EA004375B1 - Composition containing analgetic medicaments - Google Patents

Abstract

1. A pharmaceutical composition comprising morphine, aminophenazone, analgin, acetyl-salicylic acid, indomethacin, ibuprofen diclophenac or codeine as an active analgetic ingredient and theobromine as a compound of xanthine structure, where the ratio of the analgesic active ingredient and theobromine is (1-20): 1, advantageously 10: 1. 2. The pharmaceutical composition according to claim 1, comprising analgin, S (+) ibuprophen, or diclofenac as the analgesic active ingredients. 3. The pharmaceutical composition according to claims 1-2, comprising spasmolytic, preferably papaverine, drotaverine or drotaverine theophylline-7-acetic acid as an additional active ingredient. 4. The pharmaceutical composition according to claims 1-3, comprising the analgesic active ingredient, theobromine and a spasmolytic compound separately formulated, in collective packaging. 5. The pharmaceutical composition according to claims 1-4, comprising the analgesic active ingredient, theobromine two in common and the third in separate formulation, in collective packaging.

Description

The present invention relates to a pharmaceutical composition comprising the analgesic active ingredient morphine, aminophenazone, analgin, acetylsalicylic acid, indomethacin, ibuprofen, diclofenac or codeine and, as a compound of the xanthine structure, theobromine, in which the ratio of analgesic active ingredient and xanthine derivative is 20): 1, preferably 10: 1.

In pharmacology, analgesic compounds are divided into two main groups:

1. Non-steroidal anti-inflammatory drugs (NSAIDs) (Ν8ΆΙΌ) or small analgesics.

2. Analgesics of the morphine type or large analgesics. Small analgesics are less effective for pain relief than larger analgesics, but their side effects are also significantly weaker. The use of large analgesics is limited to the risk of developing physical dependence. The effect / side effect ratio for these two pharmacological groups also limits their use. Small analgesics are used to relieve common pains (headache, toothache, rheumatoid pain), while large analgesics are used to treat pain associated with severe injury, malignant tumors, and the like. Researchers engaged in the development of new drugs, have long been trying to create compounds of non-morphine structure, the effectiveness of which would reach the effectiveness of large analgesics, but would not cause physical dependence. These attempts have so far failed. Attempts have been made to improve the effectiveness of small analgesics by combining them with excipients. Caffeine (1,3,7-trimethyl-1N-purine-2,6-dione) is one of the widely used analgesic enhancers. This compound is found in large quantities in the seeds of the coffee shrub (Soya aga), in the leaves of the tea bushes (Tyya 5shsp515) and in cocoa powder made from the fruits of the cocoa tree (Tyohegot sasao). Caffeine was isolated from the seeds of the shrub of coffee, and its chemical structure was established in 1875 (Rgd. Aegis. Cake. 31: 273-313, 1987). In clinical studies, caffeine by itself does not demonstrate an analgesic effect (RyagtasoShegaru 10: 387-393, 1990), despite the fact that \\\\\\\\\\\\\\\\\\ 'e! a1. its beneficial effect was observed at a dose of 300 mg for migraine compared with the control group (Rush, 44: 151-155, 1991). In animal experiments, this compound enhanced the effect of small analgesics, giving a picture of a dome-shaped curve in the graph, which means that in small doses (<10 mg / kg orally (p / o)) it enhanced their effect, while in smaller doses At high doses (> 10 mg / kg p / o), it inhibited their action (Me111. Είηά. Exp. Cyp. Ryagtasoy 13: 529-533, 1991). Caffeine enhances the pain relief effect of not only small analgesics, but also large analgesics (Ryagt. Keu. 45: 43-85, 1993).

In addition to caffeine, two other alkaloids of the xanthine structure were also found in higher quantities in the three plants mentioned above. One of them 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 caffeine use is that it is absolutely contraindicated for tachyarrhythmia, while relative contraindications to its use are ulcer, hyperthyroidism, hypertension, and certain neuropsychiatric diseases (Meb. Mopa18ksyg. Ryag. 15: 258-269, 1992).

The aim of the invention is to obtain an analgesic combination, in which the analgesic effect instead of caffeine provides a compound that is safer and has fewer side effects.

It has now become known which substituents in different parts of the xanthine structure are responsible for enhancing or weakening various effects. Thus, the position of N1 is responsible for antagonistic and adenosine receptors extra-pulmonary effects, the position of N3 is important from the point of view of the intensity of the bronchodilator action, while the substitution of H in the N7 position leads to a weakening of the bronchodilator action. The substitution of N in the N9 position, as a rule, causes a general weakening of the effect, while the substitution in the C8 position can lead to an increase in antiallergic, antagonistic effects on adenosine receptors and an increase in toxicity (1. A11Gep. 1Typo1. 78: 817-824 1986). As for the pharmacological effects of caffeine, theophylline and theobromine, their intensity varies depending on the type of effect. By decreasing the effects of relaxation of smooth muscles, antagonistic receptors for adenosine receptors, diuretic, cardiac and circulatory effects, these compounds can be arranged in the following order: theophylline> caffeine> theobromine; by decreasing the central nervous system stimulation effect, increasing the work of the skeletal muscles, increasing the secretion of gastric juice, these compounds can be arranged in the following order: caffeine> theophylline> theobromine. As you can see, caffeine and theophylline have a significant pharmacological effect, while, according to currently available data, theobromine is the weakest of the three xanthine derivatives. Such a specific procedure cannot be established from the point of view of potentiation of the analgesic action, since, oddly enough, systemic studies have not been conducted in this area.

To study the effect of small analgesics, models based on inflammation are most convenient, while to demonstrate the effect of large analgesics, antinociceptive models (for example, a test using thermal stimulation of the tail) are most convenient. Using these tests, it is also possible to reliably evaluate the effect of potentiation of analgesia.

In accordance with the task studied:

I. 1. effect of CH-13584 (1H-purin-2,6-dione, 3,7-dihydro-3-methyl-7/5-methyl-1,2,4-oxadiazol-3-yl / methyl), theophylline and 3-methylxanthine separately and in combination with different doses of tylxanthine separately and in combination with different doses of morphine, which were injected n / a or n / c, in a test on rats using heat stimulation of the tail.

I. 2. effect of caffeine, theobromine and 3-methylxanthine separately and in combination with various oral doses of analgin or paracetomol in a test on mice using chemical pain stimulation.

The test methods used are described below.

1. Test on rats using heat stimulation of the tail:

Studies were carried out using the E'Ltoig and 8th methods (1. Ryagtaso1. Exp. T11sg. 72:74, 1942). The principle of this technique is the direction of thermal radiation on the tail of the animal and fixing the duration of the latent period of time before the tail is withdrawn. Various analgesics lengthen this latent period. Experiments were performed on male rats of the XV Mag, weighing 120-140 g. The animals were fixed in such a way that the thermal radiation was focused on the tip of the tail. To measure the duration of the latent period before the tail was withdrawn, an automatic analgesia meter was used. This tool turned off thermal radiation and stopped the manual measurement of the latent period. In order to prevent tissue damage occurring with a strong analgesic effect, heat radiation in all cases was turned off after a period of time twice the control latent time. Morphine was dissolved in physiological saline for sc administration. CH-13584, theophylline and 3-methylxanthine were administered to animals as a 1% suspension of methylcellulose. In all cases, the injectable volume was 0.1 ml / 100 g body weight.

Before oral administration, the animals were hungry for 16 hours, but had free access to drinking water. In the case of oral administration of both substances, it was carried out simultaneously, while in the case of combinations of oral and subcutaneous administration, the substance that was injected s / c was injected 30 minutes after oral administration.

2. Test on mice using chemical pain stimulation

Adult CEDR mice of both sexes weighing 23-27 g (ILT1) were used in these experiments. The animals were fed standard laboratory rodent food (C11ag1c5 Ktueg So. Niidagu) and provided them with free access to drinking water, except for the day of the experiment, when they were hungry for 16 hours before oral administration of the test substances, but still had free access to drinking water. water. Mice were kept at room temperature 22 ± 2 ° C and cyclic illumination. In all experiments, oral administration was used. Of the tested substances produced 1% suspension of methylcellulose, which was administered to mice through a gastric tube in a volume of 0.1 ml / 10 g of body weight. (In the case of drug combinations, a mixture of powders of the two components was suspended in methylcellulose).

In these experiments, the method of Huyksh e! a1. (\ νί (1 <ίιτ L., V., Neiig S., E., 6aI1 E., O'Kee Ge, E., 8rNa1e11a R., aib P1rteg A. 1 .. Ryagtasododu oG 2-atshotbape Nubgosyopba (8i-8629 (a) Rhoagtaso1, Exp. Tieg. 133, 400–408 (1961).

Mice were placed one by one in plastic containers 1 hour before the experiment for acclimatization to the experimental conditions. On the day of the experiment, they and / n were injected with 0.2 ml of a 0.6% solution of acetic acid, then after 5 minutes of waiting, the number of wriggling body movements was counted for 5 minutes. The pain response to a chemical lesion was regularly determined in untreated animals (control), then the antinociceptive effect was expressed as a percentage compared to the control. In control experiments, the number of wriggling body movements per mouse was 24 ± 0.53 (and = 70).

Study of the time-effect relationship

The first measurement was performed 1 h after the administration of the tested substances. When treating other groups of mice with test substances, acetic acid was injected 2, 3, 4, and 5 hours after their administration, and the degree of antinociceptive effect was determined depending on the time. The effect termination was evaluated by stopping measurements in groups where the number of wriggling body movements approached the control values (20-22 wriggling body movements per mouse). The time of measurement of the first such result was regarded as the termination of the effect.

The results were presented in the form of time-effect curves, and the values of the half-life of the effect (( _1/2 min) were determined from them.

Acute toxicity study

Studies were performed on groups of 10 mice, the test substances were administered orally after 16 hours of fasting. The toxicity of the test substance was determined separately and in combination with methylxanthines. The death of animals was noted every hour, then summarized after 24 hours.

Statistical evaluation of results

The degree of antinociceptive effect was expressed as the number of wriggling body movements per mouse and indicated in% of control. The mean value of pain reactions (wriggling body movements per mouse), standard deviation (8Ό) and standard error (8E) were calculated, then the confidence was calculated using the paired 1-student's t-test, then a univariate analysis of the variant values was performed.

The following results were obtained:

1. Test on rats using heat stimulation of the tail:

As can be seen from table III. 1 (1), the antinociceptive effect of CH-13584 when administered orally was statistically significant at several time intervals, however, it was not dose-dependent, and its degree of action was not statistically significant. The maximum effect achieved was only 25.6 ± 4.8%.

Surprisingly, CH-13584, when administered orally, increased the antinociceptive effect exerted by oral morphine at an oral dose of ΕΌ50 (15 mg / kg) at several time intervals and doses (Table III. 1 (2)). This potentiating effect was significant after 30, 60, 90 min after administration of a morphine combination with 100 mg / kg CH-13584, and 30, 45, 60, 90 min after administration of its combination with 200 mg / kg CH-13584.

When s / c administration, morphine had a dose-dependent antinociceptive effect (Table I1.1 (3)).

Oral administration of 100 mg / kg of CH-13584 significantly increased the analgesic effect of the administered morphine. This effect of CH-13584 was most pronounced with the action of morphine in doses of 3.75 and 5 mg / kg. The duration of the effect of 5 mg / kg of morphine was doubled with the introduction of 100 mg / kg of CH-13584 (Table III. 1 (4) compared to Table W.1 (3)).

An oral dose of 100 mg / kg of CH-13584 potentiated the effect of orally administered morphine even more than the effect of the s / c dose. In addition to enhancing the effect of morphine, CH13584 also significantly increased its duration (Table Sh.1 (10) compared to Table Sh.1 (9)).

Neither theophylline nor 3-methylxanthin showed an antinociceptive effect after oral administration at a dose of 30 mg / kg (Table W.1 (5) and Table III. 1 (6)).

However, quite unexpectedly, the combination with one of these compounds reliably increased the antinociceptive effect induced by SC injection of morphine (Table Sh.1 (7) and Table Sh.1 (8) compared to Table Sh.1 (3)).

2. Test on mice using chemical pain stimulation

Antinociceptive effect of dipyrone

In a test on mice using chemical pain stimulation, analgin demonstrated a dose-and time-dependent antinociceptive effect (Table Sh.2 (1)).

Analgin + caffeine combination (comparative)

The combination of 50 mg / kg of dipyrone with 5 and 10 mg / kg of caffeine did not enhance the effect of dipyrone, while caffeine at a dose of 50 mg / kg more likely counteracted it (Table III.2 (2)).

The combination of 100 mg / kg of analgin with 5 and 10 mg / kg of caffeine caused only a slight, statistically unreliable, increased effect, while caffeine at a dose of 50 mg / kg rather inhibited the effect of analgin (Table III.2 (3)). The half-life of the effect of 100 mg / kg analgin was 125 minutes. The combination of 100 mg / kg analgin with 10 mg / kg of caffeine changed the half-life to 120 minutes. This change was considered to be irrelevant.

The combination of 200 mg / kg analgin with 5, 10, and 50 mg / kg of caffeine inevitably led to a weakening of the effect of analgin (Table W.2 (4)).

Analgin + 3-methylxanthin combination

The combination of 50 mg / kg analgin with 5, 10, and 50 mg / kg of 3-methylxanthine resulted in an intensifying tendency, but not to a statistically significant increase in the effect (Table III.2 (5)).

A combination of 100 mg / kg analgin with 5, 10, and 50 mg / kg 3-methylxanthine also led to potentiation of the effect. This enhancement of the effect, which also means its prolongation, turned out to be reliable for several periods of time (Table Sh.2 (6)).

The half-life of the effect of 100 mg / kg analgin was 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 led to potentiation of the effect. The degree of potentiation was lower than in the case of the previous combination, but in the case of 5 mg / kg of 3-methylxanthine, a statistically significant effect occurred after 3 and 4 hours (Table Sh.2 (7)). The half-life of the effect of 200 mg / kg analgin was 230 minutes. The combination from 5 mg / kg of 3-methylxanthine increased the half-life to 270 minutes.

Analgin + Theobromine combination

The combination of 50 mg / kg of analgin with 5 and 10 mg / kg of theobromine led to a convincing potentiation of the effect, which in the case of a dose of 10 mg / kg after 1 and 2 h was statistically significant (Table .2 (8)).

The potentiating effect of 5 and 10 mg / kg of theobromine was even more pronounced when combined with 100 mg / kg of analgin, than for combination with the previous ratio of components. Along with the potentiation, the duration of the analgin effect has also increased (table III.2 (9)). The half-life of the effect of 100 mg / kg analgin was 125 minutes. The combination of 100 mg / kg of analgin with 10 mg / kg of theobromine increased the half-life to 230 minutes. The half-life of the effect of 200 mg / kg analgin was 230 minutes and increased using a combination of 10 mg / kg of theobromine to 285 minutes.

The combination of 200 mg / kg analgin with 5, 10, and 50 mg / kg of theobromine caused a slight, statistically unreliable weakening of the antinociceptive effect (Table ΙΙΙ.2 (10)).

Antinociceptive effect of paracetamol Paracetamol in doses of 50, 100 and 200 mg / kg showed a short but dose-dependent antinociceptive effect. However, the dose of 200 mg / kg, which showed a 60% effect, is already quite close to the limits of the acute toxic dose (table .2 (11)).

Paracetamol + Caffeine Combination

The combination of 100 mg / kg paracetamol with 5 and 10 mg / kg caffeine inevitably caused a weakening of the effect of paracetamol (table таблица.2 (12)).

When combining 100 mg / kg of paracetamol with 5 and 10 and 50 mg / kg of 3-methylxanthine, doses of 5 and 10 mg / kg caused a statistically significant increase in the effect (Table ΙΙΙ.2 (13)).

The combination of 100 mg / kg paracetamol with 5, 10 and 50 mg / kg of theobromine led to a weakening of the effect 1 h after the administration (table ΙΙΙ.2 (14)).

Antinociceptive effect of 8 (+) - ibuprofen

Oral doses of 8 (+) - ibuprofen 20, 30 and 50 mg / kg showed a dose-dependent antinociceptive effect. The maximum antinociceptive effect was observed 1 h after administration. This effect gradually decreased over 4 hours to the control level, regardless of the dose (Table .2 (15)).

Combination 8 (+) - ibuprofen + theobromine

The combination of all doses of 8 (+) - ibuprofen with 5 mg / kg of theobromine led to a significant increase in the antinociceptive effect of 8 (+) ibuprofen. The antinociceptive effect persisted even 6 hours after the administration of combinations of 30 mg / kg 8 (+) - ibuprofen and 5 mg / kg of theobromine, and 50 mg / kg 8 (+) - ibuprofen and 5 mg / kg of theobromine. The combination of 20, 30 and 50 mg / kg 8 (+) - ibuprofen and 10 mg / kg of theobromine caused only a moderate increase in the antinociceptive effect as compared with the combinations of 5 mg / kg of theobromine + 8 (+) - ibuprofen. The combination of doses of 8 (+) - ibuprofen 30 and 50 mg / kg and 30 mg / kg of theobromine caused a weakening of the antinociceptive effect 1 hour after oral administration and had almost no effect on the antinociceptive effect 2 and 4 hours after administration (Table .2 (16), table ΙΙΙ.2 (17), table .2 (18)).

The half-life of the 8 (+) - ibuprofen-induced dose of 20 mg / kg of the antinociceptive effect was 105 minutes, while the combination with 5 mg / kg of theobromine increased it to 260 minutes. Increasing the dose of theobromine (up 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 h after administration. This effect gradually decreased over 4 hours to the control level, regardless of the dose (Table .2 (19)).

Diclofenac + Theobromine Combination

The antinociceptive effect provided by the oral dose of diclofenac 20 mg / kg was significantly enhanced by combining with 5 mg / kg of theobromine. This dose of theobromine not only strengthened, but also reliably 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 effective than 5 mg / kg of theobromine (table .2 (20)). Theobromine at a dose of 5 mg / kg also increased and prolonged the antinociceptive effect caused by diclofenac at doses of 30 and 50 mg / kg. When using higher doses of theobromine (10 and 30 mg / kg), the potentiation effect of theobromine antinociception was weaker than in the case of 5 mg / kg of theobromine (table .2 (21), table .2 (22)).

Theobromine at a dose of 5 mg / kg significantly increased the half-life of the antinociceptive effect caused by diclofenac at a dose of 20 mg / kg (120 min versus 300 min). Increasing the dose of theobromine in combination did not further enhance the antinociceptive effect of 8 (+) - ibuprofen.

Table ΙΙΙ.1 (1).

The dependence of the antinociceptive effect of CH-13584 on time Antinociceptive effects%

dose 15· thirty· 45 ' 60 ' mg / kg time after injection (minutes) carrier 1.2 * 0.4 1.8 * 0.3 2.5 * 1.2 4.0 * 1.2 one 17.9 * 3.3 *** 12 * 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 ten 20.2 * 4.3 *** 17.8 * 1.4 ** 9.9 * 2.7 * 4.5 * 1.2 thirty 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 ± standard error of the mean; and = 10 per dose. In a statistical evaluation, the group treated with CH-13584 was compared with the group receiving the carrier (1% methylcellulose).

Table III. 12). Antinociceptive effect of a mixture of CH13584 and 15 mg / kg p / o morphine Antinociceptive effects%

Dose 15' behind 45 ' 60 ' 90 ' 120 ' (mg / kg) Time after injection (minutes) Carrier +15 mg / kg p / o morphine 14.4 * 2.0 17.5 * 1.5 20.1 ± 5.3 48.2 * 7.2 24.1 * 6.2 ten 12.3 * 4.7 11.2 * 3.1 * 26.3 * 6.6 12.1 * 4.4 * “ - thirty 16.8 * 7.6 16.3 * 3.5 24.2 * 7.0 46.6 * 10.3 36.7 * 11.6 28.7 * 11.9 100 34.9 * 9.7 69.1 * 8.3 * 82.1 * 11.5 74.7 * 9.6 * 58.9 * 8.8 " 46,9 * 8.9 200 17.7 * 4.6 50.1 * 8.0 * 70.5 * 8.5 “ 85.4 * 5.0 "* 65.1 * 0.4 * “ 36.8 * 7.1

* p <0.05; ** p <0.01; *** p <0.001; - measurement was not carried out; n = 10 mean ± standard error of the mean. In the statistical evaluation, groups that received morphine + CH-13584 were compared with the corresponding values for groups that received only morphine.

Table III. 13).

The dependence of the antinociceptive effect of s / c morphine on time

Antinociceptive effects%

dose ¹⁵ 'I for I 45 'I ba I 90 ’I 12a I 180 ' 240 ' mg / kg Time after injection (minutes) 0.25 5.5 * 2.3 10.7 * 4.2 3.6 * 1.8 2.7 * 1.5 - - 0.5 16.9 * 4.2 25.1 * 4.3 10.6 * 2.8 7.0 * 1.5 4.2 * 1.4 2.6 * 0.5 1.25 30.5 * 6.0 47.8 * 6.9 27.5 * 7.7 14.0 * 7.1 9.7 * 5.2 4.0 * 1.2 2.5 51.1 * 10.6 70.0 * 6.6 48.1 * 8.7 28.1 * 5.2 18.5 * 3.6 9.8 * 2.7 3.75 54.1 * 6.7 79.4 * 5.4 63.6 * 6.8 37.0 * 7.8 14.9 * 4.8 6.3 * 1.9 5.0 56.7 * 12.8 92.0 * 3.9 84.8 * 6.4 66.0 * 7.6 50.4 * 7.6 19.7 * 5.5 13.2 * 5.4 7.0 * 6.2

Table III. 14).

Antinociceptive effects of a mixture of various doses p / to morphine and 100 mg / kg p / o CH-13584 Antinociceptive effects%

dose 15' thirty' 60 * 120 180 240 mg / kg Time after injection (minutes) 0.5 25.7 ± 7.3 16.616.5 31,418,5 · 9,714.4 1.25 33.4 + 11.8 28,615,0 32,216,7 31,216,4 5,311,7 2.5 60.4 ± 10.0 78,518,9 76,0110.2 53,0115,7 49,5114,9 29,816,3 3.75 54.1 ± 5.8 70,219,0 81,517,8 65,417,8 " 46,0110,8 32,818 5.0 59.9 ± 10.0 98,411.0 95,811,8 100,010.0 * " 93,914.1 · 91,715.4 * 70,416.1 " 50,012.9 *

only morphine.

Table III. 15).

The dependence of the antinociceptive effect caused by 30 mg / kg p / o theophylline, from time Antinociceptive effects%

Dose (mg / kg) 15' thirty' 45 ' 60 ' 90 ' 120 ’ Time after injection (minutes) thirty 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 III. sixteen).

The dependence of the antinociceptive effect caused by 30 mg / kg p / o 3-methylxanthine, from time Antinociceptive effect%

Dose (mg / kg) 15' thirty' 45 ' 60 ’ 90 ’ 120 ' Time after administration (minutes) thirty 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 III. 1 (7).

The dependence of the antinociceptive effect of morphine (s / c) in the presence of 30 mg / kg p / o of theophylline on time Antinociceptive effect%

Dose (mg / kg) 15· behind 45 * wa ea 120G Time after injection (minutes) 025 3.3 * 2.2 3.4 * 1.6 10.1 * 4.5 5.6 * 2.5 2.6 * 1.8 4.7 * 2.0 0.5 8.5 * 1.9 * 10.7 * 4.6 * 25.2 * 11.0 10,814.3 9.0 * 2.5 5.8 * 1.9 1.5 20.1 * 5.9 36.1 * 9.9 30.0 * 7.6 20.5 * 5.0 10.8 * 4.8 7,012,1 2.5 55.6 * 12.9 64.4 * 10.3 60.2112.7 43.0 * 11.3 * 43.2 * 132 25.1 * 6.8 3.75 49.9 * 12.4 70.3 * 13.0 812 * 9.7 68.4 * 11.4 * 48.6 * 122 23.1 * 10.2 5.0 57.1 * 14.7 91,216,0 * 100.0 * 0, (G * 96.0 * 4.0 “ 63.0 * 11.0 · 46.9 * 11.9

* p <0.05; ** p <0.01; *** p <0.001; mean ± standard error of the mean; n = 10

In the statistical evaluation, groups that received theophylline + morphine were compared with the corresponding values for groups that received only morphine.

Table III. 18).

The dependence of the antinociceptive effect of morphine (s / c) in the presence of 30 mg / kg p / o 3-methylxanthine on time Antinociceptive effects%

Dose (mg / kg) 15' behind 45 * 60 ' 90 ' 12a Time after injection (minutes) 0.25 14.6 * 4.0 20.6 * 5.5 22.8 * 7.2 * 22.2 * 5.5 "* 12.1 * 3.7 9.0 * 2.0 0.5 12.0 * 4.7 12.3 * 2.3 16.8 * 4.3 * 26.8 * 3.8 16.1 * 3.4 10.6 * 3.8 1.5 37.7 * 9.2 35.4 * 6.8 23.1 * 8.0 13.7 * 4.4 18.7 * 6.9 72 * 2.4 * 2.5 22.7 * 6.0 " 60.1 * 10.8 69.4 * 9.8 * 48.6 * 13.3 * 27.7 * 10.1 21.9 * 72 * 3.75 37.8 * 12.8 75.9 * 9.3 * 76.6 * 6.0 64.4 * 8.7 46.7 * 11.0 31.0 * 11.1 " 5.0 73.9 * 11.3 95.0 * 3.5 100.0 * 0.0 "* 90.4 * 7.4 * 80.7 * 6.2 "* 56.0 * 10.2 "

* p <0.05; ** p <0.01; *** p <0.01; - measurement was not carried out; average + standard error of the mean; n = 10

In a statistical evaluation, groups treated with 3-methylxanthine were compared with corresponding values for groups treated with morphine alone.

* p <0.05; ** p <0.01; *** p <0.001; - measurement was not carried out; n = 10

In the statistical evaluation, groups treated with morphine + CH-13584 were compared with the corresponding values for the groups, semi-Table III. nineteen).

The dependence of the antinociceptive effect of morphine p / o on time

Antinociceptive effects%

Dose (mg / kg) 15' thirty 45 ' βσ 90 ' 12σ Time after injection (minutes) Carrier 1.2 ± 0.4 1,610.3 2.511.2 4,011,2 2,210,7 4.94: 1.3 five 12.6 ± 5.7 21,519,3 · 26.1 ± 10.5 * 28.1 * 8.5 ” 12,615,6 ten 0.5 ± 0.2 24,015,2 * 29,912,9 - 39,715.4 — * - 15 14.4 ± 2.0 " 17,511.5 " 20.1 ± 5.3 48,517,2 - 23,916,2 - 17.5 8.5 ± 3.1 · 33.6 ± 4.7 " 38,614,5 - 60,217,4 - 22,314.2 " - 25 - 35.515.0 — 54,518.9 “ 67,915,8— 36,716,9 — 24,118,5 37.5 0.615.4 26.3 * 5.6 45.616.5— 81,0114.3 — 51,116,5— 30,616,5 " 50 - 33.4 * 4.6 “ 67,613.3— 95,113,4 — 80,217,9 ” 47.5111.1 *

* p <0.05; ** p <0.01; *** p <0.001; - measurement was not carried out; mean ± standard error of the mean; n = 10

Antinociceptive effect of 100 mg / kg analgin in combination with various doses of caffeine. Antinociceptive effects%

Dose 1 hour 2 hours 3 hours (mg / kg) After the introduction Carrier + 100 mg / kg analgin thirty sixteen 2 5 caffeine 46 13 2 10 caffeine 41 21 13 50 caffeine 28 -one -6

When statistical evaluation of animals treated with morphine, compared with animals treated with the carrier.

Table III. 1 (10).

The dependence of the antinociceptive effect of morphine (p / o) in the presence of 100 mg / kg p / a of CH-13584 on time Antinociceptive effects%

dose nineteen 49 60 90 ΐ2σ 1ВУ 24σ ipg burden after ekdeee (throw) 10.0 10, Sh.8 * 26.5112.6 44.9110.4 30.0 * 11.2 - • 17.5 25.854.2 52,0111.5 87L ± 5.3 “ 71,3111,8 90,616,0 " 89.5 * 6.6 58,8112,5 29.4110.7 25.0 22,5 ± th, in 52.0 ± 11, V 68.5 * 6.7 74.9112.1 B2DI *** 79,316,7 62,317.9 38,1152 37.5 27,815,5 " 41.317,0 68,2113,3 75217.9 91,915.4 " 90.616.3 *** 59.31102 38.4 * 12.3 50.0 69.1194 93312.5 " 94.6 * 2.3 ” yo, o ± o, o 97211.8 96, a ± 2.1 722110.3 52,3113,3

* p <0.05; ** p <0.01; *** p <0.001; - measurement was not carried out; mean ± standard error of the mean; n = 10

In the statistical evaluation, groups that received CH-13584 + morphine were compared with the corresponding values for groups that received only morphine.

Table III.2 (1).

Antinociceptive effect of analgin; Antinociceptive effects%

Dose 1 hour 2 hours [ 3 hours I 4 hours I 5 hours (mg / kg) Time after injection (minutes) 50 b four one - - 100 thirty sixteen 12 3 - 200 67 51 38 33 13 250 83 63 43 35 17

Table ΙΙΙ.2 (2). Antinociceptive effect of 50 mg / kg analgin in combination with various doses of caffeine. Antinociceptive effects%

Dose (mg / kg) 1 hour 2 hours 3 hours After introductions Carrier + 50 mg / kg analgin 6 four one 5 caffeine five five -13 10 caffeine 12 eleven 7 50 caffeine -22 -21 -

Table ΙΙΙ.2 (4).

Antinociceptive effect of 200 mg / kg analgin in combination with various doses of caffeine. Antinociceptive effects%

Dose 1 hour I I 2 hours 3 hours | 4 hours (mg / kg) After the introduction Media + · 200 mg / kg analgin 67 51 38 33 5 caffeine 43 37 25 3 10 caffeine 52 29 18 five 50 caffeine 38 31 ten

Table ΙΙΙ.2 (5).

Antinociceptive effect of 50 mg / kg analgin in combination with various doses of 3-methylxanthine Antinociceptive effect%

Dose 1 hour 2 hours 3 hours (mg / kg) After the introduction Carrier + 50 mg / kg analgin 6 four one 5 MTK 6 21 17 10 MTC 23 24 one 50 MTC 15 14 -2

MTC = 3-methylxanthine

Table 111.2 (6).

Antinociceptive effect of 100 mg / kg analgin in combination with various doses of 3-methylxanthine Antinociceptive effect%

Dose 1 hour I 2 hours 1 3 hours I 4 hours | 5 o'clock (mg / kg) After the introduction Carrier + 100 mg / kg analgin thirty sixteen 12 3 5 MTK 45 40 * 39 *. * sixteen 3 10 MTC 49 57 ** 40 ** 18 2 50 MTC 38 24 7 -

MTC = 3-methylxanthine; * p <0.05; ** p <0.01; *** p <0.001;

n = 10

Table ΙΙΙ.2 (3).

Table 111.2 (7).

Antinociceptive effect of 200 mg / kg analgin in combination with various doses of 3-methylxanthine Antinociceptive effect%

Dose 1 hour 2 hours 3 hours 4 hours 5 o'clock (mg / kg) After the introduction Carrier + 200 mg / kg analgin 67 51 38 33 13 5 MTK 63 56 60 ** 53 * ten 10 MTC 81 64 52 43 sixteen 50 MTC 65 61 38 thirty 25

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

Antinociceptive effect of 100 mg / kg paracetamol in combination with various doses of caffeine. Antinociceptive effects

Dose (mg / kg) 1 hour 2 hours 3 hours After the introduction Carrier 39 6 -four caffeine 5 ten -2 7 caffeine 10 -18 -2 -four caffeine 50 one eight -ten

Table ΙΙΙ.2 (8).

Antinociceptive effect of 50 mg / kg analgin in combination with various doses of theobromine Antinociceptive effect%

Dose (mg / kg) 1 hour 2 hours 3 hours After the introduction Carrier + 50 mg / kg analgin 6 four one Theobromine 5 sixteen eight five Theobromine 10 29 ** 25 * 3 Theobromine 50 five 12 -2

* p <0.05; ** p <0.01; n = 1

Table ΙΙΙ.2 (9).

Antinociceptive effect of 100 mg / kg analgin in combination with various doses of theobromine Antinociceptive effect%

Dose 1 hour 1 2 hours | 3 hours I 4 hours | 5 o'clock (mg / kg) After the introduction Carrier + 100 mg / kg analgin thirty sixteen 12 3 Theobromine 5 31 43 * thirty 12 0 Theobromine 10 42 49 * 50** 24 * five Theobromine 50 38 nineteen 15 - -

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

Table 111.2 (10).

Antinociceptive effect of 200 mg / kg analgin in combination with various doses of theobromine Antinociceptive effect%

Dose 1 hour I 2 hours 3 hours I 4 hours I 5 o'clock (mg / kg) After the introduction Carrier + 200 mg / kg analgin 67 51 39 33 13 Theobromine 5 47 39 33 25 ten Theobromine 10 52 49 49 34 28 Theobromine 50 40 43 20 - -

Table 111.2 (13).

Antinociceptive effect of 100 mg / kg paracetamol in combination with various doses of 3-methylxanthine Antinociceptive effects

Dose (mg / kg) 1 hour 2 hours 3 hours After the introduction Carrier + 200 mg / kg paracetamol 39 6 -four 5 MTK 33 26 33 ** 10 MTC 47 37 *** 23 * 50 MTC thirty 21 21

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

Table 111.2 (14).

Antinociceptive effect of 100 mg / kg paracetamol in combination with various doses of theobromine Antinociceptive effect%

Dose (mg / kg) 1 hour 2 hours 3 hours After the introduction Carrier + 100 mg / kg paracetamol 39 6 -four Theobromine 5 ten - - Theobromine 10 five - - Theobromine 50 eight 2 -four

Table 111.2 (15).

Antinociceptive effect of 8 (+) ibuprofen Antinociceptive effect%

Dose 1 hour I 2 hours | 3 hours | 4 hours (mg / kg) After the introduction 20 25 eleven eight 7 thirty 60 32 22 13 50 77 49 21 13

Table Ш.2 (11). Antinociceptive effect of paracetamol Antinociceptive effects

Dose (mg / kg) 1 hour 2 hours 3 hours After the introduction 50 2 -one 0 100 39 6 -four 200 60 14 12

Table 111.2 (16).

Antinociceptive effect of 20 mg / kg 8 (+) ibuprofen in combination with various doses of theobromine Antinociceptive effects%

Dose 1 hour 1 2 hours I 3 hours , 4 hours 15 hours 1 6 o'clock (mg / kg) Time after injection (minutes) Carrier + 20 mg / kg 3 (+) ibuprofen 25 eleven eight 7 Theobromine 5 43 38 37 23 ten - Theobromine 10 33 6 eight four - - Theobromine 50 37 28 20 15 - -

Table 111.2 (12).

Table 111.2 (17).

Antinociceptive effect of 30 mg / kg 8 (+) ibuprofen in combination with various doses of theobromine Antinociceptive effects%

Dose 1 hour 2 hours 3 hours 4 hours 5 o'clock 6 o'clock (mg / kg) Time after injection (minutes) Carrier + 30 mg / kg 5 (+) ibuprofen 60 32 22 13 Theobromine 5 56 53 51 43 45 32 Theobromine 10 53 75 27 sixteen - Theobromine 50 29 35 46 14 -

Table 111.2 (18).

Antinociceptive effect of 50 mg / kg 8 (+) ibuprofen in combination with various doses of theobromine Antinociceptive effects%

Dose 1 hour 2 hours 3 hours 4 hours 5 o'clock 6 o'clock (mg / kg) Time after injection (minutes) Carrier + 50 mg / kg 8 (+) ibulrofen 77 49 21 13 Theobromine 5 75 68 65 61 52 42 Theobromine 10 63 60 50 22 - - Theobromine 50 37 41 thirty 9 - -

Table Ш.2 (19). Antinociceptive effect of diclofenac Antinociceptive effect%

Dose 1 hour 2 hours 3 hours 4 hours (mg / kg) After the introduction 20 24 eight - - thirty 42 nineteen 9 - 50 68 31 18 ten

Table 111.2 (20). Antinociceptive effect of 20 mg / kg of diclofenac in combination with various doses of theobromine Antinociceptive effects%

Dose 1 hour 2 hours 3 hours 4 hours 5 o'clock 6 o'clock (mg / kg) Time after injection (minutes) Carrier + 20 mg / kg diclofenac 24 eight Theobromine 5 49 56 50 43 22 - Theobromine 10 29 34 thirty 15 - - Theobromine 30 43 39 35 17 - -

Table 111.2 (21). Antinociceptive effect of 30 mg / kg of diclofenac in combination with various doses of theobromine Antinociceptive effects%

Dose 1 hour 2 hours 3 hours 4 hours 5 o'clock 6 o'clock (mg / kg) Time after injection (minutes) Carrier + 30 mg / kg diclofenac 42 nineteen 9 Theobromine 5 58 63 52 45 41 12 Theobromine 10 47 39 29 sixteen - - Theobromine 30 48 25 21 12 - -

Table 111.2 (22). Antinociceptive effect of 50 mg / kg of diclofenac in combination with various doses of theobromine Antinociceptive effects%

Dose 1 hour 2 hours 3 hours 4 hours 5 o'clock 6 o'clock (mg / kg) Time after injection (minutes) Carrier + 50 mg / kg diclofenac 68 31 18 ten Theobromine 5 62 70 57 48 43 23 Theobromine 10 69 48 38 37 31 - Theobromine 30 61 43 42 32 - -

Brief description of the invention

CH-13584 unambiguously increased and prolonged the effect of morphine. This phenomenon undoubtedly indicates that this compound can be used to reduce the dose of morphine in patients requiring treatment with morphine. The acute and chronic side effects of morphine can thus be reduced.

In combination with the ratio of (1-20): 1, preferably 10: 1, theobromine, significantly prolonged the analgesic effect of analgin. Caffeine was deprived of this effect.

The potentiation effect of theobromine analgesia becomes even more obvious if the half-life of the analgesic effect is compared with the group that received 100 mg / kg of analgin alone or in combination with caffeine or theobromine.

The half-life (ΐι _{/ 2} ) of the analgesic effect of dipyrone is 125 min.

11/2 analgin 100 mg / kg + caffeine 5 mg / kg 105 min + caffeine 10 mg / kg 120 min analgin 100 mg / kg + theobromine 5 mg / kg 204 min + theobromine 10 g / kg 230 min

As you can see, while in the case of caffeine, the half-life is reduced, theobromine almost doubles it. Thus, the half-life of analgin at a dose of 100 mg / kg approached that of analgin at a dose of 200 mg / kg and was found to be 220 minutes.

The prolongation effect of the antinociceptive effect inherent in theobromine is more apparent in combination with 8 (+) ibuprofen. The half-life of 20 mg / kg p / o 8 (+) ibuprofen is 105 minutes. In a combination of 20 mg / kg 8 (+) ibuprofen with 5 mg / kg of theobromine, the half-life of the antinociceptive effect increases to 260 minutes.

The combination of 20 mg / kg of diclofenac and 5 mg / kg of theobromine demonstrates a similar prolongation of the antinociceptive effect, which was also observed in the case of the combination of 8 (+) ibuprofen and theobromine (120 min versus 300 min).

In the combined preparation of the present invention, replacing caffeine with a safer xanthine derivative having fewer side effects, such as theobromine, leads not only to a reduction in side effects, but also to a more favorable effect.

The above facts are even more surprising, since in the case of paracetamol, which in the test with pain irritation with acetic acid showed a weak analgesic effect in doses close to toxic, the analgesic effect of theobromine, caffeine and 3-methylxanthine did not have a significant effect. In general, theobromine and caffeine rather inhibited the effect of paracetamol 1 h after administration, while 3-methylxanthine had almost no effect on it.

Since only the fact that xanthine derivatives with a significant stimulating effect on the central nervous system (caffeine, theophylline) potentiate the analgesic effect of morphine and minor analgesics has been described so far, the fact that a xanthine derivative, such as CH-13584, which is not has effects on the central nervous system, and can also potentiate the effect of morphine. Even more surprisingly, 3-methylxanthine (one of the theophylline metabolites in humans), as well as theophylline, showed the same effect. In connection with theophylline, this phenomenon deserves interest, since, according to literature data, it strongly depends on the site of administration and dose, regardless of whether it enhances or inhibits the effect of morphine. In the dose and with the method of administration of theophylline used by the applicants, he invariably enhanced the effect of morphine.

The most surprising was that theobromine, whose known pharmacological effects were much weaker than the effects of caffeine, and which, accordingly, had minor side effects, much more potentiated analgesia than caffeine.

The present invention relates to a pharmaceutical composition comprising as an active ingredient an analgesic compound and a compound of the xanthine structure theobromine, in which the ratio of analgesic and xanthine derivative is (1-20): 1, preferably 10: 1.

The preparations according to the present invention contain as an analgesic compound morphine, aminophenazone, analgin, acetylsalicylic acid, indomethacin, ibuprofen, diclofenac, codeine, preferably analgin, ibuprofen, codeine; as the xanthine derivative - theobromine.

The preparations according to the present invention may contain as an additional active ingredient a antispasmodic, preferably papaverine, drotaverine or theophylline-7-acetate of drotaverine.

The above preparations can be successfully used to treat headaches and bone pains of various nature, toothache, pain after tooth extraction, arthralgia, ostealgia, pain associated with surgery and childbirth, as well as less severe pain caused by tumors.

The preparations according to the present invention can be made in various ways:

1. Three components are manufactured separately, but packaged together.

2. Two of the three components are optionally manufactured as one composition, the third component is manufactured separately, but packaged together.

3. All three components are in the same preparation. The dosage form may be a tablet, dragee, lozenge, pill, capsule, suppository, cream, solution, drops, emulsion, injection product, patch, eye drops.

These preparations contain, in addition to the active ingredients, the usual excipients.

The preparations of the present invention are illustrated by the following examples, not intended to be limiting. Dosage Forms

1) Tablets

Analgin 400 mg

Drotaverin 40 mg

Theobromine 40 mg

Microcrystalline cellulose 70 mg

Polyvinylpyrrolidone 20 mg

Polyvinylpolypyrrolidone 5 mg

Magnesium stearate 5 mg

Amidazofen 400 mg

Drotaverin 40 mg

Theobromine 40 mg

Microcrystalline cellulose 70 mg

Polyvinylpyrrolidone 20 mg

Polyvinylpolypyrrolidone 5 mg

Magnesium stearate 5 mg

2) Film coated tablets

Analgin 400 mg

Drotaverin 40 mg

Theobromine 40 mg

Microcrystalline cellulose 70 mg

Polyvinylpyrrolidone 20 mg

Polyvinylpolypyrrolidone 5 mg

Magnesium stearate 5 mg

Hydroxypropyl methylcellulose 9 mg

Polyethylene glycol 6 mg

Dye quinoline yellow 1 mg

3) Hard gelatin capsule

Indomethacin 40 mg

Drotaverin 40 mg

Theobromine 40 mg

Starch 198 mg

Lactose 150 mg

Microcrystalline cellulose 150 mg

Claims (5)

CLAIM 1. Pharmaceutical composition comprising morphine, aminophenazone, analgin, acetylsalicylic acid, indomethacin, ibuprofen, diclofenac or codeine as the analgesic active ingredient, and theobromine as the xanthine compound, in which the ratio of the analgesic active ingredient and theobromine is (1-20) 1, preferably 10: 1. 2. The pharmaceutical composition according to claim 1, comprising as analgesic active ingredient analgin, 8 (+) ibuprofen or diclofenac. 3. The pharmaceutical composition according to claims 1 and 2, comprising as an additional active ingredient an antispasmodic, preferably papaverine, drotaverin or theophylline-7 acetadate drotaverine. 4. The pharmaceutical composition according to claims 1 to 3, including the analgesic active ingredient, theobromine and a separately manufactured antispasmodic composition, in a common package. 5. The pharmaceutical composition according to PP.14, comprising of the analgesic active ingredient, theobromine and antispasmodic, two components in the form of a joint composition and the third in the form of a separate dosage form in the total package.