CS202326B1 - Combined analgetic - Google Patents

Description

Combined analgesic

The present invention relates to a combination analgesic for wide consumption in mild and moderate non-visceral pain.

Combination analgesics used so far contain substances which suppress the cognitive (algognostic) component of pain (most often acetylsalicylic acid, phenacetin, paracetamol, aminophenazone, codeine) and possibly also substances that should suppress the emotional (algothymic) component of pain (most often barbiturates, codeine). However, some of these substances can seriously endanger health, eg aminophenazone induces agranulocytosis and is, according to recent findings, carcinogenic, barbiturates and codeine can cause drug dependence. Therefore, over-the-counter prescription analgesics containing aminophenazone, barbiturates and codeine are increasingly restricted and even banned in most countries.

Already MS. Author's Certificate No. 196459 addresses some of the disadvantages of previously known combined analgesics. However, the combined analgesic according to the said certificate contains only acetylsalicylic acid and guaifenesin.

It is an object of the present invention that, in addition to conventional tablet binders and admixtures, it consists of a mixture of three active substances, namely acetylsalicylic acid in an amount of 35 to 75% by weight of the mixture and the corresponding amount of guaifenesin and caffeine. : 0,7.

All three active ingredients of the present invention are known for decades, widely used drugs, acetylsalicylic acid mainly as an analgesic, antipyretic and anti-inflammatory, guaifenesin as an expectorant and anxiolytic and caffeine as a mild psychostimulant.

Acetylsalicylic acid is one of the relatively least toxic analgesic-antipyretic substances and is therefore over-the-counter in all countries. For example, a dose of 325 mg per tablet represents a commonly used single dose of acetylsalicylic acid in Anglo-Saxon countries. In the United States, this dose is also recommended as a standard dose for future analgesic compositions (Pharm. J. 219, 160, 1977). The advantage of the dose of 325 mg acetylsalicylic acid is the fact that even at its triple the maximum single dose allowed by ČSL 3 and other pharmacopoeias is not exceeded.

Guaifenesin ie 3- (O-methoxyphenoxypropane-1,2-diol) is a substance that, due to its anxiolytic and centrally muscle relaxant activity, can suppress the emotional component of pain. A great advantage over barbiturates is the higher therapeutic breadth of guaifenesin and in particular the much lower risk of developing drug dependence on guaifenesin. A further advantage of guaifenesin is its expectorant activity, which can be advantageously employed when using the composition of the invention for cold pain (acute respiratory diseases). E.g. doses of 100 to 200 mg guaifenesin per tablet correspond to a conventional expectorant or anxiolytic dose (eg in Guanar Spofa or Guajacuran Spofa mite).

Caffeine (1,3,7-trimethylxanthin) is a mild psychostimulans practically non-drug addictive. Caffeine is a common part of various drinks. Caffeine alleviates some of the headaches associated with vascular disorders (Goodman-Gilman: The Pharmacological Basis of Therapeutics, 5th ed., MacMillan, NY 1975 pp. 367-378; Modr-Hejlek: Praescriptiones magistralos, Avicenum Prague) 1974 p. 203). Caffeine is added to analgesic combinations generally at doses of 25 to 100 mg per tablet, which are at least five times lower than the maximum single dose of caffeine according to CSL 3.

Example 1

The analgesic efficacy of a mixture of acetylsalicylic acid with guaifenesin and caffeine in a ratio corresponding to 325 mg of acetylsalicylic acid, 130 mg of guaifenesin and 70 mg of caffeine per tablet and acetylsalicylic acid alone at the corresponding dose (325 mg / tbl) was compared. Analgesic. efficacy was measured by standard intraperitoneal acetic acid irritation in mice (Witkin et al., J. Pharm. 133, 400, 1961). The analgesic effect was measured every 60 minutes after oral administration of the compounds in at least 4 doses to groups of 12 mice. Mean effective analgesic doses were calculated and the significance of their difference was evaluated by the method of Litchfield and Wilcoxon (J. Pharmac. Exp. Therap. 95, 99, 1949).

Mean effective analgesic doses in tbl / kg are shown in Table 1:

Tab. 1. Medium effective analgesic doses with confidence limits and relative efficacy

Tbl / kg Relat. efficiency

A mixture of 325 mg of acelylosal acid. 130 mg guaifenesin No.47 r 70 mg caffeine in I tbl (0.34-0.65)

262 (144-477%) P < 0.05

Kys. acetylsalicylic 325 mg in 1 tbl

1.23 (0.82 - 1.85) 100

It can be seen from Table 1 that the combined analgesic containing acetylsalicylic acid, guaifenesin and caffeine in the indicated ratio has a significantly higher analgesic activity than the corresponding dose of acetylsalicylic acid alone. Example 2

The analgesic efficacy and acute toxicity of a mixture of acetylsalicylic acid with guaifenesin and caffeine in a ratio corresponding to 325 mg of acetylsalicylic acid, 130 mg of guaifenesin and 70 mg of caffeine in 1 tablet with analgesic activity and acute toxicity of the following three combined analgesics were compared:

Dinyl Spofa (which is now the most widely used over-the-counter combined analgesic), Mironal Spofa (a widely used combined analgesic abroad, the production of which was recently introduced in the Czech Republic) and Fenalgin III (a developmental preparation of the Research Institute for Pharmacy and Biochemistry Spofa). from abroad much used Darvon products from Lilly). Dinyl contains 200 mg of phenacetin, 200 mg of aminophenazone, 18 mg of allobarbital, 12 mg of butobarbital and 50 mg of caffeine in 1 tablet, Mironal contains 225 mg of acetylsalicylic acid, 150 mg of phenacetin and 30 mg of caffeine in 1 tablet and Fenalgin III contains 400 mg of acetylsalicylic acid , 83 mg of D-propoxyphene, 20 mg of phenobarbital and 50 mg of caffeine in 1 tablet. The analgesic effect was measured by intraperitoneal acetic acid irritation in mice in the same configuration as in Example 1. The acute toxicity of a mixture of acetylsalicylic acid with guaifenesin and caffeine, Dinyl and Mironal was determined after their single oral administration in at least five doses to groups of 10 male mice, lethality was measured for 7 days after application. Mean lethal doses were determined by the method of Janků et al. (Biom. Z. 18, 205 (1976)). The results are shown in Tab. 2 (data on Fenalgin III are taken from a note by J. Grimová and O. Němeček from the Proceedings of Clinical Pharmacology of Widespread Analgesics, OTS n. P. Léčiva Prague 1978, pp. 118–123);

Tab. 2. Mean effective doses in tbl / kg with confidence limits

Analgesia Death

A mixture of 325 mg of acetylsalic acid. t 130 mg guaifenesin t 70 mg caffeine in 1 tbl

Dinyl

Mironal

Fenalgin III

0.47 2.67 (0.34-0.65) (2.29-3.04)

0.75 2.41 (0.44-1.29) (2.21-2.62)

1.05 3.35 (0.56-1.53X2.70-4.15)

0.58 2.25 (0.43-0.78) (1.88 2.76)

Table 2 shows that the analgesic efficacy of the acetylsalicylic acid / guaifenesin / caffeine mixture is greater and its acute toxicity is approximately the same as that of Dinyl, Mironal and Fenalgin III, but containing some substances (aminophenazone, phenacetin, barbiturates, D-propoxyphene) may cause serious side effects (damage to hematopoiesis, kidneys, drug addiction).

Example 3

The analgesic efficacy of acetylsalicylic acid / guaifenesin / caffeine mixtures containing different proportions of these components was compared with the analgesic efficacy of the corresponding doses of acetylsalicylic acid alone. The methodical layout was the same as in Example 1. 3:

Tab. 3. Mean effective analgesic doses in tbl / kg with confidence limits

A mixture of 200 mg acetylsalic acid. -1- 300 mg guaifenesin + 30 mg caffeine in 1 tbl 0.73 (0.43—1.03) Kys. acetylosal. 200 mg / tbl 1.9 (0,62-3,24) A mixture of 325 mg of acetylsalic acid. 4- 130 mg guaifenesin + 70 mg caffeine per 1 tbl 0.47 (0.34—0.65) Kys. acetylosal. 325 mg / tbl 1,23 (0.82—1.85)

The table shows that a mixture of acetylsalicylic acid with guaifenesin and caffeine in a ratio of 200 mg: 300 mg: 30 mg had 2.60 times higher analgesic efficacy than an equipotent dose of acetylsalicylic acid alone and a mixture of acetylsalicylic acid with guaifenesin and caffeine in a ratio of 325 mg: 130 mg: 70 mg had 2.62 times greater analgesic efficacy than the corresponding dose of acetylsalicylic acid alone.

Example 4

In the manufacture of combination analgesic tablets containing 325 mg acetylsalicylic acid,

PftEDMET

Claims (1)

PftEDMET Combination analgesic containing acetylsalicylic acid and guaifenesin, characterized in that, in addition to conventional tablet binders and admixtures, it consists of a mixture of three active substances, namely 130 mg guaifenesin and 70 mg caffeine in 1 tablet proceed as follows: Stick for 1,000,000 tablets: acetylsalicylic acid 325,00 kg 3- (O-methoxyphenoxypropane-1,2-diol) 130.00 kg 1,3,7-trimethylxanthine 70,00 kg colloidal silicon dioxide 6.50 kg hydroxypropylmethylcellulose 3.25 kg microcrystalline cellulose 76.25 kg amylopectin 19.50 kg talc 13.00 kg stearic acid 6.50 kg Manufacturing process: 130 kg of 3- (O-methoxyphenoxypropane-1,2-diol), 70 kg of 1,3,7-trimethylxanthine and 3.25 kg of colloidal silica are homogenized. The mixture is moistened with a binder prepared from 3.25 kg of hydroxypropyl methylcellulose, 15 L of ethanol and 15 L of demineralized water. Damp meat is bent, granulated, dried and sieved. The dry sieved granulate is mixed with 325 kg of acetylsalicylic acid, 76.25 kg of microcrystalline cellulose and tabletting ingredients, which is 3.25 kg of colloidal silica, 19.5 kg of amylopectin, 13 kg of talc and 6.5 kg of stearic acid. The tablets obtained are pressed into tablets having a diameter of 13 mm and a weight of 650 mg. Use: Headaches and possibly other non-visceral pains (toothache, locomotive apparatus, colds associated with pain and catarrh).