HK1110774B - Oral dosage form safeguarded against abuse containing (1r,2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol - Google Patents

Description

Abuse-resistant oral dosage form comprising (1R,2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol

Technical Field

The invention relates to an abuse-proofed oral dosage form for the controlled release of the active ingredient (1R,2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol once daily, comprising said active ingredient and/or one or more pharmaceutically acceptable salts and/or derivatives thereof (a), at least one synthetic or natural polymer (C), optionally a slow-release matrix material, optionally physiologically acceptable auxiliary substances (B) and optionally a wax (D), wherein component (C) or (D) exhibits a breaking strength of at least 500N in each case.

Background

In addition to an excellent pain relief effect, this active ingredient also shows the potential for abuse, i.e. it may be used by abusers to produce an effect that is not relevant to their intended purpose. Thus, for example, such active ingredients are used by abusers to induce the production of an anesthetic or euphoric state.

These dosage forms containing the active ingredient are generally used for long-term therapy, for example, for the treatment of chronic pain or pain caused by tumors. During long-term treatment, it is particularly important that the patient enjoys a good quality of life. Measures to improve the quality of life of patients include dosage forms that allow once daily administration. However, due to the relatively large amounts of active ingredient required, these dosage forms, which provide sustained release of the active ingredient, are particularly attractive to abusers in order to induce them the desired state of anesthesia or euphoria as quickly as possible.

However, when abuse levels are given orally, since sustained release dosage forms containing the active ingredient generally do not themselves produce the reflection desired by the abuser, these dosage forms, such as tablets or capsules, are also comminuted, e.g. ground and inhaled by the abuser for the purpose of abuse, or the active ingredient is preferably extracted from the powder obtained in this way with an aqueous liquid, followed by parenteral administration of the resulting solution, in particular by intravenous administration, optionally after filtration through a cotton wool or cellulose wadding. This mode of administration further accelerates the increase in active ingredient levels compared to oral or nasal inhalation abuse, producing the result desired by the abuser, i.e., the reflex.

US-A-4,070,494 proposes the addition of A swellable agent to the dosage form to prevent abuse. When water is added to extract the active ingredient used herein, this agent swells and ensures that the filtrate separated from the gel contains only a small amount of the active ingredient.

The multilayer tablets disclosed in WO 95/20947, which in each case contain an active ingredient with abuse potential and at least one gelling agent in separate layers, are based on a similar approach to prevent parenteral abuse.

WO 03/015531a2 discloses another method of preventing parenteral abuse. In this document a dosage form is described containing an analgesic opioid and a dye as an aversive agent. Interference by the dosage formThe use of the released color should cause the abuser to be frustrated by using the dosage form.

Another known possibility of concurrent abuse is the addition of antagonists of the active ingredient, such as naloxone hydrochloride or naltrexone, or compounds which elicit a physiological defence response, such as ipecac (ipecac) or bitter substances, to the dosage form.

However, since in the past controlled release active ingredient dosage forms had to be comminuted in most cases for abuse, the subject of the present invention was to complicate or prevent comminuted dosage forms before abuse, which are dosage forms with controlled release of (1R,2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol obtainable by the potential abuser by conventional methods, and to provide a dosage form of the active ingredient in such a way that, when administered in a targeted manner, ensures the desired therapeutic effect once daily administration, but whereby the active ingredient cannot be converted into a form which is suitable for abuse by simple comminution.

Disclosure of Invention

The object of the invention is achieved by providing an abuse-proofed oral dosage form for the controlled release of (1R,2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol once daily administration, which comprises, in addition to the active ingredient and/or one or more of its pharmaceutically acceptable compounds, preferably salts, solvates and/or derivatives, preferably esters, ethers or amides and the corresponding enantiomers and/or the corresponding pharmaceutically acceptable compounds or derivatives (A), at least one synthetic and/or natural polymer (C), at least one slow-release auxiliary substance (E), optionally at least one further physiologically acceptable auxiliary substance (B) and optionally a wax (D), wherein component (C) or (D) exhibits a breaking strength of at least 500N in each case, preferably at least 750N.

By using component (C) and optional component (D) having said minimum breaking strength (determined according to the method disclosed in the present application), preferably in such amounts that the dosage form also exhibits a minimum breaking strength of at least 500N, preferably of at least 750N, the crushing of the dosage form by conventional methods is prevented and subsequent abuse, preferably intranasal or parenteral abuse, can thereby be greatly complicated or avoided.

In the case of inadequate comminution of the dosage form, i.e. without risk, parenteral, in particular intravenous or intranasal, administration is not possible, or it takes too long for the abuser to extract the active ingredient from the dosage form, or in the case of abusive oral administration it is not possible or not sufficient to obtain stimulation, since spontaneous release cannot occur.

Comminution according to the present invention refers to comminution of the dosage form by conventional means commonly available to abusers, such as pestles and mortars, hammers, mallets or other common means of comminution by application of force.

Thus, the dosage form of the invention is suitable for the prevention of parenteral, intranasal and/or oral abuse of (1R,2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol. Such active ingredients are known from EP-A-0693475 and are useful as analgesic active agents.

The active ingredient (1R,2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol can be used not only as such, i.e. in the form of the free base, but also in the form of its pharmaceutically acceptable salts, solvates, pharmaceutically acceptable derivatives, in particular amides, esters or ethers, and/or its corresponding stereoisomers and/or corresponding pharmaceutically acceptable compounds. The preparation of this active ingredient is likewise known from EP-A-0693475A 1.

In the dosage form of the invention, the content of active ingredient is preferably between 0.5 and 80 wt.%, particularly preferably between 10 and 40 wt.%, and particularly preferably between 5 and 50 wt.%.

The dosage forms of the invention generally contain (1R,2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol itself, and/or a pharmaceutically acceptable compound thereof, in an amount of from 2.5 to 1,000mg, in particular from 5 to 800mg, particularly preferably from 5 to 600mg, calculated as (1R,2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol per dosage form or dosage unit.

According to the invention, pharmaceutically acceptable salts of the active ingredients are salts of the invention which, when used pharmaceutically, are physiologically acceptable, in particular when administered in a satisfactory manner to a mammal or a human, in particular a human. These pharmaceutically acceptable salts may be, for example, salts with inorganic or organic acids, for example, preferably hydrochloride, hydrobromide, saccharinate, sulfate, salts with methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid, and particularly preferably hydrochloride is used as the salt.

In order to obtain the necessary breaking strength of the dosage form of the present invention, at least one synthetic, semi-synthetic and/or natural polymer (C) is used, which has a breaking strength of at least 500N, preferably 750N, which is determined using the method disclosed in the present application. Preferably, for this purpose, the at least one polymer is chosen from polyalkylene oxides, preferably from polymethylene oxide, polyethylene oxide, polypropylene oxide, polyolefins, preferably polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, poly (meth) acrylates, copolymers thereof, and mixtures of at least two representatives of the polymer type or polymer. The use of water-soluble or water-swellable polymers is particularly preferred. High molecular weight thermoplastic polyalkylene oxides are preferred. Polyethylene oxides having a molecular weight of at least 50 ten thousand, preferably at least 1 million, particularly preferably from 1 to 15 million, determined by rheological measurements, are particularly preferred. These polyethylene oxides have a viscosity of 4500-17600cP, measured in a 5 wt.% aqueous solution of the polymer, using a model RVF Brookfield viscometer (Spindel No. 2/rev 2rpm), a viscosity of 400-4000cP, measured in a2 wt.% aqueous solution of the polymer, using the viscometer described (but Spindel No.1 or 3/rev 10rpm), or a viscosity of 1650-10000cP, measured in a1 wt.% aqueous solution of the polymer, using the viscometer described (but Spindel No. 2/rev 2rpm) (cf. handbook of Pharmaceutical Excipients by Raymond C.Rowe, amonogothers, 4th edition, 2003, page 460).

The polymers are preferably used in powder form to prepare the dosage forms of the invention. They may be water soluble or water swellable.

Preferably, component (C) is used in an amount of 20-99.9 wt.%, particularly preferably at least 35 wt.%, especially preferably at least 50 wt.%, relative to the total weight of the dosage form.

As auxiliary substances (B), it is generally possible to use those auxiliary substances which are known for the formulation of solid dosage forms. Preferably, these are plasticizers, such as polyethylene glycol, auxiliary substances which influence the release of the active ingredient, as listed below, preferably hydrophobic or hydrophilic, preferably hydrophilic polymers, particularly preferably hydroxypropylmethylcellulose or hydroxypropylcellulose, and/or antioxidants. As antioxidants, ascorbic acid, butylhydroxyanisole, butylated hydroxytoluene, salts of ascorbic acid, salts of thioglycerol, salts of phosphorous acid, salts of vitamin C, salts of vitamin E and derivatives thereof, sodium bisulfite are suitable, Butylated Hydroxytoluene (BHT) or Butylhydroxyanisole (BHA) and α -tocopherol being particularly preferred.

The amount of antioxidant is preferably 0.01-10 wt.%, preferably 0.03-5 wt.%, relative to the total weight of the dosage form.

Furthermore, in addition to the above polymers, at least one natural, semisynthetic or synthetic wax (D), which has a breaking strength of at least 500N, preferably 750N, can be used to achieve the necessary breaking strength of the dosage form of the invention, determined using the methods disclosed in this application. Waxes having a softening point of at least 60 ℃ are preferred. Carnauba wax and beeswax are particularly preferred. Caroba wax is particularly preferred. The carnauba wax is a natural wax obtained from the leaves of carnauba and has a softening point of at most 90 ℃. When a wax component is also used, the latter is used together with at least one polymer (C), preferably with at least one polyethylene oxide, wherein the amount of wax component used is such that the dosage form exhibits a breaking strength of at least 500N, preferably at least 750N, determined using the method described in the present application.

The dosage forms of the present invention are characterized in that, due to their hardness, they cannot be ground using conventional grinding tools such as pestles and mortars. Thus, oral, parenteral, in particular intravenous or intranasal abuse is practically avoided. However, in order to avoid any possible abuse of the dosage form of the present invention, in a preferred embodiment the dosage form of the present invention may contain other abuse-complicating or abuse-preventing agents as auxiliary substances (B).

Thus, the abuse-proofed dosage form of the invention may comprise, in addition to the active ingredients used in the invention, at least one polymer (C) and optionally at least one wax (D), and also at least one of the following components (a) to (e) as auxiliary substance (B):

(a) at least one substance which stimulates the nasal and/or pharyngeal passages,

(b) at least one viscosity increasing agent, preferably as an aqueous extract obtained from the dosage form, forms a gel with the aid of the necessary minimum amount of aqueous liquid, which preferably remains visually distinguishable when added to other amounts of aqueous liquid,

(c) at least one antagonist of the active ingredient used,

(d) at least one emetic agent is used as an emetic,

(e) at least one dye as a aversive agent,

(f) at least one bitter tasting substance.

In addition, each of components (a) - (f) individually as appropriate provides additional protection against abuse of the dosage form of the present invention. Thus, component (a) is preferably suitable for ensuring that abuse of the dosage form by intranasal, oral and/or parenteral, preferably intravenous administration is prevented, component (b) is preferably suitable for preventing abuse of the dosage form by parenteral, particularly preferably intravenous and/or intranasal administration, component (c) is preferably suitable for preventing abuse of the dosage form by intranasal and/or parenteral, particularly preferably intravenous administration, component (d) is preferably suitable for preventing abuse of parenteral, particularly preferably intravenous and/or oral and/or intranasal administration, component (e) is suitable as a component which visually prevents oral or parenteral abuse, and component (f) is suitable for preventing oral or intranasal abuse. By co-using at least one of the above components, it is possible that the dosage form of the present invention may be more effective in complicating abuse.

In one embodiment, the dosage form of the invention may further comprise a combination of two or more of components (a) - (f), preferably a combination of (a), (b) and optionally (c) and/or (f) and/or (e), or a combination of (a), (b) and optionally (d) and/or (f) and/or (e).

In another embodiment, the dosage form of the invention may comprise all of components (a) - (f).

If the dosage form of the invention comprises component (a) as an additional protection against abuse of the component, the substance stimulating the nasal passages and/or the pharyngeal passages contemplated by the invention is any substance which, when administered accordingly through the nasal passages and/or the pharyngeal passages, produces an unpleasant physical response to the abuser, which he/she does not wish or cannot administer continuously, for example a burning sensation, or which is physiologically of a kind and in a way which counteracts the administration of the active component, for example due to an increase in nasal secretions or sneezing. When administered parenterally, in particular intravenously, these substances which conventionally stimulate the nasal and/or pharyngeal passages may also give rise to a very unpleasant sensation, up to even intolerable pain, which the abuser does not wish or cannot administer for a long time.

Particularly suitable substances which stimulate the nasal and/or pharyngeal passages are those which cause burning, itching, sneezing, increased secretion production or a combination of at least two of these stimuli. The corresponding substances and the amounts usually employed are known per se to the person skilled in the art or can be ascertained by simple preliminary tests.

Component (a) stimulating the nasal and/or pharyngeal passages is preferably one or more components or one or more plant parts based on at least one drug of a pungent substance.

Corresponding peppery drugs are known per se to the person skilled in the art and are described, for example, in "Pharmazeutische biologice-drug und ihrelnhaltstoff" by Prof. Dr. Hildebert Wagner, 2nd reviewed edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 etseq. The corresponding description is incorporated herein by reference and considered to be part of the present invention.

Dosage units refer to discrete or separable dosage units, e.g., tablets or capsules.

One or more components of the at least one pungent substance drug selected from garlic (garlic), Asari rhizome collateral grass (asarum root and leaf), calamus rhizome (calamus root), capsicum fruit (capsicum), curcuma rhizome (turmeric root), curcuma javanica rhizome (turmeric root), galangal rhizome (root), nutmeg seed (nutmeg), black pepper fruit (pepper), sinapis alba seed (white mustard seed), black mustard seed (black mustard seed), zedoary rhizome (zedoary root) and ginger rhizome (ginger root), particularly preferably capsicum fruit (capsicum), capsicum fruit (acer capsicum) and black pepper fruit (pepper) may be preferably added to the dosage form of the present invention in the form of component (a).

The constituent of the peppery substance drug preferably contains an o-methoxy (methyl) phenol compound, an amide compound, mustard oil or a sulfide compound or a derivative compound thereof.

Particularly preferably, at least one component of the capsaicinoid is selected from the group consisting of myristyl ether, elemi-nol, isoeugenol, α -asarone, safrole, gingerol, xanthorrhizol, capsaicinoids, preferably capsaicin, capsaicin derivatives such as N-vanillyl-9E-octadecenamide, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, norcepharacin and nomorcapacin, piperine, preferably trans-piperine, glucosinolates, preferably based on non-volatile mustard oils, particularly preferably based on p-hydroxybenzyl mustard oil, methylmercaptomustard oil or methylsulfonyl mustard oil, and compounds derived from these components.

Preferably, the dosage form of the invention may also contain plant parts of the corresponding spicy substance drug, preferably in an amount of 0.01 to 30 wt.%, particularly preferably 0.1 to 0.5 wt.%, in each case relative to the total weight of the dosage unit.

If one or more components of the corresponding spicy substance drug are used, in a dosage unit of the invention, the amount thereof is preferably equal to 0.001-0.005 wt.%, relative to the total weight of the dosage unit.

Furthermore, another possibility for preventing abuse of the dosage form of the present invention is to add to the dosage form at least one viscosity enhancing agent as the other abuse-preventing component (b) which forms a gel in the necessary minimum amount of aqueous liquid, preferably as an aqueous extract obtained from the dosage form, which, when added to other amounts of aqueous liquid, is practically impossible to administer safely and preferably remains visually distinguishable.

Visually distinguishable for the purposes of this application means that the gel containing the active ingredient, which is formed with the aid of the minimum amount of aqueous liquid necessary, when added to a further amount of aqueous liquid at 37 ℃, preferably with the aid of a syringe needle, remains substantially insoluble and cohesive and cannot be dispersed in such a way in a simple manner that it can be safely administered parenterally, in particular intravenously. The material preferably remains visually distinguishable for at least one minute, preferably for at least 10 minutes.

Increasing the viscosity of the gel may make it more difficult or even impossible to pass through a needle or to be injected. If the gel remains visually distinguishable, this means that the gel obtained, when added to other quantities of aqueous liquid, for example introduced into the blood by injection, is first present in the form of a substantially coherent thread which, although it may indeed be mechanically disrupted into smaller fragments, cannot be dispersed or even dissolved in such a way that it can be safely administered parenterally, in particular intravenously. In combination with at least one of the other aforementioned components (a), (d) - (f) of the present invention, this will further lead to unpleasant burning, vomiting, poor taste and/or visual deterrents.

Intravenous administration of the corresponding gel will most likely result in occlusion of the blood vessel, which will seriously damage the health of the abuser.

To verify whether a viscosity increasing agent is suitable as component (b) for use in the dosage form of the present invention, the active ingredient is mixed with the viscosity increasing agent and suspended in 10ml of water at 25 ℃. If this would lead to the formation of a gel meeting the above conditions, the corresponding viscosity increasing agent is suitable for further preventing or avoiding abuse of the dosage form of the invention.

If component (b) is added to the dosage form obtained by the process of the present invention, it is preferred to use one or more viscosity increasing agents selected from the group comprising microcrystalline cellulose with 11 wt.% sodium carboxymethylcellulose(s) ((ii))RC 591), sodium carboxymethyl cellulose (sodium carboxymethyl cellulose: (sodium carboxymethyl cellulose)，CMC-Na，Frimulsion BLC-，Tylose C300) Polyacrylic acid (a)980 NF，981) Powder of kidney bean: (LA-200，LID/150.LN-1), pectin, preferably from citrus fruits or apples: (HM Medium Rapid Set), waxy corn starch (C)^*Gel) Sodium alginate (Frimusion ALG)) Guar flour (Frimusion)Polygum 26/1-) Iota carrageenan (Frimusion)) Chinese parasol, Gellan Gum (Kelcogel)，Kelcogel LT) Galactomannan (Meyprogat)) Tra stone powder (Polygum)) Propylene glycol alginate (Protanal-Ester SD-) Sodium hyaluronate, tragacanth, tara gum (Vidougm SP)) Fermented polysaccharide welan gum (K1A96), xanthans such as xanthan gum (Xantural)). Xanthenes are particularly preferred. The names described in parentheses are trade names, which are commercially known substances. In general, it is sufficient to use preferably 0.1 to 20 wt.%, particularly preferably 0.1 to 15 wt.%, of the viscosity-increasing agent, relative to the total amount of the dosage form.

The viscosity increasing agent of component (b), if provided, is preferably present in the dosage form of the invention in an amount of at least 5mg per dosage unit (i.e. per unit administered).

In a particularly preferred embodiment of the present invention, the viscosity increasing agents used as component (b) are those which form a gel containing gas bubbles, preferably by extraction from the dosage form with the minimum amount of aqueous liquid necessary. The resulting gel is characterized by a cloudy appearance which gives the potential abuser an additional visual warning preventing him/her from administering the gel parenterally.

Component (C) can also optionally be used as an additional viscosity enhancer, which forms a gel with the aid of the necessary minimum amount of aqueous liquid.

It is also possible to arrange the tackifier component and the other components of the dosage form of the present invention spatially separated from each other.

Furthermore, in order to prevent and ensure abuse, the dosage form of the invention may further comprise component (c), i.e. an antagonist of one or more of the active components used, wherein the antagonist is preferably spatially separated from the remaining components of the dosage form of the invention and should not play any role when used in a satisfactory manner.

Suitable antagonists for preventing abuse of the active ingredients used are known per se to the person skilled in the art and can be present in the dosage forms of the invention as such or in the form of the corresponding derivatives, in particular esters or ethers, or in each case in the form of the corresponding physiologically acceptable compounds, in particular in the form of salts or solvates thereof.

The antagonists used are preferably naloxone, naltrexone, nalmefene, nalide and nalmexone, selected from the group consisting of the following, in each case optionally in the form of the corresponding physiologically acceptable compounds, in particular in the form of bases, salts or solvates. Corresponding antagonist components, wherein component (c) is provided, preferably in an amount of at least 1mg, particularly preferably in an amount of from 3 to 100mg, particularly preferably in an amount of from 5 to 50mg, per dosage form, i.e. per administration unit.

The dosage forms of the invention preferably comprise the antagonist component in conventional therapeutic doses known to the person skilled in the art, which are particularly preferably 2 to 3 times the dose per administration unit compared to conventional doses.

If the other abuse-deterring or abuse-preventing combination of the dosage form of the present invention comprises component (d), it may comprise at least one emetic which is preferably spatially separated from the other components of the dosage form of the present invention and which, when used in a desirable manner, does not exert its effect in vivo.

Suitable emetics for additionally preventing abuse of the dosage form of the invention are known per se to the person skilled in the art and may be present in the dosage form of the invention as such or in the form of the corresponding derivatives, in particular esters or ethers, or in each case in the form of the corresponding physiologically acceptable compounds, in particular in the form of salts or solvates thereof.

Emetics based on one or more components of ipecac (ipecac), preferably based on the component ipecac base, may preferably be considered by the dosage forms of the present invention, as described, for example, by prof.dr.hildebertwagner in "Pharmazeutische biologice-drug und ihrehenlhahaltssoffe", 2nd revised edition, Gustav Fischer Verlag, Stuttgart, New York 1982. The corresponding literature descriptions are incorporated herein by reference and are considered part of the present invention.

The dosage forms of the invention may preferably comprise as component (d) the emetic emetine, preferably in an amount of at least 3mg, particularly preferably at least 10mg and especially preferably at least 20mg per dosage form, i.e. administration unit.

Apomorphine can likewise preferably be used as emetic for additional protection against abuse, preferably in an amount of at least 3mg, particularly preferably at least 5mg and very particularly preferably at least 7mg per unit of administration.

If the dosage form of the invention contains component (e) as an additional abuse-proofed auxiliary substance, the use of such a dye can impart an intense color to the corresponding aqueous solution, which color can serve as a deterrent to potential abusers, particularly when attempts are made to extract the active ingredient for parenteral, preferably intravenous, administration. Oral abuse, which usually starts with extraction of the active ingredient by an aqueous solution, may also be prevented by this color. The required amounts of suitable dyes and necessary deterrents can be found in WO 03/015531, the corresponding content of which should be considered as part of the present invention and which is hereby incorporated by reference.

If the dosage form of the invention contains component (f) as a further abuse-proofed auxiliary substance, this further prevents oral and/or intranasal abuse by adding at least one bitter tastant to subsequently impair the taste of the dosage form.

Suitable bitter principles and effective amounts for use can be found in US-2003/0064099, the contents of which are to be regarded as the content of the present application and are hereby incorporated by reference. Suitable bitter principles are preferably aromatic oils, preferably peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruity substances, preferably aromas from lemon, orange, lime, grapefruit or mixtures thereof, and/or denatonium benzoate(s) ((R))Is there a ) (ii) a Denatonium benzoate is particularly preferably used.

To ensure once daily administration, the dosage form of the invention comprises the active ingredient at least in partially sustained-release form, wherein the sustained release of the active ingredient can be achieved with the aid of conventional materials and methods known to the person skilled in the art, for example by embedding the active ingredient in a sustained-release matrix or by applying one or more sustained-release coatings. However, the release of the active ingredient must be controlled in order to meet the above conditions in each case, for example, if the dosage form is to be administered in a satisfactory manner, the active ingredient is almost completely released before optionally components (c) and/or (d) according to the invention can have a damaging effect. In particular, the release of the active ingredient must ensure an analgesic effect for at least 24 hours.

If the release of the active ingredient in the dosage form of the invention is controlled with the aid of at least one sustained-release coating, the sustained-release coating may consist of conventional substances known to the person skilled in the art.

In a preferred embodiment of the dosage form of the invention, the extended release coating is preferably based on a water-insoluble, optionally modified, natural and/or synthetic polymer, or on a natural, semisynthetic or synthetic wax, or on a fatty or fatty alcohol, or on a mixture of at least two of the aforementioned components.

For the preparation of a slow-release coating, the water-insoluble polymer preferably comprises a poly (meth) acrylate, particularly preferably poly (C)_1-4) Alkyl (meth) acrylates, poly (C)_1-4) -dialkylamino- (C)_1-4) Alkyl (meth) acrylates and/or copolymers thereof, particularly preferably copolymers of ethyl acrylate and methyl (meth) acrylate, the molar ratio of the monomers being 2: 1 (C: (meth))) Copolymers of ethyl acrylate, methyl (meth) acrylate and ethyl (meth) acrylate trimethylammonium chloride, in which the molar ratio of the monomers is 1: 2: 0.1 (Eudragit)) Copolymers of ethyl acrylate, methyl (meth) acrylate and ethyl (meth) acrylate trimethylammonium chloride, in which the molar ratio of the monomers is 1: 2: 0.2 (Eudragit)) Or a mixture of at least two of these copolymers. These coating materials are commercially available in the form of a 30 wt.% aqueous latex dispersion, i.e. as Eudragit、Eudragit NEOr EudragitAnd is itself also preferably used as a coating material.

Likewise, as the water-insoluble polymer used for preparing the sustained release coating of the dosage form of the present invention, polyvinyl acetate may be usedEsters, optionally together with other adjuvants. These are commercially available as aqueous dispersions containing 27 wt.% of polyvinyl acetate, 2.5 wt.% of polyvinylpyrrolidone and 0.3 wt.% of sodium lauryl sulfate (Kollicoat SR 30))。

In another preferred embodiment, the extended release coating of the dosage form of the present invention is based on a water insoluble cellulose derivative, preferably an alkyl cellulose, such as ethyl cellulose, or a cellulose ester, such as cellulose acetate. The coating of ethylcellulose or cellulose acetate is preferably applied from an aqueous pseudolatex dispersion. Aqueous ethylcellulose pseudolatex dispersions are commercially available in the form of 30 wt.% dispersion () Or in the form of a 25 wt.% dispersion

If the extended release coating is based on a water-insoluble, optionally modified, natural and/or synthetic polymer, the coating dispersion or solution may contain, in addition to the corresponding polymer, conventional physiologically acceptable plasticizers known to those skilled in the art in order to reduce the necessary minimum membrane layer temperature.

Suitable plasticizers are, for example, those from C₆-C₄₀With an aliphatic or aromatic dicarboxylic acid of₁-C₈For example dibutyl phthalate, diethyl phthalate, dibutyl sebacate or diethyl sebacate, hydrophilic or lipophilic esters of citric acid, for example triethyl citrate, tributyl citrate, acetyl tributyl citrate or acetyl triethyl citrate, polyethylene glycols, propylene glycol, esters of glycerol, for example triacetin,(acetylated mono-and diglycerides, C)₂₃H₄₄O₅-C₂₅H₄₇O₇) Medium chain triglycerides (C: (C))) Oleic acid or a mixture of at least two of said plasticizers. EudragitAnd optionally EudragitThe aqueous dispersion of (a) preferably contains triethyl citrate.

Preferably, the extended release coating of the dosage form of the present invention contains a plasticizer, wherein the amount of plasticizer is 5 to 50 wt.%, particularly preferably 10 to 40 wt.%, and especially particularly preferably 10 to 30 wt.%, relative to the amount of polymer used. In individual cases, it is also possible to use larger amounts of plasticizer, for example for cellulose acetate.

Furthermore, the slow-release coating may comprise further customary auxiliaries known to the person skilled in the art, such as slip agents, preferably talc or glycerol monostearate, colorants, preferably iron oxide or titanium dioxide, or surfactants, for example tween

Furthermore, the release profile of the active ingredient can be adjusted by conventional options known to the person skilled in the art, for example the thickness of the coating or by using other auxiliary agents as a component of the coating. Suitable auxiliaries are, for example, hydrophilic or pH-dependent pore-formers, for example sodium carboxymethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, lactose, polyethylene glycol or mannitol, or water-soluble polymers, for example polyvinylpyrrolidone or water-soluble cellulose, preferably hydroxypropylmethylcellulose or hydroxypropylcellulose.

For the release of the active ingredient used, the dosage form of the invention may also comprise a gastric juice-resistant coating which is dissolved in a pH-dependent manner. This coating ensures that the dosage form of the invention is not soluble when passing through the stomach and that the active ingredient is not released until it reaches the intestinal tract.

The gastro-resistant coating is preferably based on methacrylic acid/alkyl methacrylate copolymers, preferably methyl methacrylate, for example methacrylic acid or ethyl methacrylate copolymers, in a molar ratio of the monomers of from 1: 1 to 1: 2, for example Eudragit，Eudragit，EudragitL30D-

The sustained-release coating can be applied by customary methods known to the person skilled in the art, for example by spraying of solutions, dispersions or suspensions, by the melt process or by the powder application method. The solution, dispersion or suspension may be used in the form of an aqueous or organic solution or dispersion. In this respect, an aqueous dispersion is preferably used. Organic solvents which may be used may be alcohols, such as ethanol or isopropanol, ketones, such as acetone, esters, such as ethyl acetate, with alcohols and ketones being preferably used. Such coating methods are known in the art, e.g. h. packer, Georg Thieme Verlag, 1991, pages 347 et seq. Which are incorporated herein by reference and are therefore considered to be part of this invention.

If the dosage form of the invention is in the form of multiparticulates, the sustained-release coating is preferably applied in such a way that the multiparticulate form containing the active ingredient, after its preparation, is coated with the particular polymer and optionally further auxiliaries in an aqueous and/or organic medium, preferably an aqueous medium, with the aid of a fluidized-bed process, wherein the coating is preferably simultaneously dried in a fluidized bed at customary temperatures.

The poly (meth) acrylate-based coating is preferably dried at from 30 to 50 ℃ and particularly preferably at from 35 to 45 ℃. For cellulose-based coatings, such as ethylcellulose, the drying is preferably carried out at a temperature in the range from 50 to 80 ℃ and particularly preferably in the range from 55 to 65 ℃. Drying may be followed by a warming treatment, if necessary, in order to obtain a stable release profile.

Sustained release of the active ingredient of the dosage form of the present invention may also be achieved by embedding the active ingredient in a sustained release matrix.

Substances which can be used as sustained-release matrices are preferably physiologically acceptable, hydrophilic polymers, preferably cellulose ethers, cellulose esters and/or acrylic resins. Ethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, poly (meth) acrylic acid and/or derivatives thereof, such as salts, amides or esters thereof, are particularly preferably used.

If hydrophobic compounds are used as slow-release matrices, hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or the corresponding esters or ethers or mixtures thereof can be used. C₁₂-C₃₀Fatty acid and/or C₁₂-C₃₀Mono-or diglycerides of fatty alcohols and/or waxes or mixtures thereof are particularly preferred for use as the hydrophobic compound.

It is also possible to use mixtures of the above-mentioned hydrophilic and hydrophobic matrix materials.

Component (b) as a viscosity increasing agent can also preferably be used as a material for the slow-release matrix, if this is allowed by the structure of the dosage form of the invention.

Component (C) and optionally component (D) which are used to achieve the breaking strength necessary according to the invention of at least 500N, preferably at least 750N, can also optionally be used as additional slow-release matrix material.

Corresponding sustained release compounds and methods of sustained release of the Dosage Forms of the invention and methods of taste and/or gastric juice resistance masking using coatings are known to those skilled in the art, for example, in accordance with "Coated Pharmaceutical Dosage Forms-Fundamentals, Manufacturing Techniques, Biopharmaceutical applications, Test methods and Raw Materials" by Kurt H.Bauer, K.Lehmann, Hermann P.Osterwald, Rothgarg, Gerhart, 1st edition, 1998, medical scientific publications. The corresponding literature descriptions are incorporated herein by reference and are considered part of the present invention.

The dosage forms of the invention are suitable for oral, vaginal or rectal administration, preferably for oral administration, once daily to humans and animals.

The dosage forms of the invention may be in the form of multiparticulates, preferably microtablets, micropellets, granules, spheroids, beads or granules, optionally packaged in capsules or molded into tablets. The multiparticulate form preferably has a particle size or particle size distribution in the range of 0.1 to 3mm, particularly preferably in the range of 0.5 to 2 mm. Conventional auxiliary substances (B) are optionally also used for formulating the dosage form according to the desired dosage form.

In another preferred embodiment, the dosage form of the invention is formulated as a tablet, capsule or oral osmotic therapeutic system (OROS), preferably if at least one further abuse deterrent component (a) - (f) is also present.

The abuse-proofed solid dosage form according to the invention is preferably prepared by mixing components (a), (C), optionally (D), optionally at least one further abuse-proofed component (a) to (f) and optionally further auxiliary substances (B), in particular slow-release matrix compounds, wherein components (a) to (f), if necessary, are mixed separately with components (C) and optionally (D), and the resulting mixture is subsequently prepared, optionally after granulation, before or while exposure to heat by application of force, into the dosage form in question.

The granulation may be performed by a melting method or a wet granulation method.

This mixture or these mixtures of the components of the dosage form of the invention can be prepared in mixers known to the person skilled in the art. The mixer may be, for example, a drum mixer, a shaking mixer, a shear mixer or a paddle mixer.

The resulting mixture is preferably directly prepared into the dosage form of the present invention by application of force prior to and/or while being exposed to a heat source. The mixture can be prepared, for example, into tablets by direct compression. Direct compression is carried out while being exposed to a heat source, and the compression tools, i.e., the lower punch, the upper punch and the die, are briefly heated at least until the polymer (C) is softened and compressed together in the process. In direct compression prior to exposure to a heat source, the material to be molded is compressed, immediately heated to at least the softening temperature of component (C), and compressed.

The resulting mixture of components (a), (C), optionally (D), optionally components (a) to (f) and optionally further auxiliary substances (B), in particular the sustained-release matrix compound, may also be granulated first and then be prepared into the dosage form of the invention by application of force before or while being exposed to a heat source.

It is also possible to prepare the resulting mixtures containing the active ingredient(s) and/or one or more pharmaceutically acceptable salts thereof (a) and optionally physiologically acceptable auxiliary substances (B), for example components (a) to (f) and optionally a slow-release matrix compound and at least one synthetic or natural polymer (C) and optionally a wax (D), by applying force to form dosage forms, optionally singulating (vereinxeln) the shaped products and optionally classifying them in each case by size, exposing them to units of force after or during heating to at least the softening point of component (C), so that the shaped products exhibit a hardness at break of at least 500N, preferably a hardness at break of at least 750N, optionally coating them with a slow-release coating, and optionally remixing all these shaped products together. Such a procedure is also the object of international patent application PCT/EP2004/014679, the corresponding content of which is hereby incorporated by reference and shall be considered to be part of the content of the present patent application. The person skilled in the art knows that in this case, by using an antioxidant, optionally maintaining an inert gas atmosphere during the production process (.

Furthermore, the necessary heating of the mixture and/or the shaped product with the aid of ultrasound can be effected before or during the necessary application of force in order to achieve a breaking strength or hardness of the invention of at least 500N, preferably 750N. The corresponding procedure is disclosed in international patent application PCT/EP2005/004225, the corresponding content of which is hereby incorporated by reference and should be considered to be part of the content of the present application.

If components (c) and/or (d) and/or (f) are present in the dosage form of the invention, care must be taken to ensure that they are formulated in such a way or present in such a low dose that, when administered in a satisfactory manner, the dosage form does not actually exert an effect which would impair the patient or the efficacy of the active ingredient.

If the dosage form of the present invention contains components (d) and/or (f), the dosage must be selected so that it does not cause side effects when it is administered orally in a satisfactory manner. However, if the prescribed dose of the dosage form is inadvertently exceeded, particularly by children, or if abuse occurs, a sensation of nausea or the desire to vomit or an unpleasant taste results. In case the patient is administered orally in a satisfactory manner, the specific amount of components (d) and/or (f) which can still be tolerated by the patient can be determined by the person skilled in the art by simple preliminary tests.

If, however, the dosage form of the present invention is not practically breakable to protect said dosage form containing components (c) and/or (d) and/or (f), these components should preferably be used in such high doses that they will cause a strong side effect to the abuser when the dosage form is abused. This is preferably done by spatially separating at least the active component used from components (C) and/or (D) and/or (f), wherein the active component is preferably present in at least one sub-unit (X) and components (C) and/or (D) and/or (f) are present in at least one sub-unit (Y), and wherein, when the dosage form is administered in a suitable manner, components (C), (D) and (f) do not play a role in uptake and/or in vivo, and the remaining components of the formulation, in particular components (C) and optionally (D), are identical.

If the dosage form of the invention comprises at least two of components (c) and (d) or (f), these may be present in each case in the same or different subunits (Y). Preferably, when present, all components (c) and (d) and (f) are present in the same subunit (Y).

In the case of a spatial separation of the subunit(s) (X) and subunit(s) (Y), the subunit (X) contains the active ingredient in a sustained release form regardless of the arrangement of these subunits in the dosage form, so that the active ingredient is released in a controlled manner once a day administration.

For the purposes of the present invention, subunits are solid dosage forms which comprise, in each case, in addition to customary auxiliary substances known to the person skilled in the art, the active ingredient in question, at least one polymer (C), optionally a wax (D) and optionally at least one optionally present component (a) and/or (b) and/or (e) or in each case at least one polymer (C) and the antagonist(s) and/or emetic(s) and/or component (e) and/or component (f) and optionally at least one optionally present component (a) and/or (b) and optionally a slow-release matrix compound. Care must be taken to ensure that each subunit is formulated according to the methods described above.

A substantial advantage of the separate formulation of the active ingredients used with components (c) or (d) or (f) in subunits (X) and (Y) of the dosage form of the invention is that, when it is administered in a satisfactory manner, components (c) and/or (d) and/or (f) are released virtually no or only in small amounts on administration and/or in vivo, so that they do not exert an effect impairing the patient or the therapeutic achievement, or, when passing through the body of the patient, they are released only at a given site where they are not absorbed sufficiently effectively. When the dosage form is administered in a satisfactory manner, it is preferred that virtually no components (c) and/or (d) and/or (f) are released into the body of the patient or that they are not noticeable to the patient.

It will be appreciated by those skilled in the art that the above conditions may vary depending on the particular components (c), (d) and/or (f) used and the formulation of the sub-units or dosage forms. The optimal formulation for a particular dosage form can be determined by simple preliminary testing. It is important that the particular subunits contain polymer (C) and optionally (D) and have been formulated in the manner described.

Unexpectedly, abusers succeed in crushing a dosage form of this invention comprising in subunits (Y) components (c) and/or (e) and/or (d) and/or (f), in order to abuse the active ingredient and obtain a powder extracted with a suitable extractant, not only the active ingredient but also the specific components (c) and/or (e) and/or (f) and/or (d) will be obtained in a form that cannot be easily separated from the active ingredient, so that when the formulated dosage form is administered, in particular by oral and/or parenteral administration, it will exert its effect immediately upon the abuser and/or produce an additional side effect in vivo corresponding to components (c) and/or (d) and/or (f), or, when attempting to extract the active ingredient, the color will act as a deterrent, thus preventing misuse of the dosage form.

Formulating a dosage form according to the invention, wherein said active ingredient is spatially separated from components (c), (d) and/or (e), preferably in different subunits, can be carried out in a number of different ways, wherein the respective subunits can each be present in any desired spatial arrangement relative to each other in the dosage form of the invention, with the proviso that on the one hand the above-mentioned conditions for the release of components (c) and/or (d) are fulfilled, and on the other hand the above-mentioned conditions for the release of the active ingredient, i.e. a controlled release once daily administration, are fulfilled.

It will be appreciated by the person skilled in the art that the optional further component(s) (a) and/or (b) are preferably formulated in the dosage form of the invention, both in specific subunits (X) and (Y) and in the form of separate subunits (Y'), corresponding to subunits (X) and (Y), with the proviso that neither abuse-proofness of the dosage form nor release of the active ingredient within 24 hours is impaired, in the case of targeted administration, by the properties of the formulation, and that the polymer (C) is included in the formulation, and that the formulation is prepared according to the above-described method.

In a preferred embodiment of the dosage form of the invention, the subunits (X) and (Y) are present in multiparticulate form, wherein minitablets, microcapsules, micropellets, granules, spheroids, beads or pellets are preferred and the subunits (X) and subunits (Y) are selected in the same form, i.e. shape, such that it is not possible to separate subunits (X) from subunits (Y) by mechanical selection. The multiparticulate form preferably has a particle size in the range of 0.1 to 3mm, particularly preferably in the range of 0.5 to 2 mm.

In multiparticulate form, the subunits (X) and (Y) may also preferably be packaged in capsules or compression-molded into tablets, wherein in each case the final formulation is carried out in such a way that the subunits (X) and (Y) remain in the resulting dosage form.

The individual multiparticulate cells (X) or (Y) of the same shape should also be visually indistinguishable from each other so that an abuser cannot separate them from each other by simple sorting. This can be achieved, for example, by using the same coating, which may incorporate, in addition to the camouflage function, other functions, such as a slow release of the active ingredient or providing a gastric juice resistant product and/or masking of particular subunits.

In a further preferred embodiment of the present invention, the subunits (X) and (Y) are in each case arranged in layers with one another.

For this purpose, in the dosage forms of the invention, the lamellar subunits (X) and (Y) are preferably arranged vertically or horizontally with respect to one another, wherein in each case one or more lamellar subunits (X) and one or more lamellar subunits (Y) can also be present in the dosage form in question, so that, in addition to the preferred layer sequence (X) - (Y) or (X) - (Y) - (X), any desired further layer sequence can be taken into account, optionally in combination with layers comprising components (a) and/or (b).

Also preferred is another dosage form according to the invention, wherein the subunits (Y) form a core which is completely sealed by the delayed release subunits (X), wherein a separation layer (Z) may be present between said layers. Such a structure is preferably also suitable for the above-mentioned multiparticulate form, in which the two subunits (X) and (Y) and optionally the separating layer (Z), which must meet the hardness requirements of the present invention, are formulated in one and the same multiparticulate form.

In another preferred embodiment of the dosage form of the invention, said subunit (X) forms a core which is sealed by a subunit (Y), wherein the latter comprises at least one channel which guides said core to the surface of the dosage form.

The dosage form of the invention may comprise, between one layer of subunits (X) and one layer of subunits (Y), in each case one or more, preferably one, optionally expandable, separating layers (Z) which serve to spatially separate subunits (X) from subunits (Y).

If the dosage form of the invention comprises layered subunits (X) and (Y) and optionally a separating layer (Z), which are arranged at least partially vertically or horizontally, the dosage form preferably takes the form of a tablet, a coextrusion or a lamination.

In a particularly preferred embodiment, the entire free surface of the subunit (Y) and optionally at least part of the free surface of the subunit(s) (X) and optionally at least part of the free surface of the optionally present separating layer(s) (Z) can be coated with at least one separating layer (Z '), wherein the separating layer (Z') is intended to prevent the release of components (c) and/or (e) and/or (d) and/or (f). The barrier layer (Z') must also satisfy the hardness conditions of the invention.

In another particularly preferred embodiment of the dosage form of the invention, the dosage form of the invention comprises a layer of subunits (X) and (Y) arranged vertically or horizontally and at least one push layer (p) arranged therebetween, and optionally a separating layer (Z), wherein in the dosage form all free surfaces of the layered structure consisting of subunits (X) and (Y), said push layer and said optionally present separating layer (Z) are provided with a semi-permeable coating (E) which is permeable to the release medium, i.e. usually a physiological liquid, but substantially impermeable to the active component and to components (c) and/or (d) and/or (f), and wherein such coating (E) comprises at least one opening for release of the active component in the area of subunit (X).

Corresponding dosage forms are known to the person skilled in the art, for example under the name oral osmotic therapeutic system (OROS), suitable materials therefor and methods for their preparation, in particular according to US4,612,008, US4,765,989 and US4,783,337. The corresponding description is incorporated herein by reference and considered to be part of the present invention.

Osmotic dosage forms containing an analgesic opioid and a dye as an aversive agent are also known to those skilled in the art from the prior art (WO 03/015531). The tablet core is preferably composed of two layers, an opioid layer and a push layer, wherein the push layer contains a dye as a aversive agent. The corresponding description is incorporated herein by reference and considered to be part of the present invention.

In another preferred embodiment, the subunits (X) of the dosage form of the invention are in the form of tablets, the end faces and optionally one of the two main faces of which are coated with a separating layer (Z') comprising components (c) and/or (d) and/or (f).

The person skilled in the art will understand that the auxiliary substances of the subunit(s) (X) or (Y) and optionally the separating layer(s) (Z) and/or separating layer(s) (Z') used in the formulation of the dosage form of the invention will in each case vary with their arrangement in the dosage form of the invention, the mode of administration and the active ingredient present or optionally components (a) and/or (b) and/or (e) and components (c) and/or (d) and/or (f), while maintaining the release of the active ingredient within 24 hours. The materials which in each case have the desired properties are known per se to the person skilled in the art.

If the release of components (C) and/or (D) and/or (f) from the subunits (Y) of the dosage form according to the invention is avoided by means of a coating, preferably by means of a separating layer, said subunits may be composed of conventional materials known to the person skilled in the art, as long as it contains at least one polymer (C) and optionally component (D) to meet the hardness requirements of the dosage form according to the invention.

If no corresponding separating layer (Z') is provided to avoid the release of components (c) and/or (d) and/or (f), the material of the subunits in question should be chosen such that the release of a specific component (c) and/or (d) from subunit (Y) is virtually excluded.

For this purpose, the materials described below which are also suitable for the preparation of the separating layer can preferably be used.

Preferred materials are those selected from the group consisting of alkylcelluloses, hydroxyalkylcelluloses, dextrans, scleroglucans, mannans, xanthans, poly [ di (p-carboxyphenoxy) propane and copolymers of sebacic acid, preferably in a molar ratio of 20: 80 (in Polifeproxrosan)The name of (A) is given in the specification), carboxymethylcellulose, cellulose ethers, cellulose esters, nitrocellulose, polymers based on (meth) acrylic acid and esters thereof, polyamides, polycarbonates, polyalkylene glycol, polyalkylene oxide, polyalkylene terephthalate, polyvinyl alcohol, polyvinyl ether, polyvinyl ester, halogenated polyethylene, polyglycolic acidLactide, polysiloxanes and polyurethanes and copolymers or mixtures thereof.

Particularly suitable materials may be selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate (low, medium or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, sodium cellulose sulfate, polymethacrylates, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexamethyl methacrylate, polyisodecyl methacrylate, polylauryl methacrylate, polyphenylmethacrylate, polymethacrylates, polyisopropyl acrylate, polyisobutyl acrylate, polystearyl acrylate, polyethylene, low density polyethylene, high density polyethylene, polypropylene, polyethylene glycol, polyethylene oxide, polyethylene terephthalate, polyvinyl alcohol, polyvinyl isobutyl ether, polyvinyl acetate and polyvinyl chloride.

Particularly suitable copolymers may be selected from the group consisting of copolymers of butyl methacrylate and isobutyl methacrylate, copolymers of methyl vinyl ether and high molecular weight maleic acid, copolymers of methyl vinyl ether and monoethyl maleate, copolymers of methyl vinyl ether and maleic anhydride and copolymers of vinyl alcohol and vinyl acetate.

Other materials suitable for the formulation of the barrier layer are starch-filled polycaprolactones (WO98/20073), aliphatic polyesteramides (DE19753534A1, DE19800698A1, EP0820698A1), aliphatic and aromatic polyesterurethanes (DE19822979), polyhydroxyalkanoates, in particular polyhydroxybutyrates, polyhydroxyvalerates, casein (DE4309528), polylactides and polylactides (EP0980894A 1). The corresponding description is incorporated herein by reference and considered to be part of the present invention.

The above-mentioned materials may optionally be mixed with other conventional auxiliary substances known to those skilled in the art, preferably selected from the group consisting of glyceryl monostearate, semisynthetic triglyceride derivatives, semisynthetic glycerides, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyvinylpyrrolidone, gelatin, magnesium stearate, stearic acid, sodium stearate, talc, sodium benzoate, boric acid and colloidal silica, fatty acids, substituted triglycerides, glycerides, polyoxyalkylene glycols and derivatives thereof.

If the dosage form of the invention comprises a separating layer (Z'), said layer, such as said uncoated subunit (Y), may preferably consist of the material described above for the separating layer. It will be appreciated by those skilled in the art that the release of the active component or components (c) and/or (d) from a particular subelement can be controlled by the thickness of the separating layer.

The dosage form of the invention exhibits a controlled release of the active ingredient over at least 24 hours and is therefore suitable for once daily administration.

Method for determining breaking strength

To verify whether a material can be used as component (C) or (D), respectively, the material is compression-molded into a tablet having a diameter of 10mm and a height of 5mm at a temperature corresponding to at least the softening point of the polymer using a force of 150N and is determined with the aid of the DSC chart of the material. Using the tablets prepared in this manner, the breaking strength was measured by the method for measuring the breaking strength of tablets disclosed in european pharmacopoeia 1997, page 143,144, method No. 2.9.8, using an apparatus described below. The apparatus used for the determination is a "zwickz 2.5" Zwick material tester, Fmax ═ 2.5kN, with a maximum tensile force of 1150mm, which is adjusted by means of a column and a spindle, a gap width of 100mm (freien arbeitsraum), a test speed which can be adjusted between 0.1 and 800mm/min, and testControl software. The measurements were carried out using a pressure piston with a screw-in insert and a cylinder (diameter 10mm), a force sensor, Fmax 1kN, diameter 8mm, type 0.5 from 10N, type 1 from 2N to ISO7500-1, test certificate of the manufacturer M, DIN55350-18(Zwick grids force Fmax 1.45kN) (all instruments from Zwick GmbH & co.kg, Ulm, Germany), a testing machine model BTC-fr2.5th.d09, a force sensor model BTC-lc0050n.p01, a centering device model BO70000S 06.

Fig. 1 shows the determination of the breaking strength of a tablet, in particular the regulating device (6) of the tablet (4) used for this purpose before and during the determination. For this purpose, the tablets (4) are held between an upper pressure plate (1) and a lower pressure plate (3) of a force application device (not shown), each of which is fixed to the upper or lower pressure plate with the aid of two-part fixing devices, after setting the distance (5) required for receiving and centering the tablets to be measured (not shown). In order to set this distance (5), the two-part holding devices can each be moved horizontally outwards or inwards on the pressure plate on which they are located.

Tablets that are considered to be resistant to breakage under a particular force include not only those that are not broken, but also optionally those that undergo plastic deformation under the force.

The breaking strength of the dosage forms obtained according to the present invention was measured using the same measuring method, wherein dosage forms other than tablets were also tested.

The present invention will be explained below based on examples. These explanations are merely exemplary and do not limit the general concept of the invention.

Detailed Description

Example 1

Preparation of abuse-resistant tablets containing (1R,2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol

The active ingredient hydrochlorides in the amounts listed in Table 1, polyethylene oxide powder and hydroxypropylmethylcellulose (Metholose 90 SH 100000) as slow-release matrix material were mixed in a free-fall mixer (free-fall mixer). The tabletting tool, consisting of a die, an upper punch and a lower punch with a diameter of 13mm, was heated to 90 ℃ in a heating cabinet. Through the heated tool, 600mg parts of each of the powder mixtures were compression molded, with the pressure being maintained for at least 15 seconds.

TABLE 1

Components	Each sheet is	Whole batch (Complete batch)
			Active ingredient-HCl	200.0mg	60.0g
Polyethylene oxide, NF, MW 7000000 (Polyox WSR 303, Dow Chemicals)	360.0mg	138.0g
			Hydroxypropyl methylcellulose 100000mPas (Methosose 90 SH 100000)	40.0mg	12.0g
Total weight of	600.0mg	210.0g

The breaking strength of the tablets was measured using the method described above. When a force of 500N was applied, no failure occurred. The tablets cannot be crushed using a hammer nor with the aid of a pestle and mortar.

In vitro release of the resulting tablets

The in vitro release of the active ingredient hydrochloride from the tablets prepared was determined in a paddle stirrer with a drill press (sinker) according to the method described in the European pharmacopoeia. The temperature of the release medium was 37 ℃ and the rotational speed of the stirrer was 75min^-1. The release medium used was 600mL of intestinal fluid, pH 6.8. In each case, the amount of active ingredient hydrochloride released into the dissolution medium is determined spectrophotometrically at any one time. The percentage of the released amount in relation to the total amount of hydrochloride salt of the active ingredient at each time point is shown in table 2.

TABLE 2

Time, min.	Amount released, wt. -%)
		30	12
240	42
		480	65
720	80
		1080	94
1440	99

Claims (37)

1. An abuse resistant oral dosage form having a breaking strength of at least 500N, controlled release of (1R,2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol administered once daily, as determined according to the method for determining the breaking strength of tablets disclosed in the european pharmacopoeia 1997, page 143,144, method No. 2.9.8, said dosage form being prepared by applying a force before or simultaneously with exposure to heat, characterized in that it comprises:

-0.5 to 80 wt.% of the active ingredient and/or at least one pharmaceutically acceptable salt thereof (A),

20 to 99.9 wt.% of at least one synthetic and/or natural polymer (C) selected from polyalkylene oxides,

at least one sustained-release matrix material and/or

-optionally at least one slow release coating, and/or

At least one further physiologically acceptable auxiliary substance (B), and

-optionally at least one wax (D),

wherein the sum of the percentages of all components is 100 wt.%.

2. The dosage form of claim 1, wherein the active ingredient is present as a salt selected from the group consisting of hydrochloride, sulfate, hydrobromide, saccharinate, salts derived from: methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid.

3. The dosage form of claim 1 or 2, characterized in that the corresponding stereoisomer of the active ingredient is present.

4. The dosage form according to claim 1 or 2, characterized in that it is in the form of a tablet.

5. Dosage form according to claim 1 or 2, characterized in that it is in the form of multiparticulates, optionally moulded into tablets or packaged in capsules.

6. The dosage form of claim 1 or 2, characterized in that the polyalkylene oxide is a polymethylene oxide, a polyethylene oxide and/or a polypropylene oxide.

7. The dosage form of claim 1 or 2, wherein the polymer (C) is a water-soluble or water-swellable polymer.

8. The dosage form according to claim 1 or 2, characterized in that the polyethylene oxide (C) has a molecular weight of at least 50 ten thousand.

9. The dosage form of claim 8, wherein the polyethylene oxide (C) has a molecular weight of at least 1 million.

10. The dosage form of claim 8, wherein the polyethylene oxide (C) has a molecular weight of 1 to 15 million.

11. Dosage form according to claim 1 or 2, characterized in that the polymer component (C) is used in an amount of at least 20 wt.%, relative to the total weight of the dosage form.

12. The dosage form according to claim 11, characterized in that the polymer component (C) is used in an amount of 35 to 99.9 wt.%, relative to the total weight of the dosage form.

13. The dosage form according to claim 12, characterized in that the polymer component (C) is used in an amount of at least 50 wt.%, relative to the total weight of the dosage form.

14. The dosage form according to claim 13, characterized in that the polymer component (C) is used in an amount of at least 60 wt.%, relative to the total weight of the dosage form.

15. The dosage form according to claim 1 or 2, characterized in that the wax (D) is at least one natural, semisynthetic and/or synthetic wax having a softening point of at least 60 ℃.

16. The dosage form of claim 15, wherein the wax (D) is carnauba wax or beeswax.

17. The dosage form of claim 1 or 2, wherein the active ingredient is present in a sustained release matrix.

18. The dosage form according to claim 17, characterized in that component (C) and/or component (D) also serves as a slow-release matrix component.

19. Dosage form according to claim 1 or 2, characterised in that at least one auxiliary substance (B) is used as a slow-release matrix material.

20. The dosage form of claim 1 or 2, characterized in that it comprises a coating.

21. The dosage form of claim 20, characterized in that said coating is a slow release and/or taste masking coating.

22. Dosage form according to claim 1 or 2, characterized in that it comprises as auxiliary substances (B) at least one of the following abuse-proofed components (a) to (f):

(a) at least one substance which stimulates the nasal and/or pharyngeal passages,

(b) at least one viscosity-increasing agent which, with the aid of the minimum amount of aqueous liquid necessary, forms a gel,

(c) at least one antagonist with potential abuse potential active components,

(d) at least one emetic agent is used as an emetic,

(e) at least one dye as a aversive agent,

(f) at least one bitter principle.

23. The dosage form of claim 22, wherein said stimulant of component (a) causes burning, itching, sneezing, increased secretion formation or a combination of at least two of these stimuli.

24. The dosage form according to claim 22 or 23, characterised in that the irritant of component (a) is one or more components based on at least one drug of a pungent substance.

25. The dosage form of claim 24, wherein said pungent substance is at least one drug selected from the group consisting of garlic, Asari rhizome plus herb, calamus rhizome, capsicum fruit, turmeric rhizome, galangal rhizome, nutmeg seed, black pepper fruit, white mustard seed, black mustard seed, zedoary rhizome, and ginger rhizome.

26. The dosage form of claim 24 or 25, characterized in that the component of the pungent substance drug is an o-methoxymethylphenol compound, an amide compound, mustard oil or a sulfide.

27. The dosage form of claim 24, wherein said constituent of the pungent substance drug is at least one constituent selected from the group consisting of myristicin, elemicin, isoeugenol, β -asarone, safrole, gingerol, myrrha-type sesquiterpenes, and capsaicin.

28. The dosage form of claim 22, characterized in that said component (b) is at least one viscosity increasing agent selected from the group consisting of microcrystalline cellulose containing 11 wt.% sodium carboxymethylcellulose, polyacrylic acid, locust bean flour, pectin from citrus fruits or apples, waxy corn starch, sodium alginate, guar flour, iota-carrageenan, karaya gum, gellan gum, galactomannan, tara stone flour, propylene glycol alginate, apple pectin, sodium hyaluronate, tragacanth gum, tara gum, fermented polysaccharide-welan gum, and xanthan gum.

29. The dosage form of claim 22, wherein component (c) is at least one opioid antagonist.

30. The dosage form of claim 22, wherein said emetic, component (d), is one or more components of ipecac, and/or is apomorphine.

31. The dosage form of claim 22, wherein component (e) is at least one physiologically acceptable dye.

32. The dosage form of claim 22, wherein said component (f) is at least one bitter principle selected from the group consisting of aromatic oils, fruit flavors, denatonium benzoate and mixtures of at least two of the foregoing.

33. A process for preparing a dosage form according to any one of claims 1 to 32,

(1) mixing the components (A), (C), optionally (B) and optionally (D) and optionally a slow-release matrix compound,

(2) the resulting mixture or mixtures are prepared into dosage forms by application of force, optionally after granulation, and optionally followed by a sustained release coating, prior to or simultaneously with exposure to a heat source.

34. The process as claimed in claim 33, characterized in that the granulation is carried out by a melt process.

35. The process of claim 33, characterized in that the granulation is carried out by a wet granulation process.

36. A process for preparing a dosage form according to any one of claims 1 to 32,

(1) the mixture containing components (A), (C), optionally (B) and optionally (D) and optionally the slow-release matrix compound, optionally as separate mixtures, is prepared by application of force to form shaped products,

(2) the shaped products obtained are optionally singulated and optionally classified by size in each case, and

(3) after or during heating until at least component (C) softens, exposing the shaped product to a force until the shaped product exhibits a hardness at break of at least 500N,

(4) optionally, a coating is provided and the shaped product is again optionally mixed together in its entirety.

37. A dosage form obtained by the method of one or more of claims 33-36.