RU2497505C1 - New therapeutic composition for treating pain syndrome accompanying smooth muscle spasm - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and represents a therapeutic composition in the form of an orally dispersed tablet for treating a pain syndrome in smooth muscle spasm characterised by the fact that it contains a combination of hyoscine butylbromide and a non-steroidal anti-inflammatory drug (NSAID) in the therapeutically effective amounts as active ingredients and pharmaceutically acceptable additives.

EFFECT: invention provides the higher efficacy and improved bioavailability of the active ingredient.

5 cl, 6 ex, 1 tbl, 1 dwg

Description

The invention relates to the field of pharmaceuticals and medicine, in particular to the means used to treat pain with smooth muscle spasm, in particular, in such conditions as:

spastic dyskinesia of the biliary tract and gall bladder;

biliary colic;

cholecystitis;

intestinal colic;

renal colic;

pylorospasm;

algodismenorea;

irritable bowel syndrome.

The basis of such spastic conditions is spasm of smooth muscle of organs. It may be due to an increase in the level of response to irritation due to disturbances in the functioning of the links of the corresponding neuro-reflex arc. In addition, spasm can occur as a result of impaired functioning of the neuromuscular synapse with a change in the electrical potential of muscle cells or metabolic processes in individual muscle elements.

For example, dyskinesia of the biliary tract and gallbladder is a functional disorder of the motor function of the gallbladder and extrahepatic ducts, i.e. literally "traffic violation". In this case, it is a violation of the agreed contractions of the gallbladder and sphincters, allowing bile to exit the gallbladder into the duodenum.

The most common cause of biliary colic in adults is gallstones. The formation of gallstones occurs mainly in the gallbladder and is associated with metabolic disorders in which the chemical composition of bile is impaired. Such conditions can threaten, according to statistics, 5-10% of the population of any developed country.

Renal colic is a syndrome observed in a number of kidney diseases, the main manifestation of which is acute pain in the lumbar region. The most common causes of renal colic are kidney stone disease, hydronephrosis, nephroptosis - conditions in which urodynamics in the upper urinary tract are disturbed.

Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain, discomfort, bloating and impaired bowel behavior in the absence of any organic causes.

The prevalence of IBS among the population is 14-48%. In women, this pathology is observed 2-4 times more often than in men. According to some reports, for example, in the United States annually the cost of treating this disease is $ 2 billion

For the treatment of pain in such spastic conditions, antispasmodics are traditionally used. Usually they are used in a short course, until the pain is completely stopped, including in combination with painkillers.

Of the painkillers, NSAIDs are most common, including the following groups of drugs:

salicylates: acetylsalicylic acid (aspirin), diflunisal, lysine monoacetylsalicylate.

pyrazolidines: phenylbutazone.

derivatives of indolacetic acid: indomethacin, sulindac, etodolac.

derivatives of phenylacetic acid: diclofenac, aceclofenac.

oksikama: piroxicam, tenoxicam, lornoxicam, meloxicam.

derivatives of propionic acid: ibuprofen, naproxen, flurbiprofen, ketoprofen, thiaprofenic acid.

Antispasmodics (spasmolytica; Greek spasmos cramp, spasm + lytikos releasing, relieving) are medicines that reduce the tone and motor activity of smooth muscles and are used to prevent or eliminate spasms of smooth muscle organs. Examples of clinically significant effects of these drugs are: the elimination of pain caused by spasms of the muscles of the abdominal organs, improved ventilation of the lungs due to bronchospasm, bronchospasm, decreased blood pressure and increased blood flow in the peripheral vessels as a result of a decrease in vascular wall tone.

Myotropic S.S. reduce the tone of smooth muscle organs by directly affecting the biochemical processes taking place in smooth muscle cells. In experiments on isolated organs, they lower the tone of smooth muscles, blood vessels, bronchi, intestines, urinary and biliary tracts, etc. Under the conditions of the whole organism, separate groups of myotropic S.s. exhibit unequal tropism to various smooth muscle organs and in this regard are used mainly for certain indications.

Of the antispasmodics used in such conditions, it is possible to distinguish as Dietetel (pinaveria bromide), which relaxes mainly smooth muscles of the digestive tract, bile ducts; Duspatalin (mebeverine hydrochloride), which selectively affects the smooth muscles of the gastrointestinal tract (mainly the large intestine), eliminates its spastic contractions, but does not affect normal peristalsis; Otilonia bromide (Spasmomen), which selectively affects the smooth muscles of the gastrointestinal tract and is used to eliminate spastic pain and dyskinesias (hyperkinetic type) with esophagitis, gastritis, duodenitis, enteritis, irritable bowel syndrome, as well as other products (gimecromon, benzene , drotaverine hydrochloride, etc.)

Hyoscine butyl bromide (http://www.rlsnet.ru/mnn_index_id_1701.htm) has recently become one of the most common drugs.

Hyoscine butyl bromide was created in Germany in 1951.

Hyoscine N-butyl bromide is a derivative of the alkaloid hyoscine (scopolamine) bottled in nitrogen.

Unlike scopolamine, hyoscine N-butyl bromide is a quaternary ammonium compound that is poorly absorbed by ingestion and does not pass the blood-brain barrier. In vitro experiments have shown that hyoscine N-butyl bromide reduces the tone of smooth muscles, as a result of which it has been used in the treatment of abdominal pain caused by spasms of the gastrointestinal tract, including irritable bowel syndrome, and biliary and urinary tract spasms. Hyoscine N-butyl bromide exerts its effect due to the blockade of M-cholinergic receptors located in the intestinal muscles; its use is not associated with systemic side effects characteristic of other M-cholinergic blockers.

It is highly selective for M1 and M3 subtypes of receptors, which are most found in the upper sections of the gastrointestinal tract, gall bladder, and biliary ducts, which determines its frequent use in this pathology.

At the same time, it has a low systemic bioavailability, which leads to the variability of the manifestations of the action upon enteral administration.

Thus, the effectiveness of treatment with its help of known drugs in the form of tablets is not always evaluated as sufficient.

In addition, conventional tablets for oral administration are not always convenient for patients - they require drinking water, chewing tablets affect the teeth. Many people experience complications due to the need to swallow regular tablets, which are often quite large. Problems associated with not taking pills (difficulty breathing, choking caused by a clogged throat) often lead to non-compliance with the dosage and even refusal to take medication. These problems affect, in particular, children, the elderly, patients suffering from disorders of swallowing reflexes or pathologies that violate salivation.

For such groups of patients, rapidly dispersible forms are developed in the mouth.

RF patent 2424793 relates to a pharmaceutical composition in the form of a food film for oral administration, where the food film includes diclofenac in the form of free acid or diclofenac resinate in an amount of from 10 to 50 wt.% And a film-forming polymer in an amount of from 10 to 80 wt.% In the calculation on the dry weight of the resulting food film. The composition contains from 10 to 50 mg of diclofenac in a dissolved or uniformly dispersed state, while the food film has a thickness of 20-250 microns. The invention provides for the rapid decomposition of food film in the patient's oral cavity in less than 20 seconds.

Patent RU 2242968 C2 is known, which relates to a fast-dispersing solid dosage form which dissolves in the oral cavity within sixty (60), more preferably thirty (30), most preferably ten (10) seconds. Modified starch was used as the matrix, and hyoscine butyl bromide could be selected as the active substance.

Also known are Levsin sublingual tablets containing belladonna alkaloids as an active principle, and lactose, magnesium stearate, stearic acid, mannitol, starch and dye, which can be used in various spastic conditions, including irritable bowel syndrome, as auxiliary agents. (http://www.medapharma.us/products/pi/LevsinSLTablets_PI.pdf). It does not have a sufficiently effective effect to relieve intense pain.

Another new direction in the development of fast dispersible tablets are orodispersible tablets.

Due to the rapid destruction that becomes possible in the presence of saliva, the orodispersible tablet disintegrates into easily swallowed small particles within a few tens of seconds after ingestion. In the case of a form with instant release of the active substance, oral dispersion provides faster absorption by the body compared with swallowed forms due to the increase in the area of exchange with physiological fluids.

For example, the patent of the Russian Federation 2317812 is known, which discloses an orodisperse solid dosage form containing homogeneous granules of lactose and starch obtained by drying by co-spraying. A variety of pharmacologically active substances can be included as an active principle. However, these excipients may have a negative effect when used with irritable bowel syndrome.

Another approach to creating more effective pain relievers for smooth muscle spasms is to combine well-known drugs.

For example, a combination of diclofenac and pitophenone is known, which can be used for pain, for colic of the intestines, gall bladder and ureters (Modulatory effect of diclofenac on antispasmodic effect of pitofenone in cholinergic spasm, Kulkarni, SK, Indian Journal of Experimental Biology, Volume 42, Issue 6, June 2004, Pages 567-569).

As the closest analogue, Novigan in the form of tablets may be indicated, including NSAIDs, which is Ibuprofen, in combination with the antispasmodic Pitofenon and the anticholinergic-Fenpiverinia bromide (http://www.rlsnet.ru/tn_index_id_2346.htm). This drug has a lesser ulcerogenic effect, but is effective only for mild or moderate pain.

The objective of the present invention is to develop a more effective dosage form, which can be used to reduce pain in various spastic conditions of smooth muscles.

The problem is solved by a new drug composition in the form of an orodispersed tablet for the treatment of pain in case of smooth muscle spasm containing hyoscine butyl bromide and non-steroidal anti-inflammatory drug (NSAIDs) in therapeutically effective amounts and pharmaceutically acceptable excipients as active components.

Effect: increased efficiency, bioavailability, variability of action and reduction of side effects.

The drug composition is effective, for example, for the treatment of spastic dyskinesia of the biliary tract and gall bladder, biliary colic, cholecystitis, intestinal colic, renal colic, pylorospasm, algomenorrhea, irritable bowel syndrome.

As NSAIDs, for example, acetylsalicylic acid (aspirin), diflunisal, phenylbutazone, lysine monoacetylsalicylate, indolacetic acid derivatives (indomethacin, sulindac, ethodolac), phenylacetic acid derivatives, diclofencofenac (diclofencofenac), can be used lornoxicam, meloxicam), propionic acid derivatives (ibuprofen, naproxen, flurbiprofen, ketoprofen, thiaprofenic acid).

One of the preferred alternatives is a combination of hyoscine butyl bromide and diclofenac or its sodium salt.

The analgesic effect of NSAIDs is manifested to a greater extent with pains of weak and medium intensity, which are localized in muscles, joints, tendons, nerve trunks, as well as with headache or toothache, and to a lesser extent with severe visceral pain.

According to the present invention, the potentiating effect of this group on the effect of hyoscine butyl bromide was found even when drugs with a NSAID group weaker in analgesic effect were used. In this case, the combination can be used for both moderate and intense pain.

As a rule, NSAIDs show their pharmacological effect in high doses, which is due to the presence of a number of side effects. The main negative property of all NSAIDs is a high risk of developing adverse reactions from the gastrointestinal tract.

Therefore, the possibility of reducing them is an important task in the development of new drugs based on them. It was found that due to the introduction of hyoscine butyl bromide, the destruction of the cells of the gastric mucosa induced by NSAIDs is significantly reduced.

The composition according to the invention includes active substances in therapeutically effective doses. The indicated doses depend on the disease, the intensity of the pain, age and weight of the patient. On average, they make up 1-50 mg for butyl bromide hyoscine and from 1 to 1000 mg for NSAIDs. Doses of NSAIDs are approved for use and are known from the prior art, including from the FS. However, in the present invention, they can be reduced to 10% due to the synergy with hyoscine butyl bromide.

For example: ketorolac 10-30 mg, ketoprofen 25 mg, ibuprofen 400-700 mg; flurbiprofen 25-50 mg, acetylsalicylic acid 200-650 mg, phenoprofen 150-200 mg, naproxen 100-250 mg, etodolac 100-200 mg, diclofenac 2-200 mg, meloxicam 1-5 mg mg, nabumeton 800-1000 mg.

Another aspect of the invention is a dosage form for administering a drug composition. The proposed medicinal composition is made in the form of an orodispersed tablet, which not only reduces the ulcerogenic effect of NSAIDs, but also solves the problem of bioavailability and variability of the action of hyoscine butyl bromide.

Sugars such as lactose, sucrose can be used to create an orodispersible tablet; sugar alcohols, in particular mannitol, sorbitol, xylitol; silicon dioxide, stearic acid and its pharmaceutically acceptable salts, polyvinylpyrrolidone, microcrystalline cellulose, modified starches, sweeteners, flavoring and aromatic additives, etc.

One of the preferred options is the use of a drug composition in the form of an orodispersed tablet containing a combination of hyoscine butyl bromide and NSAIDs, the carrier of which is a composition of Mannitol, Aspartame, Crospovidone, Polyvinylpyrrolidone K30, Flavoring, colloidal silicon dioxide anhydrous.

One of the particular cases of the invention is a tablet containing hyoscine butyl bromide and diclofenac or its sodium salt with potassium polacrilin, with a ratio of diclofenac or its sodium salt with potassium polacrilin (1: 2) in the following components, wt.%:

Hyoscine butyl bromide 3.7-4.3 Diclofenac complex or diclofenac sodium with potassium polacriline 58.0-63.0 Mannitol 11/13/14.49 Aspartame 9.0-10.5 Crospovidone 6.08-6.72 Polyvinylpyrrolidone K30 1.9-2.1 Flavoring Additive 2.83-3.57 Silicon Colloidal Dioxide anhydrous 0.38-0.42

Orodispersed tablets are white, round, uncovered, flat tablets with a beveled edge.

Potassium Polacrillin (PP) is a monofunctional minimally cross-linked carboxylic acid-exchange resin obtained by co-polymerization of methacrylic acid with divinylbenzene and subsequently neutralized with potassium hydroxide:

PP is an effective disintegrating agent in a low concentration in various formulations in the form of tablets, including many hydrophobic formulations, where standard disintegrating agents are not very effective.

In the claimed composition, it can be used to obtain a complex with diclofenac or its sodium salt - diclofenac resinate.

Mannitol has an additional stabilizing effect on the composition.

Aspartame sugar substitute is used in this form as a digestible low-calorie sweetener, providing acceptable palatability in combination with other ingredients.

In the proposed composition, the optimal combination of two types of polyvinylpyrrolidone - Crospovidone and Polyvinylpyrrolidone K30 was also selected. The specified combination provides the required compressibility, stability, and also affects the taste of the tablets.

As a flavoring additive, you can enter food acceptable additives, such as lemon, tangerine, blueberry, peppermint, etc., preferably dry mint.

Anhydrous colloidal silicon dioxide was introduced into the composition as an antifriction and dispersing component, for example, Aerosil 200 brand dioxide can be used.

A method of producing tablets is as follows.

Mannitol is mixed, anhydrous colloidal silicon dioxide, a 20% solution of K30 polyvinylpyrrolidone, and the mixture is granulated by spraying in a fluidized bed. Separately, the previously prepared diclofenac or diclofenac sodium complex is mixed with potassium polacrilin (Diclofenac resinate or sodium diclofenac resinate) taken at a ratio of 1: 2 with hyoscine butyl bromide, crospovidone, aspartame and a flavoring.

Combine the resulting mixture and mix until a homogeneous state is obtained. The mixture is tabletted by the compression method in two stages: preliminary compression with a force of 2-3 kN and final compression with a force of 8-10 kN. The hardness of the tablets is 25-44 N.

Examples of carrying out the invention.

Example 1

Hyoscine butyl bromide 3.7 Diclofenac complex or diclofenac sodium with potassium polacriline 63.0 Mannitol 11/13 Aspartame 9.0 Crospovidone 6.08 Polyvinylpyrrolidone K 30 1.9 Dry mint 2.83 Aerosil 200 0.38

Stage A: Granulation

Weighing and sieving fillers for the granulation process:

Mannitolum (13.11 kg)

Aerosil 200 (0.38 kg)

Polyvinylpyrrolidone K30 (PVP K 30) (1.9 kg)

All suspended material is sieved through a 40 mesh strainer. The fluidized bed granulator is preheated before filling the mixture and before spraying the solution of the sprayed material to begin to flow the mixture of Mannitol and Aerosil 200 for at least 3 minutes.

Obtaining a 20% PVP K30 solution using purified distilled water according to the European Pharmacopoeia standard. Spraying a solution of spray material into a fluidized bed granulator tank. The moisture content in the granulate is between 1.0 and 3.0%.

Stage B: obtaining the Complex Diclofenac Sodium Resinate

Sodium Diclofenac (21.0 kg) and Potassium Polacrillin (42.0 kg) are weighed and sieved. Sifted Potassium Polacrillin is slowly added to warm purified distilled water (temperature from 35 ° C to 40 ° C) to the aforementioned distilled water with stirring and stirring is continued for 2 hours. Slowly add Diclofenac Sodium to the above resin solution with stirring. The pH of the solution of Diclofenac Sodium - Resin should be 5-6.

Stirred for 2 hours at a temperature between 35 ° C and 40 ° C.

Leave the mixture overnight. The Diclofenac Sodium - Resin complex will be stabilized, and a pop-up liquid will be present on the upper layer of the paste. Drain pop-up liquid. The paste is dried at a temperature of 60 ° C for 30 minutes or until the loss upon drying is NMT 3.0%.

The chemical reaction of the Diclofenac Sodium Complex - Rubber is indicated:

Stage C: Final Mixing

Weighing and sieving the active substances and the rest of the excipients:

Diclofenac Sodium Complex with Potassium Polacrilin,

hyoscine butyl bromide (3.7 kg)

Crospovidone (6.08 kg)

Aspartame (9 kg)

Dry Mint Flavor (2.83 kg)

All suspended materials are sieved through a 40 mesh strainer. Crospovidone, aspartame, Dry Mint flavor, Rezinat Sodium Diclofenac Complex and Hyoscine butyl bromide with Stage A granules in a blender are mixed for 50 minutes so that a homogeneous powdery mixture is mixed.

Stage D: Tableting

The method used to produce tablets is compression using a SMART Kilian 250 rotary tablet press. Compression is carried out in two stages: pre-compression and final compression. Conditions: the main compression force is 8-10 kN, the preliminary compression force is 2-3 kN. The hardness of the tablets is 40 N.

Example 2

Hyoscine butyl bromide 4.0 Diclofenac complex or diclofenac sodium with potassium polacriline 60.0 Mannitol 13.8 Aspartame 10.0 Crospovidone 6.4 Polyvinylpyrrolidone K30 2.0 Dry mint 3.4 Silicon Colloidal Dioxide anhydrous 0.4

Example 3

Hyoscine butyl bromide 4.3 Diclofenac complex or diclofenac sodium with potassium polacriline 58.0 Mannitol 14.49 Aspartame 10.5 Crospovidone 6.72 Polyvinylpyrrolidone K30 2.0 Dry mint 3.57 Silicon Colloidal Dioxide anhydrous 0.42

Example 4

Hyoscine butyl bromide 3.7 Acetylsalicylic acid 61.1 Sorbitol fifteen Aspartame 9.0 Crospovidone 6.0 Polyvinylpyrrolidone K30 1.9 Dry mint 2.9 Aerosil 200 0.4

Example 5

Hyoscine butyl bromide 4.3 ketoprofen 20.0 Mannitol 13.0 Aspartame 9.0 MCC 45.8 Polyvinylpyrrolidone K30 1.9 Dry mint 3 Aerosil 200 2.0

Example 6

To evaluate the antispasmodic and analgesic effects of substances in experiments on rodents (mice, rats), the method of inducing painful spasms (convulsions) of the abdominal wall by intraperitoneal (ip) administration of acetic acid solution is widely used. Convulsive contractions caused by acetic acid are evaluated visually, are easily counted over a specific period of time (usually 10-30 minutes), and the analgesic or antispasmodic effect is evaluated by the reduction in the number of seizures compared to control animals.

The experiments were carried out in accordance with the Guidelines for the experimental (preclinical) study of new pharmacological substances (edited by R.N. Khabriev, Moscow, 2005). Animals (80 mice in total) were divided into groups of 10 animals each. Test solutions of substances were encrypted by the study leader. The experiments were conducted by a researcher who did not know what substance was injected into mice (blind method). The groups of animals were decrypted after all the data were received.

1 group, 10 mice. Animals in this group received 1% starch paste.

2 group, 10 mice. Animals of this group received diclofenac 10 mg / kg.

3 group, 10 mice. Animals of this group received diclofenac 2.5 mg / kg

4 group, 10 mice. Animals of this group received diclofenac 10 mg / kg + hyoscine N-butyl bromide 2 mg / kg.

5 group, 10 mice. Animals of this group received diclofenac 2.5 mg / kg + hyoscine N-butyl bromide 2 mg / kg

6 group, 10 mice. Animals of this group received hyoscine N-butyl bromide 2 mg / kg

Group 7, Animals of this group received ketoprofen 10 mg / kg + hyoscine N-butyl bromide 2 mg / kg.

8 group, Animals of this group received acetylsalicylic acid 20 mg / kg + hyoscine N-butyl bromide 1 mg / kg.

All substances were injected into mice into the stomach using a metal probe for mice (FTSS-20S-38) from Salomon Scientific (USA) in a volume of 0.2 ml per 10 g of body weight. The control group was administered 1: starch paste in the same volume. After 1 hour after the introduction of this solution of substances, mice were injected intraperitoneally with a 0.75% solution of acetic acid at the rate of 0.1 ml per 10 g of animal body weight and the number of writhing in each animal was counted over 15 minutes.

Study results and discussion of results

Table 1 The effect of the test substances on the number of writhing caused by ip administration of 0.75% acetic acid in mice. The mean values ± standard errors of the mean value (M ± m) are given for groups of 10 animals N groups Test substances and doses The average number of “writhing” in 15 minutes and the standard error for it. M ± m Significant difference with control one Control: acetic acid 32.80 ± 1.227 2 hyoscine N-butyl bromide 2 mg / kg 22.40 ± 0.9092 p <0.001 3 Diclofenac 2.5 mg / kg 29.90 ± 0.8226 P> 0.05 (nd)

four Diclofenac 10 mg / kg 10.60 ± 1.869 P <0.001 5 Diclofenac 2.5 mg / kg + hyoscine N-butyl bromide 2 mg / kg 24.10 ± 0.8750 P <0.001 6 Diclofenac 10 mg / kg + hyoscine N-butyl bromide 2 mg / kg 6.80 ± 1.672 P <0.001 7 Ketoprofen 10 mg / kg + giscin N-butyl bromide 2 mg / kg 6.60 ± 1.852 P <0.001 8 Aspirin 20 mg / kg + hyoscine N-butyl bromide 1 mg / kg 9.74 ± 1.638 P <0.001

Statistical analysis of the data showed that the combination of NSAIDs + hyoscine N-butyl bromide showed a statistically significant decrease in the number of writhing in mice.

The indicators of one-way analysis of variance were: F2.29 = 103.7 (p <0.0001), a subsequent analysis of the action of individual groups using the Bonferroni test revealed a highly reliable effect of the combination in doses of diclofenac 2.5 mg / kg + hyoscine N-butyl bromide 2 mg / kg (p <0.001) and diclofenac 10 mg / kg + hyoscine N-butyl bromide 2 mg / kg (p <0.001).

A one-way variational analysis of the effects of separately administered diclofenac also revealed a statistically significant inhibitory effect of the substance: F2.29 = 76.96 (p <0.0001), however, subsequent analysis of the effect of individual groups using the Bonferroni test showed a statistically significant effect of only a dose of 10 mg / kg diclofenac ( p <0.001), and the dose of 2.5 mg / kg did not have a statistically significant effect.

Hyoscine N-butyl bromide at a dose of 2 mg / kg also exerted a depressing effect (p <0.001, Student's t-test) on cramps caused by acetic acid in mice.

The next step in the analysis was to compare the efficacy of the diclofenac + hyoscine N-butyl bromide combination with the action of the separately administered diclofenac. For this, a two-way analysis of variance was used where one factor was “substance” and another factor was “dose”.

The analysis showed a highly reliable effect of the substance factor: Fl, 36 = 5.36 (p = 0.0015), a strong dose effect: F1.36 = 77.96 (p = 0.0001), and the absence of the “substance” x “dose” interaction ": F3.36 = 0.23 (p = 0.4). Thus, the action of the combination of diclofenac + hyoscine N-butyl bromide statistically more effectively inhibits writhing caused by acetic acid than separately administered diclofenac.

The next step was to compare the strength of the combination of diclofenac + hyoscine N-butyl bromide with separately administered hyoscine N-butyl bromide. Since hyoscine N-butyl bromide was studied in only one dose, a one-way analysis of variance was applied in which the effect of the combination was compared with the action of hyoscine. Statistical analysis showed a statistically significant stronger effect of the combination: F2.29 = 62.17, p <0.0001, and Bonferroni analysis revealed a statistically stronger combination of Diclofenac 10 mg / kg + hyoscine N-butyl bromide 2 mg / kg compared to a dose of 2 mg / kg hyoscine N-butyl bromide (p <0.001). The combination of Diclofenac 2.5 mg / kg + hyoscine N-butyl bromide 2 mg / kg did not statistically differ from the separately administered hyoscine N-butyl bromide.

Comparison of the action of substances on the strength of the inhibitory effect on cramps is summarized in the figure. In this graph, cramps caused by acetic acid in the control group are taken as 100% and the effect of substances and their combinations is expressed as a percentage of the control.

Data are presented as a percentage of control taken as 100%. Each group consisted of 10 mice.

As can be seen from the figure, the studied substances and their combinations according to the strength of the inhibitory effect on cramps are located in the following order:

Diclofenac 10 mg / kg + hyoscine N-butyl bromide 2 mg / kg> Diclofenac 10 mg / kg> hyoscine N-butyl bromide 2 mg / kg = diclofenac 2.5 mg / kg + hyoscine N-butyl bromide 2 mg / kg> Diclofenac 2, 5 mg / kg.

Claims (5)

1. A drug composition in the form of an orodispersed tablet for the treatment of pain in case of smooth muscle spasm, characterized in that it contains a combination of hyoscine butyl bromide and a non-steroidal anti-inflammatory drug (NSAID) in therapeutically effective amounts as active ingredients and pharmaceutically acceptable excipients. 2. The drug composition according to claim 1, characterized in that it is used to treat spastic dyskinesia of the biliary tract and gall bladder, biliary colic, cholecystitis, intestinal colic, renal colic, pylorospasm, algomenorrhea, irritable bowel syndrome. 3. The drug composition according to claim 1, characterized in that it contains as an NSAID, an agent selected from the group: acetylsalicylic acid (aspirin), diflunisal, lysine monoacetylsalicylate, phenylbutazone, indole acetic acid derivatives (indomethacin, sulindac, etodolac), phenyl derivatives (diclofenac, aceclofenac), oxicams (piroxicam, tenoxicam, lornoxicam, meloxicam), propionic acid derivatives (ibuprofen, naproxen, flurbiprofen, ketoprofen, thiaprofenic acid). 4. The drug composition according to claim 1, characterized in that it contains diclofenac or its sodium salt as a complex with potassium polacriline as an NSAID in the ratio of diclofenac or its sodium salt with potassium polacrilin 1: 2. 5. The drug composition according to claim 4, characterized in that it contains mannitol, aspartame, crospovidone, polyvinylpyrrolidone K 30, a flavoring agent and anhydrous colloidal silicon dioxide as the pharmaceutically acceptable excipients in the following components, wt.%:
Hyoscine butyl bromide 3.7-4.3 Diclofenac complex or diclofenac sodium with potassium polacriline 58.0-63.0 Mannitol 13.11-14.49 Aspartame 9.0-10.5 Crospovidone 6.08-6.72 Polyvinylpyrrolidone K30 1.9-2.1 Flavoring Additive 2.83-3.57 Silicon Colloidal Dioxide anhydrous 0.38-0.42

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