WO2006046933A1

WO2006046933A1 - Sedative and spasmolytic medicinal agent and method for the production thereof (variants)

Info

Publication number: WO2006046933A1
Application number: PCT/UA2005/000046
Authority: WO
Inventors: Viktor Olexandrovych Rybchuk
Original assignee: Viktor Olexandrovych Rybchuk
Priority date: 2004-10-26
Filing date: 2005-10-26
Publication date: 2006-05-04
Also published as: RU2007118240A; RU2349334C2; GEP20084424B

Abstract

The invention relates to medicine. The inventive sedative and spasmolytic medicinal agent comprises an α bromomethyl butanoic acid ethyl ether, phenobarbital, brandy mint oil, microcrystalline cellulose and adjuvants for forming solid dosage form (pills) which are coated with a shell containing β cyclodextrine or the derivatives thereof. The first variant of a method for producing said medicinal agent consists in mixing the α bromomethyl butanoic acid ethyl ether with the brandy mint oil, wherein the quantity of said mixture is equal to 4.5 % of the total pill mass, in adding said mixture into the humidified β cyclodextrine, stirring for 1-2 minutes, drying, granulating, in mixing the granulate with the phenobarbital, microcrystalline cellulose and adjuvant powders, in pressing a pill and in coating said pill with the β cyclodextrine-containing shell. The second variant of said method consists in mixing the phenobarbital with the adjuvant-filler, in separately preparing the mixture of the α bromo-methyl butanoic acid ethyl ether and the brandy mint oil, in adding the microcrystalline cellulose, developed crystal face powders, openers and sliding agents, in adding said mixture into the phenobarbital-filler mixture, in pressing a pill and in coating said pill with the β cyclodextrine-containing shell.

Description

MEDICINAL PRODUCT OF SEDATIVE AND SPASMOLITIC ACTION AND METHOD OF ITS PRODUCTION (OPTIONS)

The invention relates to medicine, in particular to medicines containing organic active ingredients, namely, drugs exhibiting a sedative, vasodilator and antispasmodic effect, and methods for their preparation, and can be used to treat neurosis with increased irritability, increased irritability , insomnia, neurocirculatory dystonia, early stages of hypertension, not pronounced spasm of the heart vessels, spasms of the digestive tract, sv neurovegetative disorders associated with.

The increase in the number of neuroses, often combined with somatic pathology, in particular, with diseases of the cardiovascular system, necessitates the improvement of existing and the creation of new drugs with complex effects for their treatment.

For the treatment of this pathology, as a rule, myotropic drugs (antispasmodics) are used, acting mainly on blood vessels, and neurotropic drugs acting on the nervous system - sedatives, hypnotics, tranquilizers.

Sedatives (sedatives) are divided into herbal and synthetic. Sedative herbal remedies are obtained from medicinal valerian, canine nettle, lemon balm, peppermint, passionflower. In particular, the rhizomes and roots of Valerian officinalis contain an essential oil, the main component of which is the ester of borneol and isovalerianic acid, as well as valerianic acid, borneol, organic acids, tannins, which exhibit a sedative and antispasmodic effect. Synthetic sedative drugs include bromide, barbiturates in small doses.

There are also combined drugs that have both antispasmodic and sedative effects.

Known combination drug "Valocordin" containing: phenobarbital 2, 0 g; ethyl bromisovalerianate 2.0 g; peppermint oil 0.14 g: hop oil 0.02 g

[Modern medicines. The latest reference. Owl, St. Petersburg, - 2002, p. 149-150].

Known combination drug "Corvalol", which contains: ethyl ester of α-bromisovalerianic acid 20.0 g; phenobarbital 18.26 g; peppermint oil 1, 42 g; rectified ethyl alcohol 580 ml; stabilizer 0.2 g; purified water to 1.0 l.

[Modern medicines. The latest reference. "Owl", St. Petersburg, - 2002, p. 366-367].

Also known is the combined drug Corvaldin, containing: ethyl ester of α-bromisovalerianic acid 20.0 g; phenobarbital 18.0 g; sodium hydroxide 3.15 g; peppermint oil 1.4 g; hop oil 0.2 g; ethyl alcohol 96% or rectified ethyl alcohol 620 ml; stabilizer 0.2 g; purified water to 1.0 l.

[Instructions for medical use of the drug, JSC "F APMAK", Kiev, Ukraine].

The effects of these drugs are determined by the active substances that make up their composition.

Ethyl α-bromisovalerianic acid, which is part of Corvalol and Corvaldin, is a sedative and antispasmodic and acts like an extract of valerian.

Phenobarbital, which is ingested when taking Corvalol, Corvaldin, and Valocordin, has a mild sedative and vasodilating effect.

Peppermint oil, which has a reflex vasodilator and antispasmodic effect, it is recommended to use for nervous agitation, insomnia, various neurotic conditions as a vasodilator in angina pectoris and diseases associated with spasms of the cerebral vessels.

Hop oil, which is part of Corvaldin and Valocordin, has a mild sedative effect. Ethyl bromisovalerianate, which is part of Valocordin, has a sedative antispasmodic effect.

Closest to the proposed invention is a tool for the prevention and treatment of pathology of the nervous and cardiovascular system "Nikorval", containing May. %: ethyl ester of α-bromisovalerianic acid 0.5 to 3.0; phenobarbital 1.5-2.0; sodium hydroxide 0.2 to 0.4; peppermint oil 0.08 - 0.16; nifedipine 0.8 - 2.0 ethyl alcohol 96% 45 - 65; water 30 to 50.

[Declaration Patent of Ukraine N ° 32319, A61K 31/21, 1999].

Nifedipine, which is part of Nikorval, has a vasodilating and anti-ischemic effect, lowers blood pressure.

The specified prototype, like all previous analogues, is available in the form of a solution and is used as drops with a small amount of water. However, the use of drops is not always convenient because of the impossibility of ensuring the exact dosage, indiscretion or inexperience of the patient preparing the drug, or its critical condition, or inconvenience when using the drug on the road. In addition, as part of Nikorval, ethyl alcohol of 96% was used to dissolve ethyl ester of α-bromisovalerianic acid, which, when used, leads to drying of the mucous membranes of the mouth and throat.

Due to the fact that the composition of Nikorval includes ethyl ester of α-bromisovalerianic acid, which is a liquid that is easily volatile and insoluble in water, up to now it has not been possible to create a solid dosage form in tablets or capsules on the basis of this substance. In addition, volatiles are not stable when stored.

A known method of obtaining the drug "Nikorval", consisting in the fact that in an alcohol-containing ethyl mixer or flask, nifedipine is added in portions and mix thoroughly until completely dissolved. Then, in another mixer or flask with water, phenobarbital, sodium hydroxide and ethyl ester of α-bromisovalerianic acid are added in small portions and mixed until the components are completely dissolved. The resulting two solutions are mixed together to obtain a clear liquid [Declaration Patent of Ukraine N ° 32319, A61K 31/21, 1999].

The specified method does not make it possible to transfer into the solid dosage form liquid components that are in the composition of the product, that is, tablets or capsules. In addition, the method is only suitable for the manufacture of "Nikorval".

The basis of the invention is the task of creating a selection of components and their amount of the drug sedative and antispasmodic action of a solid form in the form of tablets, which in its sedative and antispasmodic action would correspond to drops of a similar action and ensure stability of volatile ingredients.

The second task, which is the basis of the invention, is to create due to the selection of the components of the modes and parameters, the sequence of steps in the technological cycle of a method for producing a solid form of a sedative and antispasmodic drug.

The problem is solved in that the sedative and antispasmodic drug containing ethyl ester of α-bromisovalerianic acid, phenobarbital and peppermint oil, according to the invention, additionally contains microcrystalline cellulose, auxiliary substances for creating a solid dosage form in the form of tablets in the following ratio of components, May. %: ethyl ester of α-bromisovalerianic acid 1.37 - 8.2 phenobarbital 1.25 - 7.5 peppermint oil 0.16 - 0.58 microcrystalline cellulose 2 - 15 excipients the rest, and the tablets are coated with a coating of includes β-cyclodextrin or its derivatives.

The drug may additionally contain β-cyclodextrin in a dose until May 70. %

The drug may additionally contain hop oil in a dose of 0.0229 - 0.09 may. %

The drug may further contain powders with advanced crystal surface in a dose until May 6. %

Aerosil, calcium alginate, pectin and / or mixtures thereof are used as powders with a developed surface.

As excipients, fillers, disintegrants, glidants are used.

The fillers used are lactose, starch, glycine, calcium diphosphate, calcium dihydrogen phosphate, glucose, sorbitol and / or mixtures thereof.

Starch and its derivatives: crospovidone, croscarmellose and / or mixtures thereof are used as disintegrants.

Magnesium stearate, sodium fumarate, talc, polyvinylpyrrolidone and / or mixtures thereof are used as glidants.

As the shell used film, sugar coating and / or combinations thereof.

The film may include Oradru II from Kolorkon and β-cyclodextrin or its derivatives in the following ratio, May. %: β-cyclodextrin or its derivatives up to 10

Oradru II firm Kolorkon rest.

The following components may be part of the sugar coating, May. %: magnesium carbonate up to 15.0 polyvinylpyrrolidone up to 2.0 talc up to 1.0 aerosil up to 1.0 titanium dioxide up to 2.0 β-cyclodextrin or its derivatives up to 3.0. sugar rest.

It is also possible to use other compositions of the components that are used in the pharmaceutical industry for coating tablets.

The second task is solved by the fact that in the method for the manufacture of a medicinal product of sedative and antispasmodic action, comprising mixing phenobarbital, ethyl ester of α-bromisovalerianic acid, peppermint oil with auxiliary substances, according to the invention, ethyl ester of α-bromisovalerianic acid and peppermint oil are first mixed moreover, the amount of the mixture is more than 4.5% of the total weight of the tablet, tablet core or mass of the capsule content, the mixture is added to moistened β-cyclodextrin, mixed for 1-2 minutes, the resulting mixture is dried, granulated, after which the granulate is mixed with phenobarbital, microcrystalline cellulose powders, excipients, disintegrants and glidants, tablets are compressed, and then they are coated with a β-cyclodextrin shell

Additionally, hop oil may be added.

The second task is also solved by the fact that in the method of manufacturing a medicinal product of sedative and antispasmodic action, including mixing phenobarbital, ethyl ester of α-bromisovalerianic acid, peppermint oil with excipients, according to the invention, phenobarbital is first mixed with excipient-filler, separately prepared a mixture of ethyl ester of α-bromisovalerianic acid and peppermint oil, and the mixture of essential oils is less than 4.5% of the weight of the tablet, tablet- kernels or masses of the contents of the capsule, add microcrystalline cellulose, powders with a developed surface of the crystals, excipients, disintegrants and glidants, the resulting mixture is added to a mixture of phenobarbital with a filler and tablets are pressed and then coated with a coating containing β-cyclodextrin

Additionally, hop oil may be added.

In both process variants, lactose, starch, glycine, calcium diphosphate, calcium dihydrogen phosphate, glucose, sorbitol and / or mixtures thereof are used as fillers.

As leavening agents, starch and its derivatives are used: crospovidone, croscarmellose and / or mixtures thereof.

In the process of coating, the tablets are heated and treated with heated air.

As a shell, a film, a sugar shell, or combinations thereof are used.

The film is made by mixing the film-forming substance and a 1% solution of β-cyclodextrin. As a film-forming substance, Oradru II of the Colorcon firm is used.

A sugar shell is made by mixing sugar, magnesium carbonate, aerosil, polyvinylpyrrolidone, titanium dioxide, talc and a solution of β-cyclodextrin.

The use of microcrystalline cellulose reduces volatility and also improves the physicomechanical properties of medicinal substances (solubility, stability, bioavailability) intended for oral use. In addition, microcrystalline cellulose, which is characterized by more plastic deformation, reduces the necessary pressure forces in the tablets. presses, and having lower specific gravity at high flow rates, increases the fluidity of the tablet mixture.

The quantitative content of ethyl ester of α-bromisovalerianic acid in the claimed agent is determined by the dose necessary to achieve the optimal therapeutic effect, and the quantitative content of phenobarbital is dose-dependent.

Violation of the quantitative and qualitative composition of the drug leads to a decrease in the level and narrowing of the spectrum of its specific activity, as well as to technological complications.

The choice of fillers is determined by the weight of the tablet and the possibility of using direct compression technology or granulation of powders. In turn, these factors determine the choice of substances for the manufacture of granules, the distribution of disintegrants between the phases of the tablet. All components together affect the final result - the mechanical properties of the tablets, their uniformity and appearance.

The selection of components and their quantitative composition, stages, modes and parameters of the technological cycle allows to obtain a sedative and antispasmodic drug in the form of tablets or capsules, which ensures accurate dosage and the impossibility of overdose due to inexperience and carelessness of patients or in critical situations, the convenience of using the product on the road .

It is known that the sheath protects volatile components from evaporation during storage. However, during the coating process, the tablets are always heated and treated with heated air, which causes increased evaporation. Improving stability is achieved by the fact that a β-cyclodextrin solution is introduced into the coating composition at a dose of up to 10% of the dry coating weight. An increase in the amount of β-cyclodextrin is impossible, because the shell loses its elasticity and adhesiveness to the tablet surface. Example 1

Phenobarbital is mixed with calcium diphosphate, a mixture of ethyl ester of α-bromisovalerianic acid and peppermint oil, microcrystalline cellulose, aerosil, starch, polyvinylpyrrolidone, magnesium stearate, talc are added and tablets with an average weight of 200 mg are pressed. The tablets are coated with a film coating from Oradrou-P, Kolorcon company. In the manufacture of the Oradr-II solution, a 1% aqueous solution of β-cyclodextrin or its derivatives is used instead of water.

The composition per tablet is shown in table 1.

Table 1

Due to the fact that calcium diphosphate has a significant specific gravity and requires considerable pressure to compress, in order to reduce these parameters and achieve optimal compression of the tablet mass, it is necessary to increase the amount of microcrystalline cellulose, which also provides a more efficient pore system in tablets, and, thus contributing to greater effectiveness of the loosening properties of starch.

Shell, mg:

Oradru II 3.14 β-cyclodextrin 0.3.

Example 2

Α-bromisovalerianic acid ethyl ester is mixed with peppermint oil, the resulting mixture is added to moistened cyclodextrin and mixed for 1-2 minutes, dried and granulated, after which the granulate is mixed with powders of phenobarbital, glucose, starch, microcrystalline cellulose, lactose, magnesium stearate. The resulting mixture was tabletted.

Table 2 shows the ratio of the components of the claimed composition. table 2

Shell, mg:

Oradru II 3.14 β-cyclodextrin 0.3.

Example 3

The inventive composition is obtained analogously to example 1. The composition per tablet is shown in table 3.

Table 3

Shell, mg:

Oradru II 3.14 β-cyclodextrin 0.3. Example 4

The inventive composition is obtained analogously to example 2. The composition per tablet is shown in table 4.

Table 4

Shell, mg:

Oradr-II 2.91 β-cyclodextrin 0.3.

Example 5

The inventive composition is obtained analogously to example 2. The composition per tablet is shown in table 5.

Table 5

Example 7

Phenobarbital is mixed with lactose, a mixture of ethyl ester of α-bromisovalerianic acid and peppermint oil, microcrystalline cellulose, aerosil, starch, talc, polyvinylpyrrolidone, magnesium stearate are added and tablets with an average weight of 100 mg are pressed. The resulting tablets are sugar coated. Coating weight 100 mg.

The composition per tablet is shown in table 7 Table 7

Shell, mg: sugar 36.6 magnesium carbonate 7.5 polyvinylpyrrolidone 0.67 aerosil 0.5 talc 0.5 titanium dioxide 1.0 β-cyclodextrin 0.62

Example 8

Phenobarbital is mixed with lactose, a mixture of ethyl ester of α-bromisovalerianic acid, peppermint oil and hop oil is added. Microcrystalline cellulose, aerosil, starch, talc, polyvinylpyrrolidone, magnesium stearate are added and tablets with an average weight of 100 mg are pressed. The resulting tablets are sugar coated. Coating weight 100 mg.

The composition per tablet is shown in table 8.

Table 8

Shell, mg: sugar 36.6 magnesium carbonate 7.5 polyvinylpyrrolidone 0.67 aerosil 0.5 talc 0.5 titanium dioxide 1.0 β-cyclodextrin 0.6.

The data presented indicate the multifunctional action of the excipient system, which ensures the optimality of the physicomechanical properties of the solid dosage form.

The solid dosage form, which is obtained according to the claimed invention, has advantages over the prototype.

Thus, the claimed invention fulfills the task of creating tablets of a combined preparation of sedative and antispasmodic action, which according to the kinetics of antispasmodic action correspond to the dosage form - drops and have an advantage over it in the accuracy and affordability of the dosage.

Claims

CLAIM

1. A drug of sedative and antispasmodic action, containing ethyl ester of α-bromisovalerianic acid, phenobarbital and peppermint oil, characterized in that it additionally contains microcrystalline cellulose, auxiliary substances for creating a solid dosage form in the form of tablets in the following ratio of components, May. %: ethyl ester of α-bromisovalerianic acid 1.37 - 8.2 phenobarbital 1.25 - 7.5 peppermint oil 0.16 - 0.58 microcrystalline cellulose 2 - 15 excipients the rest, and the tablets are coated with a coating of includes β-cyclodextrin or its derivatives.

2. The drug according to claim 1, characterized in that it further comprises β-cyclodextrin in a dose until May 70. %

3. The drug under item 1, characterized in that it further comprises hop oil in a dose of 0.0229 - 0.09 may. %

4. The drug under item 1, characterized in that it further comprises powders with a developed surface of the crystals in a dose until May 6. %

5. The drug according to claim 4, characterized in that aerosil, calcium alginate, pectin and / or mixtures thereof are used as powders with a developed surface.

6. The drug according to any one of paragraphs. 1-4, characterized in that as excipients used fillers, disintegrants, glidants.

7. The drug according to claim 6, characterized in that the fillers used are lactose, starch, glycine, calcium diphosphate, calcium dihydrogen phosphate, glucose, sorbitol and / or mixtures thereof.

8. The drug according to claim 6, characterized in that the starch and its derivatives are used as disintegrants: crospovidone, croscarmellose and / or mixtures thereof.

9. The drug according to claim 6, characterized in that magnesium stearate, sodium fumarate, talc, polyvinylpyrrolidone and / or mixtures thereof are used as moving substances.

10. The drug according to any one of claims 1 to 4, characterized in that in as the shell used film, sugar coating and / or combinations thereof.

11. The drug of claim 10, characterized in that the film includes Oradru II from Kolorkon and β-cyclodextrin in the following ratio, May. %: β-cyclodextrin or its derivatives up to 10

Oradru II firm Kolorkon rest.

12. The drug according to claim 10, characterized in that the composition of the sugar coating includes the following components, May. %: magnesium carbonate up to 15.0 polyvinylpyrrolidone up to 2.0 talc up to 1.0 aerosil up to 1.0 titanium dioxide up to 2.0 β-cyclodextrin or its derivatives up to 3.0 sugar rest.

13. A method of manufacturing a medicinal product of sedative and antispasmodic action, comprising mixing phenobarbital, ethyl ester of α-bromisovalerianic acid, peppermint oil with auxiliary substances, characterized in that the ethyl ester of α-bromisovalerianic acid is first mixed with peppermint oil, the amount of the mixture being more than 4.5% of the total weight of the tablet, tablet core or capsule content, the mixture is added to moistened β-cyclo-dextrin, mixed for 1-2 minutes, the resulting mixture is dried ayut, granulated, and then the granulate is mixed with powders of phenobarbital, microcrystalline cellulose, with auxiliaries, excipients, disintegrants and glidants, tablets are pressed and are then coated with a shell containing β-cyclodextrin.

14. The method according to item 13, wherein the hop oil is additionally added.

15. The method according to p. 13 or p. 14, characterized in that during the coating process, the tablets are heated and treated with heated air.

16. The method according to item 13 or 14, characterized in that the fillers used are lactose, starch, glycine, calcium diphosphate, calcium dihydrogen phosphate, glucose, sorbitol and / or mixtures thereof.

17. The method according to item 13 or 14, characterized in that the starch and its derivatives are used as baking powder: crospovidone, croscarmellose and / or mixtures thereof.

18. The method according to item 13 or 14, characterized in that as the moving substances use magnesium stearate, sodium fumarate, talc, polyvinylpyrrolidone and / or mixtures thereof.

19. The method according to p. 13 or p. 14, characterized in that the film, sugar coating or combinations thereof are used as a coating.

20. The method according to claim 19, characterized in that the film is made by mixing the substance forming the film and a 1% solution of β-cyclo-dextrin or its derivatives.

21. The method according to p. 20, characterized in that as the substance forming the film, use Oradru II firm "Colorcon".

22. The method according to claim 19, characterized in that the sugar shell is made by mixing sugar, magnesium carbonate, aerosil, polyvinylpyrrolidone, titanium dioxide, talc and a solution of β-cyclodextrin or their derivatives or other components used in the industry for coating tablets.

23. A method of manufacturing a sedative and antispasmodic drug, including mixing phenobarbital, ethyl ester of α-bromisovalerianic acid, peppermint oil with excipients, characterized in that the phenobarbital is first mixed with excipient, filler, separately preparing a mixture of ethyl ester of α-bromisovalerianic peppermint acid and oil, and the mixture of essential oils is less than 4.5% of the weight of the tablet, core tablet or capsule content, add mik okristallicheskuyu cellulose powders with a developed surface crystals, adjuvants, disintegrants and lubricants, the resulting mixture was added to a mixture of phenobarbital with filler and compressed into tablets, then they are coated with a shell containing β-cyclodextrin.

24. The method according to p. 23, characterized in that as fillers use lactose, starch, glycine, calcium diphosphate, calcium dihydrogen phosphate, glucose, sorbitol and / or mixtures thereof.

25. The method according to p. 23, characterized in that the starch and its derivatives are used as baking powder: crospovidone, croscarmellose and / or mixtures thereof.

26. The method according to p. 23, characterized in that the use of magnesium stearate, sodium fumarate, talc, polyvinylpyrrolidone and / or mixtures thereof as sliding substances.

27. The method according to p. 23, characterized in that during the coating process, the tablets are heated and treated with heated air.

28. The method according to p. 23, characterized in that the film, sugar coating or combinations thereof are used as a coating.

29. The method according to p. 28, characterized in that the film is made by mixing the substance forming the film and a 1% solution of β-cyclo-dextrin or its derivatives.

30. The method according to p. 29, characterized in that as the substance forming the film, use Oradru II firm "Colorcon".

31. The method according to p. 28, wherein the sugar shell is made by mixing sugar, magnesium carbonate, aerosil, polyvinylpyrrolidone, titanium dioxide, talc and a solution of β-cyclodextrin or other components used in the industry for coating tablets.