HU221313B - Synergetic analgesic pharmaceutical composition and process for their preparation - Google Patents

Abstract

SUMMARY OF THE INVENTION The present invention relates to a synergistic pharmaceutical composition and methods for the preparation of one of the components comprising a listed opioid analgesic and a second component of a synergistic effect of opiate analgesics, in conventional solid or liquid pharmaceutical carriers and / or vaginal aids. Preferably, the synergistic composition of the present invention comprises morphine as analgesics and Girisopam or Nerisopam as a second component. The advantage of the synergistic drug combination according to the invention is that the synergist component enhances the analgesic efficacy of the opiate and consequently the analgesic dose of the opiate can be reduced thereby reducing the risk of addiction or addiction. ŕ

Description

The present invention relates to a pharmaceutical composition and a synergistic analgesic comprising an opiate analgesic and a compound called a "second component".

The use of morphine and analgesics, commonly known as opiate analgesics, in mechanisms of action and chemical structure, is widely and long known. The great benefit of using these drugs is that human pain, of whatever origin, such as severe injury, pain caused by surgery, pain caused by intestinal, gallbladder or kidney cramps, obstruction of organs or severe reduction of blood supply, pain caused by malignant tumors, can be effectively eliminated by administering these compounds as medicaments. A major disadvantage of opiate dosing is that it gradually diminishes its analgesic efficacy with repeated dosing, a so-called tolerance state, and at the same time withdrawal symptoms occur when opiate dosing is discontinued. Any intervention that enhances the efficacy of morphine or other opiate analgesics, thereby reducing the dose of the opiate analgesic, will advantageously alter the potential for opiate analgesics. Such interventions may include the concomitant use of drugs that enhance the effects of morphine or other opiate analgesics without themselves having any specific effects similar to opiate analgesics.

It is an object of the present invention to provide synergistic pharmaceutical compositions which increase the efficacy of opiate analgesics and thereby reduce their dose.

According to the present invention, the above object is achieved by the preparation of a pharmaceutical composition having the following composition. The pharmaceutical composition of the present invention enhances the efficacy of morphine or other opiate analgesics without any specific synergistic component present in the composition having an effect similar to opiate analgesic.

SUMMARY OF THE INVENTION The present invention provides a synergistic analgesic pharmaceutical composition comprising an opiate analgesic and a substance synergistic to the analgesic effect of opiate (hereinafter referred to as "second component"), in addition to customary solid or liquid pharmaceutical carriers and / or excipients.

The present invention is based on the discovery that certain 2,3-benzodiazepine derivatives and other compounds which bind with high affinity to the specific binding sites of these compounds (FEBS Letters 308, 215-217 (1992)) significantly enhance the effect of morphine and other opiate analgesics, and increase the affinity of morphine and other opiate analgesics for the opiate receptor in vitro.

Med. Bull. According to Fukuoka Univ. 8 (3), 283-296, 1981, the tofisopam compound slightly potentiates the analgesic effect of morphine.

Compounds that synergize with the analgesic effect of opiate significantly inhibit the protein phosphatase enzyme. Thus, the "second component" in the opiate receptor binding assay increases the binding of morphine and other opiate analgesics. In the case of pre-inhibition of the protein phosphatase enzyme by okadaic acid, the "second components" become ineffective in opiate receptor binding.

Preferably, the pharmaceutical composition of the invention comprises morphine, codeine, dihydrocodeine, noscapine, ethylmorphine, methadone, pethidine, fentanyl, meperidine, loperamide, sufentanyl, alfentanyl or pentazocine as opiate analgesics.

The pharmaceutical composition according to the invention is preferably a "second component" of 1-aryl-2,3-benzodiazepine, 1-ethenylaryl-2,3-benzodiazepine,

Contains 1,4-benzoquinone, 1,2,3,4-tetrahydroisoquinoline, isoquinoline, pyrimido [6,1-a] isoquinoline or pyrrolo [2,1a] isoquinoline.

The pharmaceutical composition according to the invention comprises as a "second component" synergistically opiate to the analgesic effect of opiate: 1-aryl-2,3-benzodiazepines, preferably 1- (3,4-dimethoxyphenyl) -4-methyl-5-ethyl -7,8-dimethoxy-5H-2,3-benzodiazepine (Tofizopam, reference);

1- (3-chlorophenyl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (Girisopam);

1- (4-aminophenyl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (Nerisopam);

l- (3-chlorophenyl) -4- (hydroxymethyl) -7,8-dimethoxy-5H2,3-benzodiazepine;

l- (4-acetylamino-phenyl) -4-methyl-7,8-dimethoxy-5H-2,3benzodiazepin;

1-ethenylaryl-2,3-benzodiazepines, preferably 1- (E) - (4-hydroxy-styryl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine;

l- (2,4-dimethoxystyryl) -4-methyl-7,8-dimethoxy-5H-2,3benzodiazepin;

l- (2-bromostyryl) -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;

l- (3-chlorophenyl) -4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3benzodiazepin;

l- (3-chloro-4-methoxy-styryl) -4-methyl-7,8-dimethoxy-5H2,3-benzodiazepine;

l- (4-trifluoromethyl-styryl) -4-methyl-7,8-dimethoxy-5H2,3-benzodiazepine;

- (4-nitrostyryl) -3-acetyl-4-methyl-7,8-dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine;

l- [2- (3-indolyl) ethenyl] -4-methyl-7,8-dimethoxy-5H-2,3benzodiazepin;

l- (4-acetylamino-styryl) -4-methyl-7,8-dimethoxy-5H-2,3benzodiazepin;

l- (4-acetylamino-styryl) -3-acetyl-4-methyl-7,8-dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine;

l- (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-dimethoxy-5H-2,3-benzodiazepine;

Al 1- (2-fluorostyryl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine;

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

isoquinolines, preferably Papaverine; Perparin Drotaver;

l- (4-trifluoromethyl-styryl) -6,7-methylenedioxy-isoquinoline;

l-phenyl-6,7-dimethoxy-isoquinoline hydrobromide; pyrimido [6,1-a] isoquinolines, preferably 9,10-dimethoxy-2-mesityl-imino-3-methyl-3,4,6,7-tetrahydro-2H-pyrimido [6,1-a] isoquinolin-4-one;

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

The synergistic effect of the pharmaceutical compositions of the present invention is demonstrated by the following tests:

1. Tailflick test

The procedure followed was that of D'Amour and Smith (J. Pharma. Exptl. Ther. 72: 74.1941). The pain response was triggered by focused light on the tail. The analgesic effect was considered to be positive if the animal did not pull the tail from the light at two and a half times the reaction time when untreated. The results were also evaluated using the Litchfield Wilcoxon method, mathematically determining the dose at which 50% of the animals were pain-free (ED ₅₀ ).

The animals were given i.p. various 2,3-benzodiazepine derivatives were administered. Morphine was administered at 0.5-10 mg / kg s.c. dose. Animals in the control group received physiological saline instead of the 2,3-benzodiazepine derivative.

The results obtained are summarized in Table 1. The test determined the extent to which the 50% effective dose of morphine was reduced by 2,3-benzodiazepines.

Table 1

Tesztvegyülct Morfin ED ₅₀ Control (saline) 2.55 mg / kg C 10 mg / kg i.p. 0.10 mg / kg B 20 mg / kg i.p. 0.10 mg / kg

From the above results it can be seen that the effect of nerisopam and girisopam decreases the ED ₅₀ of morphine by 1/25 of the control.

2. Hotplate ”test

In the hot plate method (Eddy and Leimbach 1953, J. Pharmac. Exptl. Ther. 107: 385), mice were treated with various doses of morphine and the pain response was measured every 15 hours for 1 hour after dosing. The pain reaction was elicited by placing the mice on a 56 ° C plate, in which the mice respond with a typical paw reaction within 5 seconds. The animal was considered pain-free if no pain reaction was observed within 2.5 times the baseline response time. Litchfield Wilcoxon (J. Pharmac. Exptl. Ther. 96:99, 1949) determined the dose at which 50% of the animals were pain-free (ED ₅₀ ) by mathematical statistical method. The results obtained are summarized in Table 2.

Table 2

test Compound Analgesic effect (ED ₅₀ ) C 17.4 mg / kg B 108.7 mg / kg Codeine 139.8 mg / kg Codeine + B 20 mg / kg 41.3 mg / kg Codeine + C 5 mg / kg 28.0 mg / kg Ethylmorphine 161.8 mg / kg Ethylmorphine + B 20 mg / kg 85.0 mg / kg

3. "Receptor Binding" test

The receptor binding assay was performed according to the following references: Murányi A, Gergely P, Nagy G, Black M: The potential role of protein phosphatase 2A in sodium binding to the opiate antagonists naloxone and naltrindole. Brain Slit. Bull. 44 (3): 273-279, 1997.

We found that the morphina affinity of the test compounds was significantly increased for mu receptors (IC ₅₀ values were 2-8 χ lower, see Table 3). This increase in morphine affinity explains and further demonstrates the potentiating effect of morphine on the measurement of in vivo analgesia. Thus, our compounds produce an increase in opiate efficiency by altering the biological properties of the receptor protein.

This finding represents a new therapeutic opportunity for all compounds capable of enhancing morphine - DADLE competition.

The results obtained are summarized in Table 3.

Table 3

Treatment Solvent IC ₅₀ (M) I IC ₅₀ solvent / IC _{5 ()} treated control c l, 2e-6 ethanol 1:10,000 v / v the 4,37-7 2.75 v.Kontroll ethanol 1:20,000 v / v b 9.43-c7 1.27 v.Kontroll THE the 5,30-8 8.24 B the l, 7-02e 4.28 C the l, 7-63e 2.68 D the 2,86-7 1.53

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Table 3 (continued)

Treatment Solvent IC _S0 (M) 1C _5O solvent scr / IC 10 treated control c l, 2e-6 ethanol 1:10,000 v / v the 4,37-7 2.75 v.Kontroll ethanol 1:20,000 v / v b 9.43-e7 1.27 v.Kontroll E the l, 7-66e 2.64 F the 5,77-7 0.76 G b l, 7-94e 4.86 H b l, 7-81E 5.21 I b 8,78-7 1.07 K b 5,73-7 1.65 L b l, 39e-6 0.68 M b 5,99-7 1.57 N b l, 7-45e 0.65 SHE b 7.46-8 12.64 P b l, 7-53e 6.16 R b 3.99-6 0.24 S b l, 7-96e 4.81 T b 3.26-6 0.29 u b 3,60-6 0.26 V c l, 7-05E 11.43 w the 4,12-8 10.61 X the 3.68-7 1.19 Y b l, 86e-6 0.51 Zxx b 3,35-7 2.81 AA b 3.00 to 7 3.14 BB b 2,14-6 0.44 CC b 3.79-8 24.88

Abbreviations used in the table have the following meanings:

v. Control = Which value was compared to the given value, for example "Ethanol 1; 10,000 v / v ”group versus control group.

v / v = dilution ratio, for example ethanol 1:10,000 v / v = 1 unit ethanol in 10,000 units solution (1 mL in 10,000 mL) 1.2e-6 = 1.2 χ 10-6 M xx = mixture of diastereomeric isomers a = ethanol: water = 1:10 000 b = ethanol: water = 1:20 000 c = distilled water.

IC ₅₀ = the value of binding of morphine to mu receptor, the concentration in moles (M) where the binding is 50%.

IC ₅₀ solvent / IC ₅₀ treated = value of binding of morphine to artificial receptors alone (data in column IC _{5 ()} for the first three rows using solvents of different compositions а, b, c) and substances (A, B etc.) is the quotient of the IC ₅₀ values stored together with the appropriate solvent, which expresses the increase in binding of morphine by the compound.

The following test compounds were used: A = 1- (3,4-dimethoxyphenyl) -4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine (Tofizopam, reference);

B = 1- (3-chlorophenyl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (Girisopam);

C = 1- (4-aminophenyl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (Nerisopam);

D = l- (3-chlorophenyl) -4- (hydroxymethyl) -7,8-dimethoxy-5H

2,3-benzodiazepine;

E = l- (4-acetylamino-phenyl) -4-methyl-7,8-dimethoxy-5H

2,3-benzodiazepine;

F = 1- (E) - (4-hydroxystyryl) -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;

1 = 1- (3,4-dimethoxy-styryl) -4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine;

K = l- (3-chlorophenyl) -4-methyl-5-ethyl-7,8-dimethoxy-5H

2.3-benzodiazepine;

L = l- (3-chloro-4-methoxy-styryl) -4-methyl-7,8-dimethoxy

5H-2,3-benzodiazepine;

M = l- (4-trifluoromethyl-styryl) -4-methyl-7,8-dimethoxy

5H-2,3-benzodiazepine;

N = 1- (4-nitro-styryl) -3-acetyl-4-methyl-7,8-dimethoxy

3,4-dihydro-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-3,4-dihydro-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-5H2,3-benzodiazepine;

U = 1- (2-fluoro-styryl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine;

V = papaverine;

W = drotaverin;

X = 1- (4-trifluoromethyl-styryl-6,7-methylenedioxy-isoquinoline;

Y = l-phenyl-6,7-dimethoxy-isoquinoline hydrobromide;

Z = racemic 2- (N-ethylpyrrolidon-2-yl) methyl-4-hydroxy-b, 7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline

AA = 9,10-dimethoxy-2-mesityl-imino-3-methyl-3,4,6,7-tetrahydro-2H-pyrimido [6,1-a] isoquinolin-4-one;

BB = 2,3,5,6-tetrahydro-8,9-dimethoxy-3- (3 '-carbomethoxypyridyl-6' -methylene) -2-oxo-pyrrolo [2,1-a] isoquinoline;

HU 221 313 Al

CC = (E) -2- (2-Acetoxy-3-penten-1-yl) -3,5,6-trimethyl-1,4-benzoquinone.

The ratio of the "second component" of the opiate analgesic and its synergist in the pharmaceutical composition of the present invention may vary within wide limits. Preferably, the pharmaceutical compositions of the present invention may contain from 0.05 to 100 mg of opiate analgesic and from 5 to 1000 mg of synergistic "second component" per dosage unit.

The pharmaceutical compositions of the present invention may be prepared by methods well known in the art of pharmaceutical manufacture.

Combinations of the above-described active ingredients in drug therapy may be combined with the use of formulations containing the appropriate active ingredients already on the market, but for the sake of patient comfort, quality of life, patient compliance, formulations.

These combination compositions are preferably oral, i.e., tablets, coated tablets, soft or hard gelatine capsules, or solution / suspension (e.g., syrups), but may also be administered parenterally, i.e., by multiple dose (subcutaneous, intramuscular, intravenous) injection / infusion. , or aerosol (e.g., nasal) formulations. Formulations may be immediate in that the duration of the therapeutic effect will be determined solely by the duration of action of the active substances used alone, or that by the use of a special formulation, the duration of the therapeutic effect in the formulation may be prolonged. (prolonged-release or prolonged-release preparations).

Formulations of the formulations may be carried out in accordance with the customary methods employed in the manufacture of the pharmaceutical formulations listed above, of course, having regard to the prior experience in formulating the mono-constituents of each active ingredient.

Tablet formulations include lactose sugars (monohydrate, anhydrate, spray-dried, etc.), mannitol, cellulose (pulverized, microcrystalline, etc.), inorganic acids (secondary calcium phosphate, calcium, calcium) as tabletting fillers. apply. Gelatin, polyvinylpyrrolidone (various molecular weights), different cellulose ethers (hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, etc.), hydrolysed starches, various vegetable gums (gum arabic) , guar gum, etc.) may be used in their aqueous or C 1-4 aliphatic alcohol solutions or in a mixture thereof.

As disintegrants, starch species (potato, maize, wheat, etc.) and so-called super disintegrants (carboxymethylcellulose (trade name of Ac-diol), carboxymethyl starch Na [Primojel, Ultra) are used as disintegrants. , Commercial products known as Explo-Tab], etc. Alkaline metal stearates (magnesium calcium stearate), fatty acids (stearic acid), various glycerides (Precirol, Cutina Η, brand oil) , silicone oil emulsions, talc, silica can be used.

Preparation of the active ingredients and excipients for tabletting can be accomplished by simple powder homogenization using a wet or dry granulation process, or by the use of so-called direct compression excipients (e.g., microcrystalline cellulose, spray dried milk sugar, Tablettose, Cellactose, etc.). If desired, the granules or powdered homogenate can be downloaded into hard gelatine capsules instead of tabletting, thereby providing a hard gelatine capsule formulation.

Each of the prior art manufacturing techniques can be used to formulate controlled release (retard) solid dosage forms to produce different types of chewable tablet formulations in which hydrophilic polymers (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxylic acid, methyl cellulose, polyacrylic acid derivatives, polysaccharoses [guar gum, xanthan gum], etc., or mixtures thereof) or hydrophobic polymers (e.g. ethyl cellulose, methacrylic acid ester, copolymers, polyvinyl acetate), polyvinyl butyral), etc., or mixtures thereof, but the matrix for slowing the dissolution may also be formed using mixtures of hydrophilic and hydrophobic polymers, or mixtures of polymeric materials and fatty substances. The active ingredient is individually coated and thus the release profile of the active ingredients can be better adapted to the individual pharmacokinetic properties of the active ingredients.

Prolonged-release formulations containing the active compounds of the invention may also be formulated as coated pellet-type prolonged-release formulations. The pellets can be prepared from the active ingredients individually or from a mixture of the active ingredients. The preparation of pellets can be accomplished by either extrusion spheronization, rotogranulation, or layering on pellets. Coating of the pellets can be accomplished in rotary-bed or fluidized bed equipment. As coatings, solutions or aqueous dispersions of organic insoluble polymeric materials in organic solvents (usually C1-C3 aliphatic alcohols and / or C1-C2 polychlorinated hydrocarbons and / or acetone and / or ethyl acetate or mixtures thereof) may be used. .

The compositions of the present invention may be formulated, if desired, into osmotic or diffusion-osmotic compositions. In this case, the active compounds are hydrophilic polymers (e.g., hydroxypropylmethyl)

Tablets containing allyl cellulose are prepared and coated according to the state of the art with a semi-permeable (e.g. cellulose acetate) or permeable (e.g. aminomethacrylate copolymer) film on the active ingredient and coated therewith. a borehole is provided through which an osmotic discharge of the active ingredient can take place in an aqueous medium.

For sustained release formulations as described above, the rate of drug release should be adjusted so that in vitro dissolution of the active compounds is at least 80% as measured in official pharmacopoeias within 2 to 24 hours.

Because of the very low solubility of the 2,3-benzodiazepine derivatives in aqueous media above pH 5, the formulations may need to be adjusted to a lower pH, or pharmaceutically acceptable solubilizers (cosolvents) may be used. Examples of such co-solvent excipients are ethyl alcohol, propylene glycol, polyethylene glycol, sorbitol, cyclodextrin species, surfactants, polyethylene glycol-polypropylene glycol copolymers and the like.

Because of the above considerations, only compositions containing organic cosolvents may be formulated for injection formulations. In addition to the aforementioned cosolvent substances, additional substances such as benzyl alcohol, dimethylacetamide, methylpyrrolidone and the like are included in these formulations. can also be applied.

If desired, the injectable preparation may be in the form of an emulsion.

In this case, the active compounds, in the form of a base, are dissolved in fatty liquid excipients, such as soybean oil, and the emulsification of the oily solution in an aqueous medium is carried out using surfactants (such as lecithins).

The formulation of the suppository compositions can be accomplished by methods known in the art. The active compounds are dissolved or suspended in the molten suppository bases and the remaining liquid mass is poured into suppository molds or polymer film preformed conical containers and cooled by cooling. Both natural (e.g. cocoa butter) and synthetic fat-like materials (e.g. Witepsol branded products) can be used as suppository mass.

The so-called aerosol formulations deliver the active ingredient into the respiratory tract in the form of spray droplets or a powder / air suspension. Nasal formulations are particularly useful for the active compounds of the present invention. The formulations are formulated into a solution or suspension of the active ingredients, with or without propellants, in dispensing valve head sealed containers. Compressed gases and hydrocarbons can be used as propellants. A nozzle fitted with a metering pump shall be used without the use of propellant gases.

The active ingredients which may be used as analgesics in the compositions and the single dose values are given below.

Name of the active ingredient Single dose (mg) Maximum daily dose (mg) morphine 5-60 150 codeine 10-60 300 dihydrocodeine 5-10 50 noscapine 15-30 300 ethylmorphine 5-20 200 methadone 2-20 200 pethidine 25-100 1200 fentanyl 0.05-0.1 2.5 sufentanil 0.01-0.1 1.0 alfentanil 0.3-0.6 2.0 pentozocin 20-60 600

The following table summarizes the 2,3-benzodiazepine derivatives and the single dose and maximum daily dose which may be used as synergistic components in the formulations:

Name of the active ingredient Single dose (mg) ---- Maximum daily dose (mg) tofizopam (reference) 25-100 600 girisopam 10-100 500 nerisopam 1-25 150

Further details of the present invention are set forth in the following examples, without limiting the invention to the examples.

Example 1 Tablets containing mg of morphine sulfate and 50 mg of tofisopam can be prepared, for example, by mixing 1 part of morphine sulfate and 5 parts of tofisopam with 9 parts of lactose and 3 parts of microcrystalline cellulose and then 0.5 parts of polyvinyl cellulose. pyrrolidone) in a solution of 4 parts deionized water in a fluidized-atomization granulator and added to the dried granulate

1.3 parts of carboxymethylcellulose and 0.2 parts of magnesium stearate are then passed through a sieve with a 1.0 mm mesh sieve. The granulate thus prepared is compressed on a rotary tabletting machine to an average weight of 200 mg tablets using an 8 mm diameter tabletting tool or filled into a size 2 hard gelatin capsule to form a hard gelatin capsule formulation.

EXAMPLE 2 For example, a prolonged release formulation containing mg codeine hydrochloride and 50 mg gyrizopam can be prepared by mixing 6 parts codeine hydrochloride and 5 parts gyrisopam with 8 parts hydroxypropylmethyl cellulose (Metocel K 4M, Colorcon Ltd) .) and 10 parts milk sugar, then powder mixture6

Two granules of 0.4 parts of polyvinylpyrrolidone in 4 parts of isopropanol are granulated in a vortex granulator, after drying, 0.3 parts of talc and 0.3 parts of magnesium stearate are added, followed by granulation of 1.0 mm. and sift through a sieve. The granulate thus prepared is compressed on a rotary tabletting machine to a tablet weight of 300 m by means of a lenticular compression tool having a diameter of 10 mm.

EXAMPLE 3 For example, a suppository composition containing mg of morphine hydrochloride and 50 mg of tofisopam was dispersed in 50 parts of morphine hydrochloride and 5 parts of tofisopam in 50 parts of melted suppository base Witepsol 58 and then in a liquid supernatant. and cooled at 25 ° C, then removed from the mold. Each suppository with a mean weight of 6 g each contained 20 mg of morphine hydrochloride and 50 mg of tofisopam.

Claims (7)

PATENT CLAIMS A synergistic analgesic pharmaceutical composition comprising, as one of the components, an opiate analgesic, preferably morphine, methylmorphine, dihydrocodeine, noscapine, ethylmorphine, methadone, pethidine, fentanyl, meperidine, loperamide, sufentanil, or alfentanil, contains one of the following: 1- (3-chlorophenyl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (Girisopam); 1- (4-aminophenyl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (Nerisopam); l- (3-chlorophenyl) -4- (hydroxymethyl) -7,8-dimethoxy-5H2,3-benzodiazepine; l- (4-acetylamino-phenyl) -4-methyl-7,8-dimethoxy-5H-2,3benzodiazepin; l- (E) - (4-hydroxy-styryl) -4-methyl-7,8-dimethoxy-5H-2,3benzodiazepin; l- (2,4-dimethoxystyryl) -4-methyl-7,8-dimethoxy-5H-2,3benzodiazepin; l- (2-bromostyryl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine; l- (3,4-dimethoxystyryl) -4-methyl-5-ethyl-7,8-dimetoxi5H-2,3-benzodiazepine; l- (3-chlorophenyl) -4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3benzodiazepin; l- (3-chloro-4-methoxy-styryl) -4-methyl-7,8-dimethoxy-5H2,3-benzodiazepine; l- (4-trifluoromethyl-styryl) -4-methyl-7,8-dimethoxy-5H2,3-benzodiazepine; 1- (4-nitro-styryl) -3-acetyl-4-methyl-7,8-dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine; l- [2- (3-indolyl) ethenyl] -4-methyl-7,8-dimethoxy-5H-2,3benzodiazepin; 1- (4-acetylamino-styryl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine; l- (4-acetylamino-styryl) -3-acetyl-4-methyl-7,8-dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine; l- (2-methoxy-3,4-methylenedioxy styryl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine; l- (3,4,5-trimethoxy-styryl) -4-methyl-7,8-dimethoxy-5H2,3-benzodiazepine; l- (2-styryl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine; (E) -2- (2-Acetoxy-3-penten-1-yl) -3,5,6-trimethyl-1,4-benzoquinone; drotaverine; racemic 2- (N-ethylpyrrolidin-2-yl) methyl-4-hydroxy-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline; papaverine; Perparin; l- (4-trifluoromethyl-styryl-6,7-methylenedioxy-isoquinoline; 1-phenyl-6,7-dimethoxyisoquinoline hydrobromide; 9,10-dimethoxy-2-mesityl-imino-3-methyl-3,4,6,7-tetrahydro-2H-pyrimido [6,1-a] isoquinolin-4-one; 2,3,5,6-tetrahydro-8,9-dimethoxy-3- (3'-carbomethoxy-6'-yl) -2-oxo-pyrrolo [2, l-a] isoquinoline; in addition to customary solid or liquid pharmaceutical carriers and / or excipients. Pharmaceutical composition according to claim 1, comprising 0.05-100 mg opiate analgesic per unit dosage and 5-1000 mg second component. A composition according to claim 1 or 2, which is in a form suitable for oral, parenteral or rectal administration or in aerosol form. A process for the preparation of a synergistic analgesic pharmaceutical composition according to claim 1, characterized in that any opiate analgesic and a compound used as the second component are mixed with inhaled solid or liquid pharmaceutical carriers and / or excipients and formulated in a galenic form. 5. The process of claim 4 wherein morphine and Girisopam or Nerisopam are used. 6. A process according to any one of claims 1 to 3, wherein 0.05 to 100 mg of opiate analgesic and 5 to 1000 mg of the compound used as the second component are used per formulation. 7. A process according to any one of claims 1 to 3, characterized in that the composition is formulated for oral, parenteral or rectal administration or in aerosol form.