RU2611194C2 - Drug based on tetrametiltetraazobitsiklooktandion and method for its production - Google Patents

Abstract

FIELD: pharmacy.

SUBSTANCE: here is a description of dosage form of tetrametiltetraazobitsiklooktandion, additionally containing a filler, granulating agent, lubricant, disintegrant, flavoring agent in certain weight ratios. Methods of preparing of the said dosage form are also described.

EFFECT: preparation of the dosage form without defects in manufacture and storage and with improved taste characteristics.

11 cl, 3 tbl

Description

The invention relates to the pharmaceutical industry, in particular to the production of finished dosage forms, in particular, medicines based on tetramethyltetraazabicyclooctanedione (Mebikara).

Mebicar (novolat. Mebicarum, INN: Tetramethyltetraazabicyclooctanedione) - psychotropic drug, anxiolytic, “daytime” tranquilizer. It has moderate tranquilizing activity; It does not have a muscle relaxant effect and does not interfere with the coordination of movements. It does not have a hypnotic effect, but it enhances the effect of sleeping pills and improves sleep during its disturbances.

Mebikar acts on the activity of structures included in the limbic-reticular complex, in particular, on the emotiogenic zones of the hypothalamus, and also acts on all 4 main neurotransmitter systems: GABA-, choline-, serotonin- and adrenergic, contributing to their balance and integration, but does not have a peripheral adrenonegative effect.

In addition to calming, it has a nootropic effect. In clinical studies, it was found that mebicar increases logicality, connectedness and speed of thinking, improves attention and mental performance, without stimulating the symptoms of productive psychopathological disorders: delirium, pathological emotional activity.

The following indications for the use of mebicar have been registered: in case of neurosis and neurosis-like conditions occurring with the phenomena of irritability, emotional excitability, anxiety, fear (in particular, in patients with alcoholism during remission); hypomanic and anxiety-delusional states without psychomotor agitation and serious behavioral disorders (including schizophrenia, involutional and vascular psychoses); residual effects after acute psychoses with phenomena of emotional instability, productive symptoms; chronic verbal hallucinosis of organic origin; in the treatment of nicotine withdrawal symptoms.

Mebikar also has a coronary activity and is used as a treatment for cardialgia and mild forms of coronary heart disease.

Mebikar has low toxicity, a wide range of therapeutic effects, namely, pronounced antianginal, cholesterol-lowering and sedative effects.

Side effects with prolonged use of Mebikar are absent.

A known method of producing Mebicard by the interaction of N, N'-dimethylurea with glyoxal in a solvent in the presence of hydrochloric acid.

Mebicar is a white crystalline powder, odorless, bitter taste, readily soluble in water and alcohol, since mebicar has a very bitter taste, it is difficult to use the drug by sensitive patients and patients with problems with the gastrointestinal tract.

There are patents for different methods for the preparation (synthesis) of 2,4,6,8-tetramethyl-2,4,6,8-tetraazabicyclo / 3.3.0 / octanedione-3.7 (MEBIKARA): No. 491619, No. 644482, No. 2108098.

In the patent No. 2108098 is protected in paragraph 1 of the claims - a method for producing the drug and in paragraph 2 - a method of tabletting (the resulting powder is pressed into tablets). The disadvantage of this composition and the method of obtaining without excipients is the mismatch of the technological characteristics of the tableted mass with tabletting conditions. This is due to the fact that mebicar powder is characterized by the absence of flowability. The obtained tablets are exfoliated due to the insufficient cohesion of mebicar microcrystals with each other.

There are patents to expand the use of the drug:

1. Patent No. 1095491 "Mebicar" for the treatment of cardialgia and mild forms of coronary heart disease.

2. Patent No. 1253002 "Means for the prevention of gastrointestinal strongilatoses of sheep."

3. Patent No. 1537259 "Means that suppress the craving for nicotine and tobacco smoke."

Closest to the claimed invention is the composition of the tablets according to the application US 2011070305 (priority from 2011.03.24). Stated prolonged form of the drug, (prototype).

A disadvantage of the known composition is that only prolonged forms are offered narrowly, and not all possible prolongation options are offered. Prolonged forms of the drug are not always used.

The aim of the invention is to develop a composition and method that improve the manufacturability and technical parameters of the drug without prolongation, the development of different dosage forms: tablets; coated tablets; granules, sachets and capsules. Also, the development of the composition and method for producing a drug of prolonged action. Another goal is to improve the taste of the drug.

The technical result of the invention is the production of a medicinal product in the form of tablets, capsules, in the form of sachets or granules without marriage in the manufacture and storage and options with improved taste. As well as the production of effective formulations of medicines in the form of tablets, capsules, in the form of sachets or granules for use in pediatric practice and sustained release formulations.

This goal is achieved by developing a new dosage form based on tetramethyltetraazabicyclooctanedione in the form of tablets and tablets, coated for oral administration, capsules, in the form of sachets or granules, drug formulations for use in pediatric practice and sustained release formulations.

Mebicar tablets, coated, completely hide the bitter taste of the drug. The use of the drug in the form of capsules also allows to achieve the same effect. The use of corrective substances in the composition reduces and masks the bitter taste of the drug, the introduction of other excipients allows you to distribute the active substance throughout the mass, which also leads to an improvement in taste.

The technical result of the proposed methods is that the granulation of the active substance proposed in the application by granulating agents can improve the manufacturability and technical parameters of the drug, also slightly improves the taste. The introduction of fillers can reduce the bitter taste of the drug.

The technical result of the proposed method in a fluidized bed is that granulation of the active substance and the introduction of fillers also reduces the bitter taste of the drug and facilitates the work of personnel, since almost all processes are carried out in a granulator dryer. This allows you to minimize direct contact of the personnel during the production process with a tranquilizing drug, i.e. protection of personnel from the therapeutic effect of the drug.

A medicament containing tetramethyltetraazabicyclooctanedione is proposed, characterized in that it additionally contains a filler, a granulating agent, a glidant, disintegrants, corrective substances in the following ratio, wt. %:

tetramethyltetraazabicyclooctanedione 50-98.9 filler - microcrystalline cellulose, or lactose monohydrate, or sucrose, or calcium basic phosphate, or mannitol, or glucose, or potato starch, or corn starch 0-20 granulating agent - 2.47% solution polyvinylpyrrolidone or 2% or 5% starch paste 1-10 glidant - calcium stearate, or magnesium stearate, or sodium stearyl fumarate, or silicon colloidal dioxide (aerosil) 0.1-8 disintegrants - carboxymethyl starch (primogel) or croscarmellose sodium (primellose) 0-6 corrective substances - fructose, or lactose, or invert sugar, or citric acid, or glycerin, or sucrose, or dulcin, or saccharin, or sorbitol, or artificial sweeteners cyclomats - sodium and calcium salts cyclohexyl sulfamic acid 0-20

At least one of the following substances can be used as fillers: microcrystalline cellulose, lactose monohydrate, basic calcium phosphate, mannitol, glucose, potato starch, corn starch, sucrose, and the list is not limited.

As the granulating agent, any pharmaceutically acceptable granulating agent is used, including a 2.47% solution of polyvinylpyrrolidone or 2 or 5% starch paste, and the list is not limited.

Polyvinylpyrrolidone is readily soluble in water and alcohol, and also, due to the formation of water-soluble complexes, improves the solubility and bioavailability of drugs.

Due to the fact that polyvinylpyrrolidone and starch do not have prolonged properties, the disintegration rate of tablets decreases. (Appendix 3, table. 3).

As glidants, at least one of the following substances selected from stearic acid derivatives is used: calcium stearate, magnesium stearate, sodium stearyl fumarate or silicon colloidal dioxide (aerosil), and the list is not limited.

Carboxymethyl starch (primogel) or croscarmellose sodium (primellose), crospovidone, pregelatinized starch are used as a disintegrant.

At least one of the following substances is used as a corrective substance: fructose, maltose, lactose, invert sugar, citric acid, glycerin, sucrose, dulcin, saccharin, sorbitol, as well as artificial cyclomat sweeteners — sodium and calcium salts of cyclohexyl sulfamic acid; moreover, the list is not limited.

A variant is also possible in the following ratio, wt. %:

tetramethyltetraazobicyclooctanedione - 50-98.9 granulating agent in the form of a 2.47% solution polyvinylpyrrolidone or 2% or 5% starch paste 1-10 glidant - calcium stearate, or magnesium stearate, or sodium stearyl fumarate, or silicon colloidal dioxide (aerosil) 0.1-8

Example 1. One of the options for the drug in the following ratio of ingredients, in wt. %:

Tetramethyltetraazabicyclooctanedione 98.9 Potato starch 0,500 Calcium stearate 0,600 Total: 100.0

The tablets obtained in example 1 are coated (Examples of shells are discussed below). The shell allows you to hide the bitter taste of the active substance - mebicar.

The drug can be performed in the dosage form in the form of capsules, granules and sachets, in these cases there is no stage of tabletting.

The technical result is also achieved by a method of manufacturing a medicinal product.

Two methods for producing tablets according to this composition are proposed: A method for producing a medicine in the form of tablets, which consists in loading tetramethyl tetraazabicyclooctanedione into a mixer, after preliminary grinding, a filler, a disintegrant, a corrective substance, is mixed for 5-10 minutes, moistened with a solution of a granulating agent , stirred for 5-10 minutes, wet granulation is carried out through a sieve with a mesh size of 3 × 3; the obtained granules are dried in a dryer for 30-40 minutes, alternating drying with stirring; dust with a sliding substance for 3-5 minutes; dry granulation is carried out through a sieve with a hole diameter of 2 × 2 mm and tableting is carried out. The technical result of this method is that granulation of the active substance and the introduction of fillers can reduce the bitter taste of the drug and also improves the manufacturability and technical parameters of the drug.

A method for producing a medicament in the form of tablets in a fluidized bed, which method comprises introducing tetramethyltetraazabicyclooctanedione into a granulator dryer after preliminary grinding; filler, disintegrant, corrective substance and mix for 5-10 minutes; granulating agent is sprayed for 60-80 minutes at a product temperature of 20 to 25 ° C; at the end of the granulation process, the mass is dried out for 15-20 minutes, dusting with a sliding substance is carried out, the mass is unloaded from the granulator and granulation of the dry mass and tabletting are carried out. The technical result of this method is that granulation of the active substance and the introduction of fillers also reduces the bitter taste of the drug and facilitates the work of personnel, since almost all processes, except dry granulation, are carried out in a granulator dryer. This allows to minimize direct contact of personnel during the production process with a tranquilizing drug, and also reduces the complexity of the granulation process and accelerates the granulation process. The method for producing a drug in a fluidized bed also contributes to a faster release of the active substance due to drying by spraying a granulating agent.

Tetramethyltetraazabicyclooctanedione, the active substance, is loaded into the mixer after preliminary grinding, since the raw material is a crystalline powder. Then moisten with a solution of 5% starch paste, mix for 5-10 minutes, carry out wet granulation through a sieve with a mesh size of 3 × 3; the obtained granules are dried in a dryer for 30-40 minutes, alternating drying with stirring; dust with calcium stearate for 3-5 minutes; dry granulation is carried out through a sieve with a hole diameter of 2 × 2 mm and tableting is carried out.

The resulting tablets have a very good appearance, strength 13-15 kgf / cm ² . The abrasion of the tablets is less than 0.17%.

Obtaining drug in the fluidized bed. Tetramethyltetraazabicyclooctanedione is loaded into a granulator dryer, after preliminary grinding, a solution of 2% starch paste is sprayed for 60-80 minutes at a product temperature of 20 to 25 ° C; at the end of the granulation process, the mass is dried out for 15-20 minutes, dusting is carried out with calcium stearate, the mass is discharged from the granulator and granulation of the dry mass and tabletting are carried out.

The resulting tablets have a very good appearance, strength 13-15 kgf / cm ² . The abrasion of the tablets is less than 0.17%.

These methods are acceptable for all subsequent examples.

Example 2

One of the options for the drug in the following ratio of ingredients, in wt. %:

Tetramethyltetraazabicyclooctanedione 98.9 Polyvinylpyrrolidone 0,500 Magnesium stearate 0,600 Total: 100.0

The tablets obtained in example 2 can also be coated, the following examples can likewise be uncoated and can be coated.

The drug can also be made in the dosage form in the form of capsules, granules and sachets, in these cases there is no stage of tabletting.

Example 3

One of the variants of the drug using the filler in the following ratio of ingredients, in wt. %:

Tetramethyltetraazabicyclooctanedione 97 Lactose Monohydrate 2.0 Polyvinylpyrrolidone 0,500 Calcium stearate 0,500 Total: 100.0

The drug can also be made in the dosage form in the form of capsules, granules and sachets.

An option is proposed for the release of a medicinal product using corrective substances for use in children's practice.

Corrective substances (flavoring agents) - a group of excipients, the use of which makes it possible to correct the taste, color, smell of various excipients, as well as the appearance of the drug.

Currently, in the domestic pharmacy, fructose, maltose, lactose, invert sugar, citric acid, glycerin, and sucrose are used as flavoring agents; Dulcin, saccharin, sorbitol, carboxymethyl cellulose, mannitol, as well as artificial sweeteners cyclomats — sodium and calcium salts of cyclohexyl sulfamic acid — are 30 times higher in sugar index than abroad.

Example 4

One of the variants of the drug using the corrective substance in the following ratio of ingredients, in wt. %:

Tetramethyltetraazabicyclooctanedione 94 Fructose 5,0 Polyvinylpyrrolidone 0,500 Aerosil 0,500 Total: 100.0

The technical result of introducing fructose into the composition of the composition is to improve the organoleptic properties of the drug, mask the bitter taste of tetramethyltetraazabicyclooctanedione and ensure the binding of the ingredients of the composition in the granulate.

Improving the taste makes it possible to use the composition in children's practice.

Example 5

One of the variants of the drug using a disintegrant is proposed in the following ratio of ingredients, in wt. %:

Tetramethyltetraazabicyclooctanedione 98 Croscarmellose 1,0 Polyvinylpyrrolidone 0,500 Calcium stearate 0,500 Total: 100.0

Due to its effectiveness at low concentrations of croscarmellose, it is ideal for formulations in which active substances and other ingredients prevent the addition of disintegrants in large quantities.

Different shell options are available.

The application of membranes has the following goals: to give the tablets a beautiful appearance, increase their mechanical strength, hide unpleasant taste, smell, protect from environmental influences (light, moisture, oxygen), localize or prolong the action of the drug, protect the mucous membranes of the esophagus and stomach from the destructive effect of a drug substance. Coatings applied to tablets can be divided into 3 groups: coated, film and extruded.

The tablets obtained in examples 1 and 2 were coated. For coating used Opadry II 12% aqueous suspension. Coating the tablets was carried out at a temperature of 40-42 ° C in an amount of 2-3% by weight of the tablets. Got a very good film coating.

Coating options based on water-soluble polymers are possible: polyvinyl alcohol, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose.

Sugar coated shells are also available.

Composition per 1 tablet shell:

1. Sugar (sucrose) 0.1359036 g 2. Polyvinylpyrrolidone n / m 0.0024074 g 3. Magnesium hydroxycarbonate 0.035211 g 4. Titanium dioxide 0.0034654 g 5. Talc 0.000225 g 6. Colloidal silicon dioxide (aerosil) 0.0024524 g 7. Beeswax 0.0000902 g 8. Edible gelatin 0,0002400 g Shell weight 0.18 g

Brief technology of coating the core tablets with a sugar coating:

1. Application of an insulating layer from a solution of PVP and gelatin.

2. Application of the suspension (sugar syrup, magnesium hydroxycarbonate, PVP solution, titanium dioxide)

3. Gloss of tablets.

The resulting tablets meet all the requirements of regulatory documentation.

Coating options are not limited to the above examples. Proposed options for a prolonged form of the drug.

The technical result is expressed in the composition and method of obtaining a dosage form of tetramethyltetraazabicyclooctanedione with modified release at a certain quantitative ratio, in wt. %:

Tetramethyltetraazabicyclooctanedione 50-98.9 Release Modifier and Excipients 10-50

The release modifier in this invention are mixtures of polymers, including mixtures of polyvinylpyrrolidone with polyvinyl acetate and hydroxypropyl methyl cellulose; or a mixture of Collidone SR and Methocel K 100M Premium hydroxypropyl methyl cellulose in an amount of 10-50% by weight of tablets.

The release modifiers included in the granules and sachets create a hydrophilic matrix that provides a modified, controlled release of tetramethyltetraazabicyclooctanedione and its prolonged action.

At least one of the following substances can be used as fillers: cellulose derivatives, sugars (mannitol, glucose, sorbitol, lactose, sucrose), polysaccharides (starch, corn starch, pregelatinized starch, maltodextrin), inorganic salts (calcium carbonate, magnesium carbonate, calcium phosphate, sodium chloride), aerosil, etc.

The drug may be in the dosage form in the form of tablets, capsules, granules and sachets.

The proposed ratio of active substance and target additives was found experimentally and is optimal, providing a prolonged preparation of tetramethyltetraazobicyclooctanedione that meets all the requirements of the Pharmacopoeia standard of the enterprise and high bioavailability. The prolonged release of tetramethyltetraazabicyclooctanedione from the dosage form is confirmed by the “Dissolution” quality indicator. The amount of tetramethyltetraazabicyclooctanedione transferred to the dissolution medium after 1 hour is from 25 to 45%, after 2 hours - from 45 to 63%, and after 8 hours - not less than 80%.

The technical result is also achieved by a method of manufacturing a dosage form. Two methods for producing modified granules, sachets for this composition:

1. The first method is that initially a mixture of Collidone SR and HPMC is prepared, followed by the addition of tetramethyl tetraazabicyclooctanedione.

2. The second method consists in sequentially mixing tetramethyltetraazabicyclooctanedione first with HPMC, then the resulting mixture with Collidone, that is, the active substance is enclosed in a double layer of release modifiers.

Embodiments of the invention:

Collidone SR and hydroxypropylmethyl cellulose K 100M are thoroughly mixed in the container, then tetramethyl tetraazabicyclooctanedione is added to the mixture and mixed thoroughly.

In another container, a mixture of fillers is prepared and, if necessary, is passed through a No. 32 sieve.

Then the two mixtures are mixed in a separate container with each other and passed through a No. 11 sieve. Only after that a sliding substance is added to dusting - everyone mixes it and sends it to tabletting.

To coat the finished cores, a 15% suspension of Opadrai II is used. The prepared suspension of Opadry II in a vertical Diosna boat is coated with tetramethyl tetraazabicyclooctanedione core tablets.

A modified release dosage form containing 50-90% tetramethyltetraazabicyclooctanedione and 10-50% pharmaceutically acceptable excipients, characterized in that a mixture of polyvinylpyrrolidone with polyvinyl acetate and hydroxypropylmethyl cellulose is used as a release modifier.

REFERENCES

1. Mashkovsky M.D. Medicines, 15th ed., New Wave, 2005

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3. Research I.O. OAO Tatkhimpharmpreparaty.

4. Paid FIPS database on the Internet.

5. Azhgikhin I.S. Technology of medicines / M. Medicine, 1975.

6. The State Pharmacopoeia of the USSR. Vol. 1, 2. Ministry of Health of the USSR - 11th ed.

7. O.I. Belova, V.V. Karchevskaya, N.A. Kulakov et al. Technology of dosage forms in 2 volumes. Textbook for high schools. T. 1.

8. Alyushin M.T., Artemyev A.I., Trakman Yu.G. Synthetic polymers in domestic pharmaceutical practice M .: "Medicine". - 1974. - 152 p.

9. Golikov S.N., Guryanov G.A., Kozlov V.K. Ways and methods of prolonging the action of drugs (state of the issue and prospects) // Pharmacology and Toxicology, 1989. No. 2. - S. 5-15.

10. Methods of drug prolongation: Educational and methodological development for self-training of students of pharmaceutical institutes and faculties / Ed. prof. L.A. Ivanova M., 1990 .-- 25 p.

11. Yasinitsky, B.G. Corrigents of smell and taste in the production of drugs / B.G. Yasinitsky, E.B. Dolberg, T.V. Medvedev. M .: UBNTIMedprom, 1987 .-- 27 p.

Annex 1.

Appendix 2

Appendix 3

FINDINGS:

These tables are obtained experimentally and confirm the technical result obtained using the claimed technical solutions.

The maximum improvement in taste was obtained in the manufacture of a medicine in the form of tablets according to any one of the examples 1 to 10, provided that they were coated or in the manufacture of a medicine in the form of capsules.

A significant improvement in the taste of the drug was obtained when using fructose as a corrective substance (9 points on a 10 point scale), while the strength and disintegration of the tablets were improved (example 9).

All variants of the compositions have good technical indicators of disintegration, tablet strength, appearance, abrasion resistance.

Claims (12)

1. A medicinal product containing tetramethyltetraazobicyclooctanedione, characterized in that it further comprises a filler, a granulating agent, a glidant, a disintegrant, a corrective substance in the following ratio, wt.%: tetramethyltetraazobicyclooctanedione 50-80 filler - microcrystalline cellulose, or lactose monohydrate, or sucrose, or calcium phosphate basic, or mannitol, or glucose, or starch potato, or corn starch up to 20 granulating agent - 2.47% solution of polyvinylpyrrolidone or 2% or 5% starch paste 1-10 a moving substance is calcium stearate, or magnesium stearate, or sodium stearyl fumarate, or silicon dioxide colloidal (aerosil) 0.1-8 disintegrant - carboxymethyl starch (primogel) or croscarmellose sodium (primellose) 0-6 corrective substance - fructose, or lactose, or invert sugar, or citric acid, or glycerin, or sugar, or dulcin, or saccharin, or sorbitol, or artificial cyclomat sweeteners - sodium and calcium salts of cyclohexyl sulfamic acid up to 20 2. The drug according to claim 1, characterized in that it is coated with a pharmaceutically acceptable coating, including sugar coating or film. 3. The drug according to claim 2, characterized in that a water-soluble coating based on one of the following polymers is used as a film membrane: polyvinyl alcohol, hydroxypropyl methyl cellulose, ethyl cellulose. 4. The drug according to claim 2, characterized in that the finished coating based on the Opadry II polyvinyl agent is used as a film membrane in an amount of 2-3% by weight of the tablet. 5. The drug according to claim 1, characterized in that it is made in the form of a prolonged form using a mixture of polymers as a modifier of release, incl. mixtures of polyvinylpyrrolidone with polyvinyl acetate and hydroxypropyl methyl cellulose; or a mixture of Collidone SR and Methocel K 100M Premium hydroxypropyl methyl cellulose in an amount of 10-50% by weight of tablets. 6. The drug according to claim 1, characterized in that it is made in the form of tablets, sachets or granules. 7. The drug according to claim 1, characterized in that it is made in the form of capsules. 8. The method of producing a medicine according to claim 1, characterized in that tetramethyltetraazobicyclooctanedione is loaded into the mixer after preliminary grinding, the filler, disintegrant, corrective substance are mixed for 5-10 minutes, moistened with a granulating agent solution, mixed for 5-10 minutes conduct wet granulation through a sieve with a mesh size of 3 × 3; the obtained granules are dried in a dryer for 30-40 minutes, alternating drying with stirring; dust with a sliding substance for 3-5 minutes; produce dry granulation through a sieve with a hole diameter of 2 × 2 mm 9. A method for producing a medicine according to claim 1, characterized in that tetramethyltetraazobicyclooctanedione is an active substance after preliminary grinding; then moisten with a solution of 5% starch paste, mix for 5-10 minutes, wet granulation is carried out through a sieve with a mesh size of 3 × 3; the obtained granules are dried in a dryer for 30-40 minutes, alternating drying with stirring; dust with a sliding substance for 3-5 minutes; produce dry granulation through a sieve with a hole diameter of 2 × 2 mm 10. The method for producing a drug in the fluidized bed according to claim 1, characterized in that tetramethyltetraazobicyclooctanedione is introduced into the fluidized bed dryer after preliminary grinding, the filler, disintegrant, corrective substance and mixed for 5-10 minutes; granulating agent is sprayed for 60-80 minutes at a product temperature of 20 to 25 ° C; at the end of the granulation process, the mass is dried out for 15-20 minutes, dusting with a sliding substance is carried out, the mass is discharged from the granulator dryer and the dry mass is granulated. 11. The method for producing a drug in the fluidized bed according to claim 1, characterized in that tetramethyl tetraazobicyclooctanedione is loaded into the granulator dryer after preliminary grinding, a solution of 2% starch paste is sprayed for 60-80 min at a product temperature of 20 to 25 ° C; at the end of the granulation process, the mass is dried out for 15-20 minutes, dusting with a sliding substance is carried out, the mass is discharged from the granulator dryer and then the dry mass is granulated.