SK6872001A3 - Composition containing an analgesic and a xanthine or a xanthine derivative - Google Patents

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

The present invention relates to a pharmaceutical composition comprising, as an active analgesic component, morphine, aminophenazone, analgin, acetylsalicylic acid, indomethacin, ibuprofen, diclofenac or codeine and as a xanthine compound

3-methylxanthine, theobromine or CH-13584 ((1H-purine-2,6-dione-3,7-dihydro-3-methyl-7/5-methyl-1,2,4-oxadiazol-2-yl) methyl), wherein the ratio of the analgesic active ingredient and the xanthine derivative is (1 to 20): 1, preferably 10: 1.

BACKGROUND OF THE INVENTION

Analgesic compounds are divided into two main groups:

1. Non-steroidal anti-inflammatory drugs (NSAIDs) or side analgesics.

2. Morphine type or major analgesics.

Side analgesics are less effective in relieving pain than the major analgesics, but their side effects are also significantly 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 the limits of their use. Secondary analgesics are used to relieve common pain (headache, toothache, rheumatic pain), while major analgesics are used to treat pain associated with severe trauma, malignant tumors, etc. Drug researchers have long sought to produce compounds of a non-morphine structure whose strength reaches the strength of major analgesics without inducing physical dependence. This has not been done so far.

Efforts have been made to increase the strength of the side analgesics by combining them with additives. One of the widely used analgesic enhancers is caffeine (1.SJ-trimethyl-1H-purine-2e-dione). This compound is found in large quantities in the seeds of coffee bush (Co / fea arabica), in leaves of the tea tree (Thea la sinensis) and in cocoa powder prepared from the fruits of the cacao tree (Theobroma cacao). Caffeine was isolated from the seeds of the coffee plant and its chemical structure was determined in 1875 (Prog. Drug. Res., 31, 273-313 (1987)). In clinical trials, caffeine alone had no analgesic effect (Pharmacotherapy, 10, 387-393 (1990)); although Ward et al. observed the beneficial effect of its 300 mg dose in migraine headache compared to the control group (Pain. 44, 151-155 (1991)). In animal experiments, the compound increased the effect of side analgesics in the manner described by the bell-shaped curve, meaning that it increased at lower doses (<10 mg / kg orally) while inhibiting their effect at higher doses (> 10 mg / kg orally) (Meth Find Exp Exp Clin Pharmol 13: 529-533 (1991)). Caffeine increases pain.

1875 (Prog. Drug. Res. 31: 273-313 (1987)). In clinical studies, caffeine alone has no analgesic effects (Pharmacotherapy, 10, 387-393 (1990)), although Ward et al. observed the beneficial effects of its 300 mg doses on migraine headache as compared to the control group (Pain, 44, 151-155 (1991)). In animal experiments, the compound increased the effect of side analgesics in the manner described by the bell-shaped curve, which means that at lower doses (<10 mg / kg orally), the compound increased their effect, whereas at higher doses (> 10 mg / kg orally) Meth Exp Clin Clinacol., 13, 529-533 (1991)). Caffeine enhances the pain relieving effect not only of the side analgesics but also of the major analgesics (Pharm. Rev., 45, 43-85 (1993)).

In addition to caffeine, two other alkaloids of the xanthine structure were also found in larger quantities in the above three plants. One is theophylline (1,3-dimethyl-1H-purine-2,6-dione), the other is theobromine (3,7-dimethyl-1H-purine-2,6-dione). The disadvantage of using caffeine is that its complete contraindication is tachyarrhythmia, whereas its relative contraindications are ulcer, thyroid disorder, hypertension and some neuropsychiatric diseases (Med. Monatsschr. Phar., 15, 258-269 (1992)).

SUMMARY OF THE INVENTION

We have set out to provide an analgesic composition in which the analgesic effect is provided by a compound that is safer and has fewer side effects.

In our time it has become known which substituents in different parts of the xanthine backbone are responsible for increasing or alleviating side effects. Thus, the N1 position is responsible for the antagonistic and extrapulmonary effects of adenosine, the N3 position is very important in terms of the intensity of the bronchodilator effect, whereas the H substitution at the N7 position results in a reduction in the bronchodilator effect. Substitution of H at the N9 position generally results in an overall decrease in effect, while substitution at the C8 position may lead to an increase in the antiallergic, antagonistic effects of adenosine and an increase in 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 antagonist, diuretic, cardiac and circulatory effects, the order of theophylline> caffeine> theobromine is sequential; effect of caffeine> theophylline> theobromine. As can be observed, caffeine and theophylline exhibit significant pharmacological effects, whereas, to date, theobromine is the weakest of the three xanthine derivatives, to the present knowledge.

The same final order of sequence cannot be made from the aspect of the analgesic effect since, surprisingly, no systematic studies have been conducted in this respect.

Inflammatory-based models are used to test the effect of side analgesics, while antinociceptive models (eg, tail flick test) are most suitable to demonstrate the effects of major analgesics. In these tests, the effect of enhancing analgesic action can be reliably evaluated.

In relation to the subject of the invention, the inventors studied

1.1. Effect of CH-13584 (1H-purine-2,6-dione-3,7-dihydro-3-methyl-7/5-methyl-1,2,4-oxadiazol-3-yl / methyl), theophylline and 3- methylxanthine alone and in combination with orally or subcutaneously administered various doses of morphine in the tail flick test in rats.

1.2. Effect of caffeine, theobromine and 3-methylxanthine alone and in combination with various oral doses of analgin or paracetamol in the wig test in mice.

The test methods used are described below

1. Tail flick test in rats:

The assays were performed according to the method of D'Amour and Smith (J. Pharmacol. Exp. Ter., 72, 74 (1942)). The principle of the method is that the thermal radiation is directed towards the tail of the animals, the time of latency to tail tearing is measured. Various analgesics prolong this latency time. The experiments were carried out on male Wistar rats weighing 120-140 g. The animals were fixed so that thermal radiation could be directed to the end of their tail. An automatic analgesic effect meter was used to measure this tail flick latency time. The instrument turned off the thermal radiation and stopped the digital clock to measure latency time. In order to avoid tissue damage due to the strong analgesic effect, the thermal radiation was in each case switched off twice as long as the latency control time. Morphine was dissolved in saline for subcutaneous administration. CH-13584, theophylline and 3-methylxanthine were administered to the animals in suspension containing 1% methylcellulose. The injection volume was in each case 0.1 ml / 100 g body weight.

Before oral administration, the animals were fasted for 16 hours but had access to drinking water ad libitum. In the case of the oral / oral combination, two substances were administered simultaneously, while in the case of the oral / subcutaneous combination, the subcutaneous substance was injected 30 minutes after oral treatment.

2. Twitch test in mice

Adult CFLP mice of both sexes weighing 23-27 g (LATI) were used for the experiments. The animals used standard laboratory nutrition for rodents (Charles River Co., Hungary) and, to taste, drinking water, except on the day of the experiment, when they starved 16 hours prior to oral administration of the test substances and had access to drinking water only. The mice were housed in a room at 22 ± 2 ° C, cyclically illuminated. All experiments were performed with oral administration. A suspension containing 1% methylcellulose was prepared from all test substances administered to mice via a gavage in a volume of 0.1 ml / 10 g body weight. (In the case of combinations, the powder mixture of the two components was suspended in methylcellulose).

In the experiments, the method of Witkin et al. (Witkin LB, Heubner CF, Galdi F., O'Keefe E., Spitaletta P. and Plumer AJ, Pharmacology of 2-amino-indan hydrochloride (Su-8629) and non-narcotic analgesic sweating, J. Pharmacol. Exp. Ther., 133, 400408 (1961).

Mice were placed one at a time in transparent boxes for acclimatization to experiment conditions 1 hour prior to measurement. On the day of the experiment, they received an intraperitoneal injection of 0.2 ml of a 0.6% acetic acid solution per animal, then after 5 minutes of waiting, the number of twitches was counted. The response to pain caused by the chemical pollutant was regularly determined in untreated animals (control), after which the antinociceptive effect was expressed as a percentage of the control.

In control experiments, the number of twitches in mice was 24 ± 0.53 (n = 70).

Time-effect relationship test

The first measurement was made 1 hour after administration of test substances. In the treatment of other groups of mice with test substances, acetic acid was injected after 2, 3, 4 and 5 hours and the antinociceptive effect was determined as a function of time. The deviation of the effect was evaluated by stopping the measurements in groups where the number of twitches approximated to control values (20-22 twitches in mice). The time of the first of these measurements is considered as a deviation of effect.

The results were presented in the form of time-effect curves and the half-life value (t _1/2 min) was read.

Acute toxicity studies

Assays were performed in groups of 10 mice, orally, after 16 hours of fasting. The toxicity of the test substances was determined for the individual substances and their combinations with methylxanthines. Deaths were recorded by hour and summarized after 24 hours.

Statistical evaluation of results

The degree of antinociceptive effect is expressed as the number of twitches in mice and given as% of the twitches in control mice. Mean pain responses (mouse twitches), standard deviation (SD), and standard error (SE) were calculated, then significance was calculated using the Student's paired test, then a one-factor analysis of the variation of significant values was performed.

The following results were obtained:

Tail Tail Tests in Rats

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

Surprisingly, orally administered CH-13584 potentiated the antinociceptive effect induced by the oral dose of morphine ED50 (15 mg / kg) at several moments and doses (Table 111.1. (2)). This enhancing effect proved significant at 30, 60 and 90 minutes after the combination of morphine with 100 mg / kg CH-13584 and at 30, 45, 60 and 90 minutes after its combination with 200 mg / kg CH-13584.

Morphine, when administered subcutaneously, produced a dose-dependent antinociceptive effect (Table 111.1. (3)).

Oral administration of 100 mg / kg CH-13584 significantly enhanced the analgesic effect of subcutaneously injected morphine. This effect of CH-13584 was most evident in effect

3.75 and 5 mg / kg doses of morphine. The duration of effect of the 5 mg / kg dose of morphine was prolonged by a factor of 2 with 100 mg / kg of CH-13584 (Table 2).

111.1. (4)) compared to Table 111.1.

An oral dose of 100 mg / kg CH-13584 even further enhanced the effect of orally administered morphine as a subcutaneous dose. In addition to enhancing the effect of morphine, CH-13584 also significantly prolongs its duration (Table 111.1. (10) compared to Table 11).

111.1. (9)).

Neither theophylline nor 3-methylxanthine showed a serious antinociceptive effect after an oral dose of 30 mg / kg (Table 111.1. (5) and Table 111.1. (6)).

However, very surprisingly, the combination of both compounds significantly enhanced the antinociceptive effect induced by subcutaneous morphine (Table 111.1. (7) and Table 111.1. (8) compared to Table 111.1. (3)).

2. Twitch test in mice

Antinociceptive effect of analgin

In the twitch test in mice, analgin showed a dose-time dependence of antinociceptive effect (Table 111.2. (1)).

Combination of analgin - caffeine (comparative)

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

The combination of 100 mg / kg of analgin with 5 and 10 mg / kg of caffeine produced only a slight, statistically insignificant increase in effect, while 50 mg / kg of caffeine rather inhibited the effect of analgin (Table III.2. (3)). The half-life of 100 mg / kg analgin is 125 minutes. The combination of 100 mg / kg analgin with 10 mg / kg caffeine changed 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 clearly results in a reduction in the effect of analgin (Table III.2 (4)).

Combination of analgin and 3-methylxanthine

The combination of 50 mg / kg analgin with 5, 10 and 50 mg / kg 3-methylxanthine results in a tendency to increase, but not a statistically significant increase in effect (Table 11.2 (5)).

The combination of 100 mg / kg analgin with 5, 10 and 50 mg / kg 3-methylxanthine also results in potentiation of the effect. This increase in effect, which also means prolonging it, appears to be significant at several times (Table III.2. (6)).

The half-life 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 results in potentiation of the effect. The degree of amplification was less than in the previous combination, but at 5 mg / kg 3-methylxanthine, a statistically significant effect occurred after 3 and 4 hours (Table III.2. (7)). The half-life of 200 mg / kg analgin is 230 minutes. Combination with 5 mg / kg 3-methylxanthine increased the half-life to 270 minutes.

Combination of analgin and theobromine

The combination of 50 mg / kg of analgin with 5 and 10 mg / kg of theobromine results in a definite potentiation of the effect, which at 1 and 2 hours is shown to be statistically significant at the 10 mg / kg dose (Table 11.2 (8)).

The potentiating effect of 5 and 10 mg / kg doses of theobromine was even more pronounced when combined with 100 mg / kg analgin than found for the above combination ratios. With its increase, the duration of action of analgin was also prolonged (III.2. (9)). The half-life 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, which was 230 minutes, was increased by a 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 insignificant decrease in antinociceptive effect (Table 111.2. (10)).

Antinociceptive effect of paracetamol

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

Combination of paracetamol and caffeine

The combination of 100 mg / kg paracetamol with 5, 10 and 50 mg / kg caffeine clearly resulted in a reduction in the effect of paracetamol (Table 111.2. (12)).

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

The combination of 100 mg / kg paracetamol with 5, 10 and 50 mg / kg theobromine results in a reduction in effect 1 hour after administration. (Table 111.2. (14)).

Antinociceptive effect of S (+) - ibuprofen

Oral doses of 20, 30 and 50 mg / kg of S (+) - ibuprofen showed a dose-dependent antinociceptive effect. The maximum antinociceptive effect was observed 1 hour after administration. This effect decreased within 4 hours to a dose-independent control level (Table 111.2. (15)).

Combination of S (+) - ibuproferia and theobromine

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

The half-life of 20 mg / kg S (+) - ibuprofen induced by antinociceptive effect was 105 minutes, while in combination with 5 mg / kg theobromine it was increased to 260 minutes. Increasing doses of theobromine (to 10 or 30 mg / kg) did not cause a further increase in the half-life of the antinociceptive effect.

Antinociceptive effect of diclofenac

Oral doses of 20, 30 and 50 mg / kg of diclofenac showed a dose-dependent antinociceptive effect. The maximum antinociceptive effect was observed 1 hour after administration. This effect decreased over 4 hours to a control level independent of doses (Table 111.2 (19)).

Combination of diclofenac and theobromine

The antinociceptive effect induced by an oral dose of 20 mg / kg diclofenac was significantly enhanced by its combination 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 of diclofenac, but less efficiently than with 5 mg / kg of theobromine (Table III.2. (20)). The 5 mg / kg dose of theobromine also increased and prolonged both 30 and 50 mg / kg doses of diclofenac induced antinociceptive effect. At higher doses of theobromine (10 and 30 mg / kg), the potentiation of the antinociceptive effect by theobromine was less than that of the 5 mg / kg dose of theobromine (Table 111.2 (21) and Table III.2 (22)).

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

Table 111.1 (1)

Time dependence of antinociceptive effect of CH-13584

dose 15 min 30 min 45 min 60 min (Mg / kg) time after administration (minute) vehicle 1.2 ± 0.4 1.8 ± 0.3 2.5 ± 1.2 4.0 ± 1.2 1 17.9 ± 3.3 *** 12.0 ± 3.5 ** 9.1 ± 2.2 * 5.6 ± 2.1 3 25.6 ± 4.8 *** 23.7 ± 3.2 *** 10.9 + 4.9 14.8 ± 7.4 10 20.2 ± 4.3 *** 17.8 ± 1.4 ** 9.9 ± 2.7 * 4.5 ± 1.2 30 20.0 ± 2.0 *** 22.2 ± 3.8 *** 14.5 ± 3.7 ** 5.1 ± 3.3 100 17.3 ± 5.0 ** 22.1 ± 7.3 * 24.4 ± 7.1 ** 7.5 ± 3.4 200 9.1 ± 2.3 ** 5.6 ± 3.2 1.8 ± 0.8 5.5 ± 2.3

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

mean ± mean error; n = 10 per dose. In the statistical evaluation, the CH-13584 treated group was compared to the vehicle (1% methylcellulose) treated group.

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Time dependence of antinociceptive effect of subcutaneously administered morphine

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240 min Time after administration (minute) 1 1 1 1 7.0 ± 6.2 180 min 1 T 1 T • 13.2 + 5.4 120 min 1 2.6 ± 0.5 4.0 ± 1.2 9.8 ± 2.7 σ> + i co_co 19.7 ± 5.5 90 min 1 4.2 + 1.4 9.7 ± 5.2 CD CO +1 m oo 14.9 ± 4.8 CD N- + 1D ID 60 min and + i Ncm ID v + l O b- ‘ 14.0 ± 7.1 CM ID +1 what CM 37.0 + 7.8 66.0 ± 7.6 45 min what + i CD_ co 10.6 + 2.8 27.5 + 7.7 co +1 oo ’ 63.6 ± 6.8 84.8 ± 6.4 30 min CM_ V +1 r> 0 ' ν 25.1 ± 4.3 47.8 + 6.9 9'9-O'OZ in ΙΩ +1 • V σ> r ^ - 92.0 ± 3.9 15 min 5.5 ± 2.3 16,9 + 4,2 30.5 ± 6.0 51.1 ± 10.6 54.1 ± 6.7 56.7 + 12.8 Dose (mg / kg) 0.25 0.5 1.25 2.5 3.75 5.0

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Table 111.1 (5)

Time dependence of the antinociceptive effect induced by an oral dose of 30 mg / kg of theophylline

ANTINOCICEPTIVE EFFECT%

Dose (mg / kg) 15 min 30 min 45 min 60 min 90 min 120 min Feed time (minute) 30 6.4 ± 3.3 11.8 ± 5.3 12.7 + 4.5 8.0 ± 2.6 8.0 ± 2.5 4.4 ± 1.1

Table 111.1 (6)

Time dependence of antinociceptive effect induced by oral dose of 30 mg / kg

3-methylxanthine

ANTINOCICEPTIVE EFFECT%

Dose (mg / kg) 15 min 30 min 45 min 60 min 90 min 120 min Time after administration (min ίθ) 30 5.8 ± 2.2 8.1 ± 5.6 16.7 ± 4.7 18.0 ± 5.0 16.9 ± 5.6 10.0 ± 3.1

Table 111.1 (7)

Time dependence of antinociceptive effect of subcutaneous morphine in the presence of an oral dose of 30 mg / kg of theophylline

ANTINOCICEPTIVE EFFECT%

120 min Time after administration (minute) 4.7 ± 2.0 cd + i 00 ID CN +1 About h- oo cd +1 tio CN 23.1 ± 10.2 46.9 ± 11.9 90 min OD + i CD CN 9.0 ± 2.5 oo + i co_o T 43.2 ± 13.2 48.6 ± 12.2 63.0 ± 11.0 * 60 min 5.6 + 2.5 10.8 ± 4.3 20.5 ± 5.0 * what T— +1 o what N «N- + i N co CD 96.0 ± 4.0 ** 45 min LO_sr + 1 Το ' 25.2 ± 11.0 30.0 ± 7.6 60.2 ± 12.7 81.2 ± 9.7 K k -k O ’+ l o_ o o 30 min 3.4 + 1.6 10.7 ± 4.6 * 36.1 ± 9.9 64.4 ± 10.3 o_co + i CO o 91.2 ± 8.0 * 15 min 3.3 + 2.2 «Σ> _ T "+1 CO oo 20.1 ± 5.9 55.6 ± 12.9 49.9 + 12.4 57.1 ± 14.7 Dose (mg / kg) 0.25 0.5 1.5 2.5 3.75 ID

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Time dependence of antinociceptive effect of subcutaneous morphine administered in the presence of an oral dose of 30 mg / kg 3-

120 min minutes (minute) 9.0 ± 2.0 10.6 ± 3.8 * in CN + 1 CN r < 21.9 + 7.2 * ♦ ♦ V " + i C3 WHAT * * CN 6 X '+ l o (D * ΙΟ 90 min 12.1 ± 3.7 16.1 ± 3.4 cn cd +1 r00 * x— 27.7 ± 10.1 46.7 ± 11.0 ♦ * ♦ CN CD * + 1 year * 00 60 min * * * in 10 -H CN CN CN 26.8 ± 3.8 13.7 ± 4.4 48.6 ± 13.3 * 64.4 ± 8.7 ** * K + l 'n cn 45 min Time after pod * CN K + 1 CO CN CN 16.8 ± 4.3 * about what '+ l CO CN 69.4 ± 9.8 * 76.6 ± 8.0. * * * o o * + l o o ’o X" 30 min 20.6 ± 5.5 12.3 ± 2.3 35.4 ± 6.8 60.1 ± 10.8 75.9 ± 9.3 * 95.0 ± 3.5 15 min o xà -H co_ • in r- 12.0 ± 4.7 37.7 ± 9.2 22.7 ± 6.0 ** 37.8 ± 12.8 73.9 ± 11.3 Dose (mg / kg) 0.25 0.5 m 2.5 3.75 m

Table 111.1 (9)

Time dependence of antinociceptive effect of oral morphine

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Table 1 (1.1. (10)

Time dependence of the antinociceptive effect of orally administered morphine in the presence of an oral dose of 100 mg / kg CH-13584

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Table 111.2 (1)

Antinociceptive effect induced by analgin

ANTINOCICEPTIVE EFFECTS%

dose 1 h 2 h 3 h 4 h 5 h (Mg / kg) Time after serving (minutes) 50 6 4 1 - - 100 30 16 12 3 200 67 51 38 33 13 250 83 63 43 35 17

Table III.2 (2)

Antinociceptive effect induced by 50 mg / kg analgin + combination of different doses of caffeine

ANTINOCICEPTIVE EFFECTS%

dose 1 h 2h 3 h (Mg / kg) after serving Vehicle + 50 mg / kg analgin 6 4 1 5 caffeine 5 5 -13 10 caffeine 12 11 7 50 caffeine -22 -21 -

Table 111.2 (3)

Antinociceptive effect induced by 100 mg / kg analgin + combination of different doses of caffeine

ANTINOCICEPTIVE EFFECTS%

dose 1 h 2 h 3h (Mg / kg) after serving Vehicle + 100 mg / kg analgin 30 16 2 5 caffeine 46 13 2 10 caffeine 41 21 13 50 caffeine 28 -1 -6

Table III.2 (4)

Antinociceptive effect induced by 200 mg / kg analgin + combination of different doses of caffeine

ANTINOCICEPTIVE EFFECTS%

dose 1 h 2h 3 h 4h (Mg / kg) after serving Vehicle + 200 mg / kg analgin 67 51 38 33 5 caffeine 43 37 25 3 10 caffeine 52 29 18 5 50 caffeine 38 31 10 -

Table III.2 (5)

Antinociceptive effect induced by 50 mg / kg analgin + combination of different doses of 3-methylxanthine

ANTINOCICEPTIVE EFFECT%

dose 1 h 2h 3h (Mg / kg) after serving Vehicle + 50 mg / kg analgin 6 4 1 5 MTX 6 21 17 10 MTX 23 24 1 50 MTX 15 14 -2

MTX = 3-methylxanthine

Table III.2 (6)

Antinociceptive effect induced by 50 mg / kg analgin + combination of different doses of 3-methylxanthine

ANTINOCICEPTIVE EFFECT%

dose 1 h 2 h 3h 4 h 5h (Mg / kg) after serving Vehicle + 100 mg / kg analgin 30 16 12 3 - 5 MTX 45 * 40 39 *** 16 3 10 MTX 49 57 ** 40 ** 18 2 50 MTX 38 24 7 - -

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

Table 111.2 (7)

Antinociceptive effect induced by 200 mg / kg analgin + combination of different doses of 3-methylxanthine

ANTINOCICEPTIVE EFFECT%

dose 1 h 2 h 3h 4 h 5h (Mg / kg) After serving Vehicle + 200 mg / kg analgin 67 51 38 33 13 5 MTX 63 56 60 ** * 53 10 10 MTX 81 64 52 43 16 50 MTX 65 61 38 30 25

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

Table III.2 (8)

Antinociceptive effect 50 mg / kg analgin + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECT%

dose 1 h 2h 3 h (Mg / kg) After serving Vehicle + 50 mg / kg analgin 6 4 1 Theobromine 5 16 8 5 Theobromine 10 29 ** * 25 3 Theobromine 50 5 12 -2

* p <0.05, “p <0.01, n = 1

Table 111.2 (9)

Antinociceptive effect induced by 100 mg / kg analgin + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECT%

dose 1 h 2 h 3 h 4 h 5 h (Mg / kg) after serving Vehicle + 100 mg / kg analgin 30 16 12 3 - Theobromine 5 31 * 43 • 30 12 0 Theobromine 10 42 * 49 50 ** * 24 5 Theobromine 50 38 19 15 - -

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

Table 111.2 (10)

Antinociceptive effect induced by 200 mg / kg analgin + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECT%

benefit 1 h 2 h 3 h 4 h 5 h (Mg / kg) after serving Vehicle + 200 mg / kg analgin 67 51 38 33 13 Theobromine 5 47 39 33 25 10 Theobromine 10 52 49 48 34 28 Theobromine 50 40 43 20 - -

Table 111.2 (11)

Antinociceptive effect induced by paracetamol

ANTINOCICEPTIVE EFFECTS

dose 1 h 2 h 3 h (Mg / kg) After serving 50 2 -1 0 100 39 6 -4 200 60 14 12

Table 111.2 (12)

Antinociceptive effect induced by 100 mg / kg paracetamol + combination of different doses of caffeine.

ANTINOCICEPTIVE EFFECTS

dose 1 h 2 h 3 h (Mg / kg) After serving vehicle 39 6 -4 Caffeine 5 10 -2 7 Caffeine 10 -18 -2 -4 Caffeine 50 1 8 -10

Table 111.2 (13)

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

ANTINOCICEPTIVE EFFECT%

dose 1 h 2h 3h (Mg / kg) after serving Vehicle + 200 mg / kg paracetamol 39 6 -4 5 MTX 33 26 33 ** 10 MTX 47 37 *** * 23 50 MTX 30 21 21

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

Table 111.2 (14)

Antinociceptive effect induced by 100 mg / kg paracetamol + different combinations of different doses of theobromine

ANTINOCICEPTIVE EFFECT%

dose 1 h 2 h 3h (Mg / kg) After serving Vehicle + 100 mg / kg paracetamol 39 6 -4 Theobromine 5 10 - - Theobromine 10 5 - - Theobromine 50 8 2 -4

Table 111.2 (15)

Antinociceptive effect induced by S (+) - ibuprofen

ANTINOCICEPTIVE EFFECT%

dose 1 h 2h 3h 4 h (Mg / kg) after serving 20 25 11 8 7 30 60 32 22 13 50 77 49 21 13

Table 111.2 (16)

Antinociceptive effect induced by 20 mg / kg S (+) - ibuprofen + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS%

dose 1 h 2 h 3h 4 h 5h 6h (Mg / kg) after serving (minutes) Vehicle + 20 mg / kg S (+) - ibuprofen 25 11 8 7 - - Theobromine 5 43 38 37 23 10 - Theobromine 10 33 6 8 4 - - Theobromine 30 37 28 20 15 - -

Table 111.2 (17)

Antinociceptive effect induced by 30 mg / kg S (+) - ibuprofen + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS%

dose 1 h 2 h 3 h 4 h 5 h 6h (Mg / kg) Time after administration (min ty) Vehicle + 30 mg / kg S (+) - ibuprofen . 60 32 22 13 - - Theobromine 5 56 53 51 43 45 32 Theobromine 10 53 75 27 16 - - Theobromine 30 29 35 48 14 - -

Table 111.2 (18)

Antinociceptive effect induced by 50 mg / kg with (+) - ibuprofen + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS%

dose 1 h 2 h 3 h 4h 5 h 6 h (Mg / kg) Time after serving (minutes) Vehicle + 50 mg / kg S (+) - ibuprofen 77 49 21 13 - - Theobromine 5 75 68 65 61 52 42 Theobromine 10 63 60 50 22 - - Theobromine 30 37 41 30 9 - -

Table 111.2 (19)

Diclofenac-induced antinociceptive effect

ANTINOCICEPTIVE EFFECT%

dose 1 h 2 h 3h 4h (Mg / kg) after serving 20 24 8 - - 30 42 19 9 - 50 68 31 18 .10

Table 111.2 (20)

Antinociceptive effect induced by 20 mg / kg diclofenac + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS%

dose 1 h 2 h 3 h 4 h 5h 6 h (Mg / kg) Time after serving (minutes) Vehicle + 20 mg / kg diclofenac 24 8 - - - - Theobromine 5 49 56 50 43 22 - Theobromine 10 29 34 30 1.5 - - Theobromine 30 43 39 35 17 - -

Table 111.2 (21)

Antinociceptive effect induced by 30 mg / kg diclofenac + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS%

dose 1 h 2h 3h. 4h 5h 6h (Mg / kg) Time after serving (minutes) Vehicle + 30 mg / kg diclofenac 42 19 9 - - - Theobromine 5 58 63 52 45 41 12 Theobromine 10 47 39 29 16 - - Theobromine 30 48 25 21 12 - -

Table 111.2 (22)

Antinociceptive effect induced by 50 mg / kg diclofenac + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS%

dose 1 h 2h 3 h 4h 5h 6h (Mg / kg) Time after serving (minutes) Vehicle + 50 mg / kg diclofenac 68 31 18 10 - - Theobromine 5 62 70 57 48 43 23 Theobromine 10 69 48 38 37 31 - Theobromine 30 61 43 42 32 - -

sum

CH-13584 definitely increases and prolongs the effect of morphine. This demonstration clearly suggests that this compound may be useful in reducing morphine doses in patients in need of morphine treatment. Thus, acute and chronic side effects of morphine could be reduced.

In a combination of (5 to 20): 1, preferably 10: 1, both theobromine and 3-methylxanthine significantly prolong the analgesic effect of analgin. Caffeine was without this effect.

The analgesic enhancing effect of theobromine became even more evident when the time course of the analgesic half-life was compared to the 100 mg / kg treatment group alone or in combination with caffeine or theobromine.

The half-life (t 1/2) of the analgesic effect of analgin is 125 minutes.

tl / 2 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 was observed that while the caffeine decreased half-life, theobromine increased it almost twice. Thus, the half-life of the 100 mg / kg analgin dose approximated the half-life of the 200 mg / kg analgin dose which was found to be 220 minutes.

The effect of theobromine prolonging the antinociceptive effect is more evident in combination with S (+) - ibuprofen. The half-life of an oral dose of 20 mg / kg S (+) - ibuprofen is 105 minutes. With the combination of 20 mg / kg S (+) - ibuprofen with 5 mg / kg theobromine, the half-life of the antinociceptive effect was increased to 260 minutes.

The combination of 20 mg / kg diclofenac and 5 mg / kg theobromine shows a similar prolongation of antinociceptive effects as seen with S (+) - ibuprofen + theobromine (120 minutes vs 300 minutes).

In the combination formulation of the present invention, replacement of caffeine by safer xanthine derivatives, such as theobromine and 3-methylxanthine, has fewer side effects and not only reduces the effects but also results in a more beneficial formulation.

The above is all the more surprising since, in the case of paracetamol, which in the acetic acid twitch test, showed a weak analgesic effect near the toxic area, the analgesic effect was not significantly affected by theobromine, caffeine and 3-methylxanthine. In general, theobromine and caffeine rather inhibit, whereas 3-methylxanthine practically does not affect the effect of paracetamol 1 hour after treatment.

To date, only xanthine derivatives with significant central nervous system stimulating effects (caffeine, theophylline) have been reported to potentiate the analgesic effect of morphine and side analgesics, and therefore it is very surprising that xanthine derivatives such as CH-13584, which show no effects on central nervous system can also potentiate the effects of morphine. Even more surprisingly, 3-methylxanthine (one of the human theophylline metabolites) and theophylline also exhibit a similar effect. In connection with theophylline, this phenomenon deserves attention because, according to literature data, it is highly dependent on the site of administration and the dose to be administered whether or not the effect of morphine is increased or inhibited. The dose and the manner in which theophylline was administered by the inventors clearly increased the effect of morphine.

Most surprisingly, the finding that theobromine, whose known pharmacological effects are rather weak compared to the effects of caffeine and consequently have milder side effects, far more potentiated analgesia than caffeine.

The present invention is a pharmaceutical composition comprising as an active ingredient an analgesic compound and a xanthine structure compound wherein the ratio of analgesic and xanthine derivatives (1 and 20): 1, preferably 10: 1.

The compositions of the invention contain as an analgesic compound morphine, aminophenazone, analgin, acetylsalicylic acid, indomethacin, ibuprofen, diclofenac, codeine, preferably analgin, ibuprofen, codeine, as xanthine derivatives 3-methylxanthine, theobromine or CH-13584 (1H-purine-13584) 6-dione-3,7-dihydro-3-methyl-7 (5-methyl-1,2,4-oxadiazol-3-yl) methyl), preferably theobromine.

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

The above compositions can advantageously be used for the treatment of head and bone pains of various origins, toothache, toothache, joint pain, bone pain, pain associated with surgery and childbirth, as well as milder pain caused by tumors.

The compositions of the invention may be formulated in various ways:

1. The three components shall be presented in separate forms but packed together.

2. The two or three components are usually in the molds of choice, the third component being formed separately but in a combined package.

3. All three components are in the form of one device.

The active ingredient may be in the form of a tablet, dragee, lozenge, pill, capsule, suppository, cream, solution, drops, emulsion, injection, patch, eye drops.

The compositions, in addition to the active ingredients, contain the usual excipients.

The compositions of the present invention are illustrated in the following examples without being limited thereto.

DETAILED DESCRIPTION OF THE INVENTION

Forms of active substance

1) Tablets

Analgin drotaverine 400 mg 40 mg theobromine 40 mg Microcrystalline cellulose Polyvinylpyrrolidone Polyvinylpolypyrrolidone Magnesium stearate 70 mg 20 mg 5 mg 5 mg Amidazofén 400 mg drotaverine 40 mg theobromine 40 mg Microcrystalline cellulose Polyvinylpyrrolidone Polyvinylpolypyrrolidone Magnesium stearate 70 mg 20 mg 5 mg 5 mg

2) Film-coated tablets

Analgin 400 mg drotaverine 40 mg theobromine 40 mg Microcrystalline cellulose polyvinylpyrrolidone polyvinyl Magnesium stearate hydroxypropyl methylcellulose Polyethylene glycol 70 mg 20 mg 5 mg 5 mg 9 mg 6 mg

Quinoline yellow dye 1 mg

3) Hard gelatin capsules indomethacin 40 mg drotaverine 40 mg theobromine 40 mg starch 198 mg lactose 150 mg Microcrystalline cellulose 150 mg

Claims (6)

A pharmaceutical composition comprising as an active analgesic component morphine, aminophenazone, analgin, acetylsalicylic acid, indomethacin, ibuprofen, diclofenac or codeine and as a xanthine compound 3-methylxanthine, theobromine or CH-13584 ((1H-purine-2) 6-dione-3,7-dihydro-3-methyl7 / 5-methyl-1,2,4-oxadiazol-2-yl / methyl) in which the ratio of the analgesic active ingredient and the xanthine derivative (1-20) is: 1, preferably 10: 1. Pharmaceutical composition according to claim 1, characterized in that it contains analgesic, S (+) - ibuprofen or diclofenac as the analgesic active ingredient. Pharmaceutical composition according to claim 1, characterized in that it contains theobromine as the xanthine compound. Pharmaceutical composition according to claims 1 to 3, characterized in that it contains, as further active ingredients, a spasmolytic for smooth muscle, preferably papaverine, drotaverine or theophylline-7-acetic acid salt with drotaverine. Pharmaceutical composition according to Claims 1 to 4, characterized in that it contains an analgesic active ingredient, a xanthine derivative and, in the present case, a spasm smoothing compound forming a smooth muscle in a separate formulation, in a combined package. Pharmaceutical composition according to claims 1 to 5, characterized in that it contains an analgesic, a xanthine derivative and a smooth muscle relaxant, two in common and third in a separate formulation, in a pack.