DD242349A5 - PROCESS FOR PREPARING A SYNERGISTIC COMBINATION OF FLUPIRTIN AND 4-ACETAMIDO-PHENOL - Google Patents

Abstract

The invention relates to methods for producing a synergistic combination of flupirtine and 4-acetamido-phenol, which is applicable as a pharmaceutical. With the invention, a combination is provided whose active ingredients potentiate each other in their synergistic effect. The object of the invention is the provision of improved medicaments with analgesic and antiphlogistic action. According to the invention, the synergistic combination is prepared by using as active ingredient flupirtine and at least one non-steroidal anti-inflammatory drug or a salt of these compounds with physiologically acceptable acids or physiologically harmless metals, optionally with other conventional carrier and / or disintegrants or excipients.

Description

Field of application of the invention

The invention relates to processes for the preparation of a synergistic combination of flupirtine and 4-acetamido-phenol, which are applicable as drugs due to their analgesic and anti-inflammatory action.

Characteristic of the known technical solutions

Flupirtin is a drug with analgesic properties. Its chemical name is 2-amino-3-carbethoxyamino-6- (4-fluorobenzylamino) pyridine having the following structural formula:

NHCOOC ₂ H ₅

L X

CH ₂ -NH

The flupirtine and its salts with physiologically acceptable acids have a pronounced anaetetische main effect as well as a small anti-inflammatory effect component. It has now been found that the effect of flupirtine and its salts is surprisingly increased synergistically by combination with 4-acetamido-phenol (paracetamol), at the same time the action of 4-acetamido-phenol also experiences a synergistic increase. The active compounds of the combination according to the invention thus potentiate each other in their action.

Object of the invention

The invention provides a process for producing a synergistic combination of flupirtine and 4-acetamidophenol, wherein the active ingredients of this combination potentiate each other in their synergistic action.

Explanation of the essence of the invention

The object of the invention is the provision of improved medicaments with analgesic and antiphlogistic action. The invention relates to the objects defined by the claims.

The weight amounts or parts by weight given in the claims relate in each case to the pure active substances, that is to say not to salts of these active substances.

The flupirtine is preferably used as the acid addition salt, with particular preference being given to the salts with hydrohalic acids (for example the hydrochloride) or organic acids (for example the maleate or the gluconate). The paracetamol is generally not used in the form of the salt.

If it is used as a salt, it is, for example, the salt with alkali metals.

The combination according to the invention shows, for example in the Randall-Selitto test, a synergism of the analgesic effect which is overadditive to the analgesia of the pure flupirtine * and the pure 4-acetamido-phenol.

The combination according to the invention is a surprising functional synergism.

The effect of the combination according to the invention is evident, for example, from the following experiments: These investigations were carried out in the Randall-Selitto test on the albino rat. Here, both the flupirtine dose (hydrochloride) is kept constant, and at a constant dose of 4-acetamidophenol the flupirtine dose changed and in each case the ED50 of the analgesic effect of 4-acetamidophenol and in the second case the Main analgesic effect of flupirtine in the combination determined (method of determination of synergism according to Forth, Henschler and Rummel, textbook Pharmacology and Toxicology, 1980 edition, page 65, Science Publishing, Bibliographic Institute Mannheim, Vienna and

Zurich).

Flupirtin is always studied as maleate, gluconate or hydrochloride.

The results are shown in Table 1:

Table 1:

Randall Selitto test according to Randall, Selitto, Arch. Int. Pharmacodyn. 111, p. 409 (1957) Animal: albino rat (Sprague-Dawley); Application: peros

Drug combination

Drug dose (mg / kg) perorally

Effect in% mean of 6 rats

30.0 mg / kg paracetamol flupirtine 0.1 (Hydrochloride) 0.3 + Paracetamol 1.0 3.0 10.0 70.0 mg / kg flupirtine paracetamol 1.0 + Flupirtin 3.0 (Hydrochloride). 10.0 30.0

25.5 44.1 48.0 65.4 99.5

ED ₅₀ in mg / kg Determination 30 minutes after substance administration, method of linear regression

flupirtine 10.0 -8.3 flupirtine (Hydrochloride) 20.0 23.2 30.0 45.8 30.94 40.0 67.5 paracetamol 30.0 38.2 paracetamol alone 100.0 43.0 71.47 300.0 88.1

Paracetamol in the combination

0.6

41.3

60.9

91.8

127.3

flupirtine

in the combination

1.65

Thus, for example, in the above-mentioned test, the analgesic effective ED 50 of flupirtin of 30.94 mg / kg per os to 1.65 mg / kg and the analgesic effective ED 50 of 4-acetamido-phenol (paracetamol) of 71.47 mg / kg lowered to 0.6 mg / kg per os. In this test, therefore, an increase in the analgesic efficacy of flupirtin by a factor of 18 and in terms of the analgesic effect of paracetamol by the factor 119.

The synergistic increase in rat activity in the above test is particularly pronounced when at least 30 mg flupirtine is present in the combination.

For the combinations according to the invention, for example, the following indications are considered: inflammatory, degenerative articular and extra-articular rheumatic diseases, ankylosing spondylitis, non-rheumatic inflammatory and swelling states, non-rheumatic pain, chronic polyarthritis, arthrosis deformans, soft tissue rheumatism, postoperative pain, especially pain after cervical, nasal and ear surgery, tooth extraction and trauma surgery; Pain after trauma, especially after fractures, dislocations and distorsions; Pain in inflammatory conditions in the genital area, in particular in endometritis, adnexitis and pelvic peritonitis; Carcinoma pain; Dysmenorrhea.

Contraindications include: gastrointestinal complaints, stomach and intestinal ulcers, severely impaired kidney and liver function, asthma.

The daily doses of the combination according to the invention consist for example of 10 to 600 mg, preferably 50 to 400 mg and in particular 100 to 300 mg of flupirtine and about 4000 mg or 2000 or 1000 mg, preferably 600 mg, in particular 200 mg of paracetamol. In the case of carcinoma pain, the amount of flupirtine may in particular also be between 10 and 900 mg, preferably 50 to 600 mg, in particular 100 to 400 mg. The daily doses may be used in the form of a single administration of the entire amount or in the form of 1 to 6, in particular 1 to 4, divided doses per day. In general, administration is preferred 1 to 4 times, especially 1 to 3 times daily. For example, the

preferred dose for the combination of flupirtine and paracetamol preferably 600 mg flupirtine and about 4000 mg paracetamol once daily. In particular, this dose is about 300 mg flupirtine and about 1500 mg paracetamol once daily.

Flupirtine and paracetamol are present in a dosage unit, for example, in the following weight ratio: 1 part by weight flupirtine is combined with 1 to 400 parts by weight paracetamol, preferably 1 part by weight flupirtine with 1 to 200 parts by weight paracetamol, especially 1 part by weight flupirtine with 5 to 100 parts by weight paracetamol.

For example, for the combination of 50 to 1000 mg paracetamol and 5 to 150 mg flupirtine, preferably 100 to 600 mg paracetamol and 10 to 100 mg flupirtine, especially 200 to 400 mg paracetamol and 20 to 60 mg flupirtine easily formulate the drug.

These previously indicated amounts by weight apply only to homogeneous mixtures of paracetamol and flupirtine (for example, suppositories or monolayer tablet). Of course, in other formulations, for example capsules and bilayer tablets, the components may be combined together in other amounts by weight.

The dosage unit of the combination according to the invention may contain, for example:

a) For oral dosage forms:

10 to 300 mg flupirtine, preferably 50 to 250 mg, in particular 100 to 200 mg flupirtine and 1 to 1600 mg, preferably 50 to 1000 mg, in particular 100 to 1000 mg of paracetamol.

These doses may be administered, for example, 1 to 6, preferably 1 to 4, especially 1 to 3 times daily.

b) For parenteral dosage forms (for example, intravenous, instramuscular):

10 to 250 mg of flupirtine, preferably 20 to 200 mg, in particular 50 to 150 mg of flupirtine and 1 to 1600 mg, preferably 50 to 1000 mg, in particular 100 to 1000 mg of paracetamol.

These doses may be administered, for example, 1 to 6, preferably 1 to 4, especially 1 to 3 times daily.

c) For dosage forms for rectal or vaginal administration:

10 to 450 mg of flupirtine, preferably 50 to 400 mg, in particular 150 to 350 mg of flupirtine and 1 to 1600 mg, preferably 50 to 1000 mg, in particular 100 to 1000 mg of paracetamol.

These doses may be administered, for example, 1 to 6, preferably 1 to 4, especially 1 to 3 times daily.

d) For dosage forms for application to the skin and mucous membranes (for example as solutions, lotions, emulsions, ointments, patches and so on):

10 to 300 mg flupirtine, preferably 50 to 250 mg, in particular 100 to 200 mg flupirtine and 1 to 1600 mg, preferably 50 to 1000 mg, in particular 100 to 1000 mg paracetamol.

These doses may for example be administered 1 to 6, preferably 1 to 4, especially 1 to 3 times daily. Of course, it is also possible to prepare galenic preparations which contain the above-indicated dosage units 2 to, for example, 6 times. In particular, tablets or capsules of the combination contain 20 to 1800 mg, pellets, powders and granules 20 to 1600 mg, suppositories 75 to 2600 mg on the flupirtine component. The doses and parts by weight referred to in the preceding pages, which relate to the application to humans, are in each case based on the free bases, or free acids.

The acute toxicity of the combination according to the invention in the mouse (expressed by LD 50 mg / kg, method: Litchfield and Wilcoxon, J. Pharmacol Exper. Ther. 95: 99, 1949) is for example for the combination of flupirtine (maleate) and paracetamol ( 1: 1) when administered orally at 734 mg / kg or above 675 mg / kg body weight.

embodiment example 1

Tablets containing 100 mg flupirtine maleate and 300 mg paracetamol:

200g flupirtine maleate are mixed with 600g paracetamol, 60g cornstarch, 150g microcrystalline cellulose and 60g modified starch (Starch 1500 / Colorcon) and the mixture is granulated with a solution of 22g gelatin in 340g water usually. After drying, the granules are passed through a 3.15 mm sieve and then mixed with 7 g of magnesium stearate and 1 g of fumed silica (Aerosil 200 / Degussa). The resulting mixture is compressed into oblong tablets weighing 550 mg, 18 mm long and 8 mm wide.

Subsequently, the tablets may optionally be provided in the usual way with an enteric or gastric juice-permeable or -soluble film coating.

One tablet contains 100 mg flupirtine maleate and 300 mg paracetamol.

Example 2

Suppositories with 150mg flupirtine maleate and 500mg paracetamol:

150mg of flupirtine maleate and 500g of paracetamol and 10mg of soy lecithin are suspended in 1540g of molten hard fat.

After homogenization, the suspension is poured into usually in hollow cells of 2.3 ml and cooled.

A suppository weighing 2.2g contains 150mg of flupirtine maleate and 500mg of paracetamol.

Claims (6)

Invention claim: 1. A process for the preparation of a medicament, characterized in that one uses as active ingredient flupirtine and 4-acetamidophenol or a salt of these compounds with physiologically acceptable metals, optionally with other conventional carriers and / or diluents or excipients. 2. The method according to item 1, characterized in that in each case 1 to 400 parts by weight of 4-acetamido-phenol come in the combination per part by weight of flupirtine. 3. The method according to item 1, characterized in that in the dosage unit, the combination contains 10 to 900 mg, preferably 10 to 600mg flupirtine and 1 to 1600mg, preferably 50 to 1000mg 4-acetamido-phenol. 4. The method according to item!, Characterized in that one part by weight of flupirtine and 1-400 parts by weight of 4-acetamidophenol or salts thereof with physiologically acceptable acids or physiologically acceptable metals together with conventional carriers and / or diluents or excipients at temperatures between 20 and 8O ⁰ C mixed or homogenized, the mixture thus obtained for the production of preparations containing in the dosage unit 10 to 900mg flupirtine and 10 to 1600mg 4-acetoamido-phenol, poured into hollow cells of appropriate size or filled into capsules of appropriate size or granulated and then optionally compressed with the addition of other conventional excipients to tablets. 5. The method according to item 1, characterized in that one mixes 1 part by weight of flupirtine and 1-400 parts by weight of 4-acetamidophenol or salts thereof with physiologically acceptable acids or physiologically harmless metals with corn starch, microcrystalline cellulose and modified starch granulated the mixture with a gelatin solution and the resulting granules after addition of magnesium stearate and fumed silica pressed into tablets. 6. A process for preparing a composition according to the main claim, characterized in that 1 part by weight of flupirtine and 1-400 parts by weight of 4-acetamido-phenol or its salts with physiologically acceptable acids or physiologically acceptable metals after addition of soybean lecithin at temperatures between 33-37 ⁰ C suspended in molten hard fat and homogenized and then poured out the mixture in hollow cells.