is to be measured). The measurement is carried out tion: no correction of measuring length—actions after test on 10 dosage forms and particles, respectively, taking care ing: LE to be set after test, no unload of sample TRS: data that all fragments have been removed before each determi memory: TRS distance interval until break 1 TRS time nation. The result is expressed as the mean, minimum and interval 0.1 s, TRS force interval 1N machine; traverse maximum values of the forces measured, all expressed in distance controller: upper soft end 358 mm, lower soft end Newton. 192 mm lower test space. Parallel arrangement of the 0218. A similar description of the breaking strength upper plate and the ambos should be ensured—these parts (breaking force) can be found in the USP. The breaking must not touch during or after testing. After testing, a small strength can alternatively be measured in accordance with gap (e.g. 0.1 or 0.2 mm) should still be present between the the method described therein where it is stated that the two brackets in intimated contact with the tested particle, breaking strength is the force required to cause a dosage representing the remaining thickness of the deformed par form and particle, respectively, to fail (i.e., break) in a ticle. specific plane. The dosage forms and particle, respectively, 0221. In a preferred embodiment, the particle is regarded are generally placed between two platens, one of which as being broken if it is fractured into at least two separate moves to apply sufficient force to the dosage form and pieces of comparable morphology. Separated matter having particle, respectively, to cause fracture. For conventional, a morphology different from that of the deformed particle, round (circular cross-section) dosage forms and particles, e.g. dust, is not considered as pieces qualifying for the respectively, loading occurs across their diameter (some definition of breaking. times referred to as diametral loading), and fracture occurs 0222. The particle(s) according to the invention prefer in the plane. The breaking force of a dosage form and a ably exhibit mechanical strength over a wide temperature particle, respectively, is commonly called hardness in the range, in addition to the breaking strength (resistance to pharmaceutical literature; however, the use of this term is crushing) optionally also Sufficient hardness, yield strength, misleading. In material Science, the term hardness refers to fatigue strength, impact resistance, impact elasticity, tensile the resistance of a surface to penetration or indentation by a strength, compressive strength and/or modulus of elasticity, Small probe. The term crushing strength is also frequently optionally also at low temperatures (e.g. below -24°C., used to describe the resistance of dosage forms and particles, below -40°C. or possibly even in liquid nitrogen), for it to respectively, to the application of a compressive load. be virtually impossible to pulverize by spontaneous chew Although this term describes the true nature of the test more ing, grinding in a mortar, pounding, etc. Thus, preferably, the accurately than does hardness, it implies that dosage forms comparatively high breaking strength of the particle(s) and particles, respectively, are actually crushed during the according to the invention is maintained even at low or very test, which is often not the case. low temperatures, e.g., when the dosage form is initially 0219. Alternatively, the breaking strength (resistance to chilled to increase its brittleness, for example to tempera crushing) can be measured in accordance with WO 2008/ tures below -25° C., below -40° C. or even in liquid 107149, which can be regarded as a modification of the nitrogen. method described in the Eur, Ph. The apparatus used for the 0223) The particle(s) according to the invention are pref measurement is preferably a “Zwick Z 2.5” materials tester, erably characterized by a certain degree of breaking F=2.5 kN with a maximum draw of 1150 mm, which strength. This does not mean that the particle(s) must also should be set up with one column and one spindle, a exhibit a certain degree of hardness. Hardness and breaking clearance behind of 100 mm and a test speed adjustable strength are different physical properties. Therefore, the between 0.1 and 800 mm/min together with testControl tamper-resistance of the dosage form does not necessarily software. A skilled person knows how to properly adjust the depend on the hardness of the particle(s). For instance, due test speed, e.g. to 10 mm/min, 20 mm/min, or 40 mm/min, to their breaking strength, impact strength, elasticity modu US 2017/007 1862 A1 Mar. 16, 2017

lus and tensile strength, respectively, the particle(s) can 0229. In contrast, FIG. 2 schematically illustrates the preferably be deformed, e.g. plastically, when exerting an measurement and the corresponding force-displacement external force, for example using a hammer, but cannot be diagram of a conventional comparative particle not having pulverized, i.e., crumbled into a high number of fragments. the degree of deformability as the particle(s) according to In other words, the particle(s) according to the invention are the invention. FIG. 2A shows the initial situation at the preferably characterized by a certain degree of breaking beginning of the measurement. The comparative sample strength, but not necessarily also by a certain degree of form particle (2) is placed between upper jaw (1a) and lower jaw stability. (1b) which each are in intimate contact with the surface of 0224. Therefore, in the meaning of the specification, a the comparative particle (2). The initial displacement do particle that is deformed when being exposed to a force in between upper jaw (1a) and lower jaw (1b) corresponds to a particular direction of extension but that does not break the extension of the comparative particle orthogonal to the (plastic deformation or plastic flow) is preferably to be Surfaces of upper jaw (1a) and lower jaw (1b). At this time, regarded as having the desired breaking strength in said no force is exerted at all and thus, no graph is displayed in direction of extension. the force-displacement-diagram below. When the measure ment is commenced, the upper jaw is moved in direction of 0225 Preferred particle(s) present in the dosage forms lower jaw (1b), preferably at a constant speed. FIG. 2B according to the invention are those having a Suitable tensile shows a situation where due to the movement of upper jaw strength as determined by a test method currently accepted (1a) towards lower jaw (1b) a force is exerted on compara in the art. Further preferred particle(s) are those having a tive particle (2). Because of some deformability, the com Youngs Modulus as determined by a test method of the art. parative particle (2) is slightly flattened without being frac Still further preferred particle(s) are those having an accept tured. The force-displacement-diagram indicates that after a able elongation at break. reduction of the displacement do of upper jaw (1a) and lower 0226 Irrespective of whether the particle(s) according to jaw (1b) by distance X, i.e. at a displacement of d-do-X, the invention have an increased breaking strength or nor, the a force F is measured. FIG. 2C shows a situation where due particle(s) according to the invention preferably exhibit a to the continuous movement of upper jaw (1a) towards certain degree of deformability. The particle(s) contained in lower jaw (1b), the force that is exerted on particle (2) causes the dosage form according to the invention preferably have sudden fracture of the comparative particle (2). The force a deformability such that they show an increase, preferably displacement-diagram indicates that after a reduction of the a Substantially steady increase of the force at a correspond displacement do of upper jaw (1a) and lower jaw (1b) by ing decrease of the displacement in the force-displacement distance X, i.e. at a displacement of d do-X, a force F is diagram when being Subjected to a breaking strength test as measured that Suddenly drops when the particle fractures. described above. Under these circumstances, the particle (2) has been broken 0227. This mechanical property, i.e. the deformability of (fractured) and no steady increase of the force in the the individual particle(s), is illustrated in FIGS. 1 and 2. force-displacement-diagram is measured. The Sudden drop (decrease) of the force can easily be recognized and does not 0228 FIG. 1 schematically illustrates the measurement need to be quantified for the measurement. The steady and the corresponding force-displacement-diagram. In par increase in the force-displacement-diagram ends at displace ticular, FIG. 1A shows the initial situation at the beginning of the measurement. The sample particle (2) is placed ment d do-X, when the particle breaks. between upper jaw (1a) and lower jaw (1b) which each are 0230. In a preferred embodiment, the particle(s) con in intimate contact with the surface of the particle (2). The tained in the dosage form according to the invention have a initial displacement do between upper jaw (1a) and lower deformability such that they show an increase, preferably a jaw (1b) corresponds to the extension of the particle Substantially steady increase of the force at a corresponding orthogonal to the Surfaces of upper jaw (1a) and lower jaw decrease of the displacement in the force-displacement (1b). At this time, no force is exerted at all and thus, no graph diagram when being Subjected to a breaking strength test as is displayed in the force-displacement-diagram below. When described above (“Zwick Z 2.5” materials tester, constant the measurement is commenced, the upper jaw is moved in speed), preferably at least until the displacement d of upper direction of lower jaw (1b), preferably at a constant speed. jaw (1a) and lower jaw (1b) has been reduced to a value of FIG. 1B shows a situation where due to the movement of 90% of the original displacement do (i.e. d=0.9 do), prefer upper jaw (1a) towards lower jaw (1b) a force is exerted on ably to a displacement d of 80% of the original displacement particle (2). Because of its deformability, the particle (2) is do more preferably to a displacement d of 70% of the flattened without being fractured. The force-displacement original displacement do still more preferably to a displace diagram indicates that after a reduction of the displacement ment d of 60% of the original displacement do, yet more do of upper jaw (1a) and lower jaw (1b) by distance X, i.e. preferably to a displacement d of 50% of the original at a displacement of d-do-X, a force F is measured. FIG. displacement do even more preferably to a displacement d 1C shows a situation where due to the continuous movement of 40% of the original displacement do, most preferably to of upper jaw (1a) towards lower jaw (1b), the force that is a displacement d of 30% of the original displacement do, and exerted on particle (2) causes further deformation, although in particular to a displacement d of 20% of the original the particle (2) does not fracture. The force-displacement displacement do or to a displacement d of 15% of the diagram indicates that after a reduction of the displacement original displacement do to a displacement d of 10% of the do of upper jaw (1a) and lower jaw (1b) by distance X, i.e. original displacement do, or to a displacement d of 5% of the at a displacement of d do-X, a force F is measured. Under original displacement do. these circumstances, the particle (2) has not been broken 0231. In another preferred embodiment, the particle(s) (fractured) and a substantially steady increase of the force in contained in the dosage form according to the invention the force-displacement-diagram is measured. have a deformability such that they show an increase, US 2017/007 1862 A1 Mar. 16, 2017

preferably a substantially steady increase of the force at a (i.e. d.s0.6 do), yet more preferably at most 50% of the corresponding decrease of the displacement in the force original displacement do (i.e. d.s0.5do), even more prefer displacement-diagram when being Subjected to a breaking ably at most 40% of the original displacement do (i.e. strength test as described above (“Zwick Z 2.5” materials dis0.4d), most preferably at most 30% of the original tester, constant speed), preferably at least until the displace displacement do (i.e. d.s0.3do), and in particular at most ment d of upper jaw (1a) and lower jaw (1b) has been 20% of the original displacement do (i.e. d.s0.2d), or at reduced to 0.80 mm or 0.75 mm, preferably 0.70 mm or 0.65 most 15% of the original displacement do (i.e. d.s0.15"do), at mm, more preferably 0.60 mm or 0.55 mm, still more most 10% of the original displacement do (i.e. d.s0.1 do), or preferably 0.50 mm or 0.45 mm, yet more preferably 0.40 at most 5% of the original displacement do (i.e. d.s0.05 do). mm or 0.35 mm, even more preferably 0.30 mm or 0.25 mm. 0235 Preferably, the particle(s) contained in the dosage most preferably 0.20 mm or 0.15 mm and in particular 0.10 form according to the invention have a deformability Such or 0.05 mm. that they are deformed without being fractured when sub 0232. In still another preferred embodiment, the particle jected to a constant force of e.g. 50 N, 100 N, 200 N, 300 (s) contained in the dosage form according to the invention N, 400 N, 500 N or 600 N in a breaking strength test as have a deformability such that they show an increase, described above (“Zwick Z 2.5” materials tester, constant preferably a substantially steady increase of the force at a force), until the displacement d of upper jaw (1a) and lower corresponding decrease of the displacement in the force jaw (1b) is reduced so that no further deformation takes displacement-diagram when being Subjected to a breaking place at said constant force, whereas at this equilibrated State strength test as described above (“Zwick Z 2.5” materials the displacement d of upper jaw (1a) and lower jaw (1b) is tester, constant speed), at least until the displacement d of at most 0.80 mm or at most 0.75 mm, preferably at most 0.70 upper jaw (1a) and lower jaw (1b) has been reduced to 50% mm or at most 0.65 mm, more preferably at most 0.60 mm of the original displacement do (i.e. d-do/2), whereas the or at most 0.55 mm, still more preferably at most 0.50 mm force measured at said displacement (d do/2) is at least 25 or at most 0.45 mm, yet more preferably at most 0.40 mm N or at least 50 N, preferably at least 75 N or at least 100 or at most 0.35 mm, even more preferably at most 0.30 mm N, still more preferably at least 150 N or at least 200 N, yet or at most 0.25 mm, most preferably at most 0.20 mm or at more preferably at least 250 N or at least 300 N. even more most 0.15 mm and in particular at most 0.10 or at most 0.05 preferably at least 350 N or at least 400 N., most preferably at least 450 N or at least 500 N. and in particular at least 625 0236. In another embodiment, the particle(s) contained in N, or at least 750 N, or at least 875 N, or at least 1000 N. the dosage form according to the invention have a deform or at least 1250 N, or at least 1500 N. ability such that they are deformed without being fractured 0233. In another preferred embodiment, the particle(s) when subjected to a constant force of e.g. 50 N. 100 N. 200 contained in the dosage form according to the invention N, 300 N, 400 N, 500 N or 600 N in a breaking strength test have a deformability such that they show an increase, as described above (“Zwick Z 2.5” materials tester, constant preferably a substantially steady increase of the force at a force), until the displacement d of upper jaw (1a) and lower corresponding decrease of the displacement in the force jaw (1b) is reduced so that no further deformation takes displacement-diagram when being Subjected to a breaking place at said constant force, whereas at this equilibrated State strength test as described above (“Zwick Z 2.5” materials the displacement d of upper jaw (1a) and lower jaw (1b) is tester, constant speed), at least until the displacement d of at least 5% of the original displacement do (i.e. de0.05 do), upper jaw (1a) and lower jaw (1b) has been reduced by at preferably at least 10% of the original displacement do (i.e. least 0.1 mm, more preferably at least 0.2 mm, still more da0.1 do), more preferably at least 15% of the original preferably at least 0.3 mm, yet more preferably at least 0.4 displacement do (i.e. de0.15-do), still more preferably at mm, even more preferably at least 0.5 mm, most preferably least 20% of the original displacement do (i.e. deO.2do), yet at least 0.6 mm, and in particular at least 0.7 mm, whereas more preferably at least 30% of the original displacement do the force measured at said displacement is within the range (i.e. de0.3 do), even more preferably at least 40% of the of from 5.0 N to 250 N., more preferably from 7.5 N to 225 original displacement do (i.e. deO.4"do), most preferably at N, still more preferably from 10 N to 200 N, yet more least 50% of the original displacement do (i.e. de0.5-do), and preferably from 15 N to 175 N, even more preferably from in particular at least 60% of the original displacement do (i.e. 20 N to 150 N., most preferably from 25 N to 125 N, and in de0.6 do), or at least 70% of the original displacement do particular from 30 N to 100 N. (i.e. de0.7d), at least 80% of the original displacement do 0234. In yet another embodiment, the particle(s) con (i.e. de0.8-do), or at least 90% of the original displacement tained in the dosage form according to the invention have a do (i.e. de0.9d). deformability such that they are deformed without being 0237 Preferably, the particle(s) contained in the dosage fractured when subjected to a constant force of e.g. 50 N. form according to the invention have a deformability Such 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a breaking that they are deformed without being fractured when sub strength test as described above (“Zwick Z 2.5” materials jected to a constant force of e.g. 50 N, 100 N, 200 N, 300 tester, constant force), until the displacement d of upper jaw N, 400 N, 500 N or 600 N in a breaking strength test as (1a) and lower jaw (1b) is reduced so that no further described above (“Zwick Z 2.5” materials tester, constant deformation takes place at said constant force, whereas at force), until the displacement d of upper jaw (1a) and lower this equilibrated State the displacement d of upper jaw (1a) jaw (1b) is reduced so that no further deformation takes and lower jaw (1b) is at most 90% of the original displace place at said constant force, whereas at this equilibrated State ment do (i.e. d.s0.9-do), preferably at most 80% of the the displacement d of upper jaw (1a) and lower jaw (1b) is original displacement do (i.e. d.s0.8d), more preferably at at least 0.05 mm or at least 0.10 mm, preferably at least 0.15 most 70% of the original displacement do (i.e. d.s0.7 do), still mm or at least 0.20 mm, more preferably at least 0.25 mm more preferably at most 60% of the original displacement do or at least 0.30 mm, still more preferably at least 0.35 mm US 2017/007 1862 A1 Mar. 16, 2017

or at least 0.40 mm, yet more preferably at least 0.45 mm or present pharmacologically active ingredient b is contained at least 0.50 mm, even more preferably at least 0.55 mm or elsewhere in the dosage form according to the invention. at least 0.60 mm, most preferably at least 0.65mm or at least 0257. When a portion of the optionally present pharma 0.70 mm and in particular at least 0.75 or at least 0.80 mm. cologically active ingredient b is present in the one or more 0238. In particularly preferred embodiments, the dosage particle(s) A, said portion is referred to as "portion b. Said form according to the invention comprises a multitude of portion b is neither contained in particle(s) B, nor is it particles A which contained in a coating of particle(s) A, nor is it present in 0239 amount to a total number within the range of form of a powder, nor is it present in form of granules. from 20 to 600; and/or 0258 When a portion of the optionally present pharma 0240 are made from substantially the same mixture of cologically active ingredient b is present outside the particle ingredients; and/or (s) A in one or more particle(s) B, said portion is referred to 0241 have substantially of the same size, shape, as "portion b. Said portion b is neither contained in weight and composition; and/or particle(s) A, nor is it contained in a coating of particle(s) A, 0242 have cylindrical shape; and/or nor is it present in form of a powder, nor is it present in form 0243 have substantially the same breaking strength; of granules. 0244 have a breaking strength of at least 300 N; and/or 0259 When a portion of the optionally present pharma 0245 have an average individual weight within the cologically active ingredient b is present outside the particle range of from 0.1 mg to 5 mg; and/or (S) A in a coating of particle(s) A, said portion is referred to as "portion b. Said portion be is neither contained in 0246 have a total weight within the range of from 10 particle(s) A, nor is it contained in particle(s) A, nor is it mg to 500 mg; and/or present in form of a powder, nor is it present in form of 0247 amount to a total content within the range of granules. from 10 wt.-% to 80 wt.-%, based on the total weight 0260. When a portion of the optionally present pharma of the dosage form; and/or cologically active ingredient b is present outside the particle 0248 are tamper-resistant as such so that they also (S) A in the outer matrix material, preferably in the granules provide tamper-resistance after they have been sepa that are part of said outer matrix material, said portion is rated from the remaining constituents of the dosage referred to as “portion b. Said portion b is neither form; and/or contained in particle(s) A, nor is it contained in a coating of 0249 contain the total amount of the pharmacologi particle(s) A, nor is it contained in particle(s) B, nor is it cally active ingredient a that is contained in the dosage present in form of a powder. form; and/or 0261) When a portion of the optionally present pharma 0250) have substantially the same content of pharma cologically active ingredient b is present outside the particle cologically active ingredient a, and/or (S) A in form of a powder, said portion is referred to as 0251 show substantially the same in vitro release "portion b. Said portion be is neither contained in particle profile; and/or (s) A, nor is it contained in a coating of particle(s) A, nor is 0252 after 30 min under in vitro conditions have it contained in particle(s) B, nor is it present in form of released at least 80 wt.-% of the pharmacologically granules. active ingredient a that was originally contained in the 0262 Preferably, when the total amount of the optionally dosage form; and/or present pharmacologically active ingredient b is divided into 0253) are thermoformed by hot-melt extrusion. portions that are present at different locations of the dosage 0254. In preferred embodiments, the dosage form accord form, the total amount of the optionally present pharmaco ing to the invention comprises at least a portion of the logically active ingredient b is preferably divided in not optionally present pharmacologically active ingredient b more than three portions, more preferably not more than two outside the particle(s) A in an outer matrix material, which portions. preferably comprises granules comprising optionally present 0263 Thus, when the total amount of the optionally pharmacologically active ingredient b and excipients present pharmacologically active ingredient b is divided into selected from binders, fillers, disintegrants, lubricants, and two portions, portion be is present the outer matrix material, the like. The outer matrix material may also comprise the preferably in the granules that are part of said outer matrix optionally present granule(s) B and the optionally present material, whereas preferably the entire remainder amount of portion be of the optionally present pharmacologically the optionally present pharmacologically active ingredient b, active ingredient b that is present in form of a powder which is not present in the granules that are part of said outer outside particle(s) A and B. matrix material, is present either as portion b in the particle 0255. In a preferred embodiment, the total amount of the (s) A, or as portion be in particle(s) B, or as portion be in a optionally present pharmacologically active ingredient b coating of particle(s) A, or as portion be outside particle(s) that is contained in the dosage form according to the A in form of a powder. invention is contained outside the particle(s) A in the outer 0264. Preferably, the relative weight ratio of portion be to matrix material, preferably in the granules that are part of portion b, or the relative weight ratio of portion be to said outer matrix material. portion b, or the relative weight ratio of portion be to 0256 In another preferred embodiment, a portion be of portion b, or the relative weight ratio of portion be to the total amount of the optionally present pharmacologically portion be, is within the range of from 100:1 to 1:100, more active ingredient b that is contained in the dosage form preferably 50:1 to 1:50, still more preferably 10:1 to 1:10, according to the invention is contained in the outer matrix yet more preferably 5:1 to 1:5. material, preferably in the granules that are part of said outer 0265. In a preferred embodiment, the weight of portion matrix material, whereas the remainder of the optionally b is greater than the weight of portion b, or the weight of US 2017/007 1862 A1 Mar. 16, 2017 20 portion be is greater than the weight of portion b, or the oxide, but optionally polyethylene glycol which differs from weight of portion be is greater than the weight of portion be, polyethylene oxide in its molecular weight. or the weight of portion be is greater than the weight of 0273 When portion be of the pharmacologically active portion be. ingredient is present in form of a powder, said powder is a 0266. In another preferred embodiment, the weight of constituent of the outer matrix material of the preferred portion b is greater than the weight of portion b, or the tablet according to the invention. When portion be of the weight of portion b is greater than the weight of portion b, pharmacologically active ingredient is present in form of or the weight of portion b is greater than the weight of granules, said granules are a constituent of the outer matrix portion be, or the weight of portion be is greater than the material of the preferred tablet according to the invention. weight of portion b. 0274. A purpose of the outer matrix material in the 0267 In a preferred embodiment, the dosage form preferred tablet according to the invention is to ensure rapid according to the invention is a tablet, wherein the particle(s) disintegration and Subsequent release of the pharmacologi A are contained in an outer matrix material. The “outer cally active ingredients a and b from the disintegrated matrix material' is not to be confused with the “polymer preferred tablet according to the invention, i.e. from the matrix' of the particle(s) A and the optionally present particle(s) A and optionally from particle(s) B, from the particle(s) B. In the following, this preferred embodiment is coating of particle(s) A, from the granules and from the referred to as the “preferred tablet according to the inven powder, respectively. Thus, the outer matrix material pref tion. erably does not contain any excipient that might have a 0268 When the preferred tablet according to the inven retardant effect on disintegration and drug release, respec tion comprises particle(s) B, the following preferred tively. Thus, the outer matrix material preferably does not embodiments described for particles(s) A may also analo contain any polymer that is typically employed as outer gously and independently apply to particle(s) B. Thus, in the matrix material in prolonged release formulations. following it is generally referred to “the particle(s)' when no 0275. The preferred tablet according to the invention specific distinction between particle(s) A and the optionally preferably comprises the outer matrix material in an amount present particle(s) B is necessary, nevertheless implying the of more than one third of the total weight of the preferred quality and quantity of particle(s) A and particle(s) B are still tablet according to the invention. Thus, the polymer matrix independent of one another. which preferably comprises polyalkylene oxide and which is contained in the particle(s) A of the preferred tablet accord 0269. The preferred tablet according to the invention ing to the invention is preferably not also contained in the comprises subunits having different morphology and prop outer matrix material. erties, namely particle(s) and outer matrix material, wherein 0276 Preferably, the pharmacologically active ingredient the particle(s) form a discontinuous phase within the outer a which is contained in the particle(s) A of the preferred matrix material. The particle(s) typically have mechanical tablet according to the invention is preferably not also properties that differ from the mechanical properties of the contained in the outer matrix material. Thus, in a preferred outer matrix material. Preferably, the particle(s) have a embodiment, the total amount of pharmacologically active higher mechanical strength than the outer matrix material. ingredient a contained in the preferred tablet according to The particle(s) within the preferred tablet according to the the invention is present in the particle(s) A which form a invention can be visualized by conventional means such as discontinuous phase within the outer matrix material; and X-ray, Solid State nuclear magnetic resonance spectroscopy, the outer matrix material forming a continuous phase does raster electron microscopy, terahertz spectroscopy and the not contain any pharmacologically active ingredient a. like. 0277 Preferably, the optionally present pharmacologi 0270. In the preferred tablet according to the invention, cally active ingredient b, at least a portion of which is the particle(s) are incorporated in an outer matrix material. preferably present as a powder and/or in form of granules, From a macroscopic perspective, the outer matrix material is contained in the outer matrix material, whereas compac preferably forms a continuous phase in which the particle(s) tion of the preferred tablet according to the invention has are embedded as discontinuous phase. typically caused compaction of said powder and/or granules, 0271 Preferably, the outer matrix material is a homog typically in admixture with the other constituents of the enous coherent mass, preferably a homogeneous mixture of outer matrix material. solid constituents, in which the particle(s) are embedded 0278 Preferably, the content of the outer matrix material thereby spatially separating the particle(s) from one another. is at least 35 wt.-%, at least 37.5 wt.-% or at least 40 wt.-%; While it is possible that the surfaces of particle(s) are in more preferably at least 42.5 wt.-%, at least 45 wt.-%, at contact or at least in very close proximity with one another, least 47.5 wt.-% or at least 50 wt.-%; still more preferably the plurality of particle(s) preferably cannot be regarded as at least 52.5 wt.-%, at least 55 wt.-%, at least 57.5 wt.-% or a single continuous coherent mass within the preferred tablet at least 60 wt.-%; yet more preferably at least 62.5 wt.-%, at according to the invention. least 65 wt.-%, at least 67.5 wt.-% or at least 60 wt.-%: most 0272. In other words, the preferred tablet according to the preferably at least 72.5 wt.-%, at least 75 wt.-%, at least 77.5 invention comprises the particle(s) as Volume element(s) of wt.-% or at least 70 wt.-%; and in particular at least 82.5 a first type in which the pharmacologically active ingredient wt.-%, at least 85 wt.-%, at least 87.5 wt.-% or at least 90 a and the polymer matrix, which preferably comprises wt.-%; based on the total weight of the preferred tablet polyalkylene oxide, are contained, preferably homoge according to the invention. neously, and the outer matrix material as Volume element of (0279 Preferably, the content of the outer matrix material a second type differing from the material that forms the is at most 90 wt.-%, at most 87.5 wt.-%, at most 85 wt.-%, particle(s), preferably containing neither pharmacologically or at most 82.5 wt.-%: more preferably at most 80 wt.-%, at active ingredient afb nor polymer matrix, polyalkylene most 77.5 wt.-%, at most 75 wt.-% or at most 72.5 wt.-%: US 2017/007 1862 A1 Mar. 16, 2017

still more preferably at most 70 wt.-%, at most 67.5 wt.-%, many fillers can be regarded as binders and vice versa, for at most 65 wt.-% or at most 62.5 wt.-%; yet more preferably the purpose of the specification “filler/binder” refers to any at most 60 wt.-%, at most 57.5 wt.-%, at most 55 wt.-% or excipient that is suitable as filler, binder or both. Thus, the at most 52.5 wt.-%: most preferably at most 50 wt.-%, at particle(s), the coating, the outer matrix material, the capsule most 47.5 wt.-%, at most 45 wt.-% or at most 42.5 wt.-%; filling, and/or the granules independently preferably com and in particular at most 40 wt.-%, at most 37.5 wt.-%, or at prise a filler/binder. most 35 wt.-%; based on the total weight of the preferred tablet according to the invention. (0287 Preferred fillers (filler/binders) are selected from 0280. In a preferred embodiment, the content of the outer the group consisting of silicium dioxide (e.g. Aerosil R), matrix material is within the range of 40+5 wt.-%, more microcrystalline cellulose (e.g. Avicel(R), Elcema(R), Emo preferably 40+2.5 wt.-%, based on the total weight of the cel(R), ExCel (R), Vitacell(R); cellulose ether (e.g. Natrosol(R), preferred tablet according to the invention. In another pre Klucel(R), Methocel(R), Blanose(R), Pharmacoat(R), Viscon ferred embodiment, the content of the outer matrix material tranR); mannitol; dextrines; dextrose; calciumhydrogen is within the range of 45+10 wt.-%, more preferably 45+7.5 phosphate (e.g. Emcompress(R); tricalcium phosphate, wt.-%, still more preferably 45+5 wt.-%, and most prefer maltodextrine (e.g. EmdeX(R); lactose (e.g. Fast-Flow Lac ably 45+2.5 wt.-%, based on the total weight of the preferred tose(R); Ludipress(R), Dosage Formtose(R), Zeparox(R); poly tablet according to the invention. In still another preferred vinylpyrrolidone (PVP) (e.g. Kollidone(R), Polyplasdone(R), embodiment, the content of the outer matrix material is Polydone(R); saccharose (e.g. Nu-Tab(R), Sugar Tab(R); mag within the range of 50+10 wt.-%, more preferably 50+7.5 nesium salts (e.g. MgCO, MgO, MgSiO); starches and wt.-%, still more preferably 50+5 wt.-%, and most prefer pretreated starches (e.g. Prejel(R), Primotab(R) ET, Starch(R) ably 50+2.5 wt.-%, based on the total weight of the preferred tablet according to the invention. In yet another preferred 1500). Preferred binders are selected from the group con embodiment, the content of the outer matrix material is sisting of alginates; chitosanes; and any of the fillers men within the range of 55+10 wt.-%, more preferably 55+7.5 tioned above (fillers/binders). wt.-%, still more preferably 55+5 wt.-%, and most prefer 0288. Some fillers/binders may also serve other purposes. ably 55+2.5 wt.-%, based on the total weight of the preferred It is known, for example, that silicium dioxide exhibits tablet according to the invention. excellent function as a glidant. Preferably, the particle(s), the 0281 Preferably, the outer matrix material is a mixture, coating, the outer matrix material, the capsule filling, and/or preferably a homogeneous mixture of at least two different the granules independently comprise a glidant such as constituents, more preferably of at least three different silicium dioxide. constituents. In a preferred embodiment, all constituents of 0289. In a preferred embodiment, the content of the the outer matrix material are homogeneously distributed in filler/binder or mixture of fillers/binders in the particle(s), the continuous phase that is formed by the outer matrix the coating, the outer matrix material, the capsule filling, material. and/or the granules independently is within the range of 0282 Preferably, the outer matrix material is a homog 50+25 wt.-%, more preferably 50+20 wt.-%, still more enous powdery or coherent mass, preferably a homogeneous preferably 50+15 wt.-%, yet more preferably 50+10 wt.-%, mixture of solid constituents, in which the particle(s) A are most preferably 50+7.5 wt.-%, and in particular 50+5 wt.-%, embedded. According to this embodiment, the particle(s) A based on the total weight of the particle(s), the coating, the are preferably spatially separated from one another. While it outer matrix material, the capsule filling, and/or the gran is possible that the Surfaces of particle(s) Aare in contact or ules, respectively. In another preferred embodiment, the at least in very close proximity with one another, the content of the filler/binder or mixture of fillers/binders in the plurality of particle(s) A preferably cannot be regarded as a particle(s), the coating, the outer matrix material, the capsule single continuous coherent mass within the dosage form. filling, and/or the granules independently is within the range 0283. The dosage form according to the invention may of 65+25 wt.-%, more preferably 65+20 wt.-%, still more contain additional pharmaceutical excipients conventionally preferably 65+15 wt.-%, yet more preferably 65+10 wt.-%, contained in dosage forms in conventional amounts, such as most preferably 65+7.5 wt.-%, and in particular 65+5 wt.-%, fillers, binders, dispersing agents, wetting agents, disinte based on the total weight of the particle(s), the coating, the grants, gelling agents, antioxidants, preservatives, lubri outer matrix material, the capsule filling, and/or the gran cants, plasticizer, fillers, binders, and the like. ules, respectively. In still another preferred embodiment, the 0284 Said excipients may independently of one another content of the filler/binder or mixture of fillers/binders in the be present in the particle(s) A, the matrix material of the particle(s), the coating, the outer matrix material, the capsule preferred tablet according to the invention, the optionally filling, and/or the granules independently is within the range present particle(s) B, the optionally present coating of par of 80+19 wt.-%, more preferably 80+17.5 wt.-%, still more ticle(s) A, and the optionally present granules, respectively. preferably 80+15 wt.-%, yet more preferably 80+10 wt.-%, 0285. The skilled person will readily be able to determine most preferably 80+7.5 wt.-%, and in particular 80+5 wt.-%, appropriate excipients as well as the quantities of each of based on the total weight of the particle(s), the coating, the these excipients. Specific examples of pharmaceutically outer matrix material, the capsule filling, and/or the gran acceptable carriers and excipients that may be used to ules, respectively. In another preferred embodiment, the formulate the dosage forms according to the invention are content of the filler/binder or mixture of fillers/binders in the described in the Handbook of Pharmaceutical Excipients, particle(s), the coating, the outer matrix material, the capsule American Pharmaceutical Association (1986). filling, and/or the granules independently is within the range 0286 Preferably, the particle(s), the coating, the outer of 90+9 wt.-%, more preferably 90+8 wt.-%, still more matrix material, the capsule filling, and/or the granules preferably 90+7 wt.-%, yet more preferably 90+6 wt.-%, independently comprise one or more fillers or binders. As most preferably 90+5 wt.-%, and in particular 90+4 wt.-%, US 2017/007 1862 A1 Mar. 16, 2017 22 based on the total weight of the particle(s), the coating, the more preferably 65+25 wt.-%, still more preferably 65+20 outer matrix material, the capsule filling, and/or the gran wt.-%, yet more preferably 65+15 wt.-%, even more pref ules, respectively. erably 65+10 wt.-%, and most preferably 65+5 wt.-%, based 0290. In a preferred embodiment, the total content of the on the total weight of the dosage form. filler/binder or mixture of fillers/binders in the dosage form 0293. It has been surprisingly found that the filler/binder is within the range of 25+24 wt.-%, more preferably 25+20 in the capsule filling can accelerate in vitro release of the wt.-%, still more preferably 25+16 wt.-%, yet more prefer pharmacologically active ingredient a and/or of the option ably 25+12 wt.-%, most preferably 25+8 wt.-%, and in ally present pharmacologically active ingredient b from the particular 25+4 wt.-%, based on the total weight of dosage dosage form according to the invention. form. In another preferred embodiment, the total content of 0294 Preferably, the filler/binder is contained in the the filler/binder or mixture of fillers/binders in the dosage optionally present particle(s) B but not in the particle(s) A of form is within the range of 30+29 wt.-%, more preferably the dosage form according to the invention. 30+25 wt.-%, still more preferably 30+20 wt.-%, yet more 0295 Preferably, the particle(s), the coating, the outer preferably 30+15 wt.-%, most preferably 30+10 wt.-%, and matrix material, the capsule filling, and/or the granules in particular 30+5 wt.-%, based on the total weight of dosage independently comprise a disintegrant, wherein the content form. In still another preferred embodiment, the total content of the disintegrant is more than 5.0 wt.-%, based on the total of the filler/binder or mixture of fillers/binders in the dosage weight of the dosage form and/or based on the total weight form is within the range of 35+34 wt.-%, more preferably of the particle(s), the coating, the outer matrix material, the 35+28 wt.-%, still more preferably 35+22 wt.-%, yet more capsule filling, and/or the granules, respectively. preferably 35+16 wt.-%, most preferably 35+10 wt.-%, and 0296. In a preferred embodiment, particularly when the in particular 35+4 wt.-%, based on the total weight of dosage dosage form is a capsule, the dosage form contains the entire form. In another preferred embodiment, the total content of amount of disintegrant within the particle(s), i.e. outside the the filler/binder or mixture of fillers/binders in the dosage particle(s) there is preferably no disintegrant. Furthermore, form is within the range of 40+39 wt.-%, more preferably the disintegrant is preferably homogeneously distributed in 40+32 wt.-%, still more preferably 40+25 wt.-%, yet more the particle(s). Preferably, when the particle(s) are coated, preferably 40+18 wt.-%, most preferably 40+11 wt.-%, and the coating does not contain disintegrant. in particular 40+4 wt.-%, based on the total weight of dosage 0297. In another preferred embodiment, particularly form. when the dosage form is a tablet, the dosage form contains 0291. In a preferred embodiment, particularly when the the disintegrant within the particle(s) as well as outside the dosage form is a capsule, the capsule is preferably filled with particle(s). In a preferred embodiment, the nature of disin particle(s) A, which are optionally coated comprising por tegrant within the particle(s) is identical with the nature of tion be of the optionally present pharmacologically active disintegrant outside the particle(s). However, different dis ingredient b, and/or with the outer matrix material and/or integrants inside the particle(s) and outside the particle(s) with portion be of the optionally present pharmacologically are also possible in accordance with the invention. Further active ingredient b in form of a powder, and/or with option more, the disintegrant is preferably homogeneously distrib ally present particle(s) B, and/or with the optionally present uted in the particle(s). Preferably, when the particle(s) are granules comprising portion be of the optionally present coated, the coating does not contain disintegrant. pharmacologically active ingredient b; and additionally with 0298. In still another preferred embodiment, particularly a filler/binder, preferably lactose or mannitol. when the dosage form is the preferred tablet according to the 0292. In a preferred embodiment, the total content of the invention, the dosage form contains the disintegrant outside filler/binder is preferably within the range of 25+20 wt.-%, the particle(s), and optionally also within the particle. more preferably 25+15 wt.-%, still more preferably 25+10 0299 Suitable disintegrants are known to the skilled wt.-%, and most preferably 25+5 wt.-%, based on the total person and are preferably selected from the group consisting weight of the dosage form. In another preferred embodi of starches, starch derivatives, cellulose derivatives and gas ment, the total content of the filler/binder is preferably releasing Substances. CroScarmellose ist particularly pre within the range of 35+30 wt.-%, more preferably 35+25 ferred as disintegrant. wt.-%, still more preferably 35+20 wt.-%, yet more prefer 0300 Preferred starches include but are not limited to ably 35+15 wt.-%, even more preferably 35+10 wt.-%, and 'standard Starch” (e.g. native maize starch) and pregelati most preferably 35+5 wt.-%, based on the total weight of the nized starch (e.g. starch 1500). dosage form. In still another preferred embodiment, the total 0301 Preferred starch derivatives include but are not content of the filler/binder is preferably within the range of limited to Sodium starch glycolate (e.g. Vivastar(R). 45+40 wt.-%, more preferably 45+35 wt.-%, still more 0302 Preferred cellulose derivatives include but are not preferably 45+30 wt.-%, yet more preferably 45+25 wt.-%, limited to croScarmellose sodium (crosslinked sodium car even more preferably 45+20 wt.-%, and most preferably boxymethylcellulose; e.g. Vivasol(R). 45+15 wt.-%, and in particular 45+10 wt.-%, based on the 0303 Preferred gas releasing substances include but are total weight of the dosage form. In yet another preferred not limited to sodium bicarbonate. embodiment, the total content of the filler/binder is prefer 0304 Preferred disintegrants include but are not limited ably within the range of 55-40 wt.-%, more preferably to crosslinked sodium carboxymethylcellulose (Na-CMC) 55+35 wt.-%, still more preferably 55+30 wt.-%, yet more (e.g. Crosscarmellose, Vivasol(R), Ac-Di-SolR); crosslinked preferably 55+25 wt.-%, even more preferably 55+20 wt.-%, casein (e.g. Esma-SprengR); polysaccharide mixtures and most preferably 55+15 wt.-%, and in particular 55+10 obtained from soybeans (e.g. EmcoSoyR); maize starch or wt.-%, based on the total weight of the dosage form. In pretreated maize starch (e.g. Amijel(R); Sodium alginate; another preferred embodiment, the total content of the polyvinylpyrrolidone (PVP) (e.g. Kollidone(R), Polyplas filler/binder is preferably within the range of 65+30 wt.-%, done(R), Polydone(R); crosslinked polyvinylpyrrolidone US 2017/007 1862 A1 Mar. 16, 2017

(PVP CI) (e.g. PolyplasdoneR XL); starch and pretreated weight of the particle(s), the coating, the outer matrix starch Such as Sodium carboxymethyl starch (Sodium material, the capsule filling, and/or the granules, respec starch glycolate, e.g. Explotab(R), Preel(R), Primotab(R) ET, tively. In another preferred embodiment, the content of the Starch(R) 1500, Ulmatry1(R), and the mixtures thereof. Cross disintegrant is within the range of 20+3.0 wt.-%, more linked polymers are particularly preferred disintegrants, preferably 20+2.5 wt.-%, still more preferably 20+2.0 wt.- especially crosslinked sodium carboxymethylcellulose (Na %, yet more preferably 20+1.5 wt.-%, most preferably CMC) or crosslinked polyvinylpyrrollidone (PVP CI). 20+1.0 wt.-%, and in particular 20+0.5 wt.-%, based on the 0305 Preferably, the content of the disintegrant is at least total weight of the dosage form and/or based on the total 6.0 wt.-%, at least 7.0 wt.-%, at least 8.0 wt.-%, at least 9.0 weight of the particle(s), the coating, the outer matrix wt.-%, or at least 10 wt.-%, more preferably at least 12 material, the capsule filling, and/or the granules, respec wt.-%, still more preferably at least 14 wt.-%, yet more tively. preferably at least 15 wt.-%, even more preferably at least 16 0308. In still another preferred embodiment, the content wt.-%, most preferably at least 18 wt.-%, and in particular at of the disintegrant is within the range of 25+9.0 wt.-%, more least 19 wt.-%, based on the total weight of the dosage form preferably 25+8.5 wt.-%, still more preferably 25+8.0 wt.- and/or based on the total weight of the particle(s), the %, yet more preferably 25+7.5 wt.-%, most preferably coating, the outer matrix material, the capsule filling, and/or 25+7.0 wt.-%, and in particular 25+6.5 wt.-%, based on the the granules, respectively. total weight of the dosage form and/or based on the total 0306 In a preferred embodiment, the content of the weight of the particle(s), the coating, the outer matrix disintegrant is within the range of 15-9.0 wt.-%, more material, the capsule filling, and/or the granules, respec preferably 15+8.5 wt.-%, still more preferably 15+8.0 wt.- tively. In still another preferred embodiment, the content of %, yet more preferably 15+7.5 wt.-%, most preferably the disintegrant is within the range of 25+6.0 wt.-%, more 15+7.0 wt.-%, and in particular 15+6.5 wt.-%, based on the preferably 25+5.5 wt.-%, still more preferably 25+5.0 wt.- total weight of the dosage form and/or based on the total %, yet more preferably 25+4.5 wt.-%, most preferably weight of the particle(s), the coating, the outer matrix 25+4.0 wt.-%, and in particular 25+3.5 wt.-%, based on the material, the capsule filling, and/or the granules, respec total weight of the dosage form and/or based on the total tively. In still another preferred embodiment, the content of weight of the particle(s), the coating, the outer matrix the disintegrant is within the range of 15+6.0 wt.-%, more material, the capsule filling, and/or the granules, respec preferably 15+5.5 wt.-%, still more preferably 15+5.0 wt.- tively. In another preferred embodiment, the content of the %, yet more preferably 15+4.5 wt.%, most preferably disintegrant is within the range of 25+3.0 wt.-%, more 15+4.0 wt.-%, and in particular 15+3.5 wt.-%, based on the preferably 25+2.5 wt.-%, still more preferably 25+2.0 wt.- total weight of the dosage form and/or based on the total %, yet more preferably 25+1.5 wt.-%, most preferably weight of the particle(s), the coating, the outer matrix 25+1.0 wt.-%, and in particular 25+0.5 wt.-%, based on the material, the capsule filling, and/or the granules, respec total weight of the dosage form and/or based on the total tively. In another preferred embodiment, the content of the weight of the particle(s), the coating, the outer matrix disintegrant is within the range of 15+3.0 wt.-%, more material, the capsule filling, and/or the granules respectively. preferably 15+2.5 wt.-%, still more preferably 15+2.0 wt.- 0309 When the dosage form according to the invention %, yet more preferably 15+1.5 wt.-%, most preferably contains more than a single disintegrant, e.g. a mixture of 15+1.0 wt.-%, and in particular 15+0.5 wt.-%, based on the two different disintegrants, the above percentages preferably total weight of the dosage form and/or based on the total refer to the total content of disintegrants. weight of the particle(s), the coating, the outer matrix 0310 Preferably, the relative weight ratio of the poly material, the capsule filling, and/or the granules, respec alkylene oxide to the disintegrant is within the range of 8:1 tively. to 1:5, more preferably 7:1 to 1:4, still more preferably 6:1 0307. In another preferred embodiment, the content of to 1:3, yet more preferably 5:1 to 1:2, most preferably 4:1 to the disintegrant is within the range of 20+15 wt.-% or 2014 1:1, and in particular 3:1 to 2:1. wt.-%, more preferably 20+13 wt.-%, still more preferably 0311 Preferably, the relative weight ratio of the pharma 20+12 wt.-%, yet more preferably 20+11 wt.-%, most pref cologically active ingredient a to the disintegrant is within erably 20+10 wt.-%, and in particular 20+9.5 wt.-%, based the range of 4:1 to 1:10, more preferably 3:1 to 1:9, still on the total weight of the dosage form and/or based on the more preferably 2:1 to 1:8, yet more preferably 1:1 to 1:7, total weight of the particle(s), the coating, the outer matrix most preferably 1:2 to 1:6, and in particular 1:3 to 1:5. material, the capsule filling, and/or the granules, respec 0312 The dosage form may contain a single disintegrant tively. In another preferred embodiment, the content of the or a mixture of different disintegrants. Preferably, the dosage disintegrant is within the range of 20+9.0 wt.-%, more form contains a single disintegrant. preferably 20+8.5 wt.-%, still more preferably 20+8.0 wt.- 0313 Preferably, the dosage form according to the inven %, yet more preferably 20+7.5 wt.-%, most preferably tion and/or the particle(s), the coating, the outer matrix 20+7.0 wt.-%, and in particular 20+6.5 wt.-%, based on the material, the capsule filling, and/or the granules indepen total weight of the dosage form and/or based on the total dently further comprise an antioxidant. Suitable antioxidants weight of the particle(s), the coating, the outer matrix include ascorbic acid, butylated hydroxyanisole (BHA), material, the capsule filling, and/or the granules, respec butylated hydroxytoluene (BHT), salts of ascorbic acid, tively. In still another preferred embodiment, the content of monothioglycerol, phosphorous acid, vitamin C. vitamin E the disintegrant is within the range of 20+6.0 wt.-%, more and the derivatives thereof, coniferyl benzoate, nordihy preferably 20+5.5 wt.-%, still more preferably 20+5.0 wt.- droguajaretic acid, gallus acid esters, Sodium bisulfate, par %, yet more preferably 20+4.5 wt.-%, most preferably ticularly preferably butylhydroxytoluene or butylhydroxy 20+4.0 wt.-%, and in particular 20+3.5 wt.-%, based on the anisole and a-tocopherol. The antioxidant is preferably total weight of the dosage form and/or based on the total present in quantities of 0.01 wt.-% to 10 wt.-%, more US 2017/007 1862 A1 Mar. 16, 2017 24 preferably of 0.03 wt.-% to 5 wt.-%, most preferably of 0.05 preferably of C to C fatty acids; especially preferred wt.-% to 2.5 wt.-%, based on the total weight of the dosage are partial glycerides of the C to C fatty acids such form and/or based on the total weight of the particle(s), the as glycerol behenat, glycerol palmitostearate and glyc coating, the outer matrix material, the capsule filling, and/or erol monostearate; the granules, respectively. 0323 polyoxyethylene glycerol fatty acid esters, such 0314. In a preferred embodiment, the dosage form as mixtures of mono-, di- and triesters of glycerol and according to the invention and/or the particle(s), the coating, di- and monoesters of macrogols having molecular the outer matrix material, the capsule filling, and/or the weights within the range of from 200 to 4000 g/mol, granules independently further comprise an acid, preferably e.g., macrogolglycerolcaprylocaprate, macrogolglycer citric acid. The amount of acid is preferably in the range of ollaurate, macrogolglycerolococoate, macrogolglycer 0.01 wt.-% to 20 wt.-%, more preferably in the range of 0.02 ollinoleate, macrogol-20-glycerolmonostearate, mac wt.-% to 10 wt.-%, and still more preferably in the range of rogol-6-glycerolcaprylocaprate, 0.05 wt.-% to 5 wt.-%, and most preferably in the range of macrogolglycerololeate; macrogolglycerolstearate, 0.1 wt.-% to 1.0 wt.-%, based on the total weight of the macrogolglycerolhydroxyStearate, and macrogolglyc dosage form and/or based on the total weight of the particle erolrizinoleate; (S), the coating, the outer matrix material, the capsule filling, 0324 polyglycolyzed glycerides, such as the one and/or the granules, respectively. known and commercially available under the trade 0315. In a preferred embodiment, the dosage form name "Labrasol': according to the invention and/or the particle(s), the coating, 0325 fatty alcohols that may be linear or branched, the outer matrix material, the capsule filling, and/or the Such as cetylalcohol, Stearylalcohol, cetylstearyl alco granules independently further comprise another polymer hol, 2-octyldodecane-1-ol and 2-hexyldecane-1-ol; which is preferably selected from cellulose esters and cel 0326 polyethylene glycols having a molecular weight lulose ethers, in particular hydroxypropyl methylcellulose between 10.000 and 60.000 g/mol; and (HPMC). 0327 natural semi-synthetic or synthetic waxes, pref 0316 The amount of the further polymer, preferably erably waxes with a softening point of at least 50° C., hydroxypropyl methylcellulose, preferably ranges from 0.1 more preferably 60°C., and in particular carnauba wax wt.-% to 30 wt.-%, more preferably in the range of 1.0 wt.-% and bees wax. to 20 wt.-%, most preferably in the range of 2.0 wt.-% to 15 0328 Preferably, the amount of the lubricant ranges from wt.-%, and in particular in the range of 3.5 wt.-% to 10.5 0.01 wt.-% to 10 wt.-%, more preferably in the range of 0.05 wt.-%, based on the total weight of the dosage form and/or wt.-% to 7.5 wt.-%, most preferably in the range of 0.1 based on the total weight of the particle(s), the coating, the wt.-% to 5 wt.-%, and in particular in the range of 0.1 wt.-% outer matrix material, the capsule filling, and/or the gran to 1 wt.-%, based on the total weight of the dosage form ules, respectively. and/or based on the total weight of the particle(s), the 0317. When the polymer matrix of the particle(s) com coating, the outer matrix material, the capsule filling, and/or prises polyalkylene oxide, in a preferred embodiment, the the granules, respectively. relative weight ratio of the polyalkylene oxide to the further 0329. In another preferred embodiment, the dosage form polymer is within the range of 4.5+2:1, more preferably contains no lubricant. 4.5+1.5:1, still more preferably 4.5+1:1, yet more preferably 0330 Preferably, the dosage form according to the inven 4.5+0.5:1, most preferably 4.5+0.2:1, and in particular tion and/or the particle(s), the coating, the outer matrix 4.5+0.1:1. In another preferred embodiment, the relative material, the capsule filling, and/or the granules indepen weight ratio of the polyalkylene oxide to the further polymer dently further comprise a plasticizer. The plasticizer is within the range of 8+7:1, more preferably 8+6:1, still improves the processability of the polymer matrix that more preferably 8+5:1, yet more preferably 8+4:1, most preferably comprises polyalkylene oxide. A preferred plas preferably 8+3:1, and in particular 8+2:1. In still another ticizer is polyalkylene glycol, like polyethylene glycol, preferred embodiment, the relative weight ratio of the poly triacetin, fatty acids, fatty acid esters, waxes and/or micro alkylene oxide to the further polymer is within the range of crystalline waxes. Particularly preferred plasticizers are 11+8:1, more preferably 11+7:1, still more preferably 11+6: polyethylene glycols, such as PEG 6000 (Macrogol 6000). 1, yet more preferably 11+5:1, most preferably 11+4:1, and 0331 Preferably, the content of the plasticizer is within in particular 11+3:1. the range of from 0.5 to 30 wt.-%, more preferably 1.0 to 25 0318. In another preferred embodiment, the dosage form wt.-%, still more preferably 2.5 wt.-% to 22.5 wt.-%, yet and/or the particle(s) according to the invention do not more preferably 5.0 wt.-% to 20 wt.-%, most preferably 6 to contain any further polymer besides the polyalkylene oxide 20 wt.-% and in particular 7 wt.-% to 17.5 wt.-%, based on and optionally, polyethylene glycol. the total weight of the dosage form and/or based on the total 0319. In a preferred embodiment, the dosage form weight of the particle(s), the coating, the outer matrix according to the invention contains at least one lubricant. material, the capsule filling, and/or the granules, respec Preferably, the lubricant is contained in the dosage form tively. outside the particle(s), i.e. the particle(s) as such preferably 0332. In a preferred embodiment, the plasticizer is a do not contain lubricant. The lubricant can be independently polyalkylene glycol having a content within the range of 7-6 contained in the coating, the outer matrix material, and/or wt.-%, more preferably 7+5 wt.-%, still more preferably 7+4 the granules. wt.-%, yet more preferably 7+3 wt.-%, most preferably 7+2 0320 Especially preferred lubricants are selected from wt.-%, and in particular 7+1 wt.-%, based on the total weight 0321 magnesium Stearate and Stearic acid; of the dosage form and/or based on the total weight of the 0322 glycerides of fatty acids, including monoglycer particle(s), the coating, the outer matrix material, the capsule ides, , triglycerides, and mixtures thereof; filling, and/or the granules, respectively. In another preferred US 2017/007 1862 A1 Mar. 16, 2017 25 embodiment, the plasticizer is a polyalkylene glycol having heat. In a preferred embodiment, the particle(s) are thermo a content within the range of 10-8 wt.-%, more preferably formed by hot-melt extrusion. 10+6 wt.-%, still more preferably 10+5 wt.-%, yet more preferably 10+4 wt.-%, most preferably 10+3 wt.-%, and in 0338. In a preferred embodiment, the particle(s) are pre particular 10+2 wt.-%, based on the total weight of the pared by hot melt-extrusion, preferably by means of a dosage form and/or based on the total weight of the particle twin-screw-extruder. Melt extrusion preferably provides a (S), the coating, the outer matrix material, the capsule filling, melt-extruded strand that is preferably cut into monoliths, and/or the granules, respectively. which are then optionally compressed and formed into 0333. In a preferred embodiment, the relative weight particle(s). Preferably, compression is achieved by means of ratio of the polyalkylene oxide to the polyalkylene glycol is a die and a punch, preferably from a monolithic mass within the range of 5.4+2:1, more preferably 5.4+1.5:1, still obtained by melt extrusion. If obtained via melt extrusion, more preferably 5.4+1:1, yet more preferably 5.4+0.5:1, the compressing step is preferably carried out with a mono most preferably 5.4+0.2:1, and in particular 5.4+0.1:1. This lithic mass exhibiting ambient temperature, that is, a tem ratio satisfies the requirements of relative high polyalkylene perature in the range from 20 to 25°C. The strands obtained oxide content and good extrudability. by way of extrusion can either be subjected to the compres 0334 Plasticizers can sometimes act as a lubricant, and sion step as such or can be cut prior to the compression step. lubricants can sometimes act as a plasticizer. This cutting can be performed by usual techniques, for 0335. In preferred compositions of the particle(s) A that example using rotating knives or compressed air, at elevated are preferably hot-melt extruded and that are contained in temperature, e.g. when the extruded Stand is still warm due the dosage form according to the invention, the polymer to hot-melt extrusion, or at ambient temperature, i.e. after matrix comprises a polyalkylene oxide, preferably a poly the extruded strand has been allowed to cool down. When ethylene oxide with a weight average molecular weight the extruded strand is still warm, singulation of the extruded within the range of from 0.5 to 15 million g/mol. strand into extruded particle(s) is preferably performed by 0336. The particle(s) A comprise pharmacologically cutting the extruded strand immediately after it has exited active ingredient a. Particularly preferred embodiments C the extrusion die. It is possible to subject the extruded to C are summarized in the tables here below: Strands to the compression step or to the cutting step when per particle Awt.-% Cl C2 C3 C4 pharmacologically active ingredient a S.SO S.OO 5.50 - 4.OO S.SO 3.00 S.SO 2.00 polyalkylene oxide 6O.OO 35.00 6O.OO 30.00 6O.OO 25.OO 6O.OO 15.OO optionally acid, e.g. citric acid O.80 - 0.75 O.80 - 0.65 O.80 OSO O.80 O.35 optionally plasticizer, e.g. polyethylene 14.00 - 13.5O 1400 10.00 14.OO 7.5O 14.OO S.OO glycol optionally antioxidant, e.g. C-tocopherol O.2O 0.18 O.20 - 0.14 O.20 - 0.10 O.2O O.O6 per particle Awt.-% C5 C6 C7 C8 pharmacologically active ingredient a 15.OO 25.OO 15.OO 20.00 15.OO 15.OO 15.OO 10.OO polyalkylene oxide 6O.OO 35.00 6O.OO 30.00 6O.OO 25.OO 6O.OO 15.OO optionally acid, e.g. citric acid O.80 - 0.75 O.80 - 0.65 O.80 OSO O.80 O.35 optionally plasticizer, e.g. polyethylene 11.OO 8.00 11.OO 6.OO 11.00 S.OO 11.00 - 4.00 glycol optionally antioxidant, e.g. C-tocopherol O.2O 0.18 O.20 - 0.14 O.20 - 0.10 O.2O O.O6 per particle Awt.-% C9 C 10 C11 C12 pharmacologically active ingredient a 3O.OO 25.00 30.00 20.00 3O.OO 15.OO 3OOO 10.OO polyalkylene oxide 6O.OO 35.00 6O.OO 30.00 6O.OO 25.OO 6O.OO 15.OO optionally acid, e.g. citric acid O.80 - 0.75 O.80 - 0.65 O.80 OSO O.80 O.35 optionally plasticizer, e.g. polyethylene 9.OO - 8.00 9.00 - 6.OO 9.OO S.OO 9.OO 4.OO glycol optionally antioxidant, e.g. C-tocopherol O.2O 0.18 O.20 - 0.14 O.20 - 0.10 O.2O O.O6 (all percentages relative to the total weight of the particle(s) A).

0337. In a preferred embodiment of the dosage form still warm, that is more or less immediately after the according to the invention, the particle(s) A and/or the extrusion step. The extrusion is preferably carried out by optionally present particle(s) B are hot melt-extruded. Thus, means of a twin-screw extruder. the particle(s) according to the invention are preferably prepared by melt-extrusion, although also other methods of 0339. The particle(s) of the dosage form according to the thermoforming may be used in order to manufacture the invention may be produced by different processes, the particle(s) according to the invention Such as press-molding particularly preferred of which are explained in greater at elevated temperature or heating of particle(s) that were detail below. Several suitable processes have already been manufactured by conventional compression in a first step described in the prior art. In this regard it can be referred to, and then heated above the softening temperature of the e.g., WO 2005/016313, WO 2005/016314, WO 2005/ polyalkylene oxide in the particle(s) in a second step to form 063214, WO 2005/102286, WO 2006/002883, WO 2006/ hard dosage forms. In this regards, thermoforming means 002884, WO 2006/002886, WO 2006/082097, and WO the forming, or molding of a mass after the application of 2006/082099. US 2017/007 1862 A1 Mar. 16, 2017 26

0340. In general, the process for the production of the 0356. The components may also be mixed in a mixer particle(s) according to the invention preferably comprises known to the person skilled in the art. The mixer may, for the following steps: example, be a roll mixer, shaking mixer, shear mixer or 0341 (a) mixing all ingredients; compulsory mixer. 0342 (b) optionally pre-forming the mixture obtained 0357 The preferably molten, mixture which has been from step (a), preferably by applying heat and/or force to heated in the extruder at least up to the softening point of the mixture obtained from step (a), the quantity of heat polyalkylene oxide is extruded from the extruder through a supplied preferably not being sufficient to heat the poly die with at least one bore, preferably a multitude of bores. alkylene oxide up to its softening point; 0358. The process according to the invention requires the 0343 (c) hardening the mixture by applying heat and use of suitable extruders, preferably screw extruders. Screw force, it being possible to Supply the heat during and/or extruders which are equipped with two screws (twin-screw before and/or after the application of force and the quan extruders) are particularly preferred. tity of heat supplied being sufficient to heat the polyalky 0359 Preferably, extrusion is performed in the absence of lene oxide at least up to its softening point; and thereafter water, i.e., no water is added. However, traces of water (e.g., allowing the material to cool and removing the force caused by atmospheric humidity) may be present. 0344 (d) optionally singulating the hardened mixture; 0360. The extruder preferably comprises at least two and temperature Zones, with heating of the mixture at least up to the softening point of the polyalkylene oxide proceeding in 0345 (e) optionally providing a film coating. the first Zone, which is downstream from a feed Zone and 0346. In a preferred embodiment, the mixture is com optionally mixing Zone. The throughput of the mixture is pressed and Subsequently heated. In another preferred preferably from 1.0 kg to 15 kg/hour. In a preferred embodi embodiment, the mixture is heated and Subsequently com ment, the throughput is from 0.5 kg/hour to 3.5 kg/hour. In pressed. In still another preferred embodiment, the mixture another preferred embodiment, the throughput is from 4 to is heated and compressed simultaneously. A skilled person 15 kg/hour. recognizes that combinations of these embodiments accord 0361. In a preferred embodiment, the die head pressure is ing to the invention are also possible. within the range of from 25 to 200bar. The die head pressure 0347 Heat may be supplied directly, e.g. by contact or by can be adjusted inter alia by die geometry, temperature means of hot gas such as hot air, or with the assistance of profile, extrusion speed, number of bores in the dies, screw ultrasound; or is indirectly supplied by friction and/or shear. configuration, first feeding steps in the extruder, and the like. Force may be applied and/or the particle(s) may be shaped 0362. The die geometry or the geometry of the bores is for example by direct tabletting or with the assistance of a freely selectable. The die or the bores may accordingly suitable extruder, particularly by means of a screw extruder exhibit a round, oblong or oval cross-section, wherein the equipped with one or two screws (single-screw-extruder and round cross-section preferably has a diameter of 0.1 mm to twin-screw-extruder, respectively) or by means of a plan 2 mm, preferably of 0.5 mm to 0.9 mm. Preferably, the die etary gear extruder. or the bores have a round cross-section. The casing of the 0348. The final shape of the particle(s) may either be extruder used according to the invention may be heated or provided during the hardening of the mixture by applying cooled. The corresponding temperature control, i.e. heating heat and force (step (c)) or in a Subsequent step (step (e)). In or cooling, is so arranged that the mixture to be extruded both cases, the mixture of all components is preferably in the exhibits at least an average temperature (product tempera plastified State, i.e. preferably, shaping is performed at a ture) corresponding to the Softening temperature of the temperature at least above the softening point of the poly polyalkylene oxide and does not rise above a temperature at alkylene oxide. However, extrusion at lower temperatures, which the pharmacologically active ingredient a to be pro e.g. ambient temperature, is also possible and may be cessed may be damaged. Preferably, the temperature of the preferred. mixture to be extruded is adjusted to below 180° C. 0349. A particularly preferred process for the manufac preferably below 150° C., but at least to the softening ture of the particle(s) according to the invention involves temperature of polyalkylene oxide. Typical extrusion tem hot-melt extrusion. In this process, the particle(s) according peratures are 120° C. and 150° C. to the invention are produced by thermoforming with the 0363. In a preferred embodiment, the extruder torque is assistance of an extruder, preferably without there being any within the range of from 30 to 95%. Extruder torque can be observable consequent discoloration of the extrudate. adjusted inter alia by die geometry, temperature profile, 0350 This process is characterized in that extrusion speed, number of bores in the dies, screw con 0351 a) all components are mixed, figuration, first feeding steps in the extruder, and the like. 0364. After extrusion of the molten mixture and optional 0352 b) the resultant mixture is heated in the extruder at cooling of the extruded strand or extruded strands, the least up to the softening point of the polyalkylene oxide extrudates are preferably singulated. This singulation may and extruded through the outlet orifice of the extruder by preferably be performed by cutting up the extrudates by application of force, means of revolving or rotating knives, wires, blades or with 0353 c) the still plastic extrudate is singulated and the assistance of laser cutters. formed into the particle(s) or 0365 Preferably, intermediate or final storage of the 0354 d) the cooled and optionally reheated singulated optionally singulated extrudate or the final shape of the extrudate is formed into the particle(s). particle(s) according to the invention is performed under 0355 Mixing of the components according to process oxygen-free atmosphere which may be achieved, e.g., by step a) may also proceed in the extruder. means of oxygen-Scavengers. US 2017/007 1862 A1 Mar. 16, 2017 27

0366. The singulated extrudate may be press-formed into 0380 Accordingly, “extruded pellets' can be obtained particle(s) in order to impart the final shape to the particle(s). either by hot-melt extrusion or by extrusion-spheronization. 0367 The application of force in the extruder onto the at 0381) “Extruded pellets' can be distinguished from other least plasticized mixture is adjusted by controlling the types of pellets, as extruded pellets typically have a different rotational speed of the conveying device in the extruder and shape. The shape of the extruded pellets is typically more the geometry thereof and by dimensioning the outlet orifice cut-rod-like than perfectly globated round. in Such a manner that the pressure necessary for extruding 0382 “Extruded pellets' can be distinguished from other the plasticized mixture is built up in the extruder, preferably types of pellets because they are structurally different. For immediately prior to extrusion. The extrusion parameters example, drug layering on nonpareils yields multilayered which, for each particular composition, are necessary to give pellets having a core, whereas extrusion typically yields a rise to a dosage form with desired mechanical properties, monolithic mass comprising a homogeneous mixture of all may be established by simple preliminary testing. ingredients. Similarly, spray drying and spray congealing 0368 For example but not limiting, extrusion may be typically yield spheres, whereas extrusion typically yields performed by means of a twin-screw-extruder type ZSE 18 cylindrical extrudates which can be Subsequently or ZSE27 (Leistritz, Nurnberg, Germany), screw diameters spheronized. of 18 or 27 mm. Screws having eccentric or blunt ends may (0383. The structural differences between “extruded pel be used. Aheatable die with a round bore or with a multitude lets' and 'agglomerated pellets” are significant because they of bores each having a diameter of 0.2,0.3, 0.4,0.5,0.6, 0.7. may affect the release of active substances from the pellets 0.8, 0.9 or 1.0 mm may be used. For a twin-screw-extruder and consequently result in different pharmacological pro type ZSE 18, the extrusion parameters may be adjusted e.g. files. Therefore, a person skilled in the pharmaceutical to the following values: rotational speed of the screws: 120 formulation art would not consider “extruded pellets” to be Upm; delivery rate 2 kg/h for a ZSE 18 or 5 kg/h, 10 kg/h, equivalent to 'agglomerated pellets'. or even 20 kg/hand more for a ZSE27; product temperature: 0384 The dosage forms according to the invention may in front of die 125° C. and behind die 135° C.; and jacket be prepared by any conventional method. Suitable methods temperature: 110° C. The throughput can generally be and apparatuses are known to the skilled person. increased by increasing the number of dies at the extruder 0385 When the dosage form is a capsule, all components outlet. may be filled separately or as admixture into the capsules. 0369 Preferably, extrusion is performed by means of Said components may include but are not limited to particle twin-screw-extruders or planetary-gear-extruders, twin (s) A, which may optionally be provided with a coating screw extruders (co-rotating or contra-rotating) being par comprising optionally present pharmacologically active ticularly preferred. ingredient b or portion b, thereof, the optionally present 0370. The particle(s) according to the invention are pref particle(s) B, the optionally present powder of optionally erably produced by thermoforming with the assistance of an present pharmacologically active ingredient b, and the extruder without any observable consequent discoloration of optionally present granules of optionally present pharmaco the extrudates. The particle(s) may be produced e.g. by logically active ingredient b, respectively. means of a Micro Pelletizer (Leistritz, Nurnberg, Germany). 0386. When the dosage form is a tablet, the tablet is 0371. The process for the preparation of the particle(s) preferably prepared by compression. Thus, particle(s) are according to the invention is preferably performed continu preferably mixed, e.g. blended and/or granulated (e.g. wet ously. Preferably, the process involves the extrusion of a granulated), e.g. with matrix material of the preferred table homogeneous mixture of all components. It is particularly according to the invention, the optionally present powder of advantageous if the thus obtained intermediate, e.g. the optionally present pharmacologically active ingredient band strand obtained by extrusion, exhibits uniform properties. the optionally present granules of optionally present phar Particularly desirable are uniform density, uniform distribu macologically active ingredient b, respectively, and the tion of the active compound, uniform mechanical properties, resulting mix (e.g. blend or granulate) is then compressed, uniform porosity, uniform appearance of the Surface, etc. preferably in moulds, to form dosage forms. It is also Only under these circumstances the uniformity of the phar envisaged that the particle(s) may be incorporated into a macological properties, such as the stability of the release matrix using other processes, such as by melt granulation profile, may be ensured and the amount of rejects can be kept (e.g. using fatty alcohols and/or water-soluble waxes and/or low. water-insoluble waxes) or high shear granulation, followed 0372 Preferably, the particle(s) according to the inven by compression. tion can be regarded as “extruded pellets”. The term 0387 When the dosage forms according to the invention “extruded pellets” has structural implications which are are manufactured by means of an eccentric press, the com understood by persons skilled in the art. A person skilled in pression force is preferably within the range of from 5 to 30 the art knows that pelletized dosage forms can be prepared kN, preferably from 15 to 25 kN. When the dosage forms by a number of techniques, including: according to the invention are manufactured by means of a 0373 drug layering on nonpareil Sugar or microcrys rotating press, the compression force is preferably within the talline cellulose beads, range of from 5 to 40 kN, in certain embodiments >25 kN, 0374 spray drying, in other embodiments 13 kN. 0388. The pharmaceutical dosage form according to the 0375 spray congealing, invention preferably comprises no wax ingredients. Wax 0376 rotogranulation, ingredients include fatty acid esters, glycerol fatty acid 0377 hot-melt extrusion, esters, fatty glyceride derivatives, waxes, and fatty alcohols 0378 spheronization of low melting materials, or Such as, for example, glycerol behenate, glycerol palmito 0379 extrusion-spheronization of a wet mass. Stearate, glycerol monostearate, Stearoyl macroglycerides. US 2017/007 1862 A1 Mar. 16, 2017 28

Other waxes more generally include insect and animal 0397) The following examples further illustrate the waxes, vegetable waxes, mineral waxes, petroleum waxes, invention but are not to be construed as limiting its scope. and synthetic waxes; particularly examples include bees 0398 Inventive Example 1 and Comparative Example 1 wax, carnauba wax, condelilla wax, montan wax, ouricury both relate to a combination comprising 10 mg hydrocodone wax, rice-bran wax, jojoba wax, microcrystalline wax, cetyl and 325 mg acetaminophen. Comparative Example 1 is ester wax, cetyl alcohol, anionic emulsifying wax, nonionic based on a commercial product. emulsifying wax and paraffin wax. 0399 Inventive Example 2 and Comparative Example 2 0389. The pharmaceutical dosage form according to the both relate to a combination comprising 5 mg hydrocodone invention comprises particle(s) A which preferably neither and acetaminophen. Inventive Example 2 relates to a dose of comprise an active pharmaceutical layer comprising a phar 325 mg acetaminophen, whereas Comparative Example 2 macologically active ingredient nor a layer comprising a relates to a dose of 300 mg acetaminophen. This minor pH-sensitive film comprising a pH-sensitive polymer that is difference, however, is not significant for the effect as insoluble in water at a pH greater than 5 and is soluble in demonstrated by this comparative experimental setting. water at a pH below 5. Comparative Example 2 is based on a commercial product. 0390 The particle(s) A and dosage forms according to the 0400 Inventive Example 3 and Comparative Example 3 invention may be used in medicine, e.g. as an . The both relate to a composition containing 10 mg amphetamine particle(s) A and dosage forms are therefore particularly as the only pharmacologically active ingredient. Compara Suitable for the treatment or management of pain. In Such dosage forms, the pharmacologically active ingredient a is tive Example 3 is based on a commercial product. preferably an analgesic. INVENTIVE EXAMPLE 1. 0391) A further aspect according to the invention relates to the dosage form as described above for use in the 10 mg Hydrocodone+325 mg Acetaminophen treatment of pain. A further aspect of the invention relates to the use of a pharmacologically active ingredient a and/or of 04.01 Tablets containing a combination of hydrocodone an optionally present pharmacologically active ingredient b with acetaminophen were manufactured from for the manufacture of a dosage form according to the 0402 hot melt extruded pellets comprising hydroco invention for the treatment of pain. A further aspect of the done (particles A comprising pharmacologically avtive invention relates to a method for the treatment of pain ingredient a); comprising the administration, preferably oral administra 0403 granules comprising acetaminophen (pharmaco tion of a dosage form according to the invention to a subject logically avtive ingredient b); and in need thereof. 0392 A further aspect according to the invention relates 04.04 powder. to the use of a dosage form according to the invention for 04.05 Powder mixtures of the various ingredients for the avoiding or hindering the abuse of the pharmacologically pellets were manufactured by weighing (10 kg balance), active ingredient a and optionally also of the optionally sieving (1.0 mm hand sieve) and blending. The thus obtained present pharmacologically active ingredient b contained powder mixtures were then hot-melt extruded (twin-screw therein. extruder, Leistritz ZSE 18, blunt ends of kneading elements, 0393 A further aspect according to the invention relates and extrusion diameter of 8x0.8 mm). The extrusion param to the use of a dosage form according to the invention for eters are summarized in the table here below: avoiding or hindering the unintentional overdose of the pharmacologically active ingredient a contained therein. Extrusion parameter set: 0394. In this regard, the invention also relates to the use of a pharmacologically active ingredient a and/or of an Extrusion temperature C. 100-135° C. nozzle C. 135 optionally present pharmacologically active ingredient b for speed screw rpm 1OO the manufacture of the dosage form according to the inven die diameter mm O.8 tion for the prophylaxis and/or the treatment of a disorder, thereby preventing an overdose of the pharmacologically active ingredient a, particularly due to comminution of the 0406. The thus obtained cut extrudates were pelletized dosage form by mechanical action. (LMP). 0395. Another aspect of the invention relates to the use of 0407. The granules comprising acetaminophen were a pharmaceutical dosage form according to the invention as separately prepared by conventional granulation. A powder described above for the prevention of an overdose of phar mixture comprising acetaminophen was prepared and thor macologically active ingredient a after accidental or inten oughly blended by means of a rapid mixer/granulator (Di tional simultaneous administration of a plurality of the osna R. P10-60, chopper switched off) for 5 min at 90 rpm. dosage forms containing an overall Supratherapeutic dose of A granulation solution was prepared from purified water and the pharmacologically active ingredient a. hypromellose. The solution was stirred for 15 min at 550 0396 Another aspect of the invention relates to method rpm and 70° C. The powder mixture was granulated by for the prevention of an overdose of pharmacologically adding the granulation solution over 1:30 min in the rapid active ingredient a after accidental or intentional simultane mixer/granulator (Diosna R. P10-60, chopper at 500 rpm) for ous administration of a plurality of dosage forms containing 5 min at 135 rpm. an overall Supratherapeutic dose of the pharmacologically 0408. The pellets were then mixed with the granules and active ingredient a, the method comprising the provision of with powder and the thus obtained mixture was subse a pharmaceutical dosage form according to the invention as quently compressed to tablets (Korsch XL400). The tablet described above. ting parameters are summarized in the table here below: US 2017/007 1862 A1 Mar. 16, 2017 29

-continued Tablet form: tableting parameter set: per tablet per tablet Amount Tablet weight = 708.2 mg tablet weight mg 708.2 mg form mg Substance %) Punch form = oblong 7 x 17 mm breaking strength (tablet) N. 86 113.73 microcrystalline cellulose, 16.06 WR 4.5 without engraving type 101

708.20 1OOOO 04.09. The compositions of the hot-melt extruded pellets, the granules and the powder as well as their relative contents 0410. While a dose of 10 mg hydrocodone in combina in the overall tablets are summarized in the table here below: tion with a dose of 325 mg acetaminophen is a therapeutic dose, a plurality of Such dosage forms contains an overall Supratherapeutic dose of hydrocodone and acetaminophen. per tablet per tablet Amount 0411. In order to simulate the situation after accidental or ng form ng Substance intentional simultaneous administration of a plurality of the dosage forms according to Inventive Example 1, the in vitro 18O.OO Pellets 10.00 hydrocodone bitartrate 1.44 citric acid release profiles were measured under modified conditions. 24.70 polyglycol 6000 The testing conditions were varied, particularly with respect O.36 C-tocopherole to the overall volume of the release medium (900 mL, 600 9.00 Xanthan gum mL, and 250 mL). The in vitro release profiles of these 98.50 polyethylene oxide 7 mio. dosage forms were measured at 37° C. by means of a paddle 36.00 croscarmellose sodium apparatus without sinker in 0.1M HCl (in each case number 528.20 Outer 325.00 acetaminiophen 57.23 of replicates n=3). Unless expressly stated otherwise, the matrix 30.00 croscarmellose sodium paddle speed was adjusted to 25 rpm. The results of the in 45.00 microcrystalline cellulose, vitro release measurements are shown in the tables here type 101 S.29 hypromellose below. 2.28 magnesium Stearate O.32 0412 Condition a) 25 rpm, 900 mL: 6.90 silicondioxide 0.97 0413 Hydrocodone—Pharmacologically Avtive Ingredi ent a:

1 5 tablets 10 tablets 1 5 10 tablet IIS IIS tablet tablets tablets mg per tablet all 5 per tablet all 10 % %) % O min O.OO O.OO O.OO O.OO O.OO O.OO O.OO O.OO 15 min 3.33 1.61 8.OS O.89 8.93 33.29 16.08 8.89 30 min 4.13 1.97 9.83 1.2O 12.00 41.33 19.70 12.01 60 min 4.87 2.43 12.17 1.46 14.63 48.69 24.35 14.64

0414. It becomes clear from the above data that the dosage forms according to Inventive Example 1 are useful for avoiding overdose upon multiple dosing. For example, while a single dosage form has released 4.13 mg hydroco done after 30 minutes, when a multitude of 5 dosage forms is tested thereby simulating 5-fold multiple dosing, one dosage form within the group of 5 dosage form has released only 1.97 mg hydrocodone after 30 minutes. When a mul titude of 10 dosage forms is tested thereby simulating 10-fold multiple dosing, one dosage form within the group of 10 dosage forms has even only released 1.20 mg hydro codone after 30 minutes. 0415 Acetaminophen Pharmacologically Avtive Ingre dient b:

1 5 tablets 10 tablets 1 5 10 tablet ng ng tablet tablets tablets

ng per tablet all 5 per tablet all 10 % %) %

O min O.OO O.OO O.OO O.OO O.OO O.OO O.OO O.OO 15 min 101.16 SO.91 2S453 31.36 313.57 31.12 15.67 9.65 30 min 123.13 60.74 303.68 51.2O 511.97 37.89 1869 15.75 60 min 141.62 72.39 361.97 45.53 455.27 43.58 22.28 14.01 US 2017/007 1862 A1 Mar. 16, 2017 30

0416. It becomes clear from the above data that the not only affect the pharmacologically active ingredient a that dosage forms according to Inventive Example 1 are useful is embedded in the polyalkylene oxide in particle(s) A, but for avoiding overdose upon multiple dosing of both phar also the optionally present pharmacologically active ingre macologically active ingredients. For example, while a single dosage form has released 123.13 mg acetaminophen dient b that may be present elsewhere in the dosage form. after 30 minutes, when a multitude of 5 dosage forms is 0418 The in vitro release profiles with respect to the tested thereby simulating 5-fold multiple dosing, one dosage release of hydrocodone (pharmacologically active ingredi form within the group of 5 dosage form has released only 60.74 mg acetaminophen after 30 minutes. When a multi ent a) are shown in FIG. 3. The in vitro release profiles with tude of 10 dosage forms is tested thereby simulating 10-fold respect to the release of acetaminophen (optionally present multiple dosing, one dosage form within the group of 10 pharmacologically active ingredient b) are shown in FIG. 4. dosage forms has even only released 51.20 mg acetamino phen after 30 minutes. 0419 Condition b)) 25 rpm, 600 mL: 0417 Thus, as demonstrated by the above data, the 0420 Hydrocodone Pharmacologically Avtive Ingredi advantages of the dosage form according to the invention do ent a:

1 5 tablets 10 tablets 1 5 10 tablet IIS IIS tablet tablets tablets le:8 mg per tablet all 5 per tablet all 10 % %) % O min O.OO O.OO O.OO O.OO O.OO O.OO O.OO O.OO 15 min 3.80 1.57 7.85 O.98 9.80 37.97 15.72 9.8O 30 min 4.65 1.94 9.68 1.32 13.23 46.45 1936 13.23 60 min 5.57 2.36 11.8O 1.65 16.53 SS-67 23.60 16.52

0421 Acetaminophen Pharmacologically Avtive Ingre dient b:

1 5 tablets 10 tablets 1 5 10 tablet IllS. IllS. tablet tablets tablets le:8 mg per tablet all 5 per tablet all 10 % %) % O min O.OO O.OO O.OO O.OO O.OO O.OO O.OO O.OO 15 min 105.72 S2.13 260.65 37.04 370.37 32.53 16.04 11.39 30 min 128.05 64.27 321.35 45.64 456.4O 39.40 1978 14.04 60 min 150.39 76.09 380.45 S3.13 531.30 46.27 23.41 16.35

0422 Condition c) 25 rpm, 250 mL: 0423 Hydrocodone Pharmacologically Avtive Ingredi ent a:

1 5 tablets 10 tablets 1 5 10 tablet IIS IIS tablet tablets tablets le:8 mg per tablet all 5 per tablet all 10 % %) % O min O.OO O.OO O.OO O.OO O.OO O.OO O.OO O.OO 15 min 2.96 1.34 6.68 122 12.23 29.63 13.39 12.24 30 min 4.25 1.76 8.78 1.61 16.1O 42.51 17.57 16.06 60 min 5.14 2.28 11.38 1.97 1973 S139 22.78 19.73

0424 Acetaminophen Pharmacologically Avtive Ingre dient b:

1 5 tablets 10 tablets 1 5 10 tablet ng ng tablet tablets tablets

le:8 mg per tablet all 5 per tablet all 10 % %) %

O min O.OO O.OO O.OO O.OO O.OO O.OO O.OO O.OO 15 min 122.35 62.82 314.08 57.73 577.30 37.65. 19.33 17.87 Mar. 16, 2017

-continued

1 5 tablets 10 tablets 1 5 10 tablet IIS IIS tablet tablets tablets le:8 mg per tablet all 5 per tablet all 10 % % % 30 min 157.45 76.26 381.28 68.26 682.63 48.45 23:46 21.01 60 min 17757 91.23 456.15 76.67 766.7O 54.64 28.07 23.59

COMPARATIVE EXAMPLE 1. 0430 Condition 2: 25 rpm, 250 mL. 0431 Hydrocodone Pharmacologically Avtive Ingredi 10 mg Hydrocodone+325 mg Acetaminophen ent a: 0425 Commercial tablets (Norco(R), Watson Pharma) containing the same dose of hydrocodone and acetamino 1 tablet 10 tablets Ing 1 tablet 10 tablets phen and having the following qualitative composition were le:8 ng per tablet all 10 % % tested for comparison: O min O.OO O.OO O.OO O.OO O.OO 15 min 4.47 4.19 41.93 44.7O 41.93 30 min 5.36 5.30 53.03 53.55 53.05 60 min 6.88 6.13 61.33 68.8O 61.33 Substance

hydrocodone bitartrate 0432 Acetaminophen Pharmacologically Avtive Ingre acetaminophen dient b: croscarmellose sodium crospovidone 1 tablet 10 tablets Ing 1 tablet 10 tablets magnesium stearate cellulose, microcrystalline (8. Ing per tablet all 10 % % povidone S O min O.OO O.OO O.OO O.OO O.OO starch, corn 15 min 142.07 133.69 1336.87 43.71 41.13 30 min 178.55 177.74 1777.37 54.94 54.69 Stearic acid 60 min 221.90 2O7.28 2O72.8O 68.28 63.78

0433. It becomes clear from the above data that the 0426. The in vitro dissolution was tested in accordance dosage forms according to Comparative Example 1 are not with Example 1. useful for avoiding overdose upon multiple dosing of both 0427 Condition 1:50 rpm, 900 mL. pharmacologically active ingredients. When a multitude of 10 dosage forms is tested thereby simulating 10-fold mul 0428 Hydrocodone Pharmacologically Avtive Ingredi tiple dosing, the release is not significantly altered (10 ent a: dosage forms according to Comparative Example 1 vs. 1 dosage form according to Comparative Example 1).

1 tablet 10 tablets Ing 1 tablet 10 tablets INVENTIVE EXAMPLE 2 le:8 ng per tablet all 10 % % 5 mg Hydrocodone+325 mg Acetaminophen O min O.OO O.OO O.OO O.OO O.OO 15 min 9.52 8.8O 88.03 95.17 88.03 0434 In accordance with Inventive Example 1, tablets 30 min 9.45 9.57 95.70 94.56 95.69 were prepared comprising hot-melt extruded pellets, gran 60 min 9.52 941 94.13 95.14 94.13 ules and powder as summarized in the table here below containing 5 mg hydrocodone+325 mg acetaminophen: 0429 Acetaminophen Pharmacologically Avtive Ingre dient b: per per tablet tablet Amount mg form mg Substance % 1 tablet 10 tablets Ing 1 tablet 10 tablets 180.00 Pellets 5.00 hydrocodone bitartrate 25.42 1.44 citric acid le:8 ng per tablet all 10 % % 26.50 macrogole 6000 O min O.OO O.OO O.OO O.OO O.OO 0.36 C-tocopherole 15 min 3.28.45 300.86 3008.63 101.06 92.57 9.00 xanthan gum 30 min 330.31 327.04 3270.37 101.63 100.63 101.70 polyethylene oxide 7 mio. 60 min 330.15 321.25 3212. SO 101.59 98.85 36.00 croscarmellose sodium 528.20 Outer 325.00 acetaminophen 57.23 matrix 30.00 croscarmellose sodium US 2017/007 1862 A1 Mar. 16, 2017 32

-continued -continued

per per TIMagc Fed state Fasted state tablet tablet Amount mg form mg Substance % Gastric start residue 10 g 30 g 45.00 microcrystalline cellulose, type 101 5.29 hypromellose Gastric electrolyte solution 70 g 2.28 magnesium stearate O.32 Gastric emptying T/3 80 min 20 min 6.90 silicondioxide 0.97 113.73 microcrystalline cellulose, type 101 16.06 Gastric pH 6.5 to 1.7 in 180 min 3.0 to 1.8 in 30 min

708.20 1OOOO 0439. The high fat meal (HFM) was used for fed state experiments as recommended by the FDA for clinical stud COMPARATIVE EXAMPLE 2 ies (FDA, CDER Guidance for Bioavailability and Fed Bioeduivalence). This meal contained 50 energy '% fat, 20 5 mg Hydrocodone-300 mg Acetaminophen energy '% protein and 30 energy '% in the form of carbohy drates. The meal was composed of eggs, bacon, toast bread, 0435 For comparative purposes, a commercial product potatoes, milk, butter and margarine. The meal was prepared (Vicodin(R), AbbVie Inc.) containing the same dose of hydro as one batch, divided in portions (160 g) and stored below codone and 300 mg acetaminophen was tested. -18°C. Per TIMagc run one portion of the meal was used. 0436. In order to even more realistically simulate the Gastric Secretions are composed of gastric enzymes, namely situation in the gastrointestinal tract, the TIMagc system was lipase, pepsin and (Swallowed) alpha-amylase, sodium used for testing release. The advanced gastric compartment acetate buffer, as well as gastric electrolyte solution (NaCl, of the TIMagc system realistically simulates gastric shape KC1, CaClx2H2O). Gastric starting fluid was composed of and motility and the consequent forces that are applied to 15 g gastric electrolyte solution and 15 g HPMC (0.4%) plus dosage forms and food. This compartment can be used as bile (0.04%). standalone or as part of the TIM gastrointestinal systems to evaluate the bio-accessibility (availability for absorption) of 0440 The in vitro gastrointestinal model TIM equipped nutrients. TIM is the dynamic in vitro gastro-intestinal with the advanced gastric compartment was used. The model that simulates very closely the Successive conditions compartment consisted of a body part and the distal and of the stomach and small intestine. In the TIMagc the proximal antrum. luminal conditions in the stomach are accurately simulated 0441 FIG. 7 schematically illustrates the TIMagc repre under computer-controlled conditions. The TIMagc system senting A: gastric body; B: proximal antrum, C: distal was designed and validated for the in Vivo situation (see (terminal) antrum; D: pyloric sphincter. Bellmann et al., Development of an advanced in vitro model of the stomach for studying the gastric behaviour of com 0442. Removal and addition of warm water (37°C.) into pounds. Food Res. Internat. 2016). the jacket results in peristaltic movements between the distal 0437. The following experiments were performed for the and proximal antrum. Gastric Secretions, comprising gastric following test products: enzymes and gastric acid entered the TIMagc in the gastric body (FIG. 7, part A). The TIMagc emptied over time as a result of the pre-set gastric emptying curve according to the hydrocodone/acetaminophen fed state or fasted state profile.

Fasted state Fed state 0443) The gastric effluent was collected at the following time points: 5, 10, 15, 20, 30, 45 and 60 minutes in the fasted 1 tablet of Inventive Example 2 1 tablet of Inventive Example 2 5 tablets of Inventive Example 2 state and at 10, 15, 20, 30, 45, 60,90, 120, 150, 180 minutes 10 tablets of Inventive Example 2 10 tablets of Inventive Example 2 in the fed state. At the end of each experiment all residual 10 tablets of Comparative Example 2 10 tablets of Comparative Example material was collected by a pipet from the TIMagc and the (Vicodin (R) 2 (Vicodin (R) compartment was rinsed once with 50 ml warm water. Withdrawn samples were directly treated for sample analy 0438. The duration of each experiment in the fasted state sis by the sponsor. was 60 minutes, in the fed state 180 minutes. Composition 0444 The absolute amount of each pharmacologically of the gastric intake (meal matrix) fasted or fed State active ingredient (hydrocodone and acetaminophen, respec conditions and simulated gastric parameters for each con tively) recovered in the gastric effluent was calculated by ditions are summarized in the table here below: multiplying the analyzed concentration in the sample with the collected Volume (equation 1). Data are expressed as cumulative percentage of the intake of pharmacologically TIMagc Fed state Fasted state active ingredient: Intake (total) 300 g 270 g High fat meal (HFM) 150 g Citrate buffer 27g Water 70 g 213 g 0445. The results of the duplicate TIMagc runs are pre sented as mean-trange. US 2017/007 1862 A1 Mar. 16, 2017 33

0446. The numerical results (cumulative values) for hydrocodone are summarized in the tables here below: 0447 Hydrocodone cumulative amount % LS-fasted State:

1 tablet 10 tables of inv. of inv. 1 tablet 10 tablets 10 tablets ex. 2 in ex. 2 in of inv. ex. of inv. ex. 5 tablets of comp. ex. Time O.1M 2 in blank 2 in blank of inv. ex. 2 in blank

min HCI HCI #1 #2 2 in blank 5 O.S2 O.12 O.S1 O.17 O.17 O.S6 O16 O16 O16 10 3.25 O.70 2.04 1.17 O.66 1.93 O.90 O.40 O.93 15 6.61 1.76 4.67 3.48 1.58 3.13 1.97 2.52 3.11 2O 11...SO 3.14 8.22 6.27 3.81 4.86 3.68 7.12 6.72 30 23.81 1S.OO 22.15 17.52 1139 12.86 1140 24.64 23.56 45 42.38 29.35 40.32 38.94 28.49 25.02 30.01 54.75 S2.36 60 60.12 44.08 58.75 54.78 44.66 35.7O 4473 69.94 68.00 Residue 84.92 62.42 93.59 83.02 64.29 SS.44 70.58 86.91 90.36 Rinse 89.32 70.68 95.36 83.83 70.21 60.45 75.89 90.48 93.06

0448 Hydrocodone cumulative amount % LSI-fed 0450 A comparison of the fasted state experiments for State: hydrocodone is shown in FIG. 8: Fasted state cumulative gastric effluent of hydrocodone as percentage (%) of intake of 1 tablet (0), 10 tablets (), 5 tablets (X) and Vicodin 10 1 tablet 10 tablets 10 tablets tablets (A), meantrange, n=2, hydrocodone 5 tablets: n=1. Time min of inv. ex. 2 of inv. ex. 2 of comp. ex. 2 gastric emptying curve (black line). 0451 A comparison of the fed state experiments for 10 O.OO O.OO O.OO hydrocodone is shown in FIG. 9: Fed state cumulative 15 O.OO O.OO O.OO 2O O.OO O.OO O.OO gastric effluent of hydrocodone as percentage (%) of intake 30 O.OO O.OO O.OO of 1 tablet (0), 10 tablets () and Vicodin 10 tablets (A) 45 O.OO O.OO O.OO state, n=1, gastric emptying curve (black line). 60 O.OO 1.93 O.OO 0452. A comparison of fasted versus fed state experi 90 O.OO 15.56 O.OO ments for hydrocodone is shown in FIGS. 10A, 10B and 120 44.31 50.53 55.57 10C: Fasted versus fed state cumulative gastric effluent of 150 67.24 78.52 82.31 hydrocodone as percentage (%) of intake of 1 tablet (A), 10 18O 93.15 91.72 94.38 tablets (B) and Vicodin 10 tablets (C) state, n=1, dotted lines Residue 106.07 97.81 98.24 indicate fasted State, Solid lines indicate fed State, gastric Rinse 106.78 98.20 99.26 emptying curve (black lines). 0453 The numerical results (cumulative values) for acet aminophen are summarized in the tables here below: 0449 The results for hydrocodone are also illustrated by 0454 Acetaminophen cumulative amount % LS fasted FIGS 8 to 10. State:

1 tablet 10 tables of inv. of inv. 1 tablet 10 tablets 10 tablets 10 tablets ex. 2 in ex. 2 in of inv. ex. of inv. ex. 5 tablets of comp. ex. of comp. ex. Time O-1M O-1M 2 in blank 2 in blank of inv. ex. 2 in blank 2 in blank

min HCI HCI #1 #2 #1 #2 2 in blank #1 #2

5 2.67 O60 140 (0.84 1.05 4:29 1.27 O.13 O.14 10 9.10 22O 4.37 3.02 2.98 12.09 4.82 O.35 O.90 15 13.88 3.80 7.51 S.89 4.84 18.66 7.68 1.76 2.45 2O 1916 5.33 10.80 8.6S 7.67 24.84 10.54 4.28 4.58 30 29.74 1839 22.00 18.86 16.19 38.85 19.72 14.45 14.78 45 44.95 32.43 37.11 39.96 32.66 53.4O 39.54 35.63 35.65 60 59.71 45.76 S1.72 SS.40 45.64 64.09 S2.77 48.90 48.91 Residue 77.60 59.3S 76.86 79.54 59.47 79.01 73.00 68.2O 72.53 Rinse 8347 65.68 81.99 84.89 64.14 82.58 77.45 82.39 83.89 US 2017/007 1862 A1 Mar. 16, 2017 34

0455 Acetaminophen cumulative amount % LSI-fed State: per capsule ng wt.-% amphetamine Sulfate 1O.OO 7.76 polyethylene oxide M.7 mio 67.32 52.21 1 tablet 10 tablets 10 tablets macrogole 6000 16.03 12.43 Time min of inv. ex. 2 of inv. ex. 2 of comp. ex. 2 C-tocopherole O.24 O.19 pregelatinized maize starch 26.41 20.48 15 O.12 O.04 O.OO Opadry (R) clear 85F 8.93 6.93 128.93 100.00 30 O3S O.15 O.OO 45 O.63 O.63 O.OO 60 O.94 2.75 O.O1 90 2.22 17.71 O48 0462. The pellets were filled into capsules (Capsugel(R) 120 37.27 49.09 39.72 150 58.46 71.41 63.09 transparent, coni Snap), size 2. 18O 8456 82.47 7434 Residue 97.72 87.71 78.34 Rinse 98.70 88.17 79.76 COMPARATIVE EXAMPLE 3

0456. The results for acetaminophen are illustrated by 10 mg Amphetamine FIGS 11 to 13. 0457. A comparison of fasted state experiments for acet 0463 For comparative purposes, commercial tablets aminophen is shown in FIG. 11: Fasted state cumulative (Evekeo(R), Arbor Pharmaceuticals) containing the same gastric effluent of acetaminophen as percentage (%) of dose of amphetamine sulfate were tested. intake of 1 tablet (0), 10 tablets (), 5 tablets (X) and Vicodin 10 tablets (A), meantrange, n=2, acetaminophen 5 0464. In accordance with Inventive Example 2 and Com tablets: n-1, gastric emptying curve (black line). parative Example 2 (TIMagc system), the following experi 0458. A comparison of fed state experiments for acet ments were performed for the following test products (the aminophen is shown in FIG. 12: Fed state cumulative gastric capsules/tablets were tested as such as well as the pellets effluent of acetaminophen as percentage (%) of intake of 1 contained in Such capsules after removal of the capsule): tablet (0), 10 tablets () and Vicodin 10 tablets (A) state, n=1, gastric emptying curve (black line). 0459. A comparison of fasted versus fed state experi amphetamine (capsules) ments for acetaminophen is shown in FIGS. 13A, 13B and 13C: Fasted versus fed state cumulative gastric effluent of Fasted state Fed state acetaminophen as percentage (%) of intake of 1 tablet (A), 1 capsule of Inventive Example 3 1 capsule of Inventive Example 3 10 tablets (B) and Vicodin 10 tablets (C) state, n=1, dotted 10 capsules of Inventive Example 3 10 capsules of Inventive lines indicate fasted State, Solid line indicate fed State, gastric Example 3 emptying curve (black line). 10 tablets of Comparative Example 3 10 tablets of Comparative Example 0460. It becomes clear from the above data that the (Evekeo (R) 3 (Evekeo (R) dosage forms according to Inventive Example 2 are useful amphetamine (pellets) for avoiding overdose upon multiple dosing of both phar Fasted state macologically active ingredients, whereas the commercial dosage forms according to Comparative Example 2 are not 1 capsule content of Inventive Example 3 useful for that purpose. 10 capsules content of Inventive Example 3 INVENTIVE EXAMPLE 3 10 mg Amphetamine 0465. The numerical results (cumulative values) for 0461. In accordance with Inventive Examples 1 and 2. amphetamine are summarized in the tables here below: pellets having the following composition were prepared and 0466 Amphetamine cumulative amount % LS-fasted coated with a protective coating (Opadry(R): State:

1 capsule 10 capsules pellets of pellets of of inv. ex. of inv. ex. 1 capsule 10 capsules 10 tablets 1 capsule 10 capsules Time 3 in 0.1M 3 in 0.1M of inv. ex. of inv. ex. of comp. ex. of inv. ex. of inv. ex. min HCI EHC 3 in blank 3 in blank 3 in blank 3 in blank 3 in blank

5 O.12 n.d. O.14 O.13 1.84 1.75 O.76 10 4.07 1.36 3.79 2.62 8.63 9.55 4.08 15 1461 3.71 10.88 7.88 16.38 20.27 8.72 2O 25.63 7.91 21.94 1431 24.89 3O.OS 14.79 30 42.17 26.51 39.17 30.87 42.76 49.49 29.13 45 61.58 48.91 60.09 53.78 64.39 67.98 47.49 60 73.24 65.15 74.63 65.70 76.41 79.94 61.01 Residue 84.57 84.52 93.41 85.38 93.76 95.90 79.82 Rinse 86.69 86. S1 93.90 86.96 94.30 97.18 80.86 US 2017/007 1862 A1 Mar. 16, 2017 35

0467 Amphetamine cumulative amount % LSI-fed i.e. that are administered simultaneously, can be distin State: guished from one another (1 vs. 5 vs. 10). For avoiding overdosing, the residence time in the stomach is of clinical relevance. The longer the residence time in the stomach, the 1 capsule of 10 capsules of 10 tablets of more difficult (less likely) it is to achieve the desired “kick” Time min inv. ex. 3 inv. ex. 3 comp. ex. 3 by simultaneously administering a plurality of dosage forms. 30 O.89 3.16 9.45 0476. The experimental data demonstrate that the inven 45 5.32 942 19.95 tive formulations provide an extended residence time in the 60 16.89 20.32 33.86 90 65.62 58.88 55.21 stomach when administered simultaneously as a plurality, 120 81.51 77.69 80.94 whereas the comparative formulations do not show Such an 150 87.79 90SO 9439 extended residence time in the stomach. 18O 91.78 95.26 99.90 Residue 94.08 96.77 101.90 1. A pharmaceutical dosage form comprising a pharma Rinse 94.08 97.29 102.33 cologically active ingredient a and a polymer matrix which comprises a polyalkylene oxide having an average molecu lar weight of at least 200,000 g/mol; wherein at least a 0468. The results for amphetamine capsules/tablets are portion of the pharmacologically active ingredient a is also illustrated by FIGS. 14 to 16. contained in one or more particles A which comprise the 0469 A comparison of fasted state experiments for polymer matrix in which the pharmacologically active ingre amphetamine (capsules) is shown in FIG. 14: Fasted state dient a is embedded; cumulative gastric effluent of amphetamine as percentage said dosage form being adapted to prevent an overdose of (%) of intake of amphetamine of 1 capsule (0), 10 capsules the pharmacologically active ingredient a after acci () and Evekeo 10 tablets (A), n=1, gastric emptying curve dental or intentional simultaneous administration of a (black line). plurality of the dosage forms containing an overall 0470 A comparison of fed state experiments for amphet Supratherapeutic dose of the pharmacologically active amine (capsules) is shown in FIG. 15: Fed state cumulative gastric effluent of amphetamine as percentage (%) of intake ingredient a. of amphetamine of 1 capsule (0), 10 capsules () and 2. The dosage form according to claim 1, wherein after 30 Evekeo 10 tablets (A), n=1, gastric emptying curve (black min under in vitro conditions at 37°C. in 900 mL 0.1M HCl line). at 25 rpm in accordance with Ph. Eur. 0471. A comparison of fasted versus fed state experi (i) a single dosage form has released at least 30 wt.-% of ments for amphetamine (capsules/tablets) is shown in FIGS. the pharmacologically active ingredient a originally 16A, 16B and 16C: Fasted versus fed state cumulative contained in the dosage form; and/or gastric effluent of amphetamine as percentage (%) of intake (ii) a multitude often dosage forms has released not more of amphetamine of 1 capsule (A), 10 capsules (B) and than 25 wt.-% of the overall content of the pharmaco Evekeo 10 tablets (C), n=1, dotted lines indicate fasted state, logically active ingredient a originally contained in the Solid line indicate fed state, gastric emptying curve (black multitude often dosage forms. lines). 3. The pharmaceutical dosage form according to claim 1, 0472. The results for the separated amphetamine pellets wherein the content of the polyalkylene oxide in the dosage are illustrated by FIG. 17. A comparison of fasted state form amounts to at least 25 mg. experiments for amphetamine (pellets) is shown in FIG. 17: 4. The pharmaceutical dosage form according to claim 3, Fasted State cumulative gastric effluent of amphetamine as wherein the content of the polyalkylene oxide in the dosage percentage (%) of intake of amphetamine of pellets of 1 form amounts to at least 50 mg. capsule (X) and pellets of 10 capsules (), n=1, gastric 5. (canceled) emptying curve (black line). 6. The pharmaceutical dosage form according to claim 1, 0473. It becomes clear from the above data that the wherein the polyalkylene oxide is a polyethylene oxide. dosage forms according to Inventive Example 3 are useful 7. The pharmaceutical dosage form according to claim 1, for avoiding overdose upon multiple dosing of the pharma wherein the polyalkylene oxide has an average molecular cologically active ingredient, whereas the commercial dos weight of at least 500,000 g/mol. age forms according to Comparative Example 3 are not 8. The pharmaceutical dosage form according to claim 7. useful for that purpose. wherein the polyalkylene oxide has an average molecular 0474. It can be concluded from a comparison of Inventive weight in the range of 1,000,000 g/mol to 15,000,000 g/mol. Example 2 with Comparative Example 2 and from a com 9. The pharmaceutical dosage form according to claim 1, parison of Inventive Example 3 with Comparative Example wherein the content of the polyalkylene oxide is at least 30 3 that under simulated fed state in vitro conditions (filled wt.-%, based on the total weight of the particle(s) A. stomach), the residence time of the dosage forms corre sponds to the stomach emptying intervals independent of the 10.-16. (canceled) number of dosage forms that are contained in the stomach, 17. The dosage form according to claim 1, wherein the i.e. that are administered simultaneously. However, under one or more particles Ahave a breaking strength of at least Such fed State conditions a potential abuser cannot achieve 3OO N. the desired kick anyway so that these conditions are not 18.-19. (canceled) relevant for a potential abuser. 20. The dosage form according to claim 1, wherein the 0475. In contrast, under simulated fasted state in vitro one or more particles A amount to a total number within the conditions, which are relevant for a potential abuser, the range of from 20 to 600. number of dosage forms that are contained in the stomach, 21.-25. (canceled) US 2017/007 1862 A1 Mar. 16, 2017 36

26. The dosage form according to claim 1, wherein the 37.-39. (canceled) one or more particles A amount to a total content of at least 40. The pharmaceutical dosage form according to claim 1, 25 wt.-%, based on the total weight of the dosage form. which is a capsule. 27. The dosage form according to claim 1, wherein the 41.-43. (canceled) one or more particles A are tamper-resistant as such so that 44. The pharmaceutical dosage form according to claim 1, they also provide tamper-resistance after they have been which is a tablet. separated from the remaining constituents of the dosage 45.-46. (canceled) form. 47. The pharmaceutical dosage form according to claim 1, 28. The dosage form according to claim 1, wherein the which additionally contains a pharmacologically active one or more particles A contain the total amount of the ingredient b which differs from the pharmacologically active pharmacologically active ingredient a that is contained in the ingredient a. dosage form. 48. (canceled) 29. The dosage form according to claim 1, wherein the 49. The pharmaceutical dosage form according to claim one or more particles A are thermoformed by hot-melt extrusion. 47, wherein the pharmacologically active ingredient b is 30. The pharmaceutical dosage form according to claim 2, selected from ATC classes M01A, MO1C, NO2B and wherein under in vitro conditions at 37°C. in 900 mL 0.1 M N02C according to the WHO. HCl at 25 rpm in accordance with Ph. Eur. 50. The pharmaceutical dosage form according to claim (i) a single dosage form has released X mg of the 49, wherein pharmacologically active ingredient a originally con the pharmacologically active ingredient a is selected from tained in the dosage form; and the group consisting of oxycodone, oxymorphone, (ii) a multitude of 10 dosage forms has released Y mg of hydrocodone, hydromorphone, morphine, tapentadol, the pharmacologically active ingredient a originally tramadol, buprenorphine, pseudoephedrine, and the contained in said multitude of 10 dosage forms; physiologically acceptable salts thereof, and wherein Y710 is not more than 50% of X. the second pharmacologically active ingredient is selected 31. The pharmaceutical dosage form according to claim 1, from the group consisting of ibuprofen, acetamino wherein the pharmacologically active ingredient a has a phen, diclofenaf, acetylsalicylic acid, and the physi psychotropic action. ologically acceptable salts thereof. 32. The pharmaceutical dosage form according to claim 1, 51-52. (canceled) wherein the pharmacologically active ingredient a is 53. The pharmaceutical dosage form according to claim 1, selected from the group consisting of analgesics, stimulants, wherein the particle(s) A comprise a disintegrant. narcotics and tranquilizers. 54-59. (canceled) 33. The pharmaceutical dosage form according to claim 1, 60. The pharmaceutical dosage form according to claim 1, wherein the pharmacologically active ingredient a is wherein the particle(s) A comprise an antioxidant. selected from opioids. 61.-64. (canceled) 34. The pharmaceutical dosage form according to claim 65. A method of treating a disease, disorder or condition 33, wherein the opioid is selected from the group consisting that is treatable with the pharmacologically active ingredient of oxycodone, hydrocodone, oxymorphone, hydromor a, said method comprising administering to a patient in need phone, morphine, tramadol, tapentadol, cebranopadol, and of Such treating at least one pharmaceutical dosage form the physiologically acceptable salts thereof. according to claim 1. 35. (canceled) 36. The pharmaceutical dosage form according to claim 66. The method according to claim 65, wherein the 32, wherein the pharmacologically active ingredient a is a disease, disorder or condition is pain. stimulant selected from the group consisting of amphet 67. (canceled) amine, dex-amphetamine, dex-methylphenidate, atomox 68. A method for the prevention of an overdose of etine, caffeine, ephedrine, phenylpropanolamine, phe pharmacologically active ingredient a after accidental or nylephrine, fencamphamin, fenozolone, fenetyline, intentional simultaneous administration of a plurality of methylenedioxymethamphetamine (MDMA), methylenedi dosage forms containing an overall Supratherapeutic dose of oxypyrovalerone (MDPV), prolintane, lisdexamfetamine, the pharmacologically active ingredient a, the method com mephedrone, methamphetamine, methylphenidate, prising providing the pharmacologically active ingredient a modafinil, nicotine, pemoline, phenylpropanolamine, pro in the form of a pharmaceutical dosage form as defined in pylhexedrine, dimethylamylamine, pseudoephedrine, and claim 1. the physiologically acceptable salts thereof.