HK1099511B - Method for the production of an administration form which is secured against misuse - Google Patents

Description

The present invention relates to a method for the manufacture of solid pharmaceutical dosage forms with at least reduced potential for abuse by means of a (a) a mixture of formulations containing at least one active substance with a potential for abuse and at least one synthetic or natural polymer (C) having a tensile strength of at least 500 N, which is formed into moulds by force, (b) where necessary, the moulds are isolated and, where appropriate, separated by size; and (c) after or during heating to at least the softening point of the polymer (C), until the mould has a tensile strength of at least 500 N, until the mould has a tensile strength of at least 500 N, where appropriate, the mould is covered and all the moulds are mixed again, where appropriate.

A large number of pharmaceutical active substances, in addition to being highly effective in their respective areas of use, also have the potential for abuse, i.e. they can be used by an abuser to produce effects that are not in accordance with their intended purpose. For example, opiates, which have shown excellent efficacy in controlling severe to very severe pain, are often used by addicts to induce noisy, euphoric states.

To facilitate abuse, the appropriate dosage forms, such as tablets or capsules, are crushed by the user, e.g. mashed, the active substance is extracted from the resulting powder with the help of a preferably aqueous liquid and the resulting solution, if necessary after filtration by cotton or cellulose, is applied parenterally, particularly intravenously.

Since delayed doses containing potentially abusive active substances do not usually produce the kick desired by the abuser, even when taken orally in abnormally high amounts, they are also crushed and extracted for abuse.

To prevent abuse, US-A-4 070 494 proposed to add a suppressing agent to the dosage form, which swells when water is added to extract the active substance, leaving the gel-separated filtrate with only a small amount of active substance.

A similar approach to preventing parenteral abuse is also underpinned by the multi-layer tablet disclosed in WO 95/20947, which contains the active substance with potential for abuse and at least one gel-forming agent separately in different layers.

A further approach to preventing parenteral abuse is revealed in WO 03/015531 A2, which describes a dosage form containing an analgesic opioid and a dye as an aversive agent.

Another known way to exacerbate abuse is to add to the dosage form antagonists of the active substances, such as naloxone or naltoxone in the case of opiates, or compounds that cause physiological defence reactions, such as Raolix Ipecacuama.

However, since in most cases the use of the drug still requires the use of a drug containing a drug that is suitable for use as a powder, the present invention was intended to provide a method for the production of drug-protected drug-forms which would make it more difficult or impossible to use the drugs normally available to a potential user to produce a drug-like form of drug that would have the desired therapeutic effect if used as intended, but from which the drug cannot be transferred to a drug-like form by simple misuse.

This problem was solved by the method of the invention for the production of solid pharmaceutical dosage forms with at least reduced potential for abuse, characterized by the fact that the (a) a mixture of formulations containing at least one active substance with a potential for abuse, at least one synthetic or natural polymer (C) having a tensile strength of at least 500 N and, where appropriate, forming excipients (B) into moulds under the action of a force;

The use of polymers (C) with the minimum refractive index in the method of the invention, preferably in such quantities that the dosage form also has such a minimum refractive index, makes it possible to make the powdering of the dosage form by conventional means considerably more difficult or prevent its subsequent abuse.

Without sufficient reduction, parenteral, particularly intravenous, safe administration is not possible or the extraction of the active substance from it is too long for the abuser or a kick is not achieved with abusive oral administration because there is no spontaneous release.

The term "crushing" in the present invention means the pulverization of the dosage form by means of ordinary means normally available to the user, such as a mortar and pestle, a hammer, a baton or other common means of pulverization by force, whereby the resulting fine particulate matter (particle size equal to or less than 0.3 mm) may not exceed 5% by weight.

The presentation form according to the invention is therefore suitable for preventing parenteral, nasal and/or oral abuse of pharmaceutical active substances with potential for abuse.

Pharmaceutical substances with potential for abuse are known to the professional, as are their amounts and methods of manufacture, and may be present as such, in the form of their corresponding derivatives, in particular esters or ethers, or in the form of corresponding physiologically compatible compounds, in particular their salts or solvates, as racemates or stereoisomers in the dosage form of the invention. The dosage form obtained according to the invention is also suitable for the administration of several active substances. It is preferably used for the administration of a specific active substance.

The presentation form according to the invention is particularly suitable for the prevention of misuse of a pharmaceutical active substance selected from the group comprising opiates, opioids, tranquilizers, preferably benzodiazepines, barbiturates, stimulants and other narcotic drugs.

The dosage form according to the invention is particularly suitable for the prevention of the abuse of an opiate, opioid, tranquilliser or other narcotic drug selected from the group consisting of N-{1-[2-(4-ethyl-5-oxo-2-tetrazoline-1-methyl) diethyl]-4-methoxymethyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-It may also be used to treat the following substances: methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionineThe active substance is a substance that is capable of being used as a solvent in the manufacture of foodstuffs for human consumption, including foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs for human consumption, foodstuffs, foodstuffs forIn particular, it includes the compounds dimethyl-1-dimethyl-1-benzodiazepine-2 (tetrazepam), dimethyl-1-dimethyl-1-phenyl-3-cyclohexene-1-carboxylate (tilidin (cis and trans)), tramadol, dimethyl-1-dimethyl-1-phenyl-1-H-dimethyl-1-methyl-1-H-dimethyl-1-benzodiazepine (triazolam), dimethyl-1-methyl-1-butyl-1-l-barbituric acid (vinylbital), and their corresponding derivatives, including dimethyl-1-methyl-1-methyl-1-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-phenyl-1-phenyl-1-phenyl-1-ethyl-1-methyl-1-methyl-1-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-2-methyl-1-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-methyl-2-methyl-methyl-2-methyl-meth

The presentation form is particularly suitable for the prevention of misuse of an opioid selected from the group consisting of oxycodone, hydromorphone, morphine, tramadol and their physiologically compatible derivatives or compounds, preferably their salts and solvates, preferably their hydrochlorides.

Furthermore, the dosage form of the invention is particularly suitable for the prevention of the misuse of an opioid agent selected from the group comprising (1R, 2R) 3- ((3-dimethylamino-1-ethyl-2-methylpropyl) phenol, (2R, 3R) 1-dimethylamino-3- ((3-methoxyphenyl) 2-methylpentan-3-ol, (1RS, 3RS, 6RS) 6- ((dimethylamino-1-ethyl-1-methoxyphenyl) cyclohexane-1,32-diol, (1R, 2R) 3- ((dimethylamino-1-ethyl-cyclohexyl) phenol) whose physiologically compatible physical salts, hydrochloride esters, tolerated esters, ester-resistant esters, diasteroids, and preferably their esters and esters, and their esters and esters.

These compounds and their manufacturing processes are described in EP-A-693475 and EP-A-780369 respectively.

The method of the invention uses at least one synthetic or natural polymer (C) with a tensile strength of at least 500 N, as measured by the method disclosed in this application.

The polymers are characterised by a molecular weight of at least 0,5 million determined by rheological measurement. Particularly preferred are thermoplastic polyalkylenoxides, such as Polypropylene oxide, with a molecular weight of at least 0,5 million, preferably at least 1 to 15 million, by means of polymeric measurement. These polymers achieve a gain of 25 to 45 V/m at a specified velocity of 1 to 400 V/m at a medium rotational speed of 1 to 2 V/m (Rm) at a medium rotational speed of 1 to 2 V/m (Rm) at a medium rotational speed of 1 to 2 V/m (Rm) at a medium rotational speed of 1 to 2 V/m (Rm) at a medium rotational speed of 1 to 2 V/m (Rm) at a rotational speed of 1 to 2 V/m) with a rotational speed of 2 to 2 V/m (Rm) at a medium rotational speed of 1 to 2 V/m) at a rotational speed of 1 to 2 V/m (Rm) at a medium rotational speed of 1 to 2 V/m) at a medium rotational speed of 1 to 2 V/m (Rm) at a medium rotational speed of 1 to 2 V/m).

The polymers are preferably used as powder.

The formulations and dosage forms of the invention contain at least 30% by weight of polymers (C) and preferably at least 50% to 99,9% by weight of polymers (C) by weight.

[EA1]

In addition, in addition to the necessary tensile strength of the dosage form obtained according to the invention, at least one natural or synthetic wax (D) with a tensile strength of at least 500 N, measured according to the method disclosed in this application, may be used.

Carnauba wax is a natural wax obtained from the leaves of the Camauba palm and has a softening point of at least 80°C. When the wax component (D) is used in addition, it is used together with at least polymers (C) in such quantities that the formulation has a strength of at least 500 N.

The excipients (B) may be the excipients commonly used in the formulation of solid dosage forms, preferably emollients such as polyethylene glycols, excipients affecting the release of the active substance, preferably hydrophobic or hydrophilic, preferably hydrophilic polymers, preferably hydroxypropyl cellulose, and/or antioxidants.

The antioxidant is preferably used in amounts of 0,01 to 10%, preferably 0,03 to 5%, by weight of the total dosage form.

To produce the safe solid formulation, the active substance, component (C), wax component (D), if applicable, excipients (B), if applicable, and at least one of the other existing anti-misuse components (a) to (f) listed below, if any, are first mixed and the resulting formulations mixture is formed by forceful application to the formulas, preferably to the formulation.

The mixture is prepared in a mixer known to the professional, which may be a roller, shaker, screwdriver or forced mixer.

The resulting formula mixture is preferably formed directly by applying force to the formulas, preferably to the dosage form, preferably without heat action. For example, the formula mixture can be formed into tablets by direct tabletisation.

The formulation mixture can also be granulated first and then shaped.

The moulding is preferably done under a force of 0.5 kN or more, preferably 1 to 100 kN. The force is preferably applied by means of a press, preferably a tablet press, with moulding rollers or moulding tape equipped with rollers. The formulation mixture can also be extruded into a strand by means of an extruder, which is extruded into the desired size.

If the mixture is processed into multi-particle moulds, such as granules or pellets, they should be at least 0,5 mm in size, preferably 1 to 3,5 mm. Before further processing, these moulds, unless they are of a largely uniform size, may preferably be separated by size, which can be done by means of the sieving technique.

The moulds are subjected to a further force in the next step (c) by heating the moulds to at least the softening point of the polymer (C) preferably 60°C, preferably 60°C, before or during the force. A force of at least 0,1 kN, preferably 1 kN to 120 kN, preferably up to 100 kN, preferably up to 90 kN is applied. The duration of the force treatment, as is known to any professional, depends on the force applied, the heating or during the force and, if necessary, the size of the mould and can be determined by simple tests to ensure that the force on the mould is at least 500 n after the force, as shown by the method described above.

The necessary heating can preferably be controlled by measuring the temperature inside a molding using a temperature sensor.

The force may be applied continuously or discontinuously by means of the apparatus described above; the whole process of the invention may be performed continuously or discontinuously.

Figure 1 shows a device with which the moulds 1, here tablets, are subjected to a force after heating between moulds by pressure rollers 2. The moulds running parallel at the top and bottom are equipped with means for absorbing the tablets. The moulds can also be accompanied by a film, preferably an aluminium film or a functional film - not shown in Figure 1 - so that during the force, a coating of the mould, here tablets, can also occur simultaneously.

The heating of the moulds can be carried out in a variety of ways. It is preferable to heat them in ovens, i.e. with the help of a heated gas atmosphere or with radiant heat. It is also possible to heat them by electromagnetic waves, especially by microwaves. In addition to ovens that are filled in discontinuous operation, tunnel ovens are also suitable, in which the moulds are continuously transported through these ovens. In another preferred process, the heat is supplied via the conveyor belt to the mould (1). The heating is preferably under a protective gas atmosphere, especially preferably under a nitrogen atmosphere.

As already shown, the force action can be performed by means of a tablet press, whereby the moulds are heated to the matrix, and in particular this can also be combined with a coat tablet manufacture, whereby the outer coating material to be pressed may be of auxiliary materials or a mixture of active substance and auxiliary material.

In particular, a method where the force is applied by means of moulds as described in (c) is preferred (see Figure 1). In this method, the heated moulds (1) are fed to two opposite pressure rollers (2) which have profile recesses to absorb the individual tablets.

This method is also suitable for continuous operation, where the moulds are fed to the rollers by means of a conveyor belt, which is used to feed the moulds directly to the tunnel heater, under a radiation source or through the belt before they are subjected to the force.

In another preferred method, the moulds (1) are transported in a carrier (3) which has a profile for the moulds (1) and is preferably designed as an endless conveyor belt, which is covered by a second moulding belt (5) which also has a partial profile of the moulds (1) and applied to both sides of the carrier belts.

In the method of the present invention, it may be advantageous to apply separators to the mould profiles in which force is applied to the moulds and to the moulds so that the moulds can be easily detached from the carrier band or the pressure rollers.

It may also be advantageous to provide mechanical separation aids in the devices which apply the force to the molding material which actively expel the moldings after the force has been applied, e.g. by means of holes through which a gas is blown under pressure or by mechanical stamping.

To speed up and optimize the process of the invention, the moulds may be rapidly cooled after the force is applied as described in (c), e.g. by transporting the moulds into or through a refrigerated room or by introducing them into a refrigerating medium such as a liquid gas.

The presentation forms according to the invention are characterized by the fact that, due to their hardness, they cannot be pulverized even after cooling to low temperatures, e.g. by mortars, which virtually eliminates oral, parenteral, particularly intravenous or nasal abuse.

However, in order to prevent any possible abuse in the event of a shrinkage and/or pulverization, which may nevertheless occur by an exceptional force, of the forms of administration obtained according to the invention, the forms of administration obtained according to the invention may contain other agents which are likely to increase or prevent abuse in a preferred embodiment as excipients (B).

Thus, the safe form of administration according to the invention, which, in addition to one or more active substances with potential for abuse, contains at least one hardening polymer (C), if any, excipients (B) and, if any, at least one wax (D), may also contain at least one of the following components (a) to (e) as additional excipients (B): (a) at least one substance irritating the nasal and/or larynx; (b) at least one viscosity enhancer which forms a gel in an extract obtained from an aqueous liquid in the form of a gel obtained by the use of a minimum necessary amount of the dosage form, which preferably remains visually distinguishable when introduced into a further amount of aqueous liquid; (c) at least one antagonist for each of the active substances with potential for abuse; (d) at least one emetic; (e) at least one colouring agent as an aversive agent; (f) at least one bitter substance.

The components (a) to (f) are each suitable, in isolation, in addition to the protection against abuse of the presentation form, such that the component (a) is preferably suitable for protection against nasal, oral and/or parenteral, preferably intravenous, abuse, the component (b) is preferable against parenteral, particularly preferably intravenous and/or nasal, the component (c) is preferable against nasal and/or parenteral, particularly preferably intravenous, abuse, the component (d) is preferably effective against parenteral, particularly preferably intravenous, and/or oral and/or misuse, the component (e) is preferable against nasal or visual abuse, and the component (e) is not yet effective against misuse, at least in the case of the use of the components mentioned above.

In one embodiment, the presentation form of the invention may also contain two or more of the components (a) to (f) in combination, preferably (a), (b) and (c) and/or (f) and/or (e) and (a), (b) and (d) and/or (f) and/or (e).

In a further embodiment, the dosage form obtained according to the invention may contain all the components (a) to (f).

If the anti-abuse form obtained according to the invention includes component (a), the substance of the invention is considered to be a substance that irritates the nasal and/or nasal cavity if it causes a reaction in the body, when applied through the nasal and/or nasal cavity, which is either so unpleasant to the abuser that he does not want or cannot continue the application, e.g. burning, or which physiologically prevents the absorption of the relevant substance, e.g. by prolonged secretion or sneezing. These substances can also be used in very common nasal and/or nasal cavity substances, especially in intravenous applications, to cause an unpleasant sensation or to irritate the user in a physiological manner that does not cause pain or irritation.

Substances which are particularly suitable for irritation of the nasal and/or larynx are those which cause burning, itching, sneezing, increased secretion or a combination of at least two of these stimuli; the corresponding substances and their usual amounts are known to the professional or can be determined by simple preliminary tests.

The nasal and/or larynx irritant of component (a) is preferably based on one or more ingredients or one or more plant parts of at least one nitrifying drug.

Err1:Expecting ',' delimiter: line 1 column 138 (char 137)

Dose unit means a separate or separable dose unit, such as a tablet or capsule.

Preferably, the presentation form according to the invention may be used as a component (a) of one or more ingredients of at least one acetic acid drug selected from the group consisting of Allii sativi Bulbus, Asari Rhizoma c. Herba, Calami Rhizoma, Capsici Fructus (Paprika), Capsici Fructus acer (Cayenne pepper), Curcumae longae Rhizoma, Curcumae xanthorrhizae Rhizoma, Galangae Rhizoma, Myristicae seeds, Piperis nigri Fructus (Papis pepper), Caperis al (Erucae) seeds, Sinbae nigri, Sinedoe Rhizoma and Zingiberi Rhizoma, in particular from the group consisting of Fructus piperis nigri (Papis pepper), Piperis acer (Piperis fructus), and Pepper.

The ingredients of the acidifying agents are preferably o-methoxy (methyl) phenolic compounds, acid amide compounds, mustard oils or sulphide compounds or compounds derived from them.

In particular, at least one ingredient of the active substance selected from the group consisting of myristicin, elimicin, isougenol, β-asaron, safrol, gingerols, xanthorrhizole, capsaicinoids, preferably capsaicin, capsaicin derivatives such as N-vanillyl-9E-octadecenamide, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, norcapsaicin, and nomorcapsaicin, piperine, preferably piperine, G transsulfates, preferably on the basis of non-volatile methanol oils, particularly preferably on the basis of p-hydroxybenzyl, methanol or methanol compounds, and derivatives thereof, shall be preferred.

Preferably, the dosage form obtained according to the invention may contain the plant parts of the corresponding actinid drugs in a quantity of 0.01 to 30% by weight, preferably 0.1 to 0.5% by weight, each in relation to the total weight of the dosage unit. If one or more ingredients of corresponding actinid drugs are used, their amount in a dosage unit of the invention shall preferably be between 0.001 and 0.005% by weight, based on the total weight of the dosage unit.

Another way of preventing abuse in the presentation form of the invention is to add at least one viscosity enhancer as another anti-abuse component (b) to the presentation form, which forms a gel in an aqueous liquid extract obtained from the presentation form with the necessary minimum amount of water, which is hardly harmlessly applicable and remains visually distinguishable preferably when introduced into another amount of aqueous liquid.

Visual distinctiveness for the purpose of the present invention means that the active substance gel formed by a minimum amount of aqueous liquid when introduced, preferably by means of a needle, into another amount of aqueous liquid at 37°C remains essentially insoluble and coherent and cannot be easily dispersed in such a way that a safe parental, particularly intravenous, application is possible.

The increased viscosity of the extract makes it difficult or even impossible to use it as a needle or as a spray. If the gel remains visually distinct, this means that when the resulting gel is introduced into another amount of aqueous liquid, e.g. by injection into blood, it is initially retained as a largely coherent strand, which, although broken into smaller fragments by mechanical action, cannot be dispersed or even dissolved in such a way that a parenteral, particularly intravenous, application is safe. In addition, in combination with at least one component (a) to (e) if present, this results in unpleasant burning, vomiting, bad taste and/or visual disturbance.

Therefore, intravenous application of such a gel would be likely to lead to vascular blockage, with serious harm to the health of the user.

To verify that a viscosity enhancer is suitable as a component (b) for use in the presentation form of the invention, the active substance is mixed with the viscosity enhancer and suspended in 10 ml of water at 25 °C. If a gel is formed which satisfies the above conditions, the corresponding viscosity enhancer is suitable for the prevention of abuse or prevention in the presentation forms of the invention.

If the component (b) is added to the form of the presentation according to the invention, it is preferable to use one or more viscosity enhancers selected from the group consisting of micro-crystalline cellulose with 11% by weight of carboxymethyl cellulose sodium (Avicel® RC 591), carboxymethyl cellulose sodium (Blanose®, CMC-Na C300P®, Frimulsion BLC-5°, Tylose C300 P®), polyacrylic acid (Carbopol® 980 NF, Carbolog® AL 981), propanol (Cesagum® LA®®, Cesagum® L 150/15®, Cesagum® L-175®), polyglycerine, polyglycerin, or pre-filled with citric acid (Citrulline, Citrulline, Citrulline, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutamate, Glutam, Glutam, Glutamate, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Glutam, Sodium hyaluronate, carrier, tarragum (Vidogum SP 200®), fermented polysaccharide Welan gum (K1A96), xanthan gum (Xantural 180®). Xanthan gum is particularly preferred. The names in brackets are the trade names under which the respective materials are marketed. Generally, a quantity of 0,1 to 20% by weight, and in particular a quantity of 0,1 to 15% by weight, by weight of the total dosage form, of the viscosity enhancer (s) mentioned above, is sufficient to satisfy the above conditions.

The viscosity enhancers of component (b), if provided, are preferably available in the presentation form of the invention in amounts equal to or greater than 5 mg per unit of dosage, i.e. per unit of dose.

In a particularly preferred embodiment of the present invention, the viscosity enhancers used as component (b) are those which, when extracted from the dosage form with the minimum amount of aqueous liquid required, form a gel including air bubbles.

Component (C) may also be used as an additional viscosity enhancer, if necessary, to form a gel with the minimum amount of aqueous liquid required.

It is also possible to form the viscosity enhancers and the other constituents in a spatially separated arrangement in the dosage form obtained according to the invention.

Furthermore, the formulation obtained in accordance with the invention for the prevention and control of abuse may contain the component (c), namely one or more antagonists for the active substance or substances with potential for abuse, the amount of antagonists preferably being separated from the other components of the formulation obtained in accordance with the invention and not having an effect when used as intended.

Appropriate antagonists to prevent the misuse of the active substances are known to the practitioner and may be present on their own or in the form of corresponding derivatives, in particular esters or ethers, or in the form of corresponding physiologically compatible compounds, in particular their salts or solvates in the dosage form obtained according to the invention.

If the active substance in the dosage form is an opiate or an opioid, the preferred antagonist is an antagonist selected from the group consisting of naloxone, naltrexone, nalmefen, nalid, nalmexon, nalorphine or naluphin, each in the form of an appropriate physiologically compatible compound, in particular a base, a salt or a solvate, where appropriate.

If the formulation obtained according to the invention contains a stimulant as active substance, the antagonist is preferably a neuroleptic, preferably at least one compound selected from the group consisting of haloperidol, promethacin, fluophenozin, perfenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chlorprotheaxin, sucropantexol, flupentexol, prithipendyl, zotepin, penperidol, piparmerone, melperol and bromperidol.

Preferably, the dosage form obtained according to the invention contains these antagonists at a usual therapeutic dose known to the practitioner, especially preferably at a dose unit dose of two to three times the usual dose.

If the combination to prevent and protect against misuse of the presentation form of the invention includes component (d), it may contain at least one emetic, preferably in a spatially separate arrangement from the other components of the presentation form of the invention, and should not have an effect on the body when used as intended.

Appropriate emetic agents to prevent the misuse of an active substance are known to the practitioner and may be available on their own or in the form of corresponding derivatives, in particular esters or ethers, or in the form of corresponding physiologically compatible compounds, in particular their salts or solvates in the dosage form obtained in accordance with the invention.

Err1:Expecting ',' delimiter: line 1 column 283 (char 282)

Preferably, the formulation obtained according to the invention may contain as a component (d) the emeticum emetin, preferably in an amount equal to or greater than 3 mg, particularly preferably equal to or greater than 10 mg and most particularly preferably in an amount equal to or greater than 20 mg per formulation, i.e. unit dose.

Also preferably, apimorphin may be used as an emetic in the anti-misuse treatment according to the invention, preferably in an amount of preferably ≥ 3 mg, particularly preferably ≥ 5 mg and most particularly preferably ≥ 7 mg per unit dose.

If the form of administration obtained in accordance with the invention contains the component (s) as an additional anti-abuse agent, the use of such a dye, particularly when attempting to extract the active substance for a parenteral, preferably intravenous application, will produce an intense colouring of an appropriate aqueous solution, which may deter potential users.

If the form of administration obtained according to the invention contains component (f) as an additional preventative agent, the addition of at least one bitter substance will further prevent oral and/or nasal abuse by the resulting deterioration in the taste of the form of administration.

The appropriate bitters and the effective amounts for use are given in US-2003/0064099 A1. The preferred bitters are aromatic oils, preferably peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruit flavourings, preferably flavourings of lemons, oranges, lemons, grapefruit or mixtures thereof, and/or denatonium benzoate.

The oral application of the solid formulation according to the invention is for oral, vaginal or rectal use, preferably in humans and animals. It is preferably non-film. The oral application of the solid formulation according to the invention may be in multiparticle form, preferably in the form of micro-tablets, micro-capsules, micro-pellets, granules, spheroids, beads or pellets, whether or not filled in capsules or compressed into tablets. Preferably, the multiparticle forms are at least 0.5 mm in size, preferably in the range of 1 to 3,5 mm, depending on the desired dose. The excipients (formulas) used for the application of the formulation may also be used.

Another preferred embodiment is the presentation form of the invention in the form of a tablet, capsule or oral osmotic therapeutic system (OROS), preferably when at least one additional preventative component (a) to (f) is present.

If the components (c) and/or (d) and/or (f) are present in the formulation of the invention, care must be taken to ensure that they are formulated or dosed in such a way that, when applied as intended, they are practically incapable of having an effect on the patient or on the efficacy of the active substance.

If the formulation of the invention contains component (d) and/or (f), the dosage should be chosen in such a way that no adverse effect is produced when the formulation is administered orally as intended. However, if the intended dosage is exceeded by accident, particularly by children, or by misuse, nausea, vomiting or bad taste will result. The amount of component (d) and/or (f) that patients can tolerate when the formulation is administered orally as intended can still be determined by a specialist by simple preliminary testing.

However, if, irrespective of the impracticability of the powder form of the dosage form according to the invention, it is intended to preserve the dosage form containing the components (c) and/or (d) and/or (f), these components should preferably be used at a dose so high that, if the dosage form is misused, they will cause an intense adverse effect in the user. This is achieved preferably by spatially separating at least the active substance (s) from the components (c) and/or (d) and/or (f), preferably with the active substance (s) present in at least one less common unit (X) and the component (s) present in at least one more common unit (C) and/or (d) and/or (c) and/or (d) and (c) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) respectively, and in particular in the case of the presentation of the active component (s) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (d) and (e) and (d) and (d) and (d) and (d) and (d) and (d) and (d

If the presentation form of the invention contains at least two of the components (c) and (d) or (f), respectively, these may be present in the same or in different subunits (Y).

For the purposes of this invention, units are solid formulations containing, in addition to the usual excipients known to the practitioner, the active substance (s), preferably at least one polymer (C) and the component (D) if any, and at least one of the components (a) and/or (b) and/or (e) if any, and preferably at least one polymer (C) and/or (D) if any, and the antagonist (s) and/or the emetic (s) and/or the component (e) and/or the component (f) if any, and at least one of the components (a) and/or (b) if any, if any, and preferably at least one of the components (C) and/or (d) if any, if any, and/or the antagonist (s) if any, if any, if any, if any, if any.

An essential advantage of the separate formulation of the active substances from the components (c) or (d) or (f) in subunits (X) and (Y) of the form of administration of the invention is that, when applied as intended, the components (c) and/or (d) and/or (f) are practically not released when ingested and/or in the body, or are released only in such small amounts that they do not have an effect on the patient or the therapy, or are only released when passing through the patient's body at such release sites where there is no absorption sufficient to ensure their efficacy.

The practitioner understands that these conditions may vary depending on the components (c), (d) and/or (f) used and the subunit formulation or dosage formulation. The optimal formulation for the particular dosage form can be determined by simple preliminary testing. It is essential, if necessary to prevent abuse, that the subunit contains the polymer (C) and is formulated and manufactured in accordance with the invention.

If the defendant succeeds in reducing such an appropriate form of administration, which contains the components (c) and/or (e) and/or (d) and/or (f) in subunits (Y), to a powder extracted by means of an appropriate extraction agent, in order to reduce the substance to a powder for the purpose of the abuse, the component (c) and/or (e) and/or (f) and/or (d) shall be obtained in addition to the active substance in a form which is not easily separated from the active substance, so that it does not become deformed when the form of administration is used, in particular by oral and/or parenteral administration, or that it does not become deformed when the substance is taken, and in addition to the active substance, the component (c) and/or (f) and/or (d) will be obtained in a form which is not easily separated from the active substance, so that it does not become deformed when the drug is taken, or that it does not produce a negative effect when the substance is used, or that it is used, or that the substance is used, or that the substance is used.

The formulation of a dosage formulation of the invention in which the active substance (s) is (are) separated from the components (c), (d) and/or (e) by a spatial separation, preferably by formulation in different subunits, may be carried out in a variety of ways, the corresponding subunits being in any spatial arrangement with each other in the dosage formulation of the invention, provided that the conditions for the release of the components (c) and/or (d) mentioned above are met.

The practitioner understands that the component (s) (a) and/or (b) (if any) also present may preferably be formulated in the dosage form of the invention in the respective subunits (X) and (Y) or in the form of independent subunits corresponding to subunits (X) and (Y) provided that the formulation does not affect the safety of the dosage form against misuse and the release of the active substance when applied as intended and the polymer (C) is preferably co-formulated and the formulation is preferably performed according to the method of the invention.

In a preferred embodiment of the presentation form according to the invention, the subunits (X) and (Y) are in multiparticle form, with preference given to granules, spheroids, beads or pellets, and the same shape, i.e. design, is chosen for both subunit (X) and (Y) so that no separation of subunit (X) from (Y) is possible by mechanical selection.

The sub-units (X) and (Y) in multi-particle form can also preferably be filled into a capsule or compressed into a tablet, with the respective final formulations being made in such a way that the sub-units (X) and (Y) remain in the resulting dosage form.

The respective multiparticle subunits (X) and (Y) of identical design should also not be visually distinguishable from each other, so that they cannot be separated by the consumer by simple sorting, for example by the application of identical coatings, which can perform additional functions in addition to this equalization function, such as the retarder of one or more active substances or a gastric-resistant equipment of the respective subunits.

The multi-particle subunits can also be formulated as slurry or suspension in pharmaceutically safe suspension media for oral administration.

In another preferred embodiment of the present invention, the subunits (X) and (Y) are each layered together.

The preferred method is to arrange the layered subunits (X) and (Y) in the formulation according to the invention vertically or horizontally, each of which may also contain one or more layered subunits (X) and one or more layered subunits (Y) in the formulation, so that any other layer sequence is considered in addition to the preferred layer sequences (X) - (Y) or (X) - (Y) - (X), if necessary in combination with layers containing the components (a) and/or (b).

A presentation form according to the invention in which the subunit (Y) forms a core completely surrounded by the subunit (X) and between these layers a separation layer (Z) may be preferable is also preferable for the multiparticle forms mentioned above, whereby both subunits (X) and (Y) and any existing separation layer (Z) which should preferably meet the hardness requirement of the invention are then formulated in one and the same multiparticle form according to the method of the invention.

In another preferred embodiment of the presentation form according to the invention, the subunit (X) forms a core enveloped by the subunit (Y), the latter having at least one channel leading from the core to the surface of the presentation form.

Between a layer of subunit (X) and a layer of subunit (Y), the dosage form of the invention may each have one or more, preferably one, if any, quenchable separation layer (Z) to separate the subunit (X) from (Y).

If the dosage form according to the invention has the layered subunits (X) and (Y) and a separating layer (Z) if any, in at least a partial vertical or horizontal arrangement, it is preferably in the form of a tablet, coextruded or laminate produced according to the invention.

In a particularly preferred embodiment, the free surface of the sub-unit (Y) may be completely covered and, if necessary, at least part of the free surface of the sub-unit (X) and, if necessary, at least part of the free surface of the existing separation layer (Z) with at least one barrier layer (Z') preventing the release of the component (c) and/or (e) and/or (d) and/or (f). The barrier layer (Z') should also preferably meet the requirements of the invention.

Also particularly desirable is an embodiment of the presentation form according to the invention which has a vertical or horizontal arrangement of the layers of subunits (X) and (Y) and at least one push layer (p) and, if applicable, a separation layer (Z) arranged between them, in which all free surfaces of the layer structure consisting of subunits (X) and (Y), the push layer and the existing separation layer (Z), if any, are equipped with a semipermeable coating (E) which is at least permeable to the application medium, i.e. an excess physiological or fluid, transparent, impermeable to the agent (s) and the component (s) and/or agent (s) and is essential for the release of the substance (s) and at least impermeable to the release of the substance (s) and (s) in the area of application.

A corresponding dosage form is known to the professional, for example, as the oral osmotic therapeutic system (OROS), as well as suitable materials and methods for its manufacture, including from US 4,612,008, US 4,765,989 and US 4,783,337.

In another preferred embodiment, the subunit (X) of the dosage formulation according to the invention is in the form of a tablet, the base of which and, if applicable, one of the two base surfaces is covered with a barrier layer (Z') containing component (c) and/or (d) and/or (f).

The expert understands that the excipients used in the manufacture of the presentation forms of the invention vary in terms of the subunit (s) (X) (Y) and (Z) (Z) and/or barrier (Z) (Z) (if any) depending on their arrangement in the presentation form, the method of application and the active substance of the components (a) and/or (b) and/or (e) and (c) and/or (d) and/or (f) if any. The materials which possess the required properties are known to the expert.

If the release of component (c) and/or (d) and/or (f) from subunit (Y) of the presentation form according to the invention is prevented by means of a casing, preferably a barrier layer, the subunit may be made of common materials known to the professional, provided that they contain at least a polymer (C) and, if applicable, (D) and are preferably manufactured according to the invention.

If a corresponding barrier layer (Z') is not provided to prevent the release of component (c) and/or (d) and/or (f), the materials of the sub-units shall be chosen in such a way that the release of the respective component (c) and/or (d) from sub-unit (Y) is practically excluded. The following materials are preferably used, which are also suitable for the construction of the barrier layer.

Preferable materials are those selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, glucans, scleroglucans, mannans, xanthanas, copolymers of poly[bis[p-carboxyphenoxy) propane and sebac acid, preferably in a molar ratio of 20:80 (marketed under the name Polyfeprosan 20®), carboxymethyl cellulose, cellulose ethers, cellulose esters, nitrocellulose, polymers based on (meth) acrylamide and their esters, polyesters, polycarbonates, polyallenes, polyallylols, polyvinyl polyvinyl oxide, polyallenes, polyethylene alcohols, polyethylene glycols, polyalurethane, polyalurethane, polyalurethane and their copolymers.

Particularly suitable materials may be selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate (of low, medium or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, sodium cellulose sulphate, polymethyl methacrylate, polyethylene polyethylene, polyethylene polyethylene, polyethylene polyethylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene, polypropylene

Particularly suitable copolymers may be selected from the group comprising copolymers of butyl methacrylate and isobutyl methacrylate, copolymers of methyl vinyl ether and maleic acid with increased molecular weight, copolymers of methyl vinyl ether and maleic acid monoethyl esters, copolymers of methyl vinyl ether and maleic acid anhydride, and copolymers of vinyl alcohol and vinyl acetate.

Other materials particularly suitable for the formulation of the barrier layer are starch-filled polycaprolactone (WO98/20073), aliphatic polyesteramides (DE 19 753 534 A1, DE 19 800 698 A1, EP 0 820 698 A1), aliphatic and aromatic polyesterurethanes (DE 19822979), polyhydroxyalkanoates, in particular polyhydroxybutyrate, polyhydroxyvaleriates), casein (DE 4 309 528), polylactides and copolylactides (EP 0 980 894 A1).

Where appropriate, the above mentioned materials may be mixed with other common auxiliaries known to the professional, preferably selected from the group comprising glyceryl monostearate, semi-synthetic triglyceride derivatives, semi-synthetic glycerides, hydrated castor oil, glyceryl palmitostearate, glyceryl benhate, polyvinylpyrrolidone, gelatine, magnesium stearate, stearic acid, sodium stearate, talcum, sodium benzoate, boric acid and colloidal silica, fatty acids, substituted triglycerides, glycerides, polyoxyalkylyol and their derivatives.

If the presentation form conforming to the invention has a separation layer (Z'), it may preferably be composed of the materials described above for the barrier layer, as may the uncoated subunit (Y).

The dosage formulation according to the invention has a controlled release of the active substance and is therefore preferably suitable for multiple daily administration to patients, such as pain management in human patients.

The dosage form of the invention may contain at least part of one or more active substances in a further delayed form, the delay being achieved by means of usual materials and processes known to the practitioner, such as embedding the active substance in a delaying matrix or by the application of one or more delaying coatings.

In addition, the addition of retardant materials must not impair the required hardness.

Controlled release from the dosage form according to the invention is preferably achieved by embedding the active substance in a matrix. The matrix materials control the release of the active substance. Matrix materials may be, for example, hydrophilic, yellowing materials, where the release of the active substance is mainly by diffusion, or hydrophobic materials, where the release of the active substance is mainly by diffusion from the pores in the matrix.

The matrix materials may be physiologically compatible, hydrophilic materials known to the professional. Preferably, polymers, especially cellulose ether, cellulose esters and/or acrylic resins, are used as hydrophilic matrix materials.

Matrix materials made from hydrophobic materials, such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof, are also preferred; mono- or diglycerides of C12-C30 fatty acids and/or C12-C30 fatty alcohols and/or waxes or mixtures thereof are particularly preferred as hydrophobic materials.

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

Furthermore, the components (C) and, if any, the existing component (D) which are used to achieve the break strength of at least 500 N obtained according to the invention may also act as additional matrix materials.

If the dosage formulation according to the invention is intended for oral application, it may preferably also have a gastric-resistant effect which dissolves depending on the pH of the environment of release.

This coating allows the dosage formulation of the invention to pass through the gastrointestinal tract undissolved and the active substance to be released into the intestinal tract, preferably dissolving the gastric-resistant coating at a pH between 5 and 7.5.

Err1:Expecting ',' delimiter: line 1 column 204 (char 203)

Method for determining the refractive index

Err1:Expecting ',' delimiter: line 1 column 745 (char 744)Err1:Expecting ',' delimiter: line 1 column 52 (char 51)The test machine is to be fitted with a new control unit (BTC-FR 2.5 TH D09) and the power supply is to be fitted with a new control unit (BTC-LC 0050N P01) and the centrifuge is to be fitted with a new control unit (BO 70000 S06). Other Figure 3 shows the measurement of the compressive strength of a tablet, in particular the adjustment device (6) used for the tablet (4) before and during the measurement, by connecting the tablet (4) between the upper pressure plate (1) and the lower pressure plate (3) of the force application device not shown by means of two two-piece clamping devices, each firmly connected to the upper or lower pressure plate after setting the distance necessary to absorb and center the tablet to be measured (5).To adjust the spacing (5), the two-piece clamping devices can be moved horizontally outwards or inwards on the pressure plate on which they are mounted. Other Tablets which are not fractured but which have undergone plastic deformation due to force are also considered to be resistant to fracture. Other For the dosage forms manufactured in accordance with the invention, the refractive index is determined by the method of measurement described, and dosage forms other than tablets are also tested.

The following illustrations of the invention are provided, which are merely illustrative and do not restrict the general idea of the invention.

Examples:

Tramadol hydrochloride has been used as an active substance in a number of examples, although Tramadol is not an active substance with a common abuse potential and is therefore not covered by the Narcotic Drugs Act because it facilitates experimental work.

Example 1:

Komponenten	Pro Tablette	Gesamtansatz
Tramadol HCL	100,0 mg	60,0 g
Polyethylenoxid, NF, MFI (190°C bei 21,6 kg / 10 min) MG 7 000 000 (Polyox WSR 303, Dow Chemicals)	221,0 mg	132,6 g
Hydroxypropylmethylcellulose 100 000 cP	20,0 mg	12,0 g
(Metholose 90 SH 100 000)
Magnesium-Stearat	9,0 mg	5,4 g
Gesamtgewicht	350,0 mg	210,0 g

The powder was pressed into tablets on a corkscrew EK0 exenter press. The tablet press has a diameter of 10 mm and a bulb radius of 8 mm. These tablets were further treated with the help of a laboratory sealing device (head laboratory sealing device SPGE 20 seal seam tightness tester Hot and COLD-Tack of the Fa. Kopp). Two metal top shapes were built on the sealing rails. In each of these, a concave wicking tube with a diameter of 10 mm was placed on the top of the wick and a radion filter of 8 mm was placed on the top of the wick. The two layers of the wick were filled with oil, which was then added to the wick. The seals were preheated to 130°C, the tablets were placed and a force of 750 N was applied for 2.5 min.

The compressive strength of the tablets is determined by the method described above. At the force of 500 N, no fracture occurred. The tablets could not be crushed with a hammer or with mortar and piston.

The in vitro release of tramadol from the tablets was determined in a Pharm Eur. leaf shaker with sink. The release medium temperature was 37°C and the shaker rotation rate 75min-1. Other

Zeit	Freigesetzte Wirkstoffmenge
30 min	21 %
240 min	70 %
480 min	94 %
720 min	100 %

Example 2:

Komponenten	Pro Tablette	Gesamtansatz
Tramadol HCL	100,0 mg	60,0 g
Polyethylenoxid, NF, MFI (190°C bei 21,6 kg / 10 min) MG 5 000 000 (Polyox WSR Coagulant, Dow Chemicals)	221,0 mg	132,6 g
Hydroxypropylmethylcellulose 100 000 cP (Metholose 90 SH 100 000)	20,0 mg	12,0 g
Magnesium-Stearat	9,0 mg	5,4 g
Gesamtgewicht	350,0 mg	210,0 g

As shown in example 1, tablets with a diameter of 10 mm and a bulb radius of 8 mm were produced.

The tablets were also further treated as in example 1, with the difference that the sealing pans were heated to 100°C.

The compressive strength of the tablets was determined by the method described above. At the force of 500 N, no fracture occurred. The tablets could not be crushed with a hammer or with mortar and piston.

The in vitro release of the active substance from the preparation was determined in the Pharm Eur. leaf agitator with sinker. The temperature of the release medium was 37°C and the rate of rotation of the agitator 75min-1.

Zeit	Freigesetzte Wirkstoffmenge
30 min	17 %
240 min	60 %
480 min	84 %
720 min	95 %

Example 3:

Komponenten	Pro Tablette	Gesamtansatz
Tramadol HCL	100,0 mg	60,0 g
Polyethylenoxid, NF, MFI (190°C bei 21,6 kg / 10 min) MG 7 000 000, Feinpulver (Polyox WSR 303 FP, Dow Chemicals)	221,0 mg	132,6 g
Hydroxypropylmethylcellulose 100 000 cP (Metholose 90 SH 100 000)	20,0 mg	12,0 g
Magnesium-Stearat	9,0 mg	5,4 g
Gesamtgewicht	350,0 mg	210,0 g

Tablets were produced as described in example 1 and further treatment of the tablets was also carried out as shown in example 1.

The strength of these tablets was determined by the method described above. At the force of 500 N, no break occurred. The tablets could not be crushed with a hammer or with the aid of a mortar and a pistol.

The in vitro release of the active substance from the preparation was determined in the Pharm Eur. leaf agitator with sinker. The temperature of the release medium was 37°C and the rate of rotation of the agitator 75min-1. Other

Zeit	Freigesetzte Wirkstoffmenge
30 min	21 %
240 min	69 %
480 min	93 %
720 min	100 %

Example 4:

Komponenten	Pro Tablette	Gesamtansatz
Tramadol HCL	100,0 mg	60,0 g
Polyethylenoxid, NF, MFI (190°C bei 21,6 kg / 10 min) MG 7 000 000 (Polyox WSR 303, Dow Chemicals)	221,0 mg	132,6 g
Hydroxypropylmethylcellulose 100 000 cP (Metholose 90 SH 100 000)	20,0 mg	12,0 g
Magnesium-Stearat	9,0 mg	5,4 g
Gesamtgewicht	350,0 mg	210,0 g

As shown in example 1, tablets were produced.

The tablets were then heated in a microwave oven for 10 min at 700 Watt, with the further treatment as shown in example 1, with the difference that the sealing machine used 2 rails with 5 concave arches each and treated 5 tablets with a 1000 N force for 30 sec. each with the help of 100°C heated sealing pans.

The compressive strength of the tablets is determined by the method described above. At the force of 500 N, no fracture occurred. The tablets could not be crushed with a hammer or with mortar and piston.

Example 5:

Komponenten	Pro Tablette	Gesamtansatz
Tramadol HCL	100,0 mg	60,0 g
Polyethylenoxid, NF, MFI (190°C bei 21,6 kg / 10 min) MG 7 000 000 (Polyox WSR 303, Dow Chemicals)	221,0 mg	132,6 g
100 000 cP (Metholose 90 SH 100 000)	20,0 mg	12,0 g
Magnesium-Stearat	9,0 mg	5,4 g
Gesamtgewicht	350,0 mg	210,0 g

As shown in example 1, tablets were produced.

The tablets were then heated in an airlock for 45 min at 110°C under N2 atmosphere, with the difference that the seals were heated to 130°C.

The compressive strength of the tablets is determined by the method described above. At the force of 500 N, no fracture occurred. The tablets could not be crushed with a hammer or with mortar and piston.

Example 6:

Komponenten	Pro Tablette	Gesamtansatz
Tramadol HCL	100,0 mg	60,0 g
Polyethylenoxid, NF, MFI (190°C bei 21,6 kg / 10 min) MG 7 000 000 (Polyox WSR 303, Dow Chemicals)	221,0 mg	132,6 g
Hydroxypropylmethylcellulose 100 000 cP (Metholose 90 SH 100 000)	20,0 mg	12,0 g
Magnesium-Stearat	9,0 mg	5,4 g
Gesamtgewicht	350,0 mg	210,0 g

As shown in example 1, tablets were produced.

They were further treated as shown in example 1, with the difference that the seals were heated to 130°C and the tablets were preheated in the gap for 2 minutes, while being loaded with a force of 10 N. The tablets were then recompressed with a force of 1000 N at 130°C for 20 sec.

The compressive strength of the tablets is determined by the method described above. At the force of 500 N, no fracture occurred. The tablets could not be crushed with a hammer or with mortar and piston.

Example 7:

Komponenten	Pro Tablette	Gesamtansatz
Tramadol HCL	100 mg	18,2 g
Polyethylenoxid, NF, MG 7 000 000 (Polyox WSR 303 FP, Dow Chemicals)	165 mg	30,0 g
Polyethylenglykol 6000	7 mg	1,3 g
Butylhydroxytoluol	0,3 mg	0,1 g
Magnesiumstearat	2,7 mg	0,5 g
Gesamtgewicht	274,8 mg	50,0 g

The indicated amount of butyl hydroxytoluol was dissolved in 0.6 g ethanol (96%), mixed with polyethylene glycol 6000 and dried at 40 °C for 12 h. All other components except magnesium stearate were added and mixed in a free-fall blender for 15 min. Then magnesium stearate was added and the mixture was screened with a 0,8 mm sieve.

The sifted mixture was used to produce EK0 tablets (diameter: 10 mm and bulb radius: 8 mm) on an EK0 cork extruder and then heated for 15 minutes in a dry closet at 80°C under N2 atmosphere.

The hot tablets were repressed on an eccentric press (Fa. Kilian/ IMA type: SP 300) with a force of 80 kN using tablet dies with a diameter of 11 mm and a bulging radius of 8 mm as the tool.

The strength of these tablets was determined by the method described above. At the force of 500 N, no break occurred. The tablets could not be crushed with a hammer or with the aid of a mortar and a pistol.

The in vitro release of the active substance from the preparation was determined in the Pharm Eur. leaf agitator with sinker. The temperature of the release medium was 37°C and the agitator rotation rate 75min. The release medium was intestinal juice with a pH of 6.8. The amount of active substance released in the solvent at any given time was determined by spectrophotometry. Other

Zeit	Freigesetzte Wirkstoffmenge
30 min	17 %
240 min	65 %
480 min	87 %
720 min	95 %

Claims (10)

1. A process for the production of a solid pharmaceutical dosage forms with at least reduced potential for abuse, characterised in that

   a) a formulation mixture containing at least one active ingredient with potential for abuse, at least one synthetic or natural polymer (C), which exhibits a breaking strength of at least 500 N, and optionally auxiliary substances (B) is shaped into formed articles by application of force,

   b) the formed articles are optionally singulated and optionally in each case graded by size and,

   c) after or during heating at least to the softening point of the polymer (C), the formed articles are exposed to force until they have a breaking hardness of at least 500 N, they are optionally provided with a cover and all the formed articles are optionally mixed back together again.
2. A process according to claim 1, characterised in that it is performed continuously or discontinuously.
3. A process according to claim 1 or claim 2, characterised in that the formulation mixture consists to an extent of at least 30 wt.% of component (C).
4. A process according to any one of claims 1 to 3, characterised in that the formulation mixture consists to an extent of at least 50 wt.% of component (C).
5. A method according to any one of claims 1 to 4, characterised in that a) shaping of the formulation mixture proceeds with application of a force of at least 0.5 kN and optionally with heating to less than 60°C.
6. A process according to any one of claims 1 to 5, characterised in that, according to c), the formed articles are heated to at least 60°C before or during application of force of at least 0.1 kN, preferably of 1 kN to 120 kN.
7. A process according to any one of claims 1 to 6, characterised in that the application of force according to a) or c) is performed with the assistance of a press, preferably a tablet press, shaping rollers or with shaping belts equipped with rollers.
8. A process according to any one of claims 1 to 7, characterised in that shaping according to a) gives rise to tablets.
9. A process according to any one of claims 1 to 7, characterised in that shaping according to a) gives rise to a multiparticulate dosage form with a minimum size of 0.5 mm, preferably of 1 to 3.5 mm.
10. A process according to any one of claims 1 to 9, characterised in that opioid active ingredients are used as active ingredients.