State of the prior art Morphine and chemically related analgesics of similar action of mechanism-known as opiate analgesic agents-are well-spreadly used as medicine for a long time. The use of such analgesics has the advantage that said agents are suitable for the efficient relief of pain of any kind, e. g. pain caused by serious injuries, surgical interventions; spasm of the intestines, gall bladder and kidney; vessel occlusion of organs or serious decrease of blood suppiy; alignant tumors etc.

The administration of opiate agents is accompanied by the drawback that in the course of dose dependent repeated administration the activity is continuously decreased, a so-called state of tolerance takes place and on stopping the addition of the opiate agents withdrawal symptoms may be observed. Any intervention which increases the efficiency of morphine or other opiate analgesic agents and decreases the dose of said opiate agent alter the applicability of opiate analgesics in a preferred and desirable manner. Such intervention may be the simultaneous use of medicines which strengthens the analgesic effect of morphine or other opiate agents without exhibiting any specific activity being similar to the effect of opiate analgesic agents.

Summarv of the invention It is the object of the present invention to prepare synergistic pharmaceutical compositions which strengthen the effect of opiate analgesic agents and reduce the dose thereof.

The above object is achieved with the aid of the present invention by preparing pharmaceutical preparations of a definite composition. The pharmaceutical preparation of the present invention strengthens the efficiency of morphine or other opiate analgesic agents whereby the synergizing compound of the compositions exhibits no specific effect being similar to the activity of said opiate analgesic agent.

According to the present invention there is provided a synergistic analgesic pharmaceutical composition comprising an opiate analgesic agent (component A) and a substance synergizing the analgesic effect of said opiate (component B) an admixture with suitable inert solid or liquid pharmaceutical carriers and/or diluents.

According to a further aspect of the present invention there is provided a process for the preparation of a synergistic analgesic pharmaceutical composition which comprises admixing an opiate analgesic agent (component A) and a substance synergizing said opiate analgesic agent (component B) with suitable inert solid or liquid pharmaceutical carriers and/or auxiliary agents and bringing said mixture into galenic form.

The present invention is based on the recognition that certain 2,3-benzodiazepine derivatives and other compounds, a significant part thereof binding with high affinity to the specific binding sites of said compounds [FEBS Letters 308, 215-217 (1992) increase the analgesic effect and also the affinity of morphine and other opiate analgesic agents to the opiate receptor to a significant extent.

Compounds synergizing the effect of opiate analgesic agents inhibit the protein phosphatase enzyme to a great extent. Thus according to the opiate receptor binding test component B increases the binding of morphine and other opiate analgesic agents. In case of previous inhibition of the protein phophatase enzyme induced by ocadainic acid, component B becomes inactive in the opiate receptor binding test. This clearly proves that the above described increase of the opiate effect is caused by the inhibition of protein phosphatase.

Detailed description of the invention The composition according to the present invention comprises as opiate analgesic agent preferably morphine, codeine, dihydrocodeine, noscapine, ethyl morphine, methadone, pethidine, phentanyl, meperidine, loperamide, sufentanyl, alfentanyl or pentazocine or an endogenic opiode peptide formed in the organism.

The composition of the present invention may comprise as component A also endogenic opioid peptides formed in the organism, derivatives of said compounds effective on the opiate receptors and compounds which increase the concentration of said peptides by enhancing the synthesis of said peptides or inhibiting the decomposition thereof.

Preferred representatives of such endogenous peptides are the following substances: methionine-encefaline, leucine- encefaline, beta-endorphine and dinorphines.

The composition of the present invention comprises as component B preferably an 1-aryl-2,3-benzodiazepine, 1- ethenyl-aryl-2, 3-benzodiazepine, 1,4-benzoquinone, 1,2,3,4- tetrahydroisoquinoline, isoquinoline, pyrimido [6,1-a] isoquinoline or pyrrolo [2,1-a] isoquinoline.

The component B synergizing the analgesic effect of component A may be preferably one of the following compounds: 1-aryl-2,3-benzodiazepines, preferably 1- (3, 4-dimethoxy-phenyl)-4-methyl-5-ethyl-7, 8-dimethoxy-5H- 2,3-benzodiazepine (tofisopam); 1- (3-chloro-phenyl)-4-methyl-7, 8-dimethoxy-5H-2,3- benzodiazepine (girisopam); 1- (4-amino-phenyl)-4-methyl-7, 8-dimethoxy-5H-2,3- benzodiazepine (nerisopam); 1- (3-chloro-phenyl)-4- (hydroxymethyl)-7,8-dimethoxy-5H-2,3- benzodiazepine; 1- (4-acetylamino-phenyl)-4-methyl-7,8-dimethoxy-5H-2,3- benzodiazepine.

1-ethenyl-aryl-2,3-benzodiazepines, preferably 1- (E)- (4- hydroxy-styryl)-4-methyl-7, 8-dimethoxy-5H-2,3- benzodiazepine; 1- (2, 4-dimethoxy-styryl)-4-methyl-7,8-dimethoxy-5H-2,3- benzodiazepine; 1- (2-bromo-styryl)-4-methyl-7,8-dimethoxy-5H-2,3- benzodiazepine; 1- (3, 4-dimethoxy-styryl)-4-methyl-5-ethyl-7, 8-dimethoxy-5H- 2,3-benzodiazepine; 1- (3-chloro-styryl)-4-methyl-5-ethyl-7, 8-dimethoxy-5H-2,3- benzodiazepine; 1- (3-chloro-4-methoxy-styryl)-4-methyl-7, 8-d imethoxy-5H-2,3- benzodiazepine; 1- (4-trifluoromethyl-styryl)-4-methyl-7, 8-dimethoxy-5H-2,3- benzodiazepine; 1- (4-nitro-styryl)-3-acetyl-4-methyl-7, 8-dimethoxy-5H-2,3- benzodiazepine; 1- 2- (3-indolyl)-ethenyl-4-methyl-7, 8-dimethoxy-5H-2,3- benzodiazepine; 1- (4-acetylamino-styryl)-4-methyl-7, 8-dimethoxy-5H-2,3- benzodiazepine; 1- (4-acetylamino-styryl)-3-acetyl-4-methyl-7, 8-dimethoxy-5H- 2,3-benzodiazepine; 1- (2-methoxy-3, 4-methylenedioxy-styryl)-4-methyl-7,8- dimethoxy-5H-2,3-benzodiazepine; 1- (3,4,5-trimethoxy-styryl)-4-methyl-7,8-d imethoxy-5H-2,3- benzodiazepine; 1- (2-fluoro-styryl)-4-methyl-7,8-dimethoxy-5H-2,3- benzodiazepine.

1,4-benzoquinones, preferably (E)-2- (2-acetoxy-3- pentene-1-yl)-3,5,6-trimethyl-1,4-benzoquinone.

Isoquinolines and 1,2,3,4-tetrahydroisoquinolines, preferably drotaverine or racemic 2-(N-ethyl-pyrrolidine-2-yl)- methyl-4-hydroxy-6, 7-methylenedioxy-1,2,3,4- tetrahydroisoquinoline; papaverine; perparine; 1- (4-trifluoromethyl-styryl)-6, 7-methylenedioxy-isoquinoline; 1-phenyl-6, 7-dimethoxy-isoquinoline-hydrobromide.

Pyrimido [6,1-a] isoquinolines, preferably 9,10- dimethoxy-2-mesitylimino-3-methyl-3,4,6,7-tetrahydro-2H- pyrimido[6,1-a]-isoquinoline-4-one.

Pyrrolo [2,1-a] isoquinolines, preferably 2,3,5,6- tetrahydro-8, 9-dimethoxy-3- (3'-carbomethoxy-pyridyl-6'- methyl)-2-oxo-pyrrolo [2,1-a] isoquinoline.

The synergistic effect of the compositions of the present invention is shown by the following test.

1)"Tail flick"test In this test the method of D'Amour and Smith was followed [J. Pharma exptl. Ther. 72: 74 (1994)]. Pain reaction was induced by directing focused light onto the tail. Analgesic effect was considered to be positive in case of animals who did not pull away their tail from the path of the light even after a time being 2.5 longer than the reaction time measured for the untreated animals. The results were evaluated by the method of Litchfield and Wilcoxon. The dose which resulted a painless state for 50 % of the animals (ED5o) was calculated mathematically.

Simultaneously with the administration of morphine the animals received various 2,3-benzodiazepine derivatives intraperitoneally. The dose of morphine was 0.5-10 mg/kg s. c.

The animals of the control group received physiological saline in the place of the 2,3-benzodiazepine derivative.

The results are summarized in Table 1. In the course of the test it was determined to what extent did the 2,3- benzodiazepine derivatives decrease the 50 % effective effect of morphine. The results are summarized in Table 1.

Table 1 Testcompo : urxd f Morphine. ED50 Control (saline) 2.55 mg/kg Compound C 10 mg/kg i. p. 0.10 mg/kg Compound B 20 mg/kg i. p. 0.10 mg/kg The above data show that as a result of the administration of nerisopam and girisopam the ED50 value of morphine is decreased to 1/25 of that of the control.

2)"Hot plate"test According to the hot plate test (Eddy and Leimbach: J.

Pharmac. Exptl. Ther. 107: 385) mice were treated with varying doses of morphine, whereupon pain reaction was measured during an hour following administration every 15th minute. Pain reaction was induced by placing the mice on a hot plate (temperature 56°C). Mice reacted on pain within 5 seconds by a typical foot licking reaction. An animal was regarded as free of pain if no pain reaction was observed within a period of time being 2.5 times longer than the control time of the untreated group. The dose which caused painfree state in 50 % of the animals was determined by methods of statistical mathematics [J. Pharm. exptl. Therm. 96: 99 (1949)]. The results are summarized in Table 2.

Table 2 Testcow7pound; Arlalgesic effect ED50 Compound C 17.4 mg/kg Compound B 108.7 mg/kg Codeine 139.8 mg/kg Codeine + Compound B 20 mg/kg 41.3 mg/kg Codeine + Compound C 5 mg/kg 28.0 mg/kg Ethyl morphine 161.8 mg/kg Ethyl morphine + Compound B 20 mg/kg 85.0 mg/kg 3)"Receptor binding"test It has been found that the test compounds significantly increase the affinity of morphine to"u" (mu) receptors; (the IC50 values became 2-8 times lower). This increase of the morphine affinity is an explanation and a further proof of the morphine potentiating effect observed on measuring the in vivo analgesic effect. Thus the test compounds cause an increase of the opiate efficiency without modifying the biological properties of the receptor protein. This recognition constitutes and opens a new therapeutical applicability for all compounds which are capable of enhancing DADLE competition.

The results are summarized in Table 3.

Table 3 Treatment Solvent IC50 iCsoSotv. mean/ -trat Control c 1.2x10-6 +0.29 Ethanol a 4.37x10-' 2. 56 1: 10,000 v/v +0.04 v. Control Ethanol 9.43x10-' 1. 19 1: 20,000 v/v b +2.52 v. Control A a 5.30x10-8 8. 24 +2.07 Table 3 (continued) Treatment Sotvent IC50 IC50 solv. mean/ IC50treat.

B a 1.02x10-7 4.28 +0.30 C a 1.63x10-' 2. 68 +0.08 D a 2.86x10-7 1.53 E a 1.66x10'' 2.64 +0.11 F a 5.77x10-7 0.75 +4.73 G b 1.94x10-7 4.86 H b 1.81x10-7 5.21 I b 8.78x10-7 1.07 K b 5.73x10-7 1.65 L b 1.39x10-6 0.67 M a 5.99x10-7 1.57 N b 1.45x10-6 0.65 O b 7.46x10-8 12.64 P b 1.53x10-7 6.16 R b 3.99x10-6 0. 24 S b 1.96x10-7 4.81 T b 3.26x10-6 0.29 U b 3.60x10-6 0.26 V c 1.05x10-7 11.43 Table 3 (continued) Treatment Solvent IC50 IC5o solv. mean/ IC50treat.

W a 4.12x10-8 10.6 X a 3.68x10-7 1.19 Y b 1.86x10-6 0.51 zxx b 3.35x10-7 2.81 AA b 3.00x10-7 3.14 BB b 2.14xi 0-6 0.44 CC b 3.79x10-8 24.9 The following abbreviations were used in the Table: xx = mixture of diastereomeric isomers; a = ethanol: water = 1: 10000 b = ethanol.: water = 1: 20000 c = distille water.

The following test compounds were used: A = 1- (3, 4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8- dimethoxy-5H-2,3-benzodiazepine (tofisopam); B = 1- (3-chloro-phenyl)-4-methyl-7, 8-dimethoxy-5H-2,3- benzodiazepine (girisopam); C = 1- (4-amino-phenyl)-4-methyl-7, 8-dimethoxy-5H-2,3- benzodiazepine (nerisopam); D = 1- (3-chloro-phenyl)-4- (hydroxymethyl)-7, 8-dimethoxy- 5H-2,3-benzodiazepine; E = 1- (4-acetylamino-phenyl)-4-methyl-7, 8-dimethoxy-5H- 2,3-benzodiazepine; F = 1- (E)- (4-hydroxy-styryl)-4-methyl-7,8-dimethoxy-5H-2,3- benzodiazepine; G = 1- (2, 4-dimethoxy-styryl)-4-methyl-7, 8-dimethoxy-5H- 2,3-benzodiazepine; H = 1- (2-bromo-styryl)-4-methyl-7,8-dimethoxy-5H-2,3- benzodiazepine; I = 1- (3, 4-dimethoxy-styryl)-4-methyl-5-ethyl-7,8- dimethoxy-5H-2,3-benzodiazepine; K = 1- (3-chloro-styryl)-4-methyl-5-ethyl-7, 8-dimethoxy-5H- 2,3-benzod. iazepine; L = 1- (3-chloro-4-methoxy-styryl)-4-methyl-7, 8-dimethoxy- 5H-2,3-benzodiazepine; M = 1- (4-trifluoromethyl-styryl)-4-methyl-7, 8-dimethoxy-5H- 2,3-benzodiazepine; N = 1- (4-nitro-styryl)-3-acetyl-4-methyl-7, 8-dimethoxy-5H- 2,3-benzodiazepine; O = 1- 2- (3-indolyl)-ethenyl-4-methyl-7,8-dimethoxy-5H-2,3- benzodiazepine; P = 1- (4-acetylamino-styryl)-4-methyl-7,8-dimethoxy-5H-2,3- benzodiazepine; R = 1- (4-acetylamino-styryl)-3-acetyl-4-methyl-7,8- dimethoxy-5H-2,3-benzodiazepine; S = 1- (2-methoxy-3, 4-methylenedioxy-styryl)-4-methyl-7,8- dimethoxy-5H-2, 3-benzodiazepine; T = 1- (3,4,5-trimethoxy-styryl)-4-methyl-7, 8-dimethoxy-5H- 2,3-benzodiazepine; U = 1- (2-fluoro-styryl)-4-methyl-7, 8-dimethoxy-5H-2,3- benzodiazepine; V = papaverine; W = drotaverine; X = 1-(4-trifluoromethyl-styryl)-6, 7-methylenedioxy- isoquinoline; Y = 1-phenyl-6, 7-dimethoxy-isoquinoline-hydrobromide; Z = racemic 2- (N-ethyl-pyrrolidine-2-yl)-methyl-4-hydroxy- 3,4-tetrahydroisoquinoline; AA = 6,7- tetrahydro-2H-pyrimido [6,1-a]-isoquinoline-4-one; BB = 2,3,5,6-tetrahydro-8,9-dimethoxy-3- (3'-carbomethoxy- pyridyl-6'-methyl)-2-oxo-pyrrolo [2,1-a] isoquinoline; CC = (E)-2- (2-acetoxy-3-pentene-1-yl)-3,5,6-trimethyl-1,4- benzoquinone.

In the compositions of the present invention the ratio of the opiate analgesic agent (component A) and the synergizing component B may vary between wide ranges. Thus the compositions of the present invention may contain preferably 0.05-100 mg of component A and 5-1000 mg of component B per dosage unit.

The compositions of the present invention may be prepared by methods of pharmaceutical industry known per se.

The combination of active ingredients according to the present invention may be used in therapy by simultaneous administration of two separate commercially available compositions containing one active ingredient each. However, in view of the comfort and convenience of patients, the improvement of the quality of life and simplification of the administration of the active ingredients (patient compliance) it is preferably to prepare and use a combined composition comprising both components A and B.

Such combination compositions according to the present invention may be suitable for oral (e. g. tablets, pills, coated pills, capsules, hard or soft gelatine capsules, solutions, suspensions, syrups), parenteral (e. g. subcutaneous, intramuscular, intravenous injections and infusions), rectal (e. g. suppositories) or nasal (e. g. aerosol) administration. From the point of view of the release of the active ingredient the compositions may be of the immediate release type, wherein the duration of the therapeutical effect is determined solely by the activity and action of the active ingredient, and of the sustained release type in which case the duration of therapeutical activity is influenced by the additives and the formulation too (sustained release or retardized compositions).

The combination compositions may be prepared according to methods generally used in the manufacture of the above enumerated types of pharmaceutical compositions, whereby experiences obtained by the preparation of the mono-compositions containing only one of the active ingredients may be utilized as well.

The tablets may contain fillers e. g. lactose (monohydrate, anhydrate, pulverized-dried etc.), mannitol, types of cellulose (e. g. powdered, microcrystalline etc.), inorganic salts (e. g. secondary calcium phosphate, calcium sulfate, calcium carbonate etc.). As binder e. g. gelatine, polyvinyl pyrrolidone (various molecular weight), various cellulose ethers (e. g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose etc.), hydrolyse starch, vegetable gums (e. g. gum arabicum, guar gum etc.) may be used in solutions formed with water or C14 aliphatic alcools or mixtures thereof. As disintegrating agent e. g. starch (potato starch, maize starch, wheat starch) or so-called super disintegrants, such as carboxymethyl cellulose (commercial product sold under the tradename Ac-di-sol), carboxymethyl starch sodium (commercial product sold under the tradename Primojel, Ultraamilopectine or Explo-Tab), polyvinyl pyrrolidone (tradename Poliplasdone) etc. may be used. From the group of applicable sliding agents alkali stearates (magnesium-calcium stearate), fatty acids (stearic acid), glycerides (tradename Precirol, Cutina-H), paraffine oil, silicon oils, silicon oil emulsions, talc, silicium dioxide etc. can be mentioned.

The active ingredients and auxiliary agents may be prepared for tabletting by wet or dry granulation procedure.

Directly pressable auxiliary agents (e. g. microcrystalline cellulose, powdered dried lactose, Tablettose, Cellactose etc.) may be subjected to simple powder homogenization. Granules or powdered homogenizates may be filled instead of tablets into hard gelatine capsules too and thus hard gelatine capsules can be prepared.

Controlled release (retardized) solid pharmaceutical compositions may be prepared by any known method of pharmaceutical industry. Thus matrix tablets may be prepared comprising as retardizing matrix material a hydrophilic polymer (e. g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose), polyacrylic acid derivatives, polysaccharose (e. g. guar gum, xanthane gum etc.) or a mixture thereof. Hydrophobic polymers (e. g. ethyl cellulose, methacrylic esters, copolymers, polyvinyl acetate, polyvinyl butyral etc. or mixtures thereof) may be applied as well. According to a further method the matrix which retardizes release of the active ingredient may be formed with the aid of a mixture of hydrophilic and hydrophobic polymers or a mixture of polymeric and fatty substances. Matrix tablets can also be prepared as multilayer tablets wherein each active ingredient is embedded in a different layer and accordingly the release profile of the active ingredient can be more readily adjusted to the individual pharmacokinetical properties.

The combined pharmaceutical compositions of the present invention can also be prepared in the form of a coated pellet type retardized composition. Pellets can be prepared from the individual active ingredients each or from a mixture of said active ingredients. Such pellets may be prepared by extrusion spheronification, rotogranulation methods or by applying onto placebo pellets. Said procedures can be performed in rotating layer or fluidization equipment. As coating agent solutions of water-insoluble polymers formed with organic solvents (e. g. lower Ci. aliphatic alcools and/or Cri-2 polychlorinated hydrocarbons and/or acetone and/or ethyl acetate or a mixture thereof) or aqueous dispersion thereof can be used.

The pharmaceutical compositions of the present invention can also be prepared in the form of osmotic or diffusion-osmotic preparations. Such preparations are manufactured by preparing tablets which comprise the active ingredients and hydrophilic polymers (e. g. hydroxypropylmethyl cellulose), coating said tablets with a layer being semipermeable (e. g. cellulose acetate) or permeable (e. g. aminomethacrylate copolymer) to the active ingredient and drilling a bore through said layer, whereby the active ingredient is osmotically pressed through said bore.

The velocity of the release of the active ingredient is preferably adjusted to such a value that according to assays performed as described in the Pharmacopoeia at least 80 % of the active ingredient is set free within 2-24 hours.

When preparing aqueous solutions it is to be taken into consideration that due to the very poor solubility of 2,3- benzodiazepine derivatives in aqueous medium at a pH value above 5, the pH of the composition is to be adjusted to a value below 5 or to an even more acidic value. One may also proceed by adding a pharmaceutical acceptable co-solvent to the composition. As co-solvent e. g. ethanol, propylene glycol, polyethylene glycol, sorbitol, cyclodextrines, surfactants, polyethylene glycol/polypropyleneglycol copolymers etc. may be used.

In view of the above factors injections are generally prepared in the form of compositions containing organic co- solvents, too. In addition to said co-solvents the compositions may contain further components, e. g. benzyl alcool, dimethyl acetamide, methyl pyrrolidone etc. The injection may also be finished in the form of an mulsion composition. Such compositions are prepared by dissolving the active ingredient in the form the base in a fatty auxiliary agent (e. g. soya oil) and emulsifying said oily liquid solution in an aqueous medium with the aid of a surfactant (e. g. lecitines).

Suppositories are generally prepared by using methods known per se. One may proceed by dissolving or suspending the active ingredients in a melt suppository base, filling the still liquid mass into suppository moulds or into conical containers pre-formed from a polymer film and solidifying said mixture by cooling. As suppository base natural (e. g. cocoa butter) or synthetic fatty substances (e. g. Witepsol-tradename) can be used.

From aerosol compositions the active ingredient is applied into the respiratory system in the form of atomized drops and/or a powder/air suspension. The active ingredient components of the present invention are suitable for nazal administration. Such compositions are prepared by filling a solution or suspension of the active ingredients in the presence or absence of a propellant into containers closed by a metered valve. As propellant a compressed gas (e. g. hydrocarbons) can be used. In the absence of a propellant a nozzle equipped with a pump is used.

The analgesic active ingredients used in the combinations of the present invention and the single dose thereof are shown in Table 4.

Table 4 Active tngred ! ent Single do Morphine 5-60 150 Codeine 10-60 300 Dihydrocodeine 5-10 50 Noscapine 15-30 300 Ethyl morphine 5-20 200 Methadone 2-20 200 Pethidine 25-100 1200 Phentanyl 0.05-0.1 2.5 Suphentanyl 0.01-0.1 1.0 Alphentanyl 0.3-0.6 2.0 Pentozocine 20-60 600 The 2,3-benzodiazepines used as synergistic component B and also the single and maximal doses thereof are summarized in Table 5.

Table 5 Active ingredient Single dose (mg) Maximal daily dose (mg) Tofisopam (A) 25-100 600 Girisopam (B) 10-100 500 Nerisopam (C) 1-25 150 Further details of the present invention are to be found in the Examples without limiting the scope of protection to said Examples.

Example 1 Preparation of tablets comprising 10 mg of morphine sulfate and 50 mg of tofisopam.

1 part by weight of morphine sulfate and 5 parts by weight of tofisopam are admixed with 9 parts by weight of lactose and 3 parts by weight of microcrystalline cellulose. The powder mixture thus obtained is granule with a solution of 0.5 part by weight of polyvinyl pyrrolidone and 4 parts by weight of ion-exchanged water in a fluidization-spraying granulation apparatus. The granules are dried, 1.3 parts by weight of carboxymethyl cellulose and 0.2 mg of magnesium stearate are added and the granules are sieved through a 1.0 mm sieve. The granules are pressed on a rotating tabletting machine with a dye having a diameter of 8 mm into tablets weighing 200 mg (average weight) or filled into hard gelatine capsules No. 2.

Example 2 Preparation of sustained release compositions comprising 60 mg of codeine hydrochloride and 50 mg of girisopam.

6 parts by weight of codeine hydrochloride and 5 parts by weight of girisopam are admixed with 8 parts by weight of hydroxypropylmethyl cellulose (tradename Methocel K 4M, manufacturer Colorcon Ltd.) and 10 parts by weight of lactose, whereupon the powder mixture is granule with a solution of 0.4 parts by weight of polyvinyl pyrrolidone and 4 parts by weight of isopropanol in a whirlpool granulating apparatus.

After drying 0.3 part of talc and 0.3 part of magnesium stearate are added and the granules are sieved through a 1.0 mm sieve. The granules are pressed on a rotating tabletting machine by using a lentil formed dye (diameter 10 mm) into tablets weighing 300 mg.

Example 3 Preparation of suppositories comprising 20 mg of morphine and 50 mg of tofisopam.

2 parts by weight of morphine hydrochloride and 5 parts by weight of tofisopam are dispersed in 53 parts by weight of Witepsol S 58 (suppository base: trade name) melt at 50°C.

The still liquid suspension is filled into conical forms, solidifie by cooling to 25°C and the suppositories are removed from the mould. Thus suppositories having an average weight of 6 g and containing 20 mg of morphine hydrochloride and 50 mg of tofisopam are obtained.