EP1131135A1

EP1131135A1 - Composition containing an analgesic and theobromine

Info

Publication number: EP1131135A1
Application number: EP99957378A
Authority: EP
Inventors: Péter AR NYI; Attila B. Kov Cs; Zsuzsanna FÜRST; Péterné KOV CS; Endre Mikus
Original assignee: Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt
Current assignee: Chinoin Private Co Ltd
Priority date: 1998-11-25
Filing date: 1999-11-23
Publication date: 2001-09-12
Also published as: HU9802716D0; BG105616A; CZ20011847A3; EA200100581A1; PL348631A1; AU1510200A; HUP9802716A3; EE200100281A; HUP9802716A2; SK6872001A3; WO2000030715A1; YU37001A; EA004375B1; HRP20010403A2

Abstract

The subject of the invention is a pharmaceutical composition comprising as active ingredient an analgesic compound and a compound of xanthine structure, where the ratio of the analgesic and the xanthine derivatives is (1-20):1, advantageously 10:1. As analgesic compound preferably morphine, aminophenazone, analgin, acetyl-salicylic acid, indomethacin, ibuprofen, diclophenac, codeine, more preferably analgin, S(+)ibuprofen, diclophenac, as a compound of xanthine structure 3-methylxanthine, theobromine, or CH-13584((1H-purine-2,6-dion-3,7-dihydro-3-methyl-7/5-methyl-1,2,4-oxadiazole-2-yl/methyl), preferably theobromine is used. The compositions of the invention may contain as further active ingredient a smooth muscle spasmolytic, preferably drotaverine.

Description

COMPOSITION CONTAINING AN ANALGESIC AND A XANTHINE OR A XANTHINE DERIVATIVE

The invention relates to pharmaceutical compositions comprising as active ingredient an analgesic compound and a compound of xanthine sturcture.

Analgesic compounds are divided pharmacologically into two main groups:

1. Non-steroidal antiinfiammatory drugs, (NSAID) or minor analgesics.

2. Morphine type or major analgesics.

The minor analgesics are less potent in relieving pain than the major analgesics, but their side-effects are also considerably milder. The use of major analgesics is limited by the risk of physical dependence. The effect/side-effect ratio of the two pharmacological groups also sets bounds to their use. Minor analgesics serve to relieve everyday pain (headache, toothache, rheumathoid pain), while major analgesics are used for the treatment of pain connected with severe trauma, malignant tumours etc. Drug researchers have since long been striving to produce compounds of non-morphine structure the potency of which reaches that of major analgesics without causing physical dependence. This dream has so far not come through.

It is strived to increase the potency of minor analgesics by combining them with additive substances. One of the widely used analgesia increasing substances is caffeine (1,3,7- trimethyl-lH-purine-2,6-dion). The compound is found in largest quantities in the seeds of the coffee-shrub (Coffea arabica), in the leaves of the tea-shrub (Thea sinensis) and in cocoa powder prepared from the fruit of the cocoa-tree (Theobroma cacao). Caffeine was isolated from the seed of coffee-shrub and its chemical structure was determined in 1875 (Prog. Drug. Res. 31:273-313,1987). In clinical studies caffeine alone had no analgesic effect (Pharmacotherapy 10:387-393,1990), although Ward et al. observed a favourable effect of its 300 mg dose in migrainous headache, compared to the control group (Pain, 44:151-155,1991). In animal experiments the compound increased the effect of minor analgesics in a manner illustrated by a bell-shaped curve, which means that in lower doses (<10 mg/kg p.o.) it increased, while in higher doses (> 10 mg/kg p.o.) it inhibited their effect (Meth. Find. Exp. Clin. Pharmacol 13:529-533. 1991). Caffeine increases the pain relieving effect not only of minor analgesics, but also that of major analgesics (Pharm.Rev. 45:43- 85,1993).

Beside caffeine, two other alkaloids of xanthine structure are also found in greater quantities in the above mentioned three plants. One of them is theophylline (1,3-dimethyl- lH-purine-2,6-dion), the other is theobromine (3,7-dimethyl-lH-purine-2,6-dion). The drawback of the use of caffeine is that its absolute contraindication is tachyarrhythmia, while its relative contraindications are ulcer, hyperthyreosis, hypertension and some neuropsychiatric diseases (Med. Monatsschr. Phar. 15,258-269.1992).

We have set the aim to prepare an analgesic combination in which instead of caffeine, the analgesic effect is provided for by a compound which is more safe and has fewer side- effects.

By our days it has become known which substituents in different parts of the xanthine skeleton are responsible for the increase or attenuation of the different effects. Thus, NI position is responsible for the adenosine antagonistic and extrapulmonary effects, N3 position has great importance from the aspect of the intensity of bronchodilator effect, while H substitution in position N7 leads to the decrease of bronchodilating effect. In position N9 H substitution as a rule causes general decrease of the effect, while substitution in position C8 may lead to the increase of antiallergic, adenosine antagonistic effects and the increase of toxicity (J. Allergy Clin. Immunol. 78:817-824,1986). Regarding the pharmacological effects of caffeine, theophylline and theobromine, their intensity varies according to the type of their effect. From the aspect of smooth muscle relaxant, adenosine receptor antagonistic, diuretic, cardiac and circulatory effects, the order of sequence is theophylline > caffeine > theobromine. from the aspect of central nervous system stimulant, skeletal muscle work increasing, gastric juice secretion increasing effect the order of sequence is caffeine > theophylline > theobromine. As it can be seen, caffeine and theophylline have significant pharmacologic effects, while according to our present knowledge, theobromine is the weakest among the three xanthine derivatives.

The same definite order of sequence can not be established from the aspect of the potentiation of analgesic action, since, surprisingly, no systematic studies have been performed in that respect. For testing the effect of minor analgesics models based on inflammation, while for the demonstration of the effect of major analgesics, antinociceptive models (e.g. Tail flick test) are the most suitable. In these tests also the analgesia potentiating action can be reliably assessed.

Corresponding to our objective we studied

I. 1. the effect of CH-13584 (lH-purine-2,6-dion-3,7-dihydro-3methyl-7/5-methyl-l,2,4- oxadiazole-3-yl/methyl), theophylline and 3-methylxanthine alone and in combination with p.o. or s.c. administered different doses of morphine in the rat tail flick test.

I. 2. the effect of caffeine, theobromine and 3-methylxanthine alone and in combination with different oral doses of analgin or paracetamol in the mouse writhing test.

In the following we describe the test methods used

1. Rat tail flick test:

The examinations were performed according to the method of D' Amour and Smith (J. Pharmacol. Exp. Ther. 72:74,1942). The principle of the method is that thermal radiation is directed to the tail of the animals and the latency period until the jerk of the tail is measured. The various analgesics prolong this latency period. The experiments were performed in male Wistar rats of 120-140 g. The animals were fixed so that thermal radiation should focus on the tip of their tail. An automatic analgesia meter was used for measuring the latency period of tail flick. The instrument turned out thermal radiation and stopped the digital clock measuring the latency period. In order to avoid tissue damage developing due to strong analgesic effect, thermal radiation was switched off in each case at periods twice as long as the control latency time. Morphine was dissolved in physiological saline for s.c. administration. CH-13584, theophylline and 3-methylxantine were administered in 1 % methylcellulose suspension to the animals. The volume injected was in each case 0,1 ml/100 g body -weight. Before oral administration the animals were starved for 16 hours but had access to tap water ad libitum. In case of p.o./p.o. combination the two substances were administered simultaneously, while in case of p.o./s.c. combinations the s. c. administered substance was injected 30 minutes after p.o. treatment.

2. Mouse writhing test

Mature CFLP mice of both sexes, weighing 23-27 g (LATI) were used for the experiments. The animals consumed a standard rodent laboratory diet (Charles River Co. Hungary) and tap water ad libitum except on the day of the experiment when they were starved for 16 hours before oral administration of the test substances and had access only to tap water. The mice were kept in a room of 22±2°C temperature, cyclic lighting. All experiments were performed at oral administration. A 1 % methylcellulose suspension was prepared from the test substances which was administered to the mice through a gastric tube in 0,1 ml/10 g body mass volume. (In case of the combinations, the powder mixture of the two components was suspended in methylcellulose).

In the experiments the method of Witkin et al. (Witkin, L. B., Heubner, C. F., Galdi, F., 0'Keefe, E. Spitaletta, P., and Plumer A. J., Pharmacology of 2-amino-indane hydrochloride (Su-8629) a potent non-narcotic analgesic, J. Pharmacol. Exp. Ther. 133,400408,1961) was used.

The mice were placed by one in transparent containers 1 hour before the measurement to get acclimatized to the experimental conditions. On the day of the experiment they were injected i. p. 0,2 ml/animal of 0,6 % acetic acid solution, then after a 5 minutes waiting period the number of writhes was counted over 5 minutes. The pain reaction to the chemical noxa was regularly determined in the untreated animals (control), then the antinociceptive effect was expressed in per cent of the control. In the control experiments the number of writhes per mouse was 24±0,53 (n=70).

Examination of the time-effect relationship

The first measurement was performed 1 hour after the administration of the test substances. At the treatment of the other groups of mice with the test substances, acetic acid was injected 2, 3, 4 and 5 hours after their administration and the degree of antinociceptive effect was determined in the function of time. Offset of the effect was assessed by stopping measurement in the groups where the number of writhes approached the control values (20-22 writhes/mouse). The time of the first of this measurement is considered as the offset of the effect. The results were represented in the form of time-effect curves and the effect-half-life values (tj_/2 min.) were read.

Acute toxicity study

The examinations were performed in groups of 10 mice, at oral administration, after 16 hours starving. The toxicity of the test substance was determined alone and in their combinations with methylxanthines. Deaths were recorded hourly, then summarized after 24 hours.

Statistical evaluation of the results

The degree of antinociceptive effect is expressed as the number of writhes/mouse and indicated as % of the control. The mean of pain reactions (writhes/mouse), standard deviation (SD) and standard error (SE) were calculated, then significance was calculated using the paired Student's "t" test, thereafter one factor analysis of variance of the significant values was performed.

The following results were obtained:

1. Rat tail flick tests

As it can be seen from Table 111.1.(1), the antinociceptive effect of orally administered CH- 13584 is statistically significant at several points of time, however, it is not dose dependent and the degree of its action is not significant either. The maximum effect attained is only 25.6±4.8 %.

In a surprising manner, orally administered CH-13584 potentiated the antinociceptive effect produced by the oral ED50 (15 mg/kg) dose of morphine at several points of time and doses (Table III. 1.(2)). This potentiating effect proved significant 30, 60, 90 minutes after the combination of morphine with 100 mg/kg CH-13584 and 30, 45, 60, 90 minutes after its combination with 200 mg/kg CH-13584.

Mophine, at s.c. administration produced dose dependent antinociceptive effect (Table

111.1.(3)). The oral administration of 100 mg/kg CH-13584 significantly increased the analgesic effect of s.c. injected morphine. This effect of CH-13584 was most expressed on the action of 3.75 and 5 mg/kg doses of morphine. The duration of the effect of 5 mg/kg morphine was prolonged to more than its twofold by 100 mg/kg CH-13584 (Table 111.1.(4) compared to Table 111.1.(3)). The 100 mg/kg oral dose of CH-13584 potentiated even more strongly the effect of p.o. administered morphine than that of the s.c. dose. Beside increasing the effect of morphine,

CH-13584 also considerably prolonged its duration (Table 111.1.(10) compared to Table III.

1. (9)).

Neither theophylline nor 3-methylxanthine showed relevant antinociceptive effect following 30 mg/kg oral dose (Table 111.1.(5) and Table 111.1.(6)).

However, very surprisingly the combination by either compounds, significantly potentiated the s.c. morphine induced antinociceptive effect (Table 111.1.(7) and Table 111.1.(8) compared to Table 111.1.(3)).

2. Mouse writhing test

THE ANTINOCICEPTIVE EFFECT OF ANALGIN

In the writhing test of the mouse analgin showed dose and time dependent antinociceptive effect (Table 111.2.(1)).

COMBINATION OF ANALGIN+CAFFEINE (comparative)

The combination of 50 mg/kg analgin with 5 and 10 mg/kg caffeine caused no increase in the effect of analgin, while 50 mg/kg caffeine rather antagonized it. (Table III. 2.(2)).

The combination of 100 mg/kg analgin with 5 and 10 mg/kg caffeine caused only a slight, statistically not significant increase of effect, while 50 mg/kg caffeine rather inhibited the effect of analgin (Table 111.2.(3)). The half-life of the effect of 100 mg/kg analgin is 125 minutes. The combination of 100 mg/kg analgin with 10 mg/kg caffeine modified the half- life to 120 minutes. This change is considered unimportant.

The combination of 200 mg/kg analgin with 5,-10 and 50 mg/kg caffeine has lead unanimously to the decrease of the effect of analgin (Table 111.2.(4)).

COMBINATION OF ANALGIN+3-METHYLXANTHINE

The combination of 50 mg/kg analgin with 5, 10 and 50 mg/kg 3-methylxanthine resulted in an increasing tendency but not in statistically significant increase of the effect (Table 111.2.(5)).

The combination of 100 mg/kg analgin with 5, 10 and 50 mg/kg 3-methylxanthine has also lead to potentiation of the effect. This increase of the effect, which also means its prolongation, appeared to be significant, at several points of time (Table 111.2.(6)).

The half-life of the effect of 100 mg/kg analgin is 125 minutes. The combination of 100 mg/kg analgin with 5 mg/kg 3-methylxanthine increased the half-life to 220 minutes.

The combination of 200 mg/kg analgin with 5, 10 and 50 mg/kg 3-methylxanthine also lead to potentiation of the effect. The degree of potentiation was smaller than in case of the former combination, but in case of 5 mg/kg 3-methylxanthine a statistically significant effect was present after 3 and 4 hours (Table III 2.(7)). The half-life of the effect of 200 mg/kg analgin is 230 minutes. The combination with 5 mg/kg 3-methylxanthine increased the half-life to 270 minutes. COMBINATION OF ANALGIN+THEOBROMINE

The combination of 50 mg/kg analgin with 5 and 10 mg/kg theobromine lead to decisive potentiation of the effect, which in case of the 10 mg/kg dose after 1 and 2 hours appeared to be statistically significant (Table 111.2.(8)).

The potentiating effect of 5 and 10 mg/kg theobromine was even more expressed when combined with 100 mg/kg analgin than found with the former ratio of combination. With its potentiation also the duration of the effect of analgin was prolonged (111.2.(9)). The half-life of the effect of 100 mg/kg analgin is 125 minutes. The combination of 100 mg/kg analgin with 10 mg/kg theobromine increased the half-life to 230 minutes. The half-life of the effect of 200 mg/kg analgin is 230 minutes, which was increased by the combination of 10 mg/kg theobromine to 285 minutes.

The combination of 200 mg/kg analgin with 5, 10, and 50 mg/kg theobromine caused a slight, statistically not significant decrease of the antinociceptive effect (Table 111.2.(10)).

THE ANTINOCICEPTIVE EFFECT OF PARACETAMOL

Paracetamol in 50, 100 and 200 mg/kg doses showed short but dose-dependent antinociceptive effect. However, the 200 mg/kg dose, which had 60 % effect, is already very near to the acute toxic range (Table 111.2.(11)).

COMBINATION OF PARACETAMOL+CAFFEINE

The combination of 100 mg/kg paracetamol with 5, 10 and 50 mg/kg caffeine unanimously lead to the decrease of the effect of paracetamol (Table 111.2.(12)).

When 100 mg/kg paracetamol was combined with 5, 10 and 50 mg/kg 3-methylxanthine, the 5 and 10 mg/kg doses caused statistically significant increase of the effect (Table 111.2.(13)).

The combination of 100 mg/kg paracetamol with 5, 10 and 50 mg/kg theobromine lead to decrease of the effect 1 hour following administration. (Table 111.2.(14)). THE ANTINOCICEPTIVE EFFECT OF S(+)-IBUPROFEN

The 20, 30 and 50 mg/kg oral doses of S(+)ibuprofen showed dose-dependent antinociceptive effect. The maximal antinociceptive effect was observed 1 hour after administration. This effect declined within 4 hours to the control level irrespectively of the dose (Table 111.2.(15).

COMBINATION OF S(+)IBUPROFEN+THEOBROMINE

The combination of all the doses of S(+)ibuproben with 5 mg/kg theobromine resulted significant increase in the antinociceptive effect of S(+)ibuprofen. The antinociceptive effect was still relevant even 6 hours after administration of both 30 mg/kg S(+)ibuprofen +5 mg/kg theobromine and 50 mg/kg S(+)ibuprofen +5 mg/kg theobromine combinations. The combination of 20, 30 and 50 mg/kg S(+)ibuprofen with 10 mg/kg theobromine resulted only a moderate increase in the antinociceptive effect compared it to the 5 mg/kg theobromine+S(+)ibuprofen combinations. The combination of the 30 and 50 mg/kg S(+)ibuprofen doses with 30 mg/kg theobromine resulted decrease in the antinociceptive effect 1 hour after oral administration while practically did not affected on the antinociceptive effect 2 and 4 hours after administration (Table 111.2.(16), Table 111.2(17), Table 111.2.(18)).

The half-life of the 20 mg/kg S(+)ibuprofen elicited antinociceptive effect was 105 min while in the combination with 5 mg/kg theobromine it increased to 260 min. The elevation of theobromine dose ( to 10 or 30 mg/kg) did not caused further increase in the half-life of antinociceptive effect.

ANTINOCICEPTIVE EFFECT OF DICLOFENAC

The 20, 30 and 50 mg/kg oral doses of diclofenac showed dose-dependent antinociceptive effect. The maximal antinociceptive effect was observed 1 hour after administration. This effect declined within 4 hours to the control level irrespectively of the dose (Table 111.2.(19). COMBINATION OF DICLOFENAC+THEOBROMINE

The antinociceptive effect elicited by 20 mg/kg p.o. dose of diclofenac was increased significantly by combining it with 5 mg/kg theobromine. This dose of theobromine not only increased but significantly prolonged the antinociceptive effect of diclofenac. Two other doses of theobromine (10 and 30 mg/kg) also prolonged the antinociceptive effect of 20 mg/kg diclofenac but less effectively than 5 mg/kg theobromine did it (Table 111.2.(20). 5 mg/kg theobromine increased and prolonged both the 30 and 50 mg/kg doses of diclofenac elicited antinociceptive effect, too. Using higher theobromine doses (10 and 30 mg/kg) the antinociception potentiating effect of theobromine was weaker than in the case of 5 mg/kg theobromine (Table 111.2.(21), Table 111.2.(22).

5 mg/kg theobromine significantly increased the half-life of 20 mg/kg diclofenac elicited antinociceptive effect (120 min versus 300 min). The increase of theobromine dose in the combination did not produce further increase in the antinociceptive effect of S(+)ibuprofen.

Table III.1. (1). Time dependence of the antinociceptive effect of CH-13584

ANTINOCICEPTIVE EFFECTS %

p<0.05; p<0.01; **# p<0.001;

mean ± S.E.M.; n = 10 per dose. At statistical evaluation the group treated with CH-13584 was compared to the group treated with the vehicle (1 % methylcellulose).

Table III.1. (2). Antinociceptive effect of the mixture of CH-13584 and 15 mg/kg p. o. morphine

ANTINOCICEPTIVE EFFECTS %

* p<0.05; **p<0.01; ***p<0.001; - no measeurement point; n=T0

mean ± S.E.M.; At statistical evaluation the groups treated with morphine + CH-13584 were compared to the corresponding values of the groups treated with morphine alone.

Table III.1. (3). Time dependence of the antinocicpetive effect of s. c. morphine

ANTINOCICEPTIVE EFFECTS %

Table III.1. (4). The antinociceptive effect of the mixture of different doses of s.c. morphine and 100 mg/kg p.o. CH-13584

ANTINOCICEPTIVE EFFECTS %

* p<0.05; ** p<0.01; *** pO.OOl; - no measurement point; n=10

At statistical evaluation the groups treated with morphine+CH- 13584 were compared to the corresponding values of groups treated with morphine alone.

Table III.1. (5).

Time dependence of the antinociceptive effect elicited by 30 mg/kg p.o. theophylline

ANTINOCICEPTIVE EFFECTS %

Table III.1.(6) Time dependence of the antinocicpetive effect elicited by 30 mg/kg p.o.3- methylxanthine

ANTINOCICEPTIVE ACTION %

Table III.1. (7) The time depencence of the antinocicpetive effect of morphine (s. c.) in the presence of 30 mg/kg p. o. theophylline

ANTINOCICEPTIVE ACTION %

*p<0.05; **p<0.01; *** p<0.001; mean ± S.E.M.; n=10

At statistical evaluation the groups treated with theophylline + morphine were compared to the corresponding values of groups treated with morphine alone.

Table III.1. (8) Time depencence of the antinociceptive effect of morphine (s.c.) in the presence of 30 mg/kg p. o.3-methylxanthine

ANTINOCICEPTIVE EFFECTS %

p<0.05; ** p<0.01; *** pθ.001: NA; mean±S.E.M.;n=10

At statistical evaluation the groups treated with 3-methylxanthine were compared to the corresponding values of groups treated with morphine alone.

Table III.1. (9). Time depencence of the antinociceptive effect of p.o. morphine

ANTINOCICEPTIVE EFFECTS %

p<0.05; **p<0.01; *** pθ.001; - NA; mean ± S.E.M.; n-l 0

At statistical evaluation the animals treated with morphine were compared to the animals treated with the vehicle.

Table III.1. (10). Time depencence of the antinociceptive effect of morphine (p. o.) in the presence of

100 mg/kg p. o. CH-13584

ANTINOCICEPTIVE EFFECTS %

*p<0.05; **p<0.01; ***p<0.001; - NA; mean± S.E.M.; n=10

At statistical evaluation the groups treated with CH-13584+morphine were compared to the corresponding values of groups treated with morphine alone.

Table III.2. (1) Antinocicepetive effect elicited by analgin

ANTINOCICEPTIVE EFFECTS %

Table III.2. (2).

Antinociceptive effect elicited by 50 mg/kg analgin

+the combination of different doses of caffeine

ANTINOCICEPTIVE EFFECTS %

Table III. 2. (3)

Antinocicepetive effect elicited by 100 mg/kg analgin

+ the combination of different doses of caffeine

ANTINOCICEPTIVE EFFECTS %

Table III. 2. (4).

Antinocicepetive effect elicited by 200 mg/kg analgin

+ the combination of different doses of caffeine

ANTINOCICEPTIVE EFFECTS %

Table III. 2. (5)

Antinocicpetive effect elicited by 50 mg/kg analgin

+ the combination of different doses of 3-methylxanthine

ANTINOCICEPTIVE EFFECT %

MTX=3- methylxanthine

Table III. 2. (6)

Antinocicepetive effect elicited by 50 mg/kg analgin

+ the combination of different doses of 3-methylxanthine

ANTINOCICEPTIVE EFFECT %

MTX =3- methylxanthine, * p<0.05; **p<0.01 ; ***p<0.001 ; n=10

Table III. 2. (7)

Antinocicepetive effect elicited by 200 mg/kg analgin

+ the combination of different doses of 3-methylxanthine

ANTINOCICEPTIVE EFFECT %

MTX-3 -methylxanthine, * p<0.05; **p<0.01; n=10

Table III.2. (8) Antinocicepetive effect elicited by 50 mg/kg analgin + the combination of different doses of theobromine

ANTINOCICEPTIVE EFFECT %

*p<0.05;**p<0.01;n=l

Table III. 2. (9) Antinocicepetive effect elicited by 100 mg/kg analgin + the combination of different doses of theobromine

ANTINOCICEPTIVE EFFECT %

p<0.05; **p<0.01; n=10

Table III. 2. (10)

Antinocicepetive effect elicited by 200 mg/kg analgin

+ the combination of different doses of theobromine

ANTINOCICEPTIVE EFFECT %

Table III. 2. (11)

Antinociceptive effect elicited by paracetamol

ANTINOCICEPTIVE EFFECTS

Table III. 2. (12).

Antinociceptive effect elicited by 100 mg/kg paracetamol + the combination of different doses of caffeine

ANTINOCICEPTIVE EFFECTS

Table III. 2. (13).

Antinociceptive effect elicited by 100 mg/kg paracetamol + the combination of different doses of 3-methylxanthine

ANTINOCICEPTIVE EFFECT %

MTX =3 -methylxanthine, * p<0.05; **p<0.01 ; n=10

Table III. 2. (14).

Antinociceptive effect elicited by 100 mg kg paracetamol + the combination of different doses of theobromine

ANTINOCICEPTIVE EFFECT %

Table III.2. (15).

Antinociceptive effect elicited by S(+)ibuprofen

ANTINOCICEPTIVE EFFECT %

Table III.2. (16).

Antinociceptive effect elicited by 20 mg/kg S(+)ibuprofen

+ the combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

Table III.2. (17).

Antinociceptive effect elicited by 30 mg/kg S(+)ibuprofen

+ the combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

Table III.2. (18).

Antinociceptive effect elicited by 50 mg/kg S(+)ibuprofen

+ the combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

Table III.2. (19).

Antinociceptive effect elicited by diclofenac

ANTINOCICEPTIVE EFFECT %

Table III.2. (20).

Antinociceptive effect elicited by 20 mg/kg diclofenac

+ the combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

Table III.2. (21).

Antinociceptive effect elicited by 30 mgkg diclofenac

+ the combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

Table III.2. (22). Antinociceptive effect elicited by 50 mg/kg diclofenac 1 the combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

SUMMARY

CH-13584 definitely increased and prolonged the effect of morphine. This phenomenon unanimously indicates that the compound may be suited to reduce the morphine doses of patients needing treatment with morphine. The acute and chronic side effects of morphine could thereby be reduced.

Combined in (5-20):l, advantageously in 10:1 ratio, both theobromine and 3- methylxanthine significantly prolonged the analgesic effect of analgin. Caffeine was devoid of this effect.

The analgesia potentiating effect of theobromine becomes even more evident if the half life of the time course of the analgesic effect is compared in a group treated with 100 mg/kg analgin alone or in combination with caffeine or theobromine.

The half-life (t]_/ ) of the analgesic effect of analgin is 125 minutes.

analgin 100 mg/kg + caffeine 5 mg/kg 105 minutes

+ caffeine 10 mg/kg 120 minutes analgin 100 mg/kg + theobromine 5 mg/kg 204 minutes

+ theobromine 10 mg/kg 230 minutes

It can be seen that while in case of caffeine the half-life decreased, theobromine increased it nearly to the twofold. Thus, the half-life of 100 mg/kg analgin approached that of 200 mg/kg analgin, found to be 220 minutes.

The antinociceptive effect prolonging effect of theobromine is more evident in the combination with S(+)ibuprofen. The half-life of 20 mg/kg p.o. S(+)ibuprofen is 105 min. In combination of 20 mg/kg S(+)ibuprofen with 5 mg/kg theobromine the half-life of the antinociceptive effect increased to 260 min.

The combination of 20 mg/kg diclofenec and 5 mg/kg theobromine shows similar antinociceptive effect prolongation as was observed in the case of S(+)ibuprofen+theobromine (120 min versus 300 min). In the combined preparation of our invention the replacement of caffeine by a safer xanthine derivative possessing less side-effects, like theobromine or 3-methylxanthine has not only lead to the reduction of side-effects but also to a preparation of more favourable effect.

The above facts are all the more surprising because in case of paracetamol, which in the acetic acid writhing test, near the toxic region showed weak analgesic effect, the analgesic effect was not significantly influenced by theobromine, caffeine and 3-methylxanthine. In general, theobromine and caffeine rather inhibited, while 3-methylxantine practically did not influence the effect of paracetamol 1 hour after treatment.

Since up to the present it has been described only of xanthine derivatives with significant central nervous system stimulating effect (caffeine, theophylline) that they potentiate the analgesic action of morphine and minor analgesics, it was very surprising that a xanthine derivative like CH-13584, which has no central nervous system effects, can also potentiate the effect of morphine. It is even more surprising that 3-methyxanthine (one of the human metabolites of theophylline) and also theophylline showed similar effect. In connection with theophylline this phenomenon deserves interest, because according to literary data, it greatly depends on the site of administration and the dose administered whether it increases or inhibits the effect of morphine. At the dose and mode theophylline was applied by us it unanimously increased the effect of morphine.

It was the most surprising recognition that theobromine, the known pharmacological effects of which were rather weak compared to those of caffeine and consequently had mild side-effects, potentiated by far more strongly analgesia than caffeine.

Our invention is a pharmaceutical composition comprising as active ingredient an analgesic compound and a compound of xanthine structure, where the ratio of the analgesic and the xanthine derivative is (1-20):1, advantageously 10:1.

The preparations according to the invention contain as analgesic compound morphine, aminophenazone, analgin, acetyl-salicylyc acid, indomethacin, ibuprofen, diclophenac, codeine, preferably analgin, ibuprofen, codeine, as xanthine derivatives 3-methylxanthine, theobromine or CH-13584 (lH-purine-2,6-dion-3,7-dihydro-3-methyl-7-(5-methyl-l,2,4- oxadiazole-3-yl)methyl), preferably theobromine.

The preparations of the invention may contain as further active ingredients a smooth muscle spasmolytic, preferably papaverine, drotaverine, or the theophylline-7-acetic acid salt of drotaverine.

The above preparations may advantageously be used for the treatment of headache and bone pains of different origin, toothache, pain after tooth extraction, arthralgiae, ostealgiae, pains connected with surgical interventions and delivery, as well as milder pains caused by tumours.

The preparations of the invention can be differently formulated:

1. The three components are separately formulated, but in collective packing.

2. Two of the three components are commonly formulated according to choice, the third component is separately formulated, but in collective packing,

3. All three components are in one preparation. The drug form may be tablet, dragee, lozenge, pill, capsule, suppository, cream, solution, drop, emulsion, injection, plaster, eye-drop.

The preparations contain, beside the active ingredients the usual auxiliary substances.

The preparations of the invention are illustrated in the following examples, without restriction to them. Drug forms

1.) Tablets

Analgin 400 : mg

Drotaverine 40 mg

Theobromine 40 mg

Microcrystalline cellulose 70 mg

Polyvinyl-pyrrolidone 20 mg

Polyvinyl-polypirrolidone 5 mg

Magnesium stearate 5 mg

Amidazophen 400 mg

Drotaverine 40 mg

Theobromine 40 mg

Microcrystalline cellulose 70 mg

Polyvinyl-pyrrolidone 20 mg

Polyvinyl-polypirrolidone 5 mg

Magnesium sterate 5 mg

2.) Film-coated tablet:

Analgin 400 mg

Drotaverine 40 mg

Theobromine 40 mg

Microcrystalline cellulose 70 mg

Polyvinyl-pyrrolidone 20 mg

Polyvinyl-polypirrolidone 5 mg

Magnesium sterate 5 mg

Hydroxypropyl-methyl-cellulose 9 mg

Polyethylene-glycol 6 mg

Quinoline yellow dye 1 mg 3.) Hard gelatine capsule

Indomethacin 40 mg

Drotaverine 40 mg

Theobromine 40 mg

Starch 198 mg

Lactose 150 mg

Microcrystalline cellulose 150 mg

Claims

1. Pharmaceutical composition comprising as active ingredient an analgesic compound and a compound of xanthine structure, where the ratio of the analgesic and the xanthine derivatives is (1-20):1, advantageously 10:1.

2. Pharmaceutical composition according to claim 1 comprising as analgesic compound morphine, aminophenazone, analgin, acetyl-salicylic acid, indomethacin, ibuprofen, diclophenac, codeine.

3. Pharmaceutical composition according to claims 1-2 comprising as analgesic compound morphine, aminophenazone, analgin, ibuprofen, diclophenac, preferably analgin,

S(+)ibuprophen, diclofenac.

4. Pharmaceutical composition according to claim 1. comprising as a compound of xanthine structure 3-methylxanthine, theobromine, or CH-13584 ((lH-purine-2,6-dion- 3,7-dihydro-3-methyl-7/5-methyl-l,2,4-oxadiazole-2-yl/methyl), preferably theobromine.

5. Pharmaceutical composition according to claims 1-4. comprising as further active ingredient a smooth muscle spasmolytic, preferably papaverine, drotaverine or drotaverine theophylline-7-acetic acid salt.

6. Pharmaceutical composition according to claims 1-5. containing the analgesic compound, the xanthine derivative and in given case, the smooth muscle spasmolytic compound separately formulated, in collective packaging.

7. Pharmaceutical composition according to claims 1-6. containing from the analgesic compound, the xanthine derivative and the smooth muscle relaxant two in common and the third in separate formulation, in collective packaging.