RU2182016C2 - Spasmolytic composition, method to obtain spasmolytic composition - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: the composition is suggested including, at least, one of steroid-free antiphlogistic preparations, their salts, their pure forms, their isomers, derivatives, analogs and adducts, and two other preparations as pitophenone hydrochloride and phenpiverinium bromide at pharmaceutically acceptable combination. It is, also, suggested the method to obtain the composition mentioned by mixing ingredients and, if necessary, addition of supplementary substances to obtain different medicinal forms. EFFECT: increased spasmolytic efficiency. 24 cl, 2 tbl, 5 ex

Description

 The invention describes a new composition comprising a non-steroidal anti-inflammatory drug, its salts, its chiral pure forms, isomers and derivatives, their analogues and adducts, and two drugs pitophenone hydrochloride and fenpiverinium bromide in a pharmaceutically acceptable combination.

 Among the various non-steroidal anti-inflammatory drugs, diclofenac, in particular diclofenac sodium, is widely used in the treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. This has been described in the following references (references from US Pat. US Pat. No. 5,202,159). As such, intestinal, renal and biliary colic are common clinical conditions and require urgent medical intervention to alleviate symptoms and help patients return to his or her work and avoid or minimize economic losses and reduce the burden on the medical institution. Conservative treatment can give immediate relief to the patient while studies are being conducted to determine the future treatment method. Modern methods of treatment include the use of anticholinergics, such as atropine and its derivatives, ambutonium, glycopyrronium, isoperopamide, etc. Combined therapy with analgin, pitophenone, and fenpiverine is also used. In addition, also in combination with them, such drugs as mebeverine valetamate bromide, wedinium are used.

 All these drugs do not give the same predicted results in all patients. All drugs used in these conditions have some side effects. Anticholinergics cause dry mouth, tachycardia in some patients, they are contraindicated in glaucoma and prostatic hypertrophy, and other antispasmodic agents can cause drowsiness as a side effect. Analgin may cause bone marrow suppression.

 A comprehensive review of the pharmacological properties of diclofenac (Brogden et al., Drugs 2024-48 (1980) noted its anti-inflammatory activity, analgesic activity and antipyretic activity. It has usually been used in clinical settings for rheumatic diseases. Recently, reports have been reported of its use in painful non-rheumatic syndromes for example, with biliary colic [Grossi et al. Current Therapeutic Research, volume 40, 5, (1986)] and acute renal colic [Garcia Alonso F. et al., Eur. J. Clin. Pnarmacol., 40, 543-546 (1991)].

 However, it was reported that Diclofenac Sodium is more effective for intramuscular administration than narcotic analgesics like pethidine for intramuscular administration in the treatment of acute renal colic and has fewer side effects. Based on marketing research of various products available on the market as an antispasmodic, the main product consists of Analgin with two antispasmodic agents, i.e. pitophenone hydrochloride and fenpiverinium bromide.

 There have been no reports of a pharmacological composition in the literature, nor is there a product on the market that uses non-steroidal anti-inflammatory drugs (NSAIDs) such as Diclofenac and Nimesulide in combination with antispasmodic agents.

 The data described in this patent application show that NSAIDs, including Diclofenac and Nimesulide, in combination with fenpiverinium / bromide and pitophenone hydrochloride form an excellent antispasmodic composition.

 After a considerable investment of time, intellectual abilities, and thorough experiments, the inventors surprisingly discovered that Diclofenac several times enhances the antispasmodic effect of pitophenone hydrochloride and fenpiverinium bromide. In addition, the safety of the combination has been proven in experimental animal models. After that, the effectiveness of this combination was established by conducting clinical trials in human volunteers. When administered orally and parenterally, the composition is not only clinically effective, but also superior to existing therapeutic agents. It has advantages in two aspects: firstly, it has a more effective effect, and secondly, it has fewer side effects.

 Thus, the aim of the present invention is the provision of a new antispasmodic composition comprising non-steroidal anti-inflammatory drugs, their salts, their chiral pure forms, isomers and their derivatives analogues and adducts, as well as pitophenone hydrochloride and fenpiverinium bromide.

 Another objective of the present invention is the provision of a method of manufacturing a new antispasmodic composition comprising diclofenac and pitophenone hydrochloride and fenpiverinium bromide.

 Another objective of the invention is the provision of a new injection system for the delivery of an antispasmodic composition.

 Another objective of the invention is the provision of an antispasmodic composition, which can be taken orally in the form of a pediatric suspension, capsule or tablet.

 An antispasmodic composition comprising non-steroidal anti-inflammatory drugs, their salts, their chirally pure forms, isomers and their derivatives analogues and adducts, and two drugs pitophenone hydrochloride and fenpiverinium bromide in a pharmaceutically acceptable combination. The composition may be used in a dosage form for oral and parenteral use.

 The various non-steroidal anti-inflammatory drugs that can be used in the present invention can be divided into two groups: phenylacetic acid derivatives and sulfonanilides. Nonsteroidal anti-inflammatory drugs that can be used together with pitofenone hydrochloride and fenpiveriny bromide in the present invention are selected from the following group: diclofenac, diclofenac sodium, diclofenac potassium, etolodak, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketrolak, trometamol, mefenamic acid, nabumetone, naproxen , naproxen sodium, nimesulide, piroxicam, sulindac, zomiperac sodium, piroxicam cyclodextrin. To identify the effect of NSAIDs on the antispasmodic activity of pitophenone hydrochloride and fenpiverinium bromide, an experiment was conducted on standard isolated tissues of an experimental animal. The tissue selected for the experiment was the distal part of the rat colon. The NSAID chosen for the experiment was diclofenac sodium.

 We studied the percentage inhibition caused by acetylcholine reduction (at a dose of 100 ng / ml) at various concentrations of pitophenone hydrochloride in a dose range of 10 to 80 ng / ml.

 Then the experiment was carried out at the same dose level of acetylcholine and pitophenone hydrochloride, but in the presence of diclofenac sodium (dose level 20 μg / ml). The results obtained in the experiment are summarized in table 1. The results clearly show that diclofenac has a synergistic (potentiating) effect with pitophenone hydrochloride as an antispasmodic when tested in the colon of rats.

 We studied the percentage inhibition caused by acetylcholine reduction (at a dose level of 100 ng / ml) at various concentrations of fenpiverinium bromide in the dose range from 0.5 to 2 ng / ml.

 Then, an experiment was conducted at the same dose level of acetylcholine and fenpiverinium bromide, but in the presence of diclofenac sodium (dose level 20 μg / ml). The experimental data are summarized in table 2. The data clearly indicate that diclofenac exhibits a synergistic (potentiating) effect with fenpiverinium bromide as an antispasmodic when tested on the colon of rats.

 In addition, to assess the safety of the new combination of the present invention, subchronic toxicity studies were conducted on oral administration (28 days) of free acid diclofenac rats, pitophenone hydrochloride and fenpiverinium bromide. For the study, 25 males and 25 female rats were selected. Animals were kept in appropriate conditions. They were divided into 5 groups of five males and five female rats.

 Each group received the following treatment (see table. L).

 Animals were weighed every day and observed, daily determining appearance, activity and behavior and every week - body weight. There were no cases of animal death during the study.

 At the end of the fourth week, bloodletting from the heart was performed in all animals and blood was collected for biochemical and hematological studies. When comparing with control, no pathology was observed in any of the studied groups. This established the safety of the combination.

 Several formulations can be made in tablet or injection form, including three ingredients: diclofenac and similar non-steroidal anti-inflammatory drugs and their salts, pitophenone hydrochloride and fenpiverinium bromide.

 In addition to the ingredients mentioned above, the composition also includes conventional excipients, such as starch, microcrystalline cellulose, dicaprylphthalate, purified talc, magnesium stearate, etc., as described in the standard text. The tablets may be soluble or film-coated, sugar-coated or coated with special coatings as described in the prior art (Pnarmacetical Dosage forms: Tablets, vol. 1-3, Eds., H. A. Liberman and L. Lachman Dekker New York).

 As described above, the composition can be used in tablet form and in injectable form. The composition of the invention may also be in any form commonly used for administration, i.e. drinking solution or suspension, concentrated drinking solution to be diluted before use, solution or suspension encapsulated in soft gelatine capsules, granules, syrups, liquids, suspensions, elixirs, caplets, powders, chewing gum, wafers, lozenges, lyophilized oral solutions or injectable dosage forms. The pharmaceutical composition may also contain flavors, colorants and / or sweeteners.

 Such compositions may be administered orally or intramuscularly, they may also be administered in the form of modified release formulations of delayed release, controlled release dosed at the time of release. They can also be administered intraocularly, intranasally, buccally, sublingually, transdermally, rectally, vaginally and using other related routes of administration.

In tablet form, the concentration of the three ingredients is as follows, wt. % / wt.%:
Nonsteroidal anti-inflammatory drugs and their salts - 6,188 - 61,88
Pitophenone hydrochloride - 0.39 - 12.38
Fenpiverinium bromide - 0.006 - 1.24
Tablets may contain specialized ingredients for modifying, slowing down or controlling the release of one or more ingredients to provide modified, delayed, or controlled release products. (Controlled Drug Devilery Fundamentals and Applications, second edition eds., JR Robinson and VHLee, Marsel Dekker, New York).

In the injectable form, the concentration of the ingredients is as follows, wt.% / Vol.%:
Nonsteroidal anti-inflammatory drugs and their salts - 1.0 - 10.0
Pitophenone hydrochloride - 0.05 - 2.0
Fenpiverinium bromide - 0.001 - 0.2
The carrier of the injectable preparation may consist of an aqueous, non-aqueous or specially formulated amphiphilic base containing suitable stabilizers, antioxidants, buffers and other additives. The drug (s) may be dissolved or suspended.

 The invention will now be described with reference to the following examples.

 Example 1. Obtaining dispersible antispasmodic tablets with diclofenac in the form of free acid as NSAIDs (see table.A).

 Example 2. Obtaining antispasmodic tablets with sodium diclofenac as NSAIDs (see tab. B).

 Stage 1. All ingredients are weighed and sieved through a mesh filter with a hole size of 60 (linear inch) (inch = 2.54 cm).

 Stage 2. Diclofenac sodium (5.0 kg) is mixed with microcrystalline cellulose (2.39 kg) and starch (6.6 kg).

 Stage 3. Pitophenone hydrochloride (0.5 kg) and fenpiverinium bromide (0.01 kg) are geometrically mixed and then added to the mixture obtained in stage 2.

 Stage 4. Prepare a solution of polyvinylpyrrolidone (0.3 kg) in isopropyl alcohol (5 l).

 Step 5. The mixture obtained in step 3 with a binder solution is granulated (mixture obtained in step 4).

Stage 6. The wet mass is passed through a sieve 18 to obtain granules that are dried at a temperature of 45-50 ^o C and sift the dry mass through a sieve 18.

 Step 7. Magnesium stearate (0.25 kg), purified talc (0.25 kg), sodium lauryl sulfate (0.15 kg) and sodium starch glycolate (0.15 kg) are passed through a size 60 strainer.

 Stage 8. The mass obtained in stage 1 is mixed with the mass obtained in stage 6.

 Stage 9. The mass obtained in stage 8 is pressed in a tablet machine into tablets with an average weight of 150.0 mg.

 Stage 10. The film coating solution is passed through a colloidal mill and the tablet core is coated with it.

 Example 3

 Obtaining antispasmodic tablets with nimesulide as NSAIDs (see table. B).

 Example 4. Preparation of an antispasmodic injection with diclofenac as NSAIDs (see table D).

Stage 1. Benzyl alcohol (1.8 kg) is distilled at a temperature of from 204 to 208 ^o C. the first and last portion is removed and stored under nitrogen.

 Stage 2. Diclofenac sodium (7.5 kg) is dissolved in water for injection (75.0 l) and heated, if necessary.

 Stage 3. Gasoline alcohol (1.536 kg) is dissolved in propylene glycol (120.0 l).

 Stage 4. The solution obtained in stage 3 is added to the solution obtained in stage 2 and mixed.

 Stage 5. Pitophenone hydrochloride (0.6 kg) is dissolved in water for injection (3.0 l), added to the solution obtained in stage 4 and mixed.

 Stage 6. Fenpiverinium bromide (0.06 kg) is dissolved in water for injection (1.0 L), added to the solution obtained in stage 5 and mixed.

 Stage 7. D-Mannitol (1.5 kg), sodium sulfite (0.3 kg) and disodium edetate (0.21 kg) are dissolved in water for injection (10.0 L), added to the solution obtained in stage 6 and mixed .

 Stage 8. The pH of the solution obtained in stage 7, if necessary, is adjusted to a level from 8.2 to 8.8 by the addition of hydrochloric acid.

 Stage 9. The volume is adjusted to 300.0 L by the addition of water for injection.

 Stage 10. The solution is sterilized by filtration under nitrogen using a preliminary filter with a pore size of 2 μm and a final filter with a pore size of 0.22 μm.

 Stage 11. The sterilized liquid is poured into amber colored ampoules (3.0 ml per ampoule), purged with nitrogen and sealed with an ampoule machine.

 Note: Steps 10 and 11 are carried out in an aseptic zone.

Example 5. Preparation of an antispasmodic injection with nimesulide as NSAIDs:
Component - Qty per 1 ml
1. Nimesulide, mg - 100
2. Pitofen hydrochloride, mg - 2.0
3. Fenpiverinium bromide, mg - 0.02
4. Benzyl alcohol, ml - 0.04
5. Benzyl benzoate, ml - 0.76
6. Dimethylacetamide, ml - 0.2 ml
7. Ethyl oleate, ml - Up to 2.0 ml
8. Benzenehexacarboxylic acid, mg - 0.002
Clinical trials
The following patients were included.

 Patients from the age group of 16 to 60 years.

 Non-pregnant women were also included.

 Patients with biliary, intestinal, or renal colic.

 Patients with any of the above conditions who could not be administered antispasmodic drugs belonging to the anticholinergic group (patients with glaucoma and prostatic hypertrophy) were also included in the trial.

 The following patients were excluded from the trial.

 Patients with peptic ulcer.

 Patients requiring emergency surgery for their underlying disease were also excluded from the study.

 Sample Size: Fifty Patients.

 Type of study: the study was open.

 The study included patients attending an outpatient department complaining of moderate to severe abdominal pain, with a diagnosis of one of the conditions listed in the inclusion criteria. According to the study protocol, patients could be hospitalized for an acute illness for observation and were allowed to parenterally administer drugs to relieve acute pain. If during observation for several hours the patient was relieved of pain, but required oral medication to continue pain relief after discharge from the hospital, the patient was prescribed test drugs if he met the inclusion criteria.

 The test drug was administered orally. The dose was one tablet three times a day for a maximum period of five days. Patients receiving the test drug were in the emergency room for observation until the patient had no symptoms of the disease.

 The protocol allowed parenteral antispasmodics to be administered to patients in cases of severe and causing disability colic. Such patients were discharged from the hospital and they were prescribed oral test drugs at a dose of one tablet three times a day for a maximum period of five days.

 During therapy, in accordance with the test protocol, the use of such drugs as antibiotics, urinary antiseptics, conservative therapy for gallstones, etc. continued at the same time. All special dietary restrictions / recommendations also continued to apply. Patients during the test were not allowed to simultaneously take any antispasmodics.

 Patients who did not respond to the test drugs for a period of two (2) hours were given parenteral analgesics. It was believed that such patients continued treatment, and they were not replaced by new patients.

All patients included in the trial had a history, conducted a clinical examination and received information about past drug therapy; this included information about:
1. The duration of the disease.

 2. The severity of pain.

 3. Frequency of taking antispasmodics.

 4. The duration of the use of antispasmodics.

 5. Improvement of well-being when using existing therapeutic agents: excellent, good, mediocre.

 6. The need for parenteral antispasmodics against the background of oral therapy.

 7. Side effects of the therapy.

The following parameters were used to determine the efficacy and safety of the test drug therapy:
1. Whether the patient received parenteral antispasmodics before oral therapy with test drugs.

 2. The severity of pain after the first dose.

 3. The speed of onset of relief.

 4. Did the patient need parenteral antispasmodics to relieve pain after the first dose of the test drug.

 5. The severity of pain at home after subsequent doses.

 6. Duration of administration of the test drug.

 7. Evaluation of the test drug by the patient.

 8. Evaluation of the test drug by the researcher.

Final grade
Excellent: the sharp pain disappeared in less than half an hour. There was no need for a parenteral drug to relieve pain. The drug was well tolerated without any side effects.

 Good: the acute pain disappeared after one to two hours without the need for a parenteral drug to relieve pain. The drug was well tolerated without any side effects.

 Bad: the drug is not effective in relieving pain. To eliminate the symptoms, the use of drugs for parenteral administration was required.

 Results.

 Total number of patients included: 50.

 Number of patients completing the study: 50.

 The distribution by diagnosis of the patients included in the test is given in table. II.

 According to the demographic data presented in the tables above, there is no statistically significant difference between the representatives of both sexes in terms of age, diagnosis and duration of the disease. However, there is a statistically significant difference in the average number of tablets per week taken to relieve renal colic in patients compared with men (p <0.05). Since there were no male patients with biliary colic, it is impossible to determine the difference between the two sexes.

 Almost all patients during the administration of antispasmodics needed parenteral administration of antispasmodics to relieve the symptoms of the disease. Although all patients could not remember exactly, the frequency of therapy with parenteral antispasmodics varied from once a month to two to four times every month.

 Most patients of both sexes equally noted a good reaction to ongoing antispasmodic drug therapy. Five patients with intestinal colic, three patients with renal colic and two patients with biliary colic reported an unpleasant side effect such as dry mouth and palpitations when taking anticholinergics.

 The need for additional parenteral administration of antispasmodics in this study.

 In this study, there were no patients requiring parenteral antispasmodics.

 The intensity of pain after the first dose (According to measurements on a visual analogue scale of 0-100 mm) (see table. 3).

 There was a statistically significant decrease in pain intensity in all groups of patients by the end of the first hour after the first dose. This indicates that the onset of action of diclofenac, pitophenone and fenpiverinium begins within this period of time.

The duration of the use of drugs in the hospital is hours
Symptom Duration
Intestinal colic - 2.8
Renal Colic - 3.9
Biliary colic - 4.3
Discharge pain intensity
Assessment of pain intensity
Intestinal colic - 7.75 **
Renal colic - 8.25 **
Biliary colic - 9.12 **
p ** <0.001
When measured using a visual analogue scale, a statistically highly significant decrease in pain was observed during discharge from the hospital.

Pain intensity on day 2-5
(When measured using a visual analogue scale of 0-100 mm) (see table. 4).

 All patients, according to measurements using a visual analogue scale, starting from the 2nd day onwards, there was practically no pain. All patients received the last dose of the test drug at approximately 8 pm on day 1. This shows that the duration of action of the test antispasmodic drug is more than 8 hours.

 Taking the test antispasmodic drug from the 1st to the 5th day (see table. 5).

 All patients, regardless of diagnosis, took three tablets on the 1st day and 2 tablets on the 2nd day. However, on day 3, patients with intestinal and renal colic took 1 tablet and did not take tablets at all on the 4th and 5th day, while patients with biliary colic continued to take 2 tablets on the 2nd and 3rd day and one pill on the 4th day. On the 5th day, patients with biliary colic did not need any medications.

 Patients were asked on the 5th day to bring a container with unused tablets to the clinic to determine the number of tablets that the patients actually took after discharge from the hospital.

Patient Evaluation
Worse than previous therapy - 0
Same as previous therapy - 24
Better than Prior Therapy - 22
Significantly better than previous therapy - 4
Evaluation of the test drug by the researcher
EXCELLENT (Relief of the sides <after 30 minutes) - 3
GOOD (pain relief after 1-2 hours) - 47
Side effects: in no patient observed side effects.

 Observations and comments.

 The combination of diclofenac + pitophenone and fenpiverinium in this open-label study yielded good results in patients of both sexes with intestinal, renal and biliary colic without any side effects.

Claims (21)

 1. An antispasmodic composition comprising an active agent, characterized in that the active agent contains at least one non-steroidal anti-inflammatory drug, its salts, its chiral-pure forms and two pitophenone hydrochloride and fenpiverinium bromide preparations.  2. The composition according to p. 1, characterized in that said non-steroidal anti-inflammatory drug is selected from the group comprising diclofenac, diclofenac sodium, diclofenac potassium, etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketrolac trometamol, mefenamone napromenone sodium, nimesulide, piroxicam, sulindac, zomiperac sodium, piroxicam dextrin.  3. The composition according to p. 1, characterized in that said non-steroidal anti-inflammatory drug is diclofenac in the form of a free acid and its salts.  4. The composition according to p. 3, characterized in that said diclofenac salts are sodium and potassium salts.  5. The composition according to p. 3, characterized in that the non-steroidal anti-inflammatory drug used in the composition is diclofenac sodium.  6. The composition according to any one of paragraphs. 1-5, characterized in that the composition is presented in tablet form. 7. The composition according to p. 6, characterized in that the ingredients are present in the following proportions, wt. % / wt. %:
Nonsteroidal anti-inflammatory drugs, their salts - 6,188 - 61,88
Pitophenone hydrochloride - 0.39 - 12.38
Fenpiverinium bromide - 0.006 - 1.24
Fillers and / or Additives - Else up to 100
8. The composition according to p. 6, characterized in that it includes ingredients for slowing down or controlling the release of one or more ingredients, providing products of delayed or controlled release.  9. The composition according to p. 1, characterized in that the composition is presented in the form of a solution for injection. 10. The composition according to p. 9, characterized in that the composition contains ingredients in the following proportions, wt. %/about. %:
Nonsteroidal anti-inflammatory drugs, their salts - 1.0 - 10.0
Pitophenone hydrochloride - 0.05 - 2.0
Fenpiverinium bromide - 0.001 - 0.2
Carrier and / or Base - Remaining up to 100
11. The composition according to p. 1, characterized in that it is presented in the form of a solution for drinking, a concentrated solution for drinking, to be diluted before use, a solution encapsulated in soft gelatin capsules, a lyophilized solution for oral or injection dosage forms, granules and systems controlled delivery of drugs, syrups, suspensions, elixirs, caplets, powders, chewing gum, wafers and lozenges.  12. The composition according to p. 11, which includes flavors, colorants and / or sweeteners.  13. An antispasmodic composition comprising the active ingredient, characterized in that the active ingredient comprises diclofenac sodium, its chiral pure forms and two preparations — pitophenone hydrochloride and fenpiverinium bromide.  14. An antispasmodic composition comprising the active ingredient, characterized in that the active ingredient comprises nimesulide, its chiral pure forms and two preparations — pitophenone hydrochloride and fenpiverinium bromide.  15. A method for producing an antispasmodic composition, which comprises mixing together at least one non-steroidal anti-inflammatory drug, its chiral-pure forms, and two other drugs — pitophenone hydrochloride and fenpiverinium bromide under ordinary conditions.  16. The method according to p. 15, which includes introducing the composition into a carrier suitable for injection.  17. The method of claim 15, which comprises separately dissolving the non-steroidal anti-inflammatory drug in a solvent, mixing pitophenone hydrochloride with said dissolved non-steroidal anti-inflammatory drug, adding fenpiverinium bromide to the mixture to form the desired composition for injection.  18. The method according to p. 15, characterized in that said non-steroidal anti-inflammatory drug is selected from the group consisting of diclofenac, diclofenac sodium, diclofenac potassium, etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketrolac trometamol, mefrocenamone napromenone sodium, nimesulide, piroxicam, sulindac, zomiperac sodium, piroxicam cyclodextrin.  19. The method according to p. 18, characterized in that said non-steroidal anti-inflammatory drug is diclofenac and its salts.  20. The method according to p. 19, characterized in that the non-steroidal anti-inflammatory drug used in the composition is diclofenac sodium. 21. The method according to p. 16, characterized in that the composition for injection includes ingredients in the following proportions, wt. %/about. %:
Nonsteroidal anti-inflammatory drugs, their salts - 1.0 - 10.0
Pitophenone hydrochloride - 0.05 - 2.0
Fenpiverinium bromide - 0.001 - 0.2
Carrier and / or Base - Remaining up to 100
22. The method according to p. 15, characterized in that the method includes subsequent tableting of the composition.  23. The method according to p. 22, characterized in that it includes mixing a non-steroidal anti-inflammatory drug with an excipient and a binder, adding to it a mixture of pitophenone hydrochloride and fenpiverinium bromide, separately preparing a mixture of polyvinylpyrrolidone in a solvent and mixing it with said mixture of three drugs, granulating the mixture adding lubricant, a gloss and a dissolution enhancer to it, and preparing tablets in the usual manner. 24. The method according to p. 22, characterized in that the ingredients of the tablet composition are present in the following proportions, wt. % / wt. %:
Nonsteroidal anti-inflammatory drugs, including diclofenac and its salts - 6.188 - 61.88
Pitophenone hydrochloride - 0.39 - 12.38
Fenpiverinium bromide - 0.006 - 1.24
Fillers and / or Additives - Else up to 100

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