# Patent

## Title
Multiparticles safeguarded against ethanolic dose-dumping

## Abstract

The invention relates to an oral pharmaceutical dosage form providing resistance against dose dumping in aqueous ethanol and comprising a pharmacologically active ingredient embedded in a matrix material,

    
    
        wherein the matrix material comprises an alkyl cellulose and a heteropolysaccharide; and
        wherein the relative weight ratio of heteropolysaccharide to alkyl cellulose is within the range of from 1:20 to 20:1; and

wherein the total content of alkyl cellulose and heteropolysaccharide is at least 35 wt.-%, relative to the total weight of the dosage form. A process of producing the dosage form and methods of using the dosage form, for example to treat pain, are also disclosed.

## Background
FIELD OF THE INVENTION
This application claims priority of European Patent Application No. 14 169 801.9, filed on May 26, 2014, the entire content of which is incorporated herein by reference.
The invention relates to an oral pharmaceutical dosage form providing resistance against dose dumping in aqueous ethanol and comprising a pharmacologically active ingredient, preferably an opioid, embedded in a matrix material,

    
    
        wherein the matrix material comprises an alkyl cellulose, preferably ethyl cellulose, and a heteropolysaccharide, preferably xanthan gum; and
        wherein the relative weight ratio of heteropolysaccharide to alkyl cellulose is within the range of from 1:20 to 20:1; and
        wherein the total content of alkyl cellulose and heteropolysaccharide is at least 35 wt.-%, relative to the total weight of the dosage form; and
        wherein preferably the content of the alkyl cellulose is at least 10 wt.-%, relative to the total weight of the dosage form; and/or
        wherein preferably the content of the alkyl cellulose in the dosage form is higher than the content of the heteropolysaccharide in the dosage form.
    
    


BACKGROUND OF THE INVENTION
A large number of pharmacologically active substances have a potential for being intentionally or unintentionally abused or misused, i.e. they can be used to produce effects which are not consistent with their intended use. Thus, e.g. opioids which exhibit an excellent efficacy in controlling severe to extremely severe pain are frequently abused to induce euphoric states similar to being intoxicated. In particular, active substances which have a psychotropic effect are abused accordingly.
To intentionally enable abuse, the corresponding pharmaceutical dosage forms, such as pharmaceutical dosage forms or capsules can be taken with alcohol (oral abuse). Alternatively, the dosage forms are crushed, for example ground by the abuser, the active substance is extracted from the thus obtained powder using a preferably aqueous liquid and after being optionally filtered through cotton wool or cellulose wadding, the resultant solution is administered parenterally, in particular intravenously. This type of dosage results in an even faster diffusion of the active substance compared to the oral abuse, with the result desired by the abuser, namely the kick. This kick or these intoxication-like, euphoric states are also reached if the powdered pharmaceutical dosage form is administered nasally, i.e. is sniffed.
However, sometimes patients unintentionally disrupt the controlled release properties of dosage forms by concomitant consumption of alcoholic beverages, thereby inducing dose dumping. Dosage forms containing active ingredients having a high solubility in water usually have a high susceptibility to ethanolic dose dumping.
Various concepts for the avoidance of intentional and unintentional drug abuse have been developed.
It has been proposed to incorporate in pharmaceutical dosage forms aversive agents and/or antagonists in a manner so that they only produce their aversive and/or antagonizing effects when the pharmaceutical dosage forms are tampered with. However, the presence of such aversive agents is principally not desirable and there is a need to provide sufficient tamper-resistance without relying on aversive agents and/or antagonists.
Another concept to prevent abuse relies on the mechanical properties of the pharmaceutical dosage forms, particularly an increased breaking strength (resistance to crushing). The major advantage of such pharmaceutical dosage forms is that comminuting, particularly pulverization, by conventional means, such as grinding in a mortar or fracturing by means of a hammer, is impossible or at least substantially impeded. Thus, the pulverization, necessary for abuse, of the pharmaceutical dosage forms by the means usually available to a potential abuser is prevented or at least complicated. Such pharmaceutical dosage forms are useful for avoiding drug abuse of the pharmacologically active ingredient contained therein, as they may not be powdered by conventional means and thus, cannot be administered in powdered form, e.g. nasally. The mechanical properties, particularly the high breaking strength of these pharmaceutical dosage forms renders them tamper-resistant. In the context of such tamper-resistant pharmaceutical dosage forms it can be referred to, e.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, WO 2006/082099, and WO2009/092601.
However, besides tampering of pharmaceutical dosage forms in order to abuse the drugs contained therein, the potential impact of concomitant intake of ethanol on the in vivo release of drugs from modified release oral formulations (dose-dumping) has recently become an increasing concern. Controlled or modified release formulations typically contain a higher amount of the pharmacologically active ingredient relative to its immediate release counterpart. If the controlled release portion of the formulation is easily defeated, the end result is a potential increase in exposure to the active drug and possible safety concerns. In order to improve safety and circumvent intentional tampering (e.g. dissolving a controlled release pharmaceutical dosage form in ethanol to extract the drug), a reduction in the dissolution of the modified release fractions of such formulations, in ethanol, may be of benefit.
For monolithic dosage forms some formulation concepts are known which provide to some degree a controlled release of the drug substance even in ethanolic media. Further, however, monolithic dosage forms are not suitable for all patient groups, as they are required to be swallowed intact. Due to the big size of such formulations this is not possible for patients having difficulties in swallowing as e.g. the elderly and children. These patients have a high risk of choking on monolithic dosage forms. Pulverization of these dosage forms on the other hand solves the choking hazard, but endangers the patients by releasing a potentially toxic dose of the drug substance.
The swallowing issue can be overcome by the use of multiparticulate dosage forms, e.g. MUPS (multiple unit pellet system) tablets or capsules filled with controlled release granules, which can be reduced in size to the size of the individual particles without losing the control of the drug release. In contrast to the above mentioned monolithic formulations, obtaining functional robustness in ethanolic media of the multiparticulate formulations is a challenge. Working examples of monolithic dosage forms contain hydrophilic polymer matrices, wherein control of drug release is achieved by a long diffusion way within the formulation. For multiparticulate forms, long diffusion ways do not exist due to the small size of the individual particles. A common technique to overcome this problem is the application of a functional barrier coating on top of the individual particle, e.g. ethylcellulose for diffusion control. However, as ethylcellulose is alcohol soluble, these formulation approaches are not resistant against ethanolic dose dumping.
Accordingly, the need exists to develop new formulations having reduced potential for dose dumping in alcohol.
US 2008/0085304 discloses robust sustained release formulations, solid dosage forms comprising robust sustained release formulations, and methods for making and using these formulations and solid dosage forms are provided. Robustness of the sustained release formulation is related to the particle size of the hydrophilic gum. Sustained release formulations resist dose-dumping when ingested with alcohol. The formulations are useful for treating a patient suffering from a condition, e.g., pain. The formulations comprise at least one drug. In one embodiment, the drug is an opioid, e.g., oxymorphone.
WO 2009/034541 relates to a solid dosage form for the controlled release of trimetazidine suitable for once-daily dosing, in which the dosage form exhibits a controlled in vitro release of trimetazidine in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours when measured using USP Apparatus I at 100 rpm, thereby decreasing the incidence and severity of burst release or dose dumping.
WO 2013/084059 relates to a pharmaceutical dosage form comprising a mixture in the form of an extended release matrix formulation, the mixture comprising at least: (1) at least one poly(ε-caprolactone), and (2) at least one polyethylene oxide, and (3) at least one active agent. The dosage form is said to be tamper resistant and to provide extended release of the active agent. However, poly(ε-caprolactone) is not a pharmacopeial excipient for oral use according to the Ph. Eur. and the USP, respectively.
WO 2012/166474 relates to a solid dose form comprising a film coating composition encapsulating a core, wherein the core comprises an active ingredient comprising at least one of a pharmaceutical, veterinary, or nutraceutical active ingredient; the film coating composition comprises ethylcellulose and guar gum; and the guar gum is present in an amount greater than 5 wt % based on the weight of the guar gum and ethylcellulose. The solid dose form is said to provide controlled release of the active ingredient and to be ethanol resistant. Extended release tablets comprising a lipid matrix containing glyceryl (di)behenate (commercially available as Compritol® 888 ATO) in which the active ingredient is embedded are said to not being susceptible to alcohol-related dose dumping. The drug substance is said to be released from the dosage form by diffusion, thereby leaving behind an in principle structurally intact tablet matrix. However, this is not satisfactory in every respect. The remaining “washed-out” lipid tablet will remain visible in human stool after excretion. This observation (“ghosting”) is known to lead to increased complaints by patients and a reduced patient compliance. Further, mechanical manipulation of the tablet e.g. dividing it to allow easier swallowing, leads to an accelerated drug release due to reduced diffusion ways eventually resulting in higher plasma concentrations of the drug substance including toxic levels.
However, the properties of these pharmaceutical dosage forms of the prior art, however, are not satisfactory in every respect.
SUMMARY OF THE INVENTION
It is an object of the invention to provide dose-dumping resistant pharmaceutical dosage forms containing a pharmacologically active ingredient, preferably an opioid, which have advantages compared to the dosage forms of the prior art.
This object has been achieved by the subject matter described hereinbelow and in the appended patent claims when issued.
A first aspect of the invention relates to an oral pharmaceutical dosage form providing resistance against dose dumping in aqueous ethanol and comprising a pharmacologically active ingredient, preferably an opioid, embedded in a matrix material,

    
    
        wherein the matrix material comprises an alkyl cellulose, preferably ethyl cellulose, and a heteropolysaccharide, preferably xanthan gum; and
        wherein the relative weight ratio of heteropolysaccharide to alkyl cellulose is within the range of from 1:20 to 20:1; and
        wherein the total content of alkyl cellulose and heteropolysaccharide is at least 35 wt.-%, relative to the total weight of the dosage form; and
        wherein preferably the content of the alkyl cellulose is at least 10 wt.-%, relative to the total weight of the dosage form; and/or
        wherein preferably the content of the alkyl cellulose in the dosage form is higher than the content of the heteropolysaccharide in the dosage form.
    
    


It has been surprisingly found that an oral pharmaceutical dosage form comprising a pharmacologically active ingredient, preferably an opioid, an alkyl cellulose and a heteropolysaccharide can be prepared, wherein the dosage form exhibits tamper resistance, especially in terms of resistance against dose-dumping of the pharmacologically active ingredient in aqueous ethanol.
Further, it has been surprisingly found that the content of the pharmacologically active ingredient, preferably the opioid in the dosage form and in the particles, respectively, can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially pharmaceutical dosage formability) and patient compliance.
Still further, it has been surprisingly found that the dosage forms provide a retarded release when the release medium additionally contains ethanol compared to the release in aqueous medium not containing ethanol. This result was completely unexpected because of the good solubility of alkyl celluloses, especially ethylcellulose in ethanol.



BRIEF DESCRIPTION OF THE DRAWINGS
The invention will now be described in greater detail with reference to the drawings, wherein:
FIG. 1 shows the release profile of the capsules of Example 1 in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively.
FIG. 2 shows the release profile of the capsules of Example 2 in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively.
FIG. 3 shows the release profile of the capsules of Example 3 in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively.
FIG. 4 shows the release profile of the capsules of Example 4 in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively.
FIG. 5 shows the release profile of the capsules of Example 5 in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively.



DETAILED DESCRIPTION OF THE INVENTION
Unless expressly stated otherwise, all percentages are by weight (wt.-%).
As used herein, the term “pharmaceutical dosage form” and “dosage form”, respectively, refers to a pharmaceutical entity that comprises a pharmacologically active ingredient, preferably an opioid, and which is actually administered to, or taken by, a patient. It may be compressed or molded in its manufacture, and it may be of almost any size, shape, weight, and color.
The dosage form is preferably solid or semisolid.
Examples of dosage forms according to the invention include, but are not limited to, tablets, capsules, pills, granules, pellets, sachets and effervescent, powders, and the like. In a preferred embodiment, the dosage form is a filled capsule or a tablet. According to this embodiment, the capsule can be a hard or soft gelatin capsule.
Most pharmaceutical dosage forms are intended to be swallowed whole and accordingly, the dosage forms according to the invention are designed for oral administration.
In a preferred embodiment, the dosage form according to the invention is particulate. According to this embodiment, the dosage form is preferably comprises a multitude of particles or granules. An advantage of particulate dosage forms is that the particles may be mixed in different amounts to thereby produce dosage forms of different strengths.
In another preferred embodiment, the dosage form according to the invention can be regarded as a MUPS formulation (multiple unit pellet system). Preferably, the dosage form according to the invention contains all ingredients in a dense compact unit which in comparison to capsules has a comparatively high density. Under these circumstances, the dosage forms according to the invention preferably comprise subunits having different morphology and properties, namely drug-containing particles and an outer matrix material, wherein the particles form a discontinuous phase within the outer matrix material. The constituents of the outer matrix material are preferably different from the constituents of the drug-containing particles. Preferably, the outer matrix material neither contains a pharmacologically active ingredient nor an alkyl cellulose nor a heteropolysaccharide.
The particles typically have mechanical properties that differ from the mechanical properties of the outer matrix material. The particles can preferably be visualized by conventional means such as solid state nuclear magnetic resonance spectroscopy, raster electron microscopy, terahertz spectroscopy and the like.
In still another preferred embodiment, the dosage form according to the invention is monolithic. In this regard, monolithic preferably means that the dosage form is formed or composed of material without joints or seams or consists of or constitutes a single unit.
The dosage form according to the invention has preferably a total weight in the range of 0.01 to 1.5 g, more preferably in the range of 0.05 to 1.2 g, still more preferably in the range of 0.1 g to 1.0 g, yet more preferably in the range of 0.2 g to 0.9 g, and most preferably in the range of 0.3 g to 0.8 g. In a preferred embodiment, the total weight of the dosage form is within the range of 350±300 mg, more preferably 350±250 mg, still more preferably 350±200 mg, yet more preferably 350±150 mg, most preferably 350±100 mg, and in particular 350±50 mg. In another preferred embodiment, the total weight of the dosage form is within the range of 500±450 mg, more preferably 500±300 mg, still more preferably 500±200 mg, yet more preferably 500±150 mg, most preferably 500±100 mg, and in particular 500±50 mg. In still another preferred embodiment, the total weight of the dosage form is within the range of 600±450 mg, more preferably 600±300 mg, still more preferably 600±200 mg, yet more preferably 600±150 mg, most preferably 600±100 mg, and in particular 600±50 mg.
In a preferred embodiment, the dosage form according to the invention is a filled capsule. Dosage forms of this embodiment preferably have a lengthwise extension (longitudinal extension) of about 4 mm to about 30 mm, more preferably about 6 mm to about 25 mm, most preferably about 8 mm to about 23 mm, and in particular about 10 mm to about 20 mm; and an internal diameter in the range of about 1 mm to about 20 mm, more preferably about 3 mm to about 17 mm, most preferably about 5 mm to about 15 mm, an in particular about 7 mm to about 13 mm.
In another preferred embodiment, the dosage form according to the invention is a round dosage form. Dosage forms of this embodiment preferably have a diameter in the range of about 1 mm to about 30 mm, more preferably about 2 mm to about 25 mm, most preferably about 5 mm to about 23 mm, and in particular about 7 mm to about 13 mm; and a thickness in the range of about 1.0 mm to about 12 mm, more preferably about 2.0 mm to about 10 mm, most preferably about 3.0 mm to about 9.0 mm, and in particular about 4.0 mm to about 8.0 mm.
In still another preferred embodiment, the dosage form according to the invention is an oblong dosage form. Dosage forms of this embodiment preferably have a lengthwise extension (longitudinal extension) of about 1 mm to about 30 mm, more preferably about 2 mm to about 25 mm, most preferably about 5 mm to about 23 mm, and in particular about 7 mm to about 20 mm; a width in the range of about 1 mm to about 30 mm, more preferably about 2 mm to about 25 mm, most preferably about 5 mm to about 23 mm, and in particular about 7 mm to about 13 mm; and a thickness in the range of about 1.0 mm to about 12 mm, more preferably about 2.0 mm to about 10 mm, most preferably about 3.0 mm to about 9.0 mm, and in particular about 4.0 mm to about 8.0 mm.
When the dosage form according to the invention is monolithic, it preferably has an extension in any direction of at least 2.0 mm, more preferably at least 2.5 mm, still more preferably at least 3.0 mm, yet more preferably at least 3.5 mm, even more preferably at least 4.0 mm, most preferably at least 4.5 mm and in particular at least 5.0 mm.
The dosage form or the particles if the dosage form is in a particulate form may optionally comprise a coating, e.g. a cosmetic coating. The coating is preferably applied after formation of the pharmaceutical dosage form. The coating may be applied prior to or after the curing process.
In a preferred embodiment, if the dosage form and the particles, respectively, is/are coated, said coating does not provide any resistance against dose dumping in aqueous ethanol. According to this embodiment, an alkyl cellulose such as ethyl cellulose and/or a heteropolysaccharide such as xanthan gum or guar gum, are preferably not contained in a coating which may be applied to the dosage form and the particles, respectively.
In a preferred embodiment, the dosage form is not coated and/or when the dosage form is particulate, the particles are not coated.
Preferably, the dosage forms according to the invention are film coated with conventional film coating compositions. Suitable coating materials are commercially available, e.g. under the trademarks Opadry® and Eudragit®.
Examples of suitable materials include cellulose esters and cellulose ethers, such as methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), poly(meth)acrylates, such as aminoalkylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers; vinyl polymers, such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinylacetate; and natural film formers.
The coating can be resistant to gastric juices and dissolve as a function of the pH value of the release environment. By means of this coating, it is possible to ensure that the dosage form according to the invention passes through the stomach undissolved and the active compound is only released in the intestines. The coating which is resistant to gastric juices preferably dissolves at a pH value of between 5 and 7.5.
The coating can also be applied e.g. to improve the aesthetic impression and/or the taste of the dosage forms and the ease with which they can be swallowed. Coating the dosage forms according to the invention can also serve other purposes, e.g. improving stability and shelf-life. Suitable coating formulations comprise a film forming polymer such as, for example, polyvinyl alcohol or hydroxypropyl methylcellulose, e.g. hypromellose, a plasticizer such as, for example, a glycol, e.g. propylene glycol or polyethylene glycol, an opacifier, such as, for example, titanium dioxide, and a film smoothener, such as, for example, talc. Suitable coating solvents are water as well as organic solvents. Examples of organic solvents are alcohols, e.g. ethanol or isopropanol, ketones, e.g. acetone, or halogenated hydrocarbons, e.g. methylene chloride. Coated pharmaceutical dosage forms according to the invention are preferably prepared by first making the cores and subsequently coating said cores using conventional techniques, such as coating in a coating pan.
For the purpose of specification, the term “particle” refers to a discrete mass of material that is solid, e.g. at 20° C. or at room temperature or ambient temperature. Preferably a particle is solid at 20° C. Preferably, the particles are monoliths. Preferably, the pharmacologically active ingredient, which is preferably an opioid, the alkyl cellulose, which is preferably ethyl cellulose, and the heteropolysaccharide, which is preferably xanthan gum, are intimately homogeneously distributed in the particles so that the particles do not contain any segments where either pharmacologically active ingredient is present in the absence of the alkyl cellulose and/or the heteropolysaccharide or the alkyl cellulose is present in the absence of the pharmacologically active ingredient and/or the heteropolysaccharide or the heteropolysaccharide is present in the absence of the pharmacologically active ingredient and/or the alkyl cellulose.
When the dosage form is particulate, it preferably comprises a multitude i.e. plurality of particles containing pharmacologically active ingredient (drug-containing particles) and may optionally further comprise particles not containing any pharmacologically active ingredient (drug-free particles). Preferably, if the dosage form is particulate, all particles are drug-containing particles. Preferably, the particles are not film coated.
In a preferred embodiment, the dosage form preferably comprises at least 2, more preferably at least 4, still more preferably at least 6, yet more preferably at least 8, even more preferably at least 10, most preferably at least 15 and in particular at least 20 or at least 100 or at least 1000 drug-containing particles. In another preferred embodiment, the dosage form preferably comprises at most 10, more preferably at most 9, still more preferably at most 8, yet more preferably at most 7, even more preferably at most 6, most preferably at most 5, and in particular at most 4 or 3 or 2 drug-containing particles.
The particles are preferably of macroscopic size, typically the average diameter is within the range of from 100 μm to 5,000 μm, preferably 200 μm to 4,000 μm, more preferably 300 μm to 3,000 μm, still more preferably 400 μm to 2,000 μm, most preferably 500 μm to 1,500 μm, and in particular 500 μm to 1,000 μm. Preferably, the particles in the dosage form have an average particle size of at least 50 μm, more preferably at least 100 μm, still more preferably at least 150 μm or at least 200 μm, yet more preferably at least 250 μm or at least 300 μm, most preferably at least 400 μm or at least 500 μm, and in particular at least 550 μm or at least 600 μm. Preferably, the particles in the dosage form have an average particle size of at least 700 μm, more preferably at least 800 μm and most preferably at least 900 μm.
In a preferred embodiment, the dosage forms according to the invention comprise particles as a discontinuous phase, i.e. the particles form a discontinuous phase in an outer matrix material which in turn preferably forms a continuous phase. In this regard, discontinuous means that not each and every particle is in intimate contact with another particle but that the particles are at least partially separated from one another by the outer matrix material in which the particles are embedded. In other words, the particles preferably do not form a single coherent mass within the dosage forms according to the invention.
Preferably, when the dosage form according to the invention is particulate, the dosage form does not contain an outer matrix material. According to this embodiment, the dosage form preferably is a filled capsule.
Preferably, when the dosage form is particulate, the content of the particles in the dosage forms according to the invention is at most 95 wt.-%, more preferably at most 90 wt.-%, still more preferably at most 85 wt.-%, yet more preferably at most 80 wt.-%, most preferably at most 75 wt.-% and in particular at most 70 wt.-%, based on the total weight of the dosage forms.
Preferably, when the dosage form is particulate, the content of the particles in the dosage forms according to the invention is at least 10 wt.-%, at least 15 wt.-%, at least 20 wt.-% or at least 25 wt.-%; more preferably at least 30 wt.-%, at least 35 wt.-%, at least 40 wt.-% or at least 45 wt.-%; most preferably at least 50 wt.-%, at least 55 wt.-%, at least 60 wt.-% or at least 65 wt.-%; and in particular at least 70 wt.-%, at least 75 wt.-%, at least 80 wt.-% or at least 85 wt.-%; based on the total weight of the dosage form.
When the dosage form is particulate, the shape of the particles is not particularly limited.
In a preferred embodiment, the particles are manufactured by granulation, preferably wet, dry or fluid bed granulation. According to this embodiment, the particles preferably have an irregular shape. When the particles have been prepared by granulation, they preferably have a particle size in the range of from 300 μm to 5 mm, more preferably 400μ to 4 mm, still more preferably 500 μm to 3 mm, yet more preferably 600 μm to 2 mm, most preferably 700μ to 1.5 mm and in particular 850 μm to 1.25 mm. When the dosage form according to the invention is particulate and when the particles are manufactured by granulation, preferably the dosage form is a filled capsule.
In another preferred embodiment, the particles are manufactured by hot-melt extrusion. According to this embodiment, the particles preferably are generally cylindrical in shape. The diameter of such particles is therefore the diameter of their circular cross section. The cylindrical shape is caused by the extrusion process according to which the diameter of the circular cross section is a function of the extrusion die and the length of the cylinders is a function of the cutting length according to which the extruded strand of material is cut into pieces of preferably more or less predetermined length.
Preferred particles manufactured by hot-melt extrusion have an average length and average diameter of about 1,000 μm or less. When the particles are manufactured by extrusion technology, the “length” of particles is the dimension of the particles that is parallel to the direction of extrusion. The minimum average length of the particles is determined by the cutting step and may be, e.g. 4.0 mm, 3.0 mm, 2.0 mm, 2.5 mm, 2.0 mm, 1.5 mm, 1.0 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm or 0.2 mm.
The “diameter” of particles is the largest dimension that is perpendicular to the direction of extrusion. When the particles have been manufactured by hot-melt extrusion, they preferably have an average diameter in the range of 200 to 1500 μm, more preferably 400 to 800 μm, still more preferably 450 to 700 μm, yet more preferably 500 to 650 μm, e.g. about 500 to 600 μm. Preferably, when the particles have been manufactured by hot-melt extrusion, they have an average length in the range of 500 to 5000 μm, more preferably 750 to 4600 μm, still more preferably 1000 to 4200 μm, yet more preferably 1250 to 3800 μm, even more preferably 1500 to 3400 μm, most preferably 1750 to 3200 μm and in particular 2000 to 3000 μm. In another preferred embodiment, particles manufactured by hot-melt extrusion have an average length in the range of 200 to 1000 μm, more preferably 400 to 800 μm, still more preferably 450 to 700 μm, yet more preferably 500 to 650 μm, e.g. about 500 to 600 μm.
The size of particles may be determined by any conventional procedure known in the art, e.g. laser light scattering, sieve analysis, light microscopy or image analysis.
Preferably, when the dosage form is particulate, the plurality of particles that is contained in the dosage form according to the invention has an arithmetic average weight, in the following referred to as “aaw”, wherein at least 70%, more preferably at least 75%, still more preferably at least 80%, yet more preferably at least 85%, most preferably at least 90% and in particular at least 95% of the individual particles contained in said plurality of particles has an individual weight within the range of aaw±30%, more preferably aaw±25%, still more preferably aaw±20%, yet more preferably aaw±15%, most preferably aaw±10%, and in particular aaw±5%. For example, if the dosage form according to the invention contains a plurality of 100 particles and aaw of said plurality of particles is 1.00 mg, at least 75 individual particles (i.e. 75%) have an individual weight within the range of from 0.70 to 1.30 mg (1.00 mg±30%).
In a preferred embodiment, the particles, more preferably the drug-containing particles, each have a weight of less than 20 mg, more preferably less than 18 mg, still more preferably less than 16 mg, yet more preferably less than 14 mg, even more preferably less than 12 mg or less than 10 mg, most preferably less than 8 mg, and in particular less than 6 or 4 mg. According to this embodiment, all individual particles each preferably have a weight of from 1 to 19 mg, more preferably 1.5 to 15 mg, still more preferably 2.0 to 12 mg, yet more preferably 2.2 to 10 mg, even more preferably 2.5 to 8 mg, most preferably 2.8 to 6 mg and in particular 3 to 5 mg.
In another preferred embodiment, the particles, more preferably the drug-containing particles, each have a weight of 20 mg or more. According to this embodiment, all individual particles preferably each have a weight of at least 30 mg, more preferably at least 40 mg, still more preferably at least 50 mg, most preferably at least 60 mg and in particular at least 100 mg. Preferably, all individual particles each have a weight of from 20 to 1000 mg, more preferably 30 to 800 mg, still more preferably 40 to 600 mg, yet more preferably 50 to 400 mg, even more preferably 60 to 200 mg, most preferably 70 to 150 mg and in particular 80 to 120 mg. According to this embodiment, the particles of the dosage form, more preferably the drug-containing particles of the dosage form, preferably each have an extension in any given direction of at least 2.0 mm or 3.0 mm and have a weight of at least 20 mg.
When the dosage form is particulate, the particles may be e.g. loosely contained in a capsule, or the particles may be incorporated into an outer matrix material. From a macroscopic perspective, the outer matrix material preferably forms a continuous phase in which the particles are embedded as discontinuous phase.
Preferably, the outer matrix material is preferably a homogenous coherent mass, preferably a homogeneous mixture of solid constituents, in which the particles are embedded thereby spatially separating the particles from one another. While it is possible that the surfaces of particles are in contact or at least in very close proximity with one another, the plurality of particles preferably cannot be regarded as a single continuous coherent mass within the dosage form.
In other words, when the dosage form is particulate and the particles are contained in an outer matrix material, the dosage form according to the invention preferably comprises the particles as volume element(s) of a first type in which the pharmacologically active ingredient, the alkyl cellulose and the heteropolysaccharide are contained, and the outer matrix material as volume element of a second type differing from the material that forms the particles, preferably containing neither pharmacologically active ingredient, nor alkyl cellulose, nor heteropolysaccharide.
When the dosage form is particulate and the particles are contained in an outer matrix material, the relative weight ratio of particles to outer matrix material is not particularly limited. Preferably, said relative weight ratio is within the range of 1:1.00±0.75, more preferably 1:1.00±0.50, still more preferably 1:1.00±0.40, yet more preferably 1:1.00±0.30, most preferably 1:1.00±0.20, and in particular 1:1.00±0.10.
Preferably, the content of the outer matrix material is at least 2.5 wt.-%, at least 5 wt.-%, at least 10 wt.-%, at least 15 wt.-%, at least 20 wt.-%, at least 25 wt.-%, at least 30 wt.-%, at least 35 wt.-% or at least 40 wt.-%; more preferably at least 45 wt.-% or at least 50 wt.-%; still more preferably at least 55 wt.-% or at least 60 wt.-%; yet more preferably at least 65 wt.-% or at least 70 wt.-%; most preferably at least 75 wt.-% or at least 80 wt.-%; and in particular at least 85 wt.-% or at least 90 wt.-%; based on the total weight of the dosage form.
Preferably, the content of the outer matrix material is at most 90 wt.-% or at most 85 wt.-%; more preferably at most 80 wt.-% or at most 75 wt.-%; still more preferably at most 70 wt.-% or at most 65 wt.-%; yet more preferably at most 60 wt.-% or at most 55 wt.-%; most preferably at most 50 wt.-% or at most 45 wt.-%; and in particular at most 40 wt.-% or at most 35 wt.-%; based on the total weight of the dosage form.
Preferably, the outer matrix material is a mixture, preferably a homogeneous mixture of at least two different constituents, more preferably of at least three different constituents. In a preferred embodiment, all constituents of the outer matrix material are homogeneously distributed in the continuous phase that is formed by the outer matrix material.
Preferably, the outer matrix material is also provided in particulate form, i.e. in the course of the manufacture of the dosage forms according to the invention, the constituents of the outer matrix material are preferably processed into particles, subsequently mixed with the particles that contain the pharmacologically active ingredient, which is preferably an opioid, the alkyl cellulose and the heteropolysaccharide, and then compressed into the dosage forms.
Preferably, the average size of the particles of the outer matrix material is within the range of ±60%, more preferably ±50%, still more preferably ±40%, yet more preferably ±30%, most preferably ±20%, and in particular ±10% of the average size of the particles that contain the pharmacologically active ingredient, which is preferably an opioid, the alkyl cellulose and the heteropolysaccharide.
The particles of the outer matrix material can be manufactured by conventional methods for the preparation of aggregates and agglomerates from powder mixtures such as granulating and compacting.
In a preferred embodiment, the mixture of all constituents of the outer matrix material is blended and pre-compacted thereby yielding a pre-compacted outer matrix material.
The outer matrix material preferably does not contain any pharmacologically active ingredient.
Preferably, the outer matrix material comprises a filler or a binder. As many fillers can be regarded as binders and vice versa, for the purpose of specification “filler/binder” refers to any excipient that is suitable as filler, binder or both. Thus, the outer matrix material preferably comprises a filler/binder.
Preferred fillers (=filler/binders) are selected from the group consisting of silicium dioxide (e.g. Aerosil®), microcrystalline cellulose (e.g. Avicel®, Elcema®, Emocel®, ExCel®, Vitacell®); cellulose ether (e.g. Natrosol®, Klucel®, Methocel®, Blanose®, Pharmacoat®, Viscontran®); mannitol; dextrines; dextrose; calciumhydrogen phosphate (e.g. Emcompress®); maltodextrine (e.g. Emdex®); lactose (e.g. Fast-Flow Lactose®; Ludipress®, Pharmaceutical dosage Formtose®, Zeparox®); polyvinylpyrrolidone (PVP) (e.g. Kollidone®, Polyplasdone®, Polydone); saccharose (e.g. Nu-Tab®, Sugar Tab®); magnesium salts (e.g. MgCO3, MgO, MgSiO3); starches and pretreated starches (e.g. Prejel®, Primotab® ET, Starch® 1500). Preferred binders are selected from the group consisting of alginates; chitosanes; and any of the fillers mentioned above (=fillers/binders).
Some fillers/binders may also serve other purposes. It is known, for example, that silicium dioxide exhibits excellent function as a glidant. Thus, preferably, the outer matrix material comprises a glidant such as silicium dioxide.
In a preferred embodiment, the content of the filler/binder or mixture of fillers/binders in the outer matrix material is within the range of from 1 to 99 wt.-%, more preferably 25 to 90 wt.-%, based on the total weight of outer matrix material.
Preferably, the filler/binder is contained in the outer matrix material but not in the drug-containing particles of the dosage form according to the invention.
Preferably, the outer matrix material comprises a diluent or lubricant, preferably selected from the group consisting of calcium stearate; magnesium stearate; glycerol monobehenate (e.g. Compritol®); Myvatex®; Precirol®; Precirol® Ato5; sodium stearylfumarate (e.g. Pruv®); and talcum. Magnesium stearate is particularly preferred. Preferably, the content of the lubricant in the outer matrix material is at most 10.0 wt.-%, more preferably at most 7.5 wt.-%, still more preferably at most 5.0 wt.-%, yet more preferably at most 2.0 wt.-%, even more preferably at most 1.0 wt.-%, and most preferably at most 0.5 wt.-%, based on the total weight of the outer matrix material and based on the total weight of the dosage form.
In particularly preferred embodiment, the outer matrix material comprises a combination of filler/binder and lubricant.
The outer matrix material of the dosage forms according to the invention may additionally contain other excipients that are conventional in the art, e.g. diluents, binders, granulating aids, colorants, flavor additives, glidants, wet-regulating agents and disintegrants. The skilled person will readily be able to determine appropriate quantities of each of these excipients.
In the dosage form according to the invention, the pharmacologically active ingredient, preferably an opioid, is embedded in the matrix material, preferably dispersed in the matrix material.
For the purpose of specification, the term “matrix” preferably refers to the matrix material comprising the embedded pharmacologically active ingredient and the term “matrix material” refers to a preferably homogeneous, intimate mixture of the alkyl cellulose, the heteropolysaccharide and optionally present excipients.
In a preferred embodiment, the pharmacologically active ingredient, more preferably the opioid is embedded in a matrix material consisting of an alkyl cellulose, a heteropolysaccharide and optional excipients approved for oral use according to the Ph. Eur. and the USP, respectively.
Preferably, the matrix comprising the alkyl cellulose and the heteropolysaccharide provides resistance against dose dumping in aqueous ethanol.
Preferably, the dosage form provides prolonged release of the pharmacologically active ingredient. Particularly preferably, the matrix comprising the alkyl cellulose and the heteropolysaccharide provides prolonged release of the pharmacologically active ingredient embedded therein.
In a preferred embodiment, the matrix provides resistance against dose dumping in aqueous ethanol and/or the matrix provides prolonged release of the pharmacologically active ingredient, preferably the opioid.
When the dosage form according to the invention is particulate, e.g. in form of granules or pellets, the particles preferably comprise the matrix material and at least a portion of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical dosage form. Preferably, the particles comprise the total amount of the pharmacologically active ingredient that is contained in the dosage form. Preferably, the pharmacologically active ingredient, the alkyl cellulose and the heteropolysaccharide are intimately homogeneously distributed within the particles so that the particles do not contain any segments where either pharmacologically active ingredient is present in the absence of the alkyl cellulose and/or the heteropolysaccharide or the alkyl cellulose is present in the absence of the pharmacologically active ingredient and/or the heteropolysaccharide or the heteropolysaccharide is present in the absence of the pharmacologically active ingredient and/or the alkyl cellulose.
When the dosage form according to the invention can be regarded as a MUPS formulation which preferably comprises drug-containing particles and an outer matrix material, the outer matrix material is not a constituent of the matrix material and, thus, is to be distinguished from the matrix material of the dosage form according to the invention.
When the dosage form according to the invention is monolithic, the matrix material in which the pharmacologically active ingredient, preferably the opioid is embedded preferably forms the body of the dosage form. Preferably, the pharmacologically active ingredient, the alkyl cellulose and the heteropolysaccharide are intimately homogeneously distributed within the monolithic dosage form so that the monolithic dosage form does not contain any segments where either pharmacologically active ingredient is present in the absence of the alkyl cellulose and/or the heteropolysaccharide or the alkyl cellulose is present in the absence of the pharmacologically active ingredient and/or the heteropolysaccharide or the heteropolysaccharide is present in the absence of the pharmacologically active ingredient and/or the alkyl cellulose.
In a preferred embodiment, the relative weight ratio of the pharmacologically active ingredient, preferably the opioid to the matrix material is in the range of from 1:1 to 1:50, more preferably 1:1.5 to 1:45, still more preferably 1:2 to 1:40, even more preferably 1:2.5 to 1:35, yet more preferably 1:3 to 1:30, most preferably 1:3.5 to 1:25, and in particular 1:4 to 1:20.
Preferably, the total content of the matrix material is at least 35 wt.-%, more preferably at least 40 wt.-%, still more preferably at least 45 wt.-%, even more preferably at least 50 wt.-%, yet more preferably at least 55 wt.-%, most preferably at least 60 wt.-%, and in particular at least 65 wt.-%, relative to the total weight of the dosage form.
Preferably, the total content of the matrix material is at most 95 wt.-%, more preferably at most 90 wt.-%, still more preferably at most 85 wt.-%, most preferably at most 80 wt.-%, and in particular at most 75 wt.-%, relative to the total weight of the dosage form.
Preferably, the total content of the matrix material is within the range of from 35 to 95 wt.-%, more preferably 45 to 85 wt.-%, most preferably 55 to 80 wt.-%, and in particular 65 to 75 wt.-%, relative to the total weight of the dosage form.
Preferably, the total content of alkyl cellulose and heteropolysaccharide is at least 50 wt.-%, more preferably at least 60 wt.-%, still more preferably at least 70 wt.-%, even more preferably at least 80 wt.-%, yet more preferably at least 90 wt.-%, most preferably at least 95 wt.-%, and in particular at least 99.999 wt.-%, relative to the total weight of the matrix material.
Preferably, the total content of alkyl cellulose and heteropolysaccharide is at most 99.999 wt.-%, more preferably at most 99 wt.-%, still more preferably at most 97 wt.-%, most preferably at most 95 wt.-%, and in particular at most 93 wt.-%, relative to the total weight of the matrix material.
Preferably, the total content of alkyl cellulose and heteropolysaccharide is within the range of from 50 to 99.999 wt.-%, more preferably 60 to 99.999 wt.-%, still more preferably 70 to 99.999 wt.-%, most preferably 80 to 99.999 wt.-%, and in particular 90 to 99.999 wt.-%, relative to the total weight of the matrix material.
The total content of alkyl cellulose and heteropolysaccharide is at least 35 wt.-%, preferably at least 40 wt.-% or at least 45 wt.-% or at least 50 wt.-%, more preferably at least 55 wt.-%, still more preferably at least 65 wt.-%, even more preferably at least 70 wt.-%, yet more preferably at least 75 wt.-%, most preferably at least 80 wt.-%, and in particular at least 85 wt.-%, relative to the total weight of the dosage form.
Preferably, the total content of alkyl cellulose and heteropolysaccharide is at most 99 wt.-%, more preferably at most 97 wt.-%, still more preferably at most 95 wt.-%, even more preferably at most 93 wt.-%, most preferably at most 91 wt.-%, and in particular at most 90 wt.-%, relative to the total weight of the dosage form.
Preferably, the total content of alkyl cellulose and heteropolysaccharide is within the range of from 35 to 99 wt.-%, more preferably 45 to 97 wt.-%, still more preferably 55 to 95 wt.-%, even more preferably 65 to 93 wt.-%, most preferably 75 to 91 wt.-%, and in particular 85 to 90 wt.-%, relative to the total weight of the dosage form.
The relative weight ratio of heteropolysaccharide to alkyl cellulose is within the range of from 1:20 to 20:1, preferably 1:19 to 15 to:1, more preferably 1:18 to 10:1, still more preferably 1:18 to 7:1 or 1:14 to 7:1, even more preferably 1:18 to 4:1 or 1:12 to 4:1, yet more preferably 1:18 to 2:1 or 1:11 to 2:1, most preferably 1:18 to 1:1 or 1:10 to 1:1, and in particular 1:18 to 1:4 or 1:8 to 1:4.
In a preferred embodiment, the relative weight ratio of heteropolysaccharide to alkyl cellulose is within the range of from 1:18 to 2:1.
In another preferred embodiment, the content of the alkyl cellulose in the dosage form is higher than the content of the heteropolysaccharide in the dosage form.
The dosage form comprises a matrix material which in turn comprises an alkyl cellulose. In a preferred embodiment, the dosage form and the matrix material, respectively, contains only one alkyl cellulose. In another preferred embodiment, the dosage form and the matrix material, respectively, contains a mixture of two or more alkyl celluloses.
For the purpose of specification, the term “alkyl cellulose” (=cellulose ether) is supposed to relate to celluloses wherein some or all of the hydroxyl groups have been transformed to alkyl ether groups, wherein the alkyl moiety preferably is unsubstituted.
Preferred alkyl celluloses are selected from C1-6-alkyl celluloses, more preferably unsubstituted C1-6-alkyl celluloses, i.e. C1-6-alkyl celluloses wherein the C1-6-alkyl moiety is not substituted.
Preferably, the alkyl cellulose has a solution viscosity within the range of from 1 mPa·s to 150 mPa·s, more preferably 1 mPa·s to 7 mPa·s, or 5 mPa·s to 10 mPa·s, or 7 mPa·s to 13 mPa·s, or 15 mPa·s to 25 mPa·s, or 38 mPa·s to 52 mPa·s, or 60 mPa·s to 140 mPa·s, measured in a 5 wt.-% solution of 80 wt.-% toluene and 20 wt.-% ethanol at 25° C. in an Ubbelohde viscosimeter. In a particularly preferred embodiment, the alkyl cellulose has a solution viscosity within the range of from 70 mPa·s to 130 mPa·s, more preferably 80 mPa·s to 120 mPa·s and most preferably 90 mPa·s to 110 mPa·s, measured in a 5 wt.-% solution of 80 wt.-% toluene and 20 wt.-% ethanol at 25° C. in an Ubbelohde viscosimeter.
Preferably, the alkyl cellulose has an alkoxyl content of from 10 wt.-% to 80 wt.-%, more preferably 20 wt.-% to 70 wt.-%, still more preferably 22 wt.-% to 40 wt.-% or 40 wt.-% to 60 wt.-%, most preferably 24 wt.-% to 35 wt.-% or 44 wt.-% to 51 wt.-%, and in particular 26 wt.-% to 33 wt.-% or 48 wt.-% to 49.5 wt.-%.
In a preferred embodiment, the alkyl cellulose is selected from the group consisting of ethyl cellulose, hydroxyethyl cellulose, ethylmethyl cellulose, hydroxyethyl methyl cellulose, ethylhydroxy ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, and carboxymethyl hydroxyethyl cellulose.
Preferred alkyl celluloses are ethyl cellulose, methyl cellulose and ethylmethyl cellulose. In a particularly preferred embodiment, the alkyl cellulose is ethyl cellulose.
Preferably, the alkyl cellulose is ethyl cellulose having an ethoxyl content of from 40 wt.-% to 60 wt.-%, more preferably 44 wt.-% to 51 wt.-%, most preferably 48 wt.-% to 49.5 wt.-%.
In a preferred embodiment, the alkyl cellulose is ethyl cellulose having a solution viscosity within the range of from 70 mPa·s to 130 mPa·s, more preferably 80 mPa·s to 120 mPa·s and most preferably 90 mPa·s to 110 mPa·s, measured in a 5 wt.-% solution of 80 wt.-% toluene and 20 wt.-% ethanol at 25° C. in an Ubbelohde viscosimeter.
Particularly preferably, the alkyl cellulose is ethyl cellulose, having

    
    
        an ethoxyl content of from 40 wt.-% to 60 wt.-%; and/or
        a solution viscosity within the range of from 70 mPa·s to 130 mPa·s, measured in a 5 wt.-% solution of 80 wt.-% toluene and 20 wt.-% ethanol at 25° C. in an Ubbelohde viscosimeter.
    
    


Preferred commercially available alkyl celluloses include ETHOCEL Polymers, in particular ETHOCEL Standard 100 Premium, ETHOCEL Standard 4 Premium, ETHOCEL Standard 7 Premium, ETHOCEL Standard 10 Premium, ETHOCEL Standard 20 Premium and ETHOCEL Standard 45 Premium.
The content of the alkyl cellulose in the matrix material is preferably at least 20 wt.-%, more preferably at least 30 wt.-%, still more preferably at least 40 wt.-%, even more preferably at least 50 wt.-%, yet more preferably at least 60 wt.-%, most preferably at least 70 wt.-%, and in particular at least 71 wt.-%, relative to the total weight of the matrix material.
The content of the alkyl cellulose in the matrix material is preferably at most 95 wt.-%, more preferably at most 94 wt.-%, still more preferably at most 93 wt.-%, even more preferably at most 92 wt.-%, most preferably at most 91 wt.-%, and in particular at most 90 wt.-%, relative to the total weight of the matrix material.
Preferably, the content of the alkyl cellulose in the matrix material is in the range of from 20 to 95 wt.-%, more preferably 30 to 94 wt.-%, still more preferably 40 to 93 wt.-%, even more preferably 50 to 92 wt.-%, most preferably 60 to 91 wt.-%, and in particular 70 to 90 wt.-% or 75 to 90 wt.-%, relative to the total weight of the matrix material.
In a preferred embodiment, the content of the alkyl cellulose is at least 10 wt.-%, more preferably at least 20 wt.-%, most preferably at least 30 wt.-%, and in particular at least 40 wt.-%, relative to the total weight of the dosage form. In another preferred embodiment, the content of the alkyl cellulose is at least 45 wt.-%, more preferably at least 50 wt.-%, still more preferably at least 55 wt.-%, most preferably at least 60 wt.-%, and in particular at least 63 wt.-%, relative to the total weight of the dosage form.
In a preferred embodiment, the content of the alkyl cellulose is at most 95 wt.-%, more preferably at most 93 wt.-%, still more preferably at most 91 wt.-%, even more preferably at most 89 wt.-%, most preferably at most 87 wt.-%, and in particular at most 86 wt.-%, relative to the total weight of the dosage form.
Preferably, the content of the alkyl cellulose is within the range of from 10 to 95 wt.-%, more preferably 25 to 93 wt.-%, still more preferably 35 to 91 wt.-%, even more preferably 45 to 89 wt.-%, most preferably 55 to 87 wt.-%, and in particular 63 to 86 wt.-%, relative to the total weight of the dosage form.
In a preferred embodiment, the alkyl cellulose is ethyl cellulose which content is within the range of from 63 to 86 wt.-%, relative to the total weight of the dosage form.
The amount of the alkyl cellulose which is contained in the dosage form is within the range of from 50 to 600 mg, more preferably 100 to 575 mg, still more preferably 150 to 550 mg, yet more preferably 200 to 525 mg, even more preferably 250 to 500 mg, most preferably 270 to 475 mg, and in particular 290 to 450 mg.
Preferably, the relative weight ratio of the pharmacologically active ingredient, preferably the opioid to the alkyl cellulose is in the range of from 1:30 to 10:1, more preferably 1:25 to 7:1, still more preferably 1:22 to 4:1, yet more preferably 1:20 to 1:1, most preferably 1:18 to 1:3, and in particular 1:17 to 1:5.
The dosage form according to the invention contains a matrix material comprising a heteropolysaccharide. In a preferred embodiment, the dosage form and the matrix material, respectively, contains only one heteropolysaccharide. In another preferred embodiment, the dosage form and the matrix material, respectively, contains a mixture of two or more heteropolysaccharides.
Heteropolysaccharides are polysaccharides which are based on two or more different monosaccharides.
The heteropolysaccharide may be acidic or neutral. For the purpose of specification, the term “acidic heteropolysaccharide” also includes any derivative of acidic heteropolysaccharides, such as e.g. salts, esters and amides.
In a preferred embodiment, the heteropolysaccharide is acidic and preferably selected from the group consisting of xanthan gum, agar, alginic acid, sodium alginate, propylene glycol alginate, gum arabic, λ-carrageenan, κ-carrageenan, τ-carrageenan, fucoidan, fucogalactan (GFS), gellan gum, gum ghatti, gum karaya, pectin, psyllium seed gum, gum tragacanth, welan gum, their corresponding salts and mixtures thereof.
In another preferred embodiment, the heteropolysaccharide is neutral and preferably selected from the group consisting of chitin, chitosan, curdlan, dextran, guar gum, inulin, ivory nut mannan, konjac glucomannan, laminaran, larch arabinogalactan, locust bean gum, pullulan, scleroglucan, tamarind gum, tara gum, their derivatives and mixtures thereof.
Preferably, the heteropolysaccharide is selected from the group consisting of xanthan gum, guar gum, alginic acid, sodium alginate, carrageenans, locust bean gum, and mixtures thereof.
In a preferred embodiment, the heteropolysaccharide is xanthan gum or guar gum. Particularly preferably, the heteropolysaccharide is xanthan gum.
Preferred commercially available heteropolysaccharides include Xanthan Gum Type 602.
Preferably, the dosage form contains a singly type of a heteropolysaccharide, preferably only xanthan gum, but no additional heteropolysaccharide. Preferably, the dosage form does not comprise a combination of xanthan gum and locust bean gum.
In a particularly preferred embodiment,

    
    
        the alkyl cellulose is ethyl cellulose; and/or
        the heteropolysaccharide is xanthan gum.
    
    


The content of the heteropolysaccharide in the matrix material is preferably at least 1 wt.-%, more preferably at least 3 wt.-%, still more preferably at least 5 wt.-%, even more preferably at least 7 wt.-%, yet more preferably at least 9 wt.-%, most preferably at least 10 wt.-%, and in particular at least 11 wt.-%, relative to the total weight of the matrix material. In another preferred embodiment, the content of the heteropolysaccharide in the matrix material is preferably at least 11 wt.-%, more preferably at least 13 wt.-%, still more preferably at least 15 wt.-%, even more preferably at least 17 wt.-%, yet more preferably at least 19 wt.-%, most preferably at least 21 wt.-%, and in particular at least 23 wt.-% or at least 25 wt.-%, relative to the total weight of the matrix material.
The content of the heteropolysaccharide in the matrix material is preferably at most 90 wt.-%, more preferably at most 80 wt.-%, still more preferably at most 70 wt.-%, even more preferably at most 60 wt.-%, yet more preferably at most 50 wt.-%, most preferably at most 40 wt.-%, and in particular at most 30 wt.-% or at most 29 wt.-%, relative to the total weight of the matrix material.
Preferably, the content of the heteropolysaccharide in the matrix material is in the range of from 1 to 90 wt.-%, more preferably 3 to 80 wt.-%, still more preferably 5 to 70 wt.-%, even more preferably 7 to 60 wt.-%, yet more preferably 8 to 50 wt.-%, most preferably 9 to 40 wt.-%, and in particular 10 to 30 wt.-% or 11 to 29 wt.-%, relative to the total weight of the matrix material.
In a preferred embodiment, the content of the heteropolysaccharide is below 80 wt.-%, more preferably below 70 wt.-%, still more preferably below 65 wt.-%, most preferably below 55 wt.-%, and in particular below 50 wt.-%, relative to the total weight of the pharmaceutical dosage form. In another preferred embodiment, the content of the heteropolysaccharide is below 45 wt.-%, more preferably below 40 wt.-%, still more preferably below 35 wt.-%, most preferably below 30 wt.-%, and in particular below 28 wt.-%, relative to the total weight of the dosage form.
In a preferred embodiment, the content of the heteropolysaccharide is above 1 wt.-%, more preferably above 3 wt.-%, still more preferably above 5 wt.-%, most preferably above 7 wt.-% or above 10 wt.-%, and in particular above 9 wt.-% or above 15 wt.-% or above 20 wt.-%, relative to the total weight of the dosage form.
Preferably, the content of the heteropolysaccharide is within the range of from 2 to 80 wt.-%, more preferably 3 to 70 wt.-%, still more preferably 4 to 60 wt.-%, yet more preferably 5 to 50 wt.-%, even more preferably 6 to 40 wt.-%, most preferably 7 to 30 wt.-%, and in particular 8 to 28 wt.-%, relative to the total weight of the dosage form.
In a preferred embodiment, the heteropolysaccharide is xanthan gum which content is within the range of from 8 to 28 wt.-%, relative to the total weight of the dosage form.
The amount of the heteropolysaccharide which is contained in the dosage form is within the range of from 5 to 300 mg, more preferably 15 to 250 mg, still more preferably 20 to 200 mg, yet more preferably 25 to 180 mg, even more preferably 30 to 160 mg, most preferably 35 to 140 mg, and in particular 40 to 130 mg.
Preferably, the relative weight ratio of the pharmacologically active ingredient, preferably the opioid to the heteropolysaccharide is in the range of from 1:10 to 10:1, more preferably 1:9 to 9:1, still more preferably 1:7 to 7:1, yet more preferably 1:5 to 5:1, most preferably 1:3 to 3:1, and in particular 1:2.5 to 2.5:1.
In a preferred embodiment, the dosage form contains only one pharmacologically active ingredient, preferably one opioid. In another preferred embodiment, the dosage form contains a combination of two or more pharmacologically active ingredients.
In a preferred embodiment, the pharmacologically active ingredient is soluble in water.
Preferably, the pharmacologically active ingredient is selected from ATC class [N], more preferably [N02] according to the WHO.
Particularly preferably, the pharmacologically active ingredient is an opioid. For the purpose of specification, the term “opioid” shall refer to any opioid as well as any physiologically acceptable salt thereof. Thus, preferably, the dosage form comprises an opioid or a physiologically acceptable salt thereof.
Opioids are active ingredients with potential for being abused and potential for dose dumping in ethanol.
According to the ATC index, opioids are divided into natural opium alkaloids, phenylpiperidine derivatives, diphenylpropylamine derivatives, benzomorphan derivatives, oripavine derivatives, morphinan derivatives and others. In a preferred embodiment, the pharmacologically active ingredient is selected from the group consisting of morphine, hydromorphone, nicomorphine, oxycodone, oxymorphone, dihydrocodeine, ketobemidone, pethidine, fenantyl, dextromoramide, piritramide, dextropropoxyphene, bezitramide, pentazocine, phenazocine, buprenorphine, butorphanol, nalbuphine, tilidine, tramadol, dezocine, meptazinol, tapentadol, and the physiologically acceptable salts thereof.
In another preferred embodiment, the pharmacologically active ingredient is selected from the group consisting of tramadol, tapentadol, faxeladol and axomadol.
In a particularly preferred embodiment, the pharmacologically active ingredient is selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, tramadol, tapentadol, morphine, buprenorphine and the physiologically acceptable salts thereof.
In yet another preferred embodiment, the pharmacologically active ingredient is selected from the group consisting of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole, particularly its hemicitrate; 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrano[3,4-b]indole, particularly its citrate; and 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrano[3,4-b]-6-fluoroindole, particularly its hemicitrate. These compounds are known from, e.g., WO 2004/043967, WO 2005/066183.
Preferably, the pharmacologically active ingredient is selected from the following compounds: alfentanil, allylprodine, alphaprodine, apocodeine, axomadol, bemidone, benzylmorphine, bezitramide, buprenorphine, butorphanol, carfentanil, clonitazene, cocaine, codeine, cyclorphan, cyprenorphine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dihydromorphone, dimenoxadol, dimephetamol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, faxeladol, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, hydroxymethylmorphinan, ketobemidone, levacetylmethadol (LAAM), levomethadone, levorphanol, levophenacylmorphane, lofentanil, meperidine, metapon, meptazinol, metazocine, methylmorphine, methadone, 3-methylfentanyl, 4-methylfentanyl, metopon, morphine, myrophine, nalbuphine, nalorphine, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxyco done, oxymorphone, Papaver somniferum, papaveretum, pentazocine, pethidine, phenadoxone, phenomorphane, phenazocine, pheno-peridine, piminodine, pholcodeine, piritramide, profadol, proheptazine, promedol, properidine, propoxyphene, remifentanil, sufentanil, tapentadol, tilidine (cis and trans), tramadol, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol, (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol, (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol, (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, preferably as racemate, 3-(2-dimethylaminomethyl-1-hydroxy-cyclo-hexyl)phenyl 2-(4-isobutyl-phenyl)propionate, 3-(2-dimethylaminomethyl-1-hydroxy-cyclo-hexyl)phenyl 2-(6-methoxy-naphthalen-2-yl)propionate, 3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(4-isobutyl-phenyl)propionate, 3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(6-methoxy-naphthalen-2-yl)propionate, (RR-SS)-2-acetoxy-4-trifluoromethyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-trifluoromethyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-4-chloro-2-hydroxy-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-methyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-methoxy-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-5-nitro-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, and corresponding stereoisomeric compounds, in each case the corresponding derivatives thereof, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemates and the physiologically acceptable derivatives thereof, e.g. ethers, esters or amides, and in each case the physiologically acceptable compounds thereof, in particular the acid or base addition salts thereof and solvates, e.g. hydrochlorides.
In another preferred embodiment, the pharmacologically active ingredient is selected from the group consisting of DPI-125, M6G (CE-04-410), ADL-5859, CR-665, NRP290 and sebacoyl dinalbuphine ester.
In another preferred embodiment, the pharmacologically active ingredient is selected from the group consisting of rabeprazole, fentanyl, risedronate, nifedipine, amphetamine salts, everolimus, alprazolam, lovastatin, zolpidem, dalfampridine, cyclobenzaprine, bupropion, mesalamine, tipranavir, donepezil, diclofenac, aspirin, sulfasalazine, morphine, dutasteride, clarithromycin, praziquantel, bisacodyl, ibandronate, verapamil, nicardipine, diltiazem, doxazosin, cefuroxime, mycophenolate, activated charcoal, ciprofloxacin, docusate, colestipol, methylphenidate, nicotine, carvedilol, pancrelipase, indinavir, duloxetine, cyclophosphamide, ganciclovir, divalproex, tolterodine, dexlansoprazole, doxylamine, pyridoxine, diltiazem, isosorbide, oxybutynin, ergocalciferol, hydroxyurea, isradipine, erythromycin, potassium bicarbonate, venlafaxine, morphine sulfate, darifenacin, budesonide, ergotamine, vismodegib, raloxifene, hydromorphone, deferasirox, piroxicam, fentanyl, ferrous sulfate, ferrous gluconate, metronidazole, tamsulosin, dexmethylphenidate, metformin, alendronate, imatinib, glipizide, gabapentin, propranolol, indomethacin, etravirine, zolpidem, guanfacine, paliperidone, isotretinoin, ruxolitinib, dutasteride, tamsulosin, sitagliptin, lopinavir, ritoavir, dexlansoprazole, clonidine, alogliptin, levetiracetam, telithromycin, desvenlafaxine, potassium salt, lamotrigine, fluvastatin, ambrisentan, hyoscyamine, lithium salt, brompheniramine, fluvoxamine, pyridostigmine, potassium chloride, pramipexole, amoxicillin, ibuprofen, guiafenesin, mycophenolate, mirabegron, memantine, naproxen, esomeprazole, nicotinic acid, nifedipine, nitroglycerin, orphenadrine, disopyramide, ritonavir, posaconazole, tapentadone, trazodone, doxycycline, oxycodone, pancrealipase, paroxetine, dabigatran, felodipide, lansoprazole, omeprazole, finasteride, ciprofloxicin, pantoprazole, fluoxetine, renolazine, sirolimus, prednisone, galantamine, sevelamer, sevelamer carbonate, ropinirole, lenalidomide, propafenone, tramadol, cinacalcet, quetiapine, levodopa, carbidopa, minocycline, chloral hydrate, dasatinib, atomoxetine, nisoldipine, hyoscyamine, nilotinib, diltiazem, dimethyl fumarate, carbamazepine, temozolomide, benzonatate, theophylline, topiramate, metoprolol, fesoterodine, bosentan, pentoxifylline, fenofibric, acetaminophen, budesonide, potassium citrate, alfuzosin, valganciclovir, didanosine, naproxen, esomeprazole, nevirapine, albuterol, pazopanib, rivaroxaban, omeprazole/NaHCO3, hydrocodone, vorinostat, everolimus, zileuton, and corresponding stereoisomeric compounds, in each case the corresponding derivatives thereof, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemates and the physiologically acceptable derivatives thereof, e.g. ethers, esters or amides, and in each case the physiologically acceptable compounds thereof, in particular the acid or base addition salts thereof and solvates, e.g. hydrochlorides.
The pharmacologically active ingredient, preferably the opioid may be present in form of a physiologically acceptable salt, e.g. physiologically acceptable acid addition salt.
Physiologically acceptable acid addition salts comprise the acid addition salt forms which can conveniently be obtained by treating the base form of the pharmacologically active ingredient, preferably the opioid with appropriate organic and inorganic acids. Pharmacologically active ingredients, preferably opioids containing an acidic proton may be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. The term addition salt also comprises the hydrates and solvent addition forms which the active ingredients are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
It has been surprisingly found that the content of the pharmacologically active ingredient, preferably the opioid in the dosage form and in the particles, respectively, can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially pharmaceutical dosage formability) and patient compliance.
The pharmacologically active ingredient, preferably the opioid is present in the dosage form in a therapeutically effective amount. The amount that constitutes a therapeutically effective amount varies according to the pharmacologically active ingredients being used, the condition being treated, the severity of said condition, the patient being treated, and the frequency of administration.
The content of the pharmacologically active ingredient in the dosage form is not limited. The dose of the pharmacologically active ingredient, preferably the opioid which is adapted for administration preferably is in the range of 0.1 mg to 500 mg, more preferably in the range of 1.0 mg to 400 mg, even more preferably in the range of 5.0 mg to 300 mg, and most preferably in the range of 10 mg to 250 mg. In a preferred embodiment, the total amount of the pharmacologically active ingredient, preferably the opioid that is contained in the dosage form is within the range of from 0.01 to 200 mg, more preferably 0.1 to 190 mg, still more preferably 1.0 to 180 mg, yet more preferably 1.5 to 160 mg, most preferably 2.0 to 100 mg and in particular 2.5 to 80 mg.
Preferably, the content of the pharmacologically active ingredient, preferably the opioid is within the range of from 0.01 to 80 wt.-%, more preferably 0.1 to 50 wt.-%, still more preferably 1 to 35 wt.-%, based on the total weight of the dosage form.
In a preferred embodiment, the content of the pharmacologically active ingredient, preferably the opioid is within the range of from 5.0±4.5 wt.-%, or 10±9.0 wt.-%, or 15±14 wt.-%, or 20±19 wt.-%, or 25±24 wt.-%; more preferably 5.0±4.0 wt.-%, or 10±8.0 wt.-%, or 15±12 wt.-%, or 20±19 wt.-%, or 25±24 wt.-%; still more preferably 5.0±3.5 wt.-%, or 10±7.0 wt.-%, or 15±10 wt.-%, or 20±17 wt.-%, or 25±21 wt.-%; yet more preferably 5.0±3.0 wt.-%, or 10±6.0 wt.-%, or 15±8.0 wt.-%, or 20±15 wt.-%, or 25±18 wt.-%; even more preferably 5.0±2.5 wt.-%, or 10±5.0 wt.-%, or 15±6.0 wt.-%, or 20±13 wt.-%, or 25±15 wt.-%; most preferably 5.0±2.0 wt.-%, or 10±4.0 wt.-%, or 15±4.0 wt.-%, or 20±11 wt.-%, or 25±12 wt.-%; and in particular 5.0±1.5 wt.-%, or 10±3.0 wt.-%, or 15±2.0 wt.-%, or 20±9 wt.-%, or 25±9 wt.-%; in each case either based on the total weight of the dosage form or, when the dosage form is particulate, based on the total weight of the particles that contain the pharmacologically active ingredient.
In another preferred embodiment, the content of the pharmacologically active ingredient, preferably the opioid is within the range of 5±4 wt.-%, more preferably 5±3 wt.-%, still more preferably 5±2 wt.-%, most preferably 5±1 wt.-%, and in particular 5±0.5 wt.-%, either based on the total weight of the dosage form or, when the dosage form is particulate, based on the total weight of the particles that contain the pharmacologically active ingredient. In still another preferred embodiment, the content of the pharmacologically active ingredient, preferably the opioid is within the range of 10±9 wt.-%, more preferably 10±7 wt.-%, still more preferably 10±5 wt.-%, yet more preferably 10±3 wt.-%, most preferably 10±1 wt.-%, and in particular 10±0.5 wt.-%, either based on the total weight of the dosage form or, when the dosage form is particulate, based on the total weight of the particles that contain the pharmacologically active ingredient. In yet another preferred embodiment, the content of the pharmacologically active ingredient, preferably the opioid is within the range of 15±14 wt.-%, more preferably 15±11 wt.-%, still more preferably 15±8 wt.-%, yet more preferably 15±5 wt.-%, most preferably 15±2 wt.-%, and in particular 15±0.5 wt.-%, either based on the total weight of the dosage form or, when the dosage form is particulate, based on the total weight of the particles that contain the pharmacologically active ingredient.
The skilled person may readily determine an appropriate amount of pharmacologically active ingredient, preferably opioid to include in a dosage form. For instance, in the case of analgesics, the total amount of pharmacologically active ingredient, preferably opioid present in the dosage form is that sufficient to provide analgesia. The total amount of pharmacologically active ingredient, preferably opioid administered to a patient in a dose will vary depending on numerous factors including the nature of the pharmacologically active ingredient, the weight of the patient, the severity of the pain, the nature of other therapeutic agents being administered etc.
In a preferred embodiment, the pharmacologically active ingredient, preferably the opioid is contained in the dosage form in an amount of 7.5±5 mg, 10±5 mg, 15±5 mg, 20±5 mg, 25±5 mg, 30±5 mg, 35±5 mg, 40±5 mg, 45±5 mg, 50±5 mg, 55±5 mg, 60±5 mg, 65±5 mg, 70±5 mg, 75±5 mg, 80±5 mg, 85±5 mg, 90±5 mg, 95±5 mg, 100±5 mg, 110±5 mg, 120±5 mg, 130±5, 140±5 mg, 150±5 mg, 160±5 mg, 170±5 mg, 180±5 mg, 190±5 mg, 200±5 mg, 210±5 mg, 220±5 mg, 230±5 mg, 240±5 mg, 250±5 mg, 260±5 mg, 270±5 mg, 280±5 mg, 290±5 mg, or 300±5 mg. In another preferred embodiment, the pharmacologically active ingredient, preferably the opioid is contained in the dosage form in an amount of 5±2.5 mg, 7.5±2.5 mg, 10±2.5 mg, 15±2.5 mg, 20±2.5 mg, 25±2.5 mg, 30±2.5 mg, 35±2.5 mg, 40±2.5 mg, 45±2.5 mg, 50±2.5 mg, 55±2.5 mg, 60±2.5 mg, 65±2.5 mg, 70±2.5 mg, 75±2.5 mg, 80±2.5 mg, 85±2.5 mg, 90±2.5 mg, 95±2.5 mg, 100±2.5 mg, 105±2.5 mg, 110±2.5 mg, 115±2.5 mg, 120±2.5 mg, 125±2.5 mg, 130±2.5 mg, 135±2.5 mg, 140±2.5 mg, 145±2.5 mg, 150±2.5 mg, 155±2.5 mg, 160±2.5 mg, 165±2.5 mg, 170±2.5 mg, 175±2.5 mg, 180±2.5 mg, 185±2.5 mg, 190±2.5 mg, 195±2.5 mg, 200±2.5 mg, 205±2.5 mg, 210±2.5 mg, 215±2.5 mg, 220±2.5 mg, 225±2.5 mg, 230±2.5 mg, 235±2.5 mg, 240±2.5 mg, 245±2.5 mg, 250±2.5 mg, 255±2.5 mg, 260±2.5 mg, or 265±2.5 mg.
In a particularly preferred embodiment, the pharmacologically active ingredient is tramadol, preferably its HCl salt, and the dosage form is adapted for administration twice daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 5 to 300 mg. In another particularly preferred embodiment, the pharmacologically active ingredient is tramadol, preferably its HCl salt, and the dosage form is adapted for administration once daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 10 to 500 mg.
In another particularly preferred embodiment, the pharmacologically active ingredient is oxycodone, preferably its HCl salt, and the dosage form is adapted for administration twice daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 1 to 80 mg. In another particularly preferred embodiment, the pharmacologically active ingredient is oxycodone, preferably its HCl salt, and the dosage form is adapted for administration once daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 2 to 320 mg.
In still another particularly preferred embodiment, the pharmacologically active ingredient is oxymorphone, preferably its HCl salt, and the dosage form is adapted for administration twice daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 5 to 40 mg. In another particularly preferred embodiment, the pharmacologically active ingredient is oxymorphone, preferably its HCl salt, and the dosage form is adapted for administration once daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 10 to 80 mg.
In yet another particularly preferred embodiment, the pharmacologically active ingredient is tapentadol, preferably its HCl salt, and the dosage form is adapted for administration once daily or twice daily. In this embodiment, pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 25 to 250 mg.
In a further particularly preferred embodiment, the pharmacologically active ingredient is hydromorphone, preferably its HCl salt, and the dosage form is adapted for administration twice daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 2 to 52 mg. In another particularly preferred embodiment, the pharmacologically active ingredient is hydromorphone, preferably its HCl salt, and the dosage form is adapted for administration once daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 4 to 104 mg.
In still a further particularly preferred embodiment, the pharmacologically active ingredient is hydrocodone, preferably its HCl salt, and the dosage form is adapted for administration twice daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 5 to 250 mg. In another particularly preferred embodiment, the pharmacologically active ingredient is hydrocodone, preferably its HCl salt, and the dosage form is adapted for administration once daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 5 to 250 mg.
In yet a further particularly preferred embodiment, the pharmacologically active ingredient is morphine, preferably its HCl or H2SO4 salt, and the dosage form is adapted for administration twice daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 5 to 250 mg. In another particularly preferred embodiment, the pharmacologically active ingredient is morphine, preferably its HCl or H2SO4 salt, and the dosage form is adapted for administration once daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 5 to 250 mg.
In another particularly preferred embodiment, the pharmacologically active ingredient is buprenorphine, preferably its HCl salt, and the dosage form is adapted for administration twice daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 1 to 12 mg. In another particularly preferred embodiment, the pharmacologically active ingredient is buprenorphine, preferably its HCl salt, and the dosage form is adapted for administration once daily. In this embodiment, the pharmacologically active ingredient is preferably contained in the dosage form in a total amount of from 2 to 12 mg.
When the pharmaceutical dosage form is particulate, the particles present in the dosage form according to the invention preferably comprise 1 to 75 wt.-% of the pharmacologically active ingredient, preferably the opioid, more preferably 2 to 60 wt.-% of the pharmacologically active ingredient, preferably the opioid, still more preferably 3 to 40 wt.-% of the pharmacologically active ingredient, preferably the opioid, most preferably 4 to 25 wt.-% of the pharmacologically active ingredient, preferably the opioid and in particular 4.5 to 17 wt.-% of the pharmacologically active ingredient, preferably the opioid, based on the total weight of a particle.
When the dosage form is particulate, the content of the pharmacologically active ingredient, preferably the opioid is preferably at least 1 wt.-%, more preferably at least 2 wt.-%, still more preferably at least 3 wt.-%, most preferably at least 4 wt.-% and in particular at least 5 wt.-%, based on the total weight of a particle.
When the dosage form is particulate, the content of the pharmacologically active ingredient, preferably the opioid is preferably at most 70 wt.-%, more preferably at most 65 wt.-%, still more preferably at most 50 wt.-%, yet more preferably at most 35 wt.-%, most preferably at most 20 wt.-%, based on the total weight of a particle.
In a preferred embodiment, when the dosage form is particulate, the content of the pharmacologically active ingredient, preferably the opioid is within the range of 5±4 wt.-%, more preferably 5±3 wt.-%, still more preferably 5±2 wt.-%, most preferably 5±1 wt.-%, and in particular 5±0.5 wt.-%, based on the total weight of a particle. In another preferred embodiment, when the dosage form is particulate, the content of the pharmacologically active ingredient, preferably the opioid is within the range of 10±9 wt.-%, more preferably 10±7 wt.-%, still more preferably 10±5 wt.-%, yet more preferably 10±3 wt.-%, most preferably 10±1 wt.-%, and in particular 10±0.5 wt.-%, based on the total weight of a particle. In still another preferred embodiment, when the dosage form is particulate, the content of the pharmacologically active ingredient, preferably the opioid is within the range of 15±14 wt.-%, more preferably 15±11 wt.-%, still more preferably 15±8 wt.-%, yet more preferably 15±5 wt.-%, most preferably 15±2 wt.-%, and in particular 15±0.5 wt.-%, based on the total weight of a particle.
The pharmacologically active ingredient, preferably the opioid that is included in the preparation of the dosage forms according to the invention preferably has an average particle size of less than 500 microns, still more preferably less than 300 microns, yet more preferably less than 200 or 100 microns. There is no lower limit on the average particle size and it may be, for example, 50 microns. The particle size of the pharmacologically active ingredient may be determined by any technique conventional in the art, e.g. laser light scattering, sieve analysis, light microscopy or image analysis. When the dosage form is particulate, it is preferable that the largest dimension of the pharmacologically active ingredient particle be less than the size of the particles (e.g. less than the smallest dimension of the particles).
In a preferred embodiment, the dosage form contains a combination of a pharmacologically active ingredient, preferably an opioid and a further pharmacologically active ingredient which is not an opioid.
In another preferred embodiment, apart from the pharmacologically active ingredient, preferably the opioid, the dosage form does not contain any further pharmacologically active ingredient.
Said further pharmacologically active ingredient is preferably selected from ATC classes [M01A], [M01C], [N02B] and [N02C] according to the WHO.
Preferably, the further pharmacologically active ingredient is selected from the group consisting of acetylsalicylic acid, aloxiprin, choline salicylate, sodium salicylate, salicylamide, salsalate, ethenzamide, morpholine salicylate, dipyrocetyl, benorilate, diflunisal, potassium salicylate, guacetisal, carbasalate calcium, imidazole salicylate, phenazone, metamizole sodium, aminophenazone, propyphenazone, nifenazone, paracetamol, phenacetin, bucetin, propacetamol, rimazolium, glafenine, floctafenine, viminol, nefopam, flupirtine, ziconotide, methoxyflurane, nabiximols, dihydroergotamine, ergotamine, methysergide, lisuride, flumedroxone, sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, frovatriptan, pizotifen, clonidine, iprazochrome, dimetotiazine, oxetorone, phenylbutazone, mofebutazone, oxyphenbutazone, clofezone, kebuzone, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, alclofenac, bumadizone, etodolac, lonazolac, fentiazac, acemetacin, difenpiramide, oxametacin, proglumetacin, ketorolac, aceclofenac, bufexamac, piroxicam, tenoxicam, droxicam, lornoxicam, meloxicam, ibuprofen, naproxen, ketoprofen, fenoprofen, fenbufen, benoxaprofen, suprofen, pirprofen, flurbiprofen, indoprofen, tiaprofenic acid, oxaprozin, ibuproxam, dexibuprofen, flunoxaprofen, alminoprofen, dexketoprofen, naproxcinod, mefenamic acid, tolfenamic acid, flufenamic acid, meclofenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, nabumetone, niflumic acid, azapropazone, glucosamine, benzydamine, glucosaminoglycan polysulfate, proquazone, orgotein, nimesulide, feprazone, diacerein, morniflumate, tenidap, oxaceprol, chondroitin sulfate, oxycinchophen, sodium aurothiomalate, sodium aurotiosulfate, auranofin, aurothioglucose, aurotioprol, penicillamine, bucillamine, their physiologically acceptable salts, as well as mixtures thereof.
If the dosage form comprises a further pharmacologically active ingredient, said further pharmacologically active ingredient preferably is present in the dosage form in a therapeutically effective amount. The amount that constitutes a therapeutically effective amount varies according to the further pharmacologically active ingredient being used, the condition being treated, the severity of said condition, the patient being treated, and the frequency of administration.
The content of the further pharmacologically active ingredient in the dosage form is not limited. The dose of the further pharmacologically active ingredient which is adapted for administration preferably is in the range of 0.1 mg to 4 g.
The matrix material and the dosage form, respectively, may contain additional pharmaceutical excipients conventionally contained in pharmaceutical dosage forms in conventional amounts, such as antioxidants, preservatives, lubricants, plasticizer, fillers, binders, and the like.
Preferably, the matrix material and the dosage form, respectively, only comprises excipients which are approved for oral use according to the Ph. Eur. and the USP, respectively. Therefore, in a preferred embodiment, the dosage form according to the present invention does not contain any compound which is not approved for oral use. More preferably, the dosage form does not contain poly(ε-caprolactone).
The skilled person will readily be able to determine appropriate further excipients as well as the quantities of each of these excipients. Specific examples of pharmaceutically acceptable carriers and excipients are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986).
In a preferred embodiment, the dosage form does not contain a disintegrant.
Preferably, the matrix material and the dosage form, respectively, further comprises an antioxidant. Suitable antioxidants include ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), salts of ascorbic acid, monothioglycerol, phosphorous acid, vitamin C, vitamin E and the derivatives thereof, coniferyl benzoate, nordihydroguajaretic acid, gallus acid esters, sodium bisulfite, particularly preferably butylhydroxytoluene or butylhydroxyanisole and α-tocopherol. The antioxidant is preferably present in quantities of 0.01 wt.-% to 10 wt.-%, more preferably of 0.03 wt.-% to 5 wt.-%, most preferably of 0.05 wt.-% to 2.5 wt.-%, based on the total weight of the dosage form and the matrix material, respectively.
In a preferred embodiment, the matrix material and the dosage form, respectively, further comprise an acid, preferably citric acid. The amount of acid is preferably in the range of 0.01 wt.-% to about 20 wt.-%, more preferably in the range of 0.02 wt.-% to about 10 wt.-%, and still more preferably in the range of 0.05 wt.-% to about 5 wt.-%, and most preferably in the range of 0.1 wt.-% to about 1.0 wt.-%, based on the total weight of the dosage form and the matrix material, respectively.
In a preferred embodiment, the matrix material and the dosage form, respectively, contain at least one lubricant.
Especially preferred lubricants are selected from

    
    
        magnesium stearate and stearic acid;
        polyoxyethylene glycerol fatty acid esters, such as mixtures of mono-, di- and triesters of glycerol and di- and monoesters of macrogols having molecular weights within the range of from 200 to 4000 g/mol, e.g., macrogolglycerolcaprylocaprate, macrogolglycerollaurate, macrogolglycerolococoate, macrogolglycerollinoleate, macrogol-20-glycerolmonostearate, macrogol-6-glycerolcaprylocaprate, macrogolglycerololeate; macrogolglycerolstearate, macrogolglycerolhydroxystearate, and macrogolglycerolrizinoleate;
        polyglycolyzed glycerides, such as the one known and commercially available under the trade name “Labrasol”;
        fatty alcohols that may be linear or branched, such as cetylalcohol, stearylalcohol, cetylstearyl alcohol, 2-octyldodecane-1-ol and 2-hexyldecane-1-ol; and
        polyethylene glycols having a molecular weight between 10.000 and 60.000 g/mol.
    
    


Preferably, the amount of the lubricant ranges from 0.01 wt.-% to about 10 wt.-%, more preferably in the range of 0.05 wt.-% to about 7.5 wt.-%, most preferably in the range of 0.1 wt.-% to about 5 wt.-%, and in particular in the range of 0.1 wt.-% to about 1 wt.-%, based on the total weight of the dosage form and the matrix material, respectively.
Preferably, the matrix material and the dosage form, respectively, further comprise a plasticizer. The plasticizer improves the matrix material. A preferred plasticizer is polyalkylene glycol, like polyethylene glycol, triacetin, fatty acids, fatty acid esters, waxes and/or microcrystalline waxes. Particularly preferred plasticizers are polyethylene glycols, such as PEG 6000.
Preferably, the content of the plasticizer is within the range of from 0.5 to 30 wt.-%, more preferably 1.0 to 25 wt.-%, still more preferably 2.5 wt.-% to 22.5 wt.-%, yet more preferably 5.0 wt.-% to 20 wt.-%, most preferably 6 to 20 wt.-% and in particular 7 wt.-% to 17.5 wt.-%, based on the total weight of the dosage form and the matrix material, respectively.
Plasticizers can sometimes act as a lubricant, and lubricants can sometimes act as a plasticizer.
In another preferred embodiment, the matrix material and the dosage form, respectively, contain no antioxidant and/or no acid and/or no lubricant and/or no plasticizer. More preferably, the matrix material and the dosage form, respectively, contain no excipients.
Preferred contents of the pharmacologically active ingredient, preferably the opioid, the alkyl cellulose, the heteropolysaccharide and excipients, relative to the total weight of the dosage form are summarized as embodiments A1 to A12 in the tables here below:














wt.-%
A1
A2
A3
A4







pharmacologically
15 ± 14
15 ± 10
15 ± 7 
15 ± 5 


active ingredient






alkyl cellulose
85 ± 70
85 ± 50
85 ± 30
85 ± 10


heteropolysaccharide
10 ± 8 
10 ± 6 
10 ± 4 
10 ± 3 


pharmaceutical excipients
20 ± 20
20 ± 20
20 ± 20
20 ± 20























wt.-%
A5
A6
A7
A8







pharmacologically
15 ± 14
15 ± 10
15 ± 7 
15 ± 5 


active ingredient






alkyl cellulose
75 ± 60
75 ± 40
75 ± 20
75 ± 10


heteropolysaccharide
15 ± 10
15 ± 8 
15 ± 6 
15 ± 5 


pharmaceutical excipients
20 ± 20
20 ± 20
20 ± 20
20 ± 20























wt.-%
A9
A10
A11
A12







pharmacologically
15 ± 14
15 ± 10
15 ± 7 
15 ± 5 


active ingredient






alkyl cellulose
65 ± 50
65 ± 35
65 ± 20
65 ± 10


heteropolysaccharide
25 ± 20
25 ± 15
25 ± 10
25 ± 5 


pharmaceutical excipients
20 ± 20
20 ± 20
20 ± 20
20 ± 20









In a preferred embodiment, the dosage form, more preferably the matrix comprising the alkyl cellulose and the heteropolysaccharide provides prolonged release of the pharmacologically active ingredient, preferably the opioid. In another preferred embodiment, the dosage form, more preferably the matrix comprising the alkyl cellulose and the heteropolysaccharide provides immediate release of the pharmacologically active ingredient, preferably the opioid.
The term “prolonged release” is known to the skilled artisan. For the purpose of specification, the term “prolonged release” preferably refers to a release rate of the pharmacologically active ingredient from the formulation that has been reduced over time in order to maintain therapeutic activity, to reduce toxic effects, or for some other therapeutic purpose such as reducing the dosing frequency.
The term “immediate release” is known to the skilled artisan. For the purpose of specification, the term “immediate release” preferably refers to a release rate of the pharmacologically active ingredient from the formulation that is comparatively fast and not retarded.
In the dosage form according to the present invention, the release of the pharmacologically active ingredient is preferably not controlled by erosion of the surface of the dosage form. If the dosage form according to the present invention is particulate, the release of the pharmacologically active ingredient is preferably neither controlled by erosion of the surface of the particles, nor by erosion of the surface of the dosage form.
In a preferred embodiment, the dosage form provides prolonged release of the pharmacologically active ingredient, preferably the opioid. Preferably, the matrix provides for a prolonged release of the pharmacologically active ingredient, preferably the opioid from dosage form.
Preferably, under in vitro conditions the dosage form has released after 30 minutes 0.1 to 75%, after 240 minutes 0.5 to 99%, after 480 minutes 1.0 to 100% and after 720 minutes 2.5 to 100% of the pharmacologically active ingredient, preferably the opioid.
Suitable in vitro conditions are known to the skilled artisan. In this regard it can be referred to, e.g., the Eur. Ph. Preferably, the release profile is measured under the following conditions: Paddle apparatus, 50 rpm, 37±5° C., 900 mL 0.1 M HCl (pH 1.0) or simulated intestinal fluid pH 6.8 (phosphate buffer) or pH 4.5. In another preferred embodiment, the rotational speed of the paddle is increased to 75 rpm. In another preferred embodiment, the release profile is determined under the following conditions: basket method, 75 rpm, 37±5° C., 900 mL 0.1 N HCl or 900 mL of SIF sp (pH 6.8) or 900 mL of 0.1 N HCl+40 vol.-% ethanol.
Preferred release profiles R1 to R7 are summarized in the table here below [all data in wt.-% of released pharmacologically active ingredient]:


















time
R1
R1
R2
R3
R4
R5
R6
R7
























60 
min
0-60
0-10
 2-20
 4-20
 5-30 
15-40 
15-50
20-65


120 
min
0-90
1-60
 5-30
10-35
10-35
20-55
25-80
30-90


240 
min 
1-99
5-95
15-45
25-85
15-45
40-80 
 35-100 
50-95


480 
min
 5-100 
 7-100 
25-85
 60-100
20-60
 60-100
 45-100
 70-100


720 
min
10-100
10-100
 35-100
 80-100
30-80
>80
>80
 70-100


960 
min
20-100
15-100
 50-100
>90
40-90
>90
>90
>80


1440 
min
50-100
30-100
 60-100
>99
>60
>99
>99
>90


2160 
min
>80
>80
>80

>80


>99









In a particularly preferred embodiment; under in vitro conditions in 900 mL 0.1 N HCl (pH 1.0), using the paddle method according to Ph. Eur. at 50 rpm, after 1 h under physiological conditions, the dosage form has released at most 80%, more preferably at most 70%, most preferably at most 65% and in particular at most 60% of the pharmacologically active ingredient, preferably the opioid relative to the total amount of the pharmacologically active ingredient originally contained in the dosage form.
In another preferred embodiment, the dosage form provides immediate release of the pharmacologically active ingredient, preferably the opioid. Preferably, the matrix provides for an immediate release of the pharmacologically active ingredient, preferably the opioid from the dosage form.
Preferably, under in vitro conditions the dosage form has released after 15 minutes 20 to 90%, after 30 minutes 35 to 99%, after 45 minutes 50 to 99% and after 60 minutes more than 60% or more than 70% or more than 80% or more than 90% or more than 95% of the pharmacologically active ingredient, preferably the opioid.
Suitable in vitro conditions are known to the skilled artisan. In this regard it can be referred to, e.g., the Eur. Ph. Preferably, the release profile is measured under the following conditions: Paddle apparatus, 50 rpm, 37±5° C., 900 mL 0.1 M HCl (pH 1.0) or simulated intestinal fluid pH 6.8 (phosphate buffer) or pH 4.5. In another preferred embodiment, the rotational speed of the paddle is increased to 75 rpm. In another preferred embodiment, the release profile is determined under the following conditions: basket method, 75 rpm, 37±5° C., 900 mL 0.1 N HCl or 900 mL of SIF sp (pH 6.8) or 900 mL of 0.1 N HCl+40% ethanol.
In a preferred embodiment, the dosage form according to the invention has a breaking strength of less than 300 N, more preferably less than 200 N, or, when the dosage form is particulate, the particles have a breaking strength of less than 300 N, more preferably less than 200 N. According to this embodiment, the dosage form preferably is particulate and in form of a filled capsule.
In another preferred embodiment, the dosage form according to the invention has a breaking strength of at least 200 N, more preferably at least 300 N, or, when the dosage form is particulate, the particles have a breaking strength of at least 200 N, more preferably at least 300 N. According to this embodiment, the dosage form or, when it is particulate, the particles according to the invention which contain the pharmacologically active ingredient preferably have a breaking strength of at least 300 N, at least 400 N, or at least 500 N, preferably at least 600 N, more preferably at least 700 N, still more preferably at least 800 N, yet more preferably at least 1000 N, most preferably at least 1250 N and in particular at least 1500 N. Further according to this embodiment, preferably, the dosage form and the particles, respectively, cannot be pulverized by the application of force with conventional means, such as for example a pestle and mortar, a hammer, a mallet or other usual means for pulverization, in particular devices developed for this purpose (dosage form crushers). In this regard “pulverization” means crumbling into small particles. Avoidance of pulverization virtually rules out oral or parenteral, in particular intravenous or nasal abuse.
The “breaking strength” (resistance to crushing) of a dosage form and of a particle is known to the skilled person. In this regard it can be referred to, e.g., W. A. Ritschel, Die Tablette, 2. Auflage, Editio Cantor Verlag Aulendorf, 2002; H Liebermann et al., Pharmaceutical dosage forms: Pharmaceutical dosage forms, Vol. 2, Informa Healthcare; 2 edition, 1990; and Encyclopedia of Pharmaceutical Technology, Informa Healthcare; 1 edition.
For the purpose of specification, the breaking strength is preferably defined as the amount of force that is necessary in order to fracture a dosage form and a particle, respectively (=breaking force). Therefore, for the purpose of specification, a dosage form and a particle, respectively, does preferably not exhibit the desired breaking strength when it breaks, i.e., is fractured into at least two independent parts that are separated from one another. In another preferred embodiment, however, the dosage form and particle, respectively, is regarded as being broken if the force decreases by 25% (threshold value) of the highest force measured during the measurement (see below).
Methods for measuring the breaking strength are known to the skilled artisan. Suitable devices are commercially available.
For example, the breaking strength (resistance to crushing) can be measured in accordance with the Eur. Ph. 5.0, 2.9.8 or 6.0, 2.09.08 “Resistance to Crushing of Pharmaceutical dosage forms”. The particles may be subjected to the same or similar breaking strength test as the dosage form. The test is intended to determine, under defined conditions, the resistance to crushing of dosage forms and individual particles, respectively, measured by the force needed to disrupt them by crushing. The apparatus consists of 2 jaws facing each other, one of which moves towards the other. The flat surfaces of the jaws are perpendicular to the direction of movement. The crushing surfaces of the jaws are flat and larger than the zone of contact with the dosage form and individual particle, respectively. The apparatus is calibrated using a system with a precision of 1 Newton. The dosage form and particle, respectively, is placed between the jaws, taking into account, where applicable, the shape, the break-mark and the inscription; for each measurement the dosage form and particle, respectively, is oriented in the same way with respect to the direction of application of the force (and the direction of extension in which the breaking strength is to be measured). The measurement is carried out on 10 dosage forms and particles, respectively, taking care that all fragments have been removed before each determination. The result is expressed as the mean, minimum and maximum values of the forces measured, all expressed in Newton.
A similar description of the breaking strength (breaking force) can be found in the USP. The breaking strength can alternatively be measured in accordance with the method described therein where it is stated that the breaking strength is the force required to cause a dosage form and particle, respectively, to fail (i.e., break) in a specific plane. The dosage forms and particles, respectively, are generally placed between two platens, one of which moves to apply sufficient force to the dosage form and particle, respectively, to cause fracture. For conventional, round (circular cross-section) dosage forms and particles, respectively, loading occurs across their diameter (sometimes referred to as diametral loading), and fracture occurs in the plane. The breaking force of dosage forms and particles, respectively, is commonly called hardness in the pharmaceutical literature; however, the use of this term is misleading. In material science, the term hardness refers to the resistance of a surface to penetration or indentation by a small probe. The term crushing strength is also frequently used to describe the resistance of dosage forms and particle, respectively, to the application of a compressive load. Although this term describes the true nature of the test more accurately than does hardness, it implies that dosage forms and particles, respectively, are actually crushed during the test, which is often not the case.
Alternatively, the breaking strength (resistance to crushing) can be measured in accordance with WO 2008/107149, which can be regarded as a modification of the method described in the Eur. Ph. The apparatus used for the measurement is preferably a “Zwick Z 2.5” materials tester, Fmax=2.5 kN with a maximum draw of 1150 mm, which should be set up with one column and one spindle, a clearance behind of 100 mm and a test speed adjustable between 0.1 and 800 mm/min together with testControl software. Measurement is performed using a pressure piston with screw-in inserts and a cylinder (diameter 10 mm), a force transducer, Fmax. 1 kN, diameter=8 mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with manufacturer's test certificate M according to DIN 55350-18 (Zwick gross force Fmax=1.45 kN) (all apparatus from Zwick GmbH & Co. KG, Ulm, Germany) with Order No BTC-FR 2.5 TH. D09 for the tester, Order No BTC-LC 0050N. P01 for the force transducer, Order No BO 70000 S06 for the centring device.
In a preferred embodiment, the dosage form and particle, respectively, is regarded as being broken if it is fractured into at least two separate pieces.
The dosage form according to the invention provides tamper resistance in terms of resistance against dose-dumping in aqueous ethanol.
In a preferred embodiment, the dosage form, more preferably the matrix, further provides resistance against solvent extraction and/or resistance against grinding.
Preferably, the dosage form, more preferably the matrix, provides tamper resistance. Tamper resistance preferably means that the dosage form and the matrix, respectively,

    
    
        (i) provides resistance against dose-dumping in aqueous ethanol; and
        (ii) preferably provides resistance against solvent extraction; and/or
        (iii) preferably provides resistance against grinding.
    
    


Thus, the dosage form and the matrix, respectively, apart from exhibiting resistance (i), does not necessarily need to further exhibit resistances (ii) and (iii); but may preferably exhibit a combination thereof; namely a combination of only (i) and (ii); a combination of only (i) and (iii); or a combination of (i) and (ii) and (iii).
As used herein, the term “tamper-resistant” refers to dosage forms or segments that are resistant to conversion into a form suitable for misuse or abuse, particular for nasal and/or intravenous administration, by conventional means.
The dosage form according to the invention provides resistance against dose dumping in aqueous ethanol. Preferably, the matrix provides the dosage form with resistance against dose dumping in aqueous ethanol.
The dosage form can be tested in vitro using 0.1 N HCl with 40 vol.-% ethanol to evaluate alcohol extractability. Testing is preferably performed using standard procedures, e.g. USP Apparatus 1 (basket) or USP Apparatus 2 (paddle) at e.g. 50 rpm in e.g. 900 mL of media at 37° C., using a Perkin Elmer UV/VIS Spectrometer Lambda 20, UV at an appropriate wavelength for detection of the pharmacologically active ingredient present therein. Sample time points preferably include 0.5 and 1 hour.
Preferably, when comparing the in vitro release profile at 37° C. in 0.1 N HCl with the in vitro release profile in 0.1 N HCl/ethanol (40 vol.-%) at 37° C., the in vitro release 0.1 N HCl/ethanol (40 vol.-%) is preferably not substantially accelerated compared to the in vitro release in 0.1 N HCl. Preferably, in this regard “substantially” means that at any given time point the in vitro release in 0.1 N HCl/ethanol (40 vol.-%) relatively deviates from the in vitro release in 0.1 N HCl by not more than +15%, more preferably not more than +10%, still more preferably not more than +8%, yet more preferably not more than +6%, even more preferably not more than +4%, most preferably not more than +2% and in particular not more than +1% or not more than +0.5% or not more than +0.1%.
Preferably, with the dosage forms according to the invention, a substantial relative deceleration of the in vitro release in 0.1 N HCl/ethanol (40 vol.-%) compared to the in vitro release in 0.1 N HCl is observed. In a particularly preferred embodiment, at any given time point the in vitro release in 0.1 N HCl/ethanol (40 vol.-%) relatively deviates from the in vitro release in 0.1 N HCl by at least −0.01%, more preferably at least −0.05%, still more preferably at least −0.1%, most preferably at least −0.5% and in particular at least −1%.
Further, the dosage form can be tested in vitro using ethanol/simulated gastric fluid of 0%, 20% and 40% to evaluate alcohol extractability. Testing is preferably performed using standard procedures, e.g. USP Apparatus 1 (basket) or USP Apparatus 2 (paddle) at e.g. 50 rpm in e.g. 900 mL of media at 37° C., using a Perkin Elmer UV/VIS Spectrometer Lambda 20, UV at an appropriate wavelength for detection of the pharmacologically active ingredient present therein. Sample time points preferably include 0.5 and 1 hour.
Preferably, when comparing the in vitro release profile at 37° C. in simulated gastric fluid with the in vitro release profile in ethanol/simulated gastric fluid (40 vol.-%) at 37° C., the in vitro release in ethanol/simulated gastric fluid (40 vol.-%) is preferably not substantially accelerated compared to the in vitro release in simulated gastric fluid. Preferably, in this regard “substantially” means that at any given time point the in vitro release in ethanol/simulated gastric fluid (40 vol.-%) relatively deviates from the in vitro release in simulated gastric fluid by not more than +15%, more preferably not more than +10%, still more preferably not more than +8%, yet more preferably not more than +6%, even more preferably not more than +4%, most preferably not more than +2% and in particular not more than +1%.
Preferably, with the dosage forms according to the invention, a substantial relative deceleration of the in vitro release in ethanol/simulated gastric fluid (40 vol.-%) compared to the in vitro release in simulated gastric fluid is observed. In a particularly preferred embodiment, at any given time point the in vitro release in ethanol/simulated gastric fluid (40 vol.-%) relatively deviates from the in vitro release in simulated gastric fluid by at least −0.01%, more preferably at least −0.05%, still more preferably at least −0.1%, most preferably at least −0.5% and in particular at least −1%.
The dosage form according to the invention preferably exhibits resistance against solvent extraction. Preferably, the matrix provides the dosage form according to the invention with resistance against solvent extraction.
Preferably, when trying to tamper the pharmaceutical dosage form in order to prepare a formulation suitable for abuse by intravenous administration, the liquid part of the formulation that can be separated from the remainder by means of a syringe at room temperature is as little as possible, preferably it contains not more than 45 or 40 wt.-%, more preferably not more than 35 wt.-%, still more preferably not more than 30 wt.-%, yet more preferably not more than 25 wt.-%, even more preferably not more than 20 wt.-%, most preferably not more than 15 wt.-% and in particular not more than 10 wt.-% of the original content of the pharmacologically active ingredient, preferably the opioid.
Preferably, this property is tested by (i) dispensing a dosage form that is either intact or has been manually comminuted by means of two spoons in 5 ml of solvent, either purified water or aqueous ethanol (40 vol. %), (ii) allowing the dispersion to stand for 10 min at room temperature, (iii) drawing up the hot liquid into a syringe (needle 21G equipped with a cigarette filter), and (iv) determining the amount of the pharmacologically active ingredient contained in the liquid within the syringe.
In a preferred embodiment, the dosage form exhibits resistance against grinding. In another preferred embodiment, the dosage form does not exhibit resistance against grinding.
Preferably, the dosage form according to the invention is particulate, wherein the particles are obtained by wet granulation, dry granulation or fluid bed granulation.
A further aspect of the invention relates to a process for the production of an oral pharmaceutical dosage form as described herein comprising the steps of

    (i) mixing a pharmacologically active ingredient, preferably an opioid; an alkyl cellulose; a heteropolysaccharide and optionally ethanol; and
    (ii) granulating the mixture obtained in step (i).


Preferably, the process further comprises the steps of

    (iii) screening the granules obtained in step (ii) through a sieve having a mesh size of preferably 1,000 μm; and
    (iv) drying the screened granules obtained in step (iii); and
    (v) filling the dried granules obtained in step (iv) in a capsule; and
    (vi) optionally providing a film coating.


In another preferred embodiment, the granules preferably obtained in any of steps (ii) to (iv), preferably in combination with an outer matrix material, are compressed into tablets.
In still another preferred embodiment, the dosage form or, when it is particulate, the particles that contain the pharmacologically active ingredient are preferably thermoformed, preferably by melt-extrusion, although also other methods of thermoforming may be useful, such as press-molding at elevated temperature or heating of compacts that were manufactured by conventional compression in a first step and then heated above the softening temperature of the matrix material, in a second step to form break resistant, hardened compacts, i.e. monolithic dosage forms or particles, respectively. In this regard, thermoforming preferably means the forming or molding of a mass after, before or during the application of heat. Preferably, thermoforming is performed by hot-melt extrusion.
In a preferred embodiment, when the dosage form is particulate and the particles are hot-melt extruded, the dosage form is a filled capsule.
In a preferred embodiment, hot-melt extrusion is performed by means of a twin-screw-extruder. Melt extrusion preferably provides a melt-extruded strand that is preferably cut into monoliths, which are then optionally compressed and formed. Preferably, compression is achieved by means of a die and a punch, preferably from a monolithic mass obtained by melt extrusion. If obtained via melt extrusion, the compressing step is preferably carried out with a monolithic mass exhibiting ambient temperature, that is, a temperature in the range from 20 to 25° C.
When the dosage forms and particles, respectively, are manufactured by thermoforming, they may be produced by different processes. Several suitable processes have already been described in the prior art. In this regard it can be referred to, e.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, and WO 2006/082099.
In a preferred embodiment, when the dosage form is in form of a tablet, it is prepared by compression. Thus, when the dosage form is particulate, the particles as hereinbefore defined are preferably mixed, e.g. blended and/or granulated (e.g. wet granulated), with outer matrix material and the resulting mix (e.g. blend or granulate) is then compressed, preferably in molds, to form dosage forms. It is also envisaged that the particles herein described may be incorporated into a matrix using other processes, such as by melt granulation (e.g. using fatty alcohols and/or water-soluble waxes and/or water-insoluble waxes) or high shear granulation, followed by compression.
When the dosage forms according to the invention are manufactured by means of an eccentric press, the compression force is preferably within the range of from 5 to 15 kN. When the dosage forms according to the invention are manufactured by means of a rotating press, the compression force is preferably within the range of from 5 to 40 kN, in certain embodiments >25 kN, in other embodiments about 13 kN.
Another aspect of the invention relates to a dosage form which is obtainable by any of the processes described above.
Preferably, the release profile, the pharmacologically active ingredient, the alkyl cellulose, the heteropolysaccharide and optionally present pharmaceutical excipients are stable upon storage, preferably upon storage at elevated temperature, e.g. 40° C., for 3 months in sealed containers.
In connection with the release profile “stable” preferably means that when comparing the initial release profile with the release profile after storage, at any given time point the release profiles deviate from one another by not more than 20%, more preferably not more than 15%, still more preferably not more than 10%, yet more preferably not more than 7.5%, most preferably not more than 5.0% and in particular not more than 2.5%.
In connection with the pharmacologically active ingredient, the alkyl cellulose, the heteropolysaccharide, the optionally present further pharmacologically active ingredient and the optionally present pharmaceutical excipients “stable” preferably means that the dosage forms satisfy the requirements of EMEA concerning shelf-life of pharmaceutical products.
Preferably, after storage for 4 weeks, more preferably 6 months, at 40° C. and 75% rel. humidity, the content of the pharmacologically active ingredient, preferably the opioid in the dosage form according to the invention amounts to at least 98.0%, more preferably at least 98.5%, still more preferably at least 99.0%, yet more preferably at least 99.2%, most preferably at least 99.4% and in particular at least 99.6%, of its original content before storage.
In a preferred embodiment, the dosage form according to the invention contains no substances which irritate the nasal passages and/or pharynx, i.e. substances which, when administered via the nasal passages and/or pharynx, bring about a physical reaction which is either so unpleasant for the patient that he/she does not wish to or cannot continue administration, for example burning, or physiologically counteracts taking of the corresponding active compound, for example due to increased nasal secretion or sneezing. Further examples of substances which irritate the nasal passages and/or pharynx are those which cause burning, itching, urge to sneeze, increased formation of secretions or a combination of at least two of these stimuli. Corresponding substances and the quantities thereof which are conventionally to be used are known to the person skilled in the art. Some of the substances which irritate the nasal passages and/or pharynx are accordingly based on one or more constituents or one or more plant parts of a hot substance drug. Corresponding hot substance drugs are known per se to the person skilled in the art and are described, for example, in “Pharmazeutische Biologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 et seq. The corresponding description is hereby introduced as a reference and is deemed to be part of the disclosure.
The dosage form according to the invention furthermore preferably contains no antagonists for the pharmacologically active ingredient, preferably the opioid and the optionally present further pharmacologically active ingredient, preferably no antagonists against psychotropic substances, in particular no antagonists against opioids. Antagonists suitable for a given pharmacologically active ingredient are known to the person skilled in the art and may be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof. The dosage form according to the invention preferably contains no antagonists selected from among the group comprising naloxone, naltrexone, nalmefene, nalide, nalmexone, nalorphine or naluphine, in each case optionally in the form of a corresponding physiologically acceptable compound, in particular in the form of a base, a salt or solvate; and no neuroleptics, for example a compound selected from among the group comprising haloperidol, promethacine, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chlorprothixine, zuclopenthixol, flupentixol, prothipendyl, zotepine, benperidol, pipamperone, melperone and bromperidol.
The dosage form according to the invention furthermore preferably contains no emetic. Emetics are known to the person skilled in the art and may be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof. The dosage form according to the invention preferably contains no emetic based on one or more constituents of ipecacuanha (ipecac) root, for example based on the constituent emetine, as are, for example, described in “Pharmazeutische Biologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart, N.Y., 1982. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure. The dosage form according to the invention preferably also contains no apomorphine as an emetic.
Finally, the dosage form according to the invention preferably also contains no bitter substance. Bitter substances and the quantities effective for use may be found in US 2003/0064099 A1, the corresponding disclosure of which should be deemed to be the disclosure of the present application and is hereby introduced as a reference. Examples of bitter substances are aromatic oils, such as peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruit aroma substances, aroma substances from lemons, oranges, limes, grapefruit or mixtures thereof, and/or denatonium benzoate.
The dosage form according to the invention accordingly preferably contains neither substances which irritate the nasal passages and/or pharynx, nor antagonists for the pharmacologically active ingredient, nor emetics, nor bitter substances.
In a preferred embodiment, the dosage form according to the invention is adapted for administration once daily, preferably orally. In another preferred embodiment, the dosage form according to the invention is adapted for administration twice daily, preferably orally. In still another preferred embodiment, the dosage form according to the invention is adapted for administration thrice daily, preferably orally. In yet another preferred embodiment, the dosage form according to the invention is adapted for administration more frequently than thrice daily, for example 4 times daily, 5 times daily, 6 times daily, 7 times daily or 8 times daily, in each case preferably orally.
For the purpose of the specification, “twice daily” means equal or nearly equal time intervals, i.e., about every 12 hours, or different time intervals, e.g., 8 and 16 hours or 10 and 14 hours, between the individual administrations.
For the purpose of the specification, “thrice daily” means equal or nearly equal time intervals, i.e., about every 8 hours, or different time intervals, e.g., 6, 6 and 12 hours; or 7, 7 and 10 hours, between the individual administrations.
The dosage forms according to the invention may be used in medicine, e.g. as an analgesic. The dosage forms are therefore particularly suitable for the treatment or management of pain.
A further aspect of the invention relates to the dosage form as described above for use in the treatment of pain.
A further aspect of the invention relates to the use of a pharmacologically active ingredient, preferably an opioid for the manufacture of a dosage form as described above for treating pain.
A further aspect of the invention relates to a method of treating pain comprising the administration of the dosage form as described above to a subject in need thereof.
A further aspect according to the invention relates to the use of a dosage form as described above for avoiding or hindering the unintentional overdose of the pharmacologically active ingredient, preferably the opioid contained therein.
In this regard, the invention also relates to the use of a dosage form as described above for the prophylaxis and/or the treatment of a disorder, thereby preventing an overdose of the pharmacologically active ingredient, preferably the opioid, particularly due to dose dumping in aqueous ethanol.
In a particularly preferred embodiment, the dosage form is particulate and in form of a filled capsule, wherein

    
    
        the pharmacologically active ingredient is selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, tramadol, tapentadol, morphine, buprenorphine and the physiologically acceptable salts thereof; and
        the alkyl cellulose is ethyl cellulose; and
        the heteropolysaccharide is xanthan gum; and
        the relative weight ratio of xanthan gum to ethyl cellulose is within the range of from 1:18 to 1:1.
    
    


In a particularly preferred embodiment

    
    
        the weight ratio of heteropolysaccharide to alkyl cellulose is within the range of from 1:18 to 1:1; and/or
        the total content of alkyl cellulose and heteropolysaccharide is at least 95 wt.-%, relative to the total weight of the matrix material, or the matrix material consists of the alkyl cellulose and the heteropolysaccharide; and/or
        the alkyl cellulose is selected from unsubstituted C1-6-alkyl celluloses; and/or
        the alkyl cellulose is ethyl cellulose having an ethoxyl content of from 40 wt.-% to 60 wt.-%; and/or having a solution viscosity within the range of from 70 mPa·s to 130 mPa·s, measured in a 5 wt.-% solution of 80 wt.-% toluene and 20 wt.-% ethanol at 25° C. in an Ubbelohde viscosimeter; and/or
        the content of the alkyl cellulose in the matrix material is at most 90 wt.-%, relative to the total weight of the matrix material; and/or
        the content of the alkyl cellulose is within the range of from 45 to 89 wt.-%, relative to the total weight of the dosage form; and/or
        the heteropolysaccharide is selected from acidic heteropolysaccharides; and/or
        the heteropolysaccharide is xanthan gum; and/or
        the content of the heteropolysaccharide in the matrix material is at least 10 wt.-%, relative to the total weight of the matrix material; and/or
        the content of the heteropolysaccharide is within the range of from 8 to 27 wt.-%, relative to the total weight of the dosage form; and/or
        the dosage form contains only one pharmacologically active ingredient selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, tramadol, tapentadol, morphine, buprenorphine and the physiologically acceptable salts thereof; and/or
        the pharmacologically active ingredient, preferably the opioid is present in the dosage form in a therapeutically effective amount; and/or
        apart from the pharmacologically active ingredient, preferably the opioid, the dosage form does not contain any further pharmacologically active ingredient; and/or
        the dosage form has a breaking strength of less than 200 N, or, when the dosage form is particulate, the particles have a breaking strength of less than 200 N; and/or
        at any given time point the in vitro release of the pharmacologically active ingredient, preferably the opioid from the dosage form in 0.1 N HCl/ethanol (40 vol.-%) relatively deviates from the in vitro release in 0.1 N HCl by not more than +1%; or by at least −1%; and/or
        the dosage form provides prolonged release of the pharmacologically active ingredient, preferably the opioid; and/or
        the dosage form is particulate, wherein the particles have been manufactured by granulation; and/or
        the dosage form is a filled capsule; and/or
        the dosage form and, when the dosage form is particulate, the particles is/are not coated; and/or
        the dosage form does not contain any outer matrix material.
    
    


EXAMPLES
General Procedure:
Mixtures of the ingredients in powder form (Tramadol HCl, Ethylcellulose Ph. Eur. (Ethocel Standard 100 Premium), Xanthan Gum Type 602) were granulated with 70% (v/v) ethanol by using a mortar and pestle. The moist granulate was screened (mesh size 1,000 μm) and the thus obtained particles were dried in a drying cabinet for 17 to 18 hours. Thereafter, the particles were filled into capsules (DBcaps AA).
The xanthan gum was found to have a viscosity of 281 mPa·s, measured in a 1% aqueous solution at a shear rate of 50 s−1 rotationally at 20° C. after 1 minute equilibration using a 6 cm acrylic cone (1°), wherein the shear was ramped up linearly from 1 to 50 s−1 in 25 steps over 29 s.
The release profiles were determined in 0.1 N HCl with and without addition of 40% (v/v) ethanol in a USP Apparatus 2 (paddle) at 75 rpm in 600 mL of media at 37° C. with a LabSwiss sinker, using a HPLC method. The mobile phase consisted of 1460 mL potassium dihydrogenphosphate buffer pH 2.7 with 540 mL methanol with a flow rate of 2.5 mL/min. The stationary phase was a Supelcosil LC-8 DB 5 μm 150*4.6 mm chromatographic column conditioned at 35° C. Injected volume was 30 μL, detection was performed by UV absorption at a wavelength of 215 nm.
The obtained release data were normalized in that always the highest value measured after quickly stirring for a longer time was taken as 100% value (“infinity value”).
Example 1
Capsules having the composition summarized in Table 1 below were prepared according to the general procedure:









TABLE 1






m in mg




(per capsule)
m in wt.-%

















Tramadol HCl
50.0
10.0


Ethylcellulose Ph. Eur.
400.0
80.0


(Ethocel Standard 100




Premium)




Xanthan Gum Type 602
50.0
10.0


total
500.0
100.0








relative weight ratio of xanthan gum to ethyl
1:8


cellulose



total content of ethyl cellulose and xanthan gum
90.0









FIG. 1 shows the release profile of the capsules in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively.
As can be seen from FIG. 1, the release of the active ingredient is prolonged and is not influenced by the addition of ethanol.
Example 2
Capsules having the composition summarized in Table 2 below were prepared according to the general procedure:









TABLE 2






m in mg




(per capsule)
m in wt.-%

















Tramadol HCl
25.0
5.0


Ethylcellulose Ph. Eur.
422.0
84.4


(Ethocel Standard 100




Premium)




Xanthan Gum Type 602
53.0
10.6


total
500.0
100.0








relative weight ratio of xanthan gum to ethyl
1:8


cellulose



total content of ethyl cellulose and xanthan gum
95.0









FIG. 2 shows the release profile of the capsules in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively. The data are also summarized in Table 10.
As can be seen from FIG. 2, the release of the active ingredient is slightly prolonged and the addition of ethanol has a retarding influence on the release.
Example 3
Capsules having the composition summarized in Table 3 below were prepared according to the general procedure:









TABLE 3






m in mg




(per capsule)
m in wt.-%

















Tramadol HCl
75.0
15.0


Ethylcellulose Ph. Eur.
378.0
75.6


(Ethocel Standard 100




Premium)




Xanthan Gum Type 602
47.0
9.4


total
500.0
100.0








relative weight ratio of xanthan gum to ethyl
1:8


cellulose



total content of ethyl cellulose and xanthan gum
85.0









FIG. 3 shows the release profile of the capsules in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively. The data are also summarized in Table 10.
As can be seen from FIG. 3, the release of the active ingredient is not prolonged. However, the addition of ethanol has a retarding influence on the release.
Example 4
Capsules having the composition summarized in Table 4 below were prepared according to the general procedure:









TABLE 4






m in mg




(per capsule)
m in wt.-%

















Tramadol HCl
50.0
10.0


Ethylcellulose Ph. Eur.
337.5
67.5


(Ethocel Standard 100




Premium)




Xanthan Gum Type 602
112.5
22.5


total
500.0
100.0








relative weight ratio of xanthan gum to ethyl
1:3


cellulose



total content of ethyl cellulose and xanthan gum
90.0









FIG. 4 shows the release profile of the capsules in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively. The data are also summarized in Table 10.
As can be seen from FIG. 4, in both media the release of the active ingredient is distinctly prolonged and is further retarded by addition of ethanol.
Example 5
Capsules having the composition summarized in Table 5 below were prepared according to the general procedure:









TABLE 5






m in mg




(per capsule)
m in wt.-%

















Tramadol HCl
50.0
10.0


Ethylcellulose Ph. Eur.
382.5
76.5


(Ethocel Standard 100




Premium)




Xanthan Gum Type 602
67.5
13.5


total
500.0
100.0 








relative weight ratio of xanthan gum to ethyl
1:5.7


cellulose



total content of ethyl cellulose and xanthan gum
90.0









FIG. 5 shows the release profile of the capsules in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively. The data are also summarized in Table 10.
As can be seen from FIG. 5, the release in 0.1 N HCl is not prolonged (i.e. immediate release). However, in the presence of ethanol, the release is distinctly prolonged.
Summing up, an extended release profile was not observed in all Examples 1 to 5. However, in all Examples the release was further retarded by the addition of ethanol. This result was completely unexpected because of the solubility of the matrix material ethylcellulose in ethanol.
An optimum extended release profile was observed in Example 4.
Example 6
Capsules having the composition summarized in Table 6 below were prepared according to the general procedure:









TABLE 6






m in mg




(per capsule)
m in wt.-%

















Tramadol HCl
45.0
10.0


Ethylcellulose Ph. Eur.
382.5
85.0


(Ethocel Standard 100




Premium)




Xanthan Gum Type 602
22.5
5.0


total
450.0
100.0








relative weight ratio of xanthan gum to ethyl
1:17


cellulose



total content of ethyl cellulose and xanthan gum
90.0









The data obtained from dissolution tests in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively, are summarized in Table 10.
Example 7
Capsules having the composition summarized in Table 7 below were prepared according to the general procedure:









TABLE 7






m in mg




(per capsule)
m in wt.-%

















Tramadol HCl
45.0
10.0


Ethylcellulose Ph. Eur.
292.5
65.0


(Ethocel Standard 100




Premium)




Xanthan Gum Type 602
112.5
25.0


total
450.0
100.0 








relative weight ratio of xanthan gum to ethyl
1:2.6


cellulose



total content of ethyl cellulose and xanthan gum
90.0









The data obtained from dissolution tests in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively, are summarized in Table 10.
Example 8
Capsules having the composition summarized in Table 8 below were prepared according to the general procedure:









TABLE 8






m in mg




(per capsule)
m in wt.-%

















Tramadol HCl
45.0
10.0


Ethylcellulose Ph. Eur.
360.0
80.0


(Ethocel Standard 100




Premium)




Xanthan Gum Type 602
45.0
10.0


total
450.0
100.0








relative weight ratio of xanthan gum to ethyl
1:8


cellulose



total content of ethyl cellulose and xanthan gum
90.0









The data obtained from dissolution tests in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively, are summarized in Table 10.
Process Parameters
The process parameters are summarized in Table 9 below.














TABLE 9





Process 









parameter
Example
Example
Example
Example
Example
Example
Example


granule:
2
3
4
5
6
7
8






















Blending 
2
2
2
2
2
2
2


time [min]









(granulated









material)









Granulation 
6
5
6
6
16
16
12


time









[min]









(granulated 









material)









Amount 
108.1
91.85
72.3
90.7
68.9
57.7
61.6


of 70%









ethanol [g]









(granulated 









material)









Drying time/
17 h 
17 h 
17 h 
17h 
18 h 
18 h 
18 h 


Drying 
50 min/50° C.
50 min/50° C.
50 min/50° C.
50 min/50° C.
03 min/50° C.
03 min/50° C.
03 min/50° C.


temperature









(granulated 









material)









Loss on 
−2.59
−2.56
−4.31
−2.98
−1.70
−2.54
−1.49


drying [%]









(granulated 









material)









Granule 
453
456
454
457
457
456
458


weight on









capsule [mg]









(granulate









in capsule)









Release Profiles
The data obtained from the dissolution tests in 0.1 N HCl and in a mixture of 0.1 N HCl and 40% ethanol, respectively, are summarized in Table 10 below.














TABLE 10





In brackets:
Example
Example
Example
Example
Example
Example 
Example


normalized values
2
3
4
5
6
7
8







Dissolution 0.1N 









HCl [%] (n = 3)









after 15 min
38 (71) 
68 (80) 
25 (28) 
46 (55) 
40 (49) 
55 (72) 
41 (58) 


after 30 min
43 (79) 
76 (89) 
39 (45) 
68 (81) 
52 (64) 
64 (84) 
50 (70) 


after 45 min
45 (84) 
79 (93) 
51 (59) 
75 (89) 
59 (73) 
68 (89) 
55 (77) 


after 60 min
47 (87) 
80 (94) 
58 (67) 
78 (93) 
63 (78) 
71 (93) 
58 (81) 


after 120 min
51 (95) 
83 (98) 
73 (83) 
82 (98) 
74 (90) 
74 (97) 
66 (92) 


after 180 min
54 (101)
84 (99) 
79 (90) 
83 (99) 
78 (95) 
76 (100)
69 (98) 


after 240 min
54 (100)
85 (100)
83 (95) 
83 (100)
79 (97) 
75 (99) 
71 (99) 


Infinity value 
54 (100)
85 (100)
88 (100) 
84 (100)
82 (100)
76 (100)
71 (100)


(30 min 250 rpm) [%]









Dissolution 0.1N HCl + 









40% Ethanol [%] (n = 3)









after 15 min
47 (47)
63 (64) 
24 (28) 
53 (54) 
53 (54) 
18 (24) 
34 (37) 


after 30 min
66 (66)
81 (82) 
37 (43) 
68 (69) 
68 (69) 
29 (39) 
45 (49) 


after 45 min
76 (76)
87 (89) 
46 (53) 
74 (75) 
74 (75) 
36 (48) 
52 (57) 


after 60 min
84 (84)
91 (92) 
52 (60) 
78 (79) 
78 (79) 
42 (56) 
59 (65) 


after 120 min
95 (95)
97 (98) 
67 (78) 
85 (86) 
85 (86) 
55 (74) 
71 (77) 


after 180 min
99 (98)
98 (99) 
77 (90) 
90 (92) 
90 (92) 
70 (93) 
80 (88) 


after 240 min
99 (99)
99 (100)
82 (96) 
93 (95) 
93 (95) 
71 (95) 
83 (91) 


Infinity value
101 (100) 
99 (100)
86 (100) 
98 (100)
98 (100)
75 (100)
91 (100)


(30 min 250 rpm) [%]

## Claims

1. An oral pharmaceutical dosage form comprising a pharmacologically active ingredient embedded in a matrix material, wherein:
the pharmacologically active ingredient is one selected from pharmacologically active ingredients classified in Anatomical Therapeutic Chemical Classification System (ATC), class Nervous System;
the matrix material comprises a mixture of an alkyl cellulose and a heteropolysaccharide;
the alkyl cellulose is present in the dosage form in an amount of at least 50 wt.-% relative to the total weight of the dosage form;
the heteropolysaccharide is present in the dosage form in an amount of below 50 wt.-% relative to the total weight of the dosage form;
the total content of alkyl cellulose and heteropolysaccharide is at least 60 wt.-% relative to the total weight of the dosage form;
the pharmaceutical dosage form releases by 60 minutes more than 60% of the pharmacologically active ingredient when release of the pharmacologically active ingredient from the pharmaceutical dosage form is measured with a paddle apparatus at 50 rpm, at 37±5° C., in 900 mL 0.1 M HCl (pH 1.0) or simulated intestinal fluid at pH 6.8 (phosphate buffer) or pH 4.5; and
the pharmaceutical dosage form provides resistance against dose dumping in aqueous ethanol.

2. The dosage form according to claim 1, wherein
the alkyl cellulose is ethyl cellulose; and/or
the heteropolysaccharide is xanthan gum.

3. The dosage form according to claim 1, which provides prolonged release of the pharmacologically active ingredient.

4. The dosage form according to claim 1, wherein the content of the heteropolysaccharide is below 45 wt.-%, relative to the total weight of the dosage form.

5. The dosage form according to claim 4, wherein the content of the heteropolysaccharide is below 30 wt.-%, relative to the total weight of the dosage form.

6. The dosage form according to claim 1, wherein the total content of alkyl cellulose and heteropolysaccharide is at least 70 wt.-%, relative to the total weight of the dosage form.

7. The dosage form according to claim 1, wherein the alkyl cellulose is ethyl cellulose having an ethoxyl content of from 40 wt.-% to 60 wt.-%.

8. The dosage form according to claim 1, wherein the alkyl cellulose is ethyl cellulose having a solution viscosity within the range of from 70 mPa·s to 130 mPa·s, measured in a 5 wt.-% solution of 80 wt.-% toluene and 20 wt.-% ethanol at 25° C. in an Ubbelohde viscosimeter.

9. The dosage form according to claim 1, wherein the pharmacologically active ingredient is an opioid.

10. The dosage form according to claim 9, wherein the pharmacologically active ingredient is selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, tramadol, tapentadol, morphine, buprenorphine, and the physiologically acceptable salts thereof.

11. The dosage form according to claim 1, which is particulate.

12. The dosage form according to claim 1, which is a filled capsule or a tablet.

13. The dosage form according to claim 1, which is particulate and in form of a filled capsule, wherein
the pharmacologically active ingredient is selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, tramadol, tapentadol, morphine, buprenorphine, and the physiologically acceptable salts thereof; and
the alkyl cellulose is ethyl cellulose; and
the heteropolysaccharide is xanthan gum; and
the relative weight ratio of xanthan gum to ethyl cellulose is within the range of from 1:18 to 1:1.

14. A method for treating pain in a patient in need thereof, said method comprising administering to said patient an effective amount therefor of a dosage form according to claim 1.

15. The dosage form according to claim 1, wherein the content of the alkyl cellulose is at least 63 wt.-%, relative to the total weight of the dosage form.

16. The dosage form according to claim 1, which releases by 3 hours at least 90% of the pharmacologically active ingredient.