RU2308941C1 - Solid medicinal formulation possessing histamine-like effect and method for its preparing - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a solid medicinal formulation of agent used in prophylaxis and elimination vertigo and a method for its preparing. Agent comprises betahistine as active pharmaceutical component and special additives in the following ratio of components, wt.-%: betahistine hydrochloride, 4-16; microcrystalline cellulose, 25-70; acid stabilizing agent, 1-3; aerosil, 1-10; disintegrating substance, 1.2-5, and lactose, the balance. Invention provides good decomposition capacity and strength of tablet, simplifying preparing the medicinal formulation.

EFFECT: valuable pharmaceutical properties of formulation, improved preparing method.

8 cl, 2 tbl, 1 dwg, 8 ex

Description

The invention relates to medicine, in particular to pharmacy, and relates to a solid dosage form for the prophylaxis and elimination of dizziness (a synthetic analogue of histamine) and contains betagistin and target additives as microcrystalline cellulose, milk sugar, acid stabilizer, substance disintegrant, aerosil, moving substances in a certain ratio. EFFECT: invention provides good disintegration and tablet strength, simplification of preparation of a dosage form.

Betagistin - an agonist of H1 receptors of vessels of the inner ear and an antagonist of H3 receptors of the vestibular nuclei of the central nervous system; improves microcirculation and capillary permeability, normalizes endolymph pressure in the labyrinth and cochlea, increases blood flow in the basilar artery, normalizes the conductivity in the neurons of the vestibular nuclei at the level of the brain stem. Reduces the frequency and intensity of dizziness, reduces tinnitus, improves hearing when it is reduced. A stable therapeutic effect occurs after 14 days.

It is used for Meniere’s disease and syndrome (including tinnitus and hearing impairment), vestibular dizziness of various origins (vertebrobasilar insufficiency, post-traumatic encephalopathy, cerebral arteriosclerosis, vestibular neuritis, labyrinthitis, benign positional dizziness after neurosurgery).

It is absorbed quickly, communication with plasma proteins is low. The maximum concentration is reached after 3 hours. It is almost completely excreted by the kidneys in the form of a metabolite (2-pyridylacetic acid) within 24 hours. The elimination half-life is 3-4 hours [1]

Chemically, betahistine - 2- [2-methylamino) ethyl] pyridine:

Betagistin and its salts are white or brownish-white powders, easily clumping and, as a rule, highly hygroscopic. In the presence of moisture, a gradual oxidation of betahistine occurs with the formation of pharmaceutically inactive decomposition products.

Document RU 2248791 C2 dated February 28, 2000, Italy, Farmacheutichi Formenti, relating to a composition based on betahistine obtained by granulation from a betahistine melt and a fat component, mixing granulate with a hydrophilic compound and suitable auxiliary ingredients, is found in the patent fund of the Russian Federation. According to the author of the invention, such a tablet form provides a controlled release of betahistine.

There is international application WO 2005/004850 with a description of a tablet form of betahistine with a two-layer coating, Italy, Farmacheutichi Formenti.

The composition of these compositions includes complex compounds, and the method for producing the compositions is a complex multilayer technology for the preparation of tablets.

Known drug "Betaserk" manufactured by Solvey Pharma, Netherlands, containing the active pharmaceutical ingredient - betahistine hydrochloride and excipients: microcrystalline cellulose, mannitol, citric acid, silicon dioxide, talc. [2]

This tool has wide solubility limits, therefore, the concentration of the active pharmaceutical ingredient in the blood plasma is not sufficiently predictable in various patients. This factor requires particularly careful dose selection for various patients in order to achieve the expected therapeutic effect and minimize side effects.

Therefore, it is still relevant to create a solid dosage form of the drug for the prevention and elimination of dizziness with the use of excipients present on the raw materials market of the Russian Federation, which meets all the requirements for a pharmaceutical agent.

The objective of the invention is the creation of a stable solid dosage form of betahistine, which meets all the requirements for a pharmaceutical product during the shelf life of the drug. The dosage form should easily release the main substance, provide high bioavailability, be safe for health, have a good appearance. (Indicators for increasing bioavailability are presented in example 5).

The problem is solved in that in a solid dosage form for the prevention and elimination of dizziness, containing betahistine as an active pharmaceutical principle, the target additives are contained: microcrystalline cellulose, milk sugar, aerosil, an acid stabilizer, a disintegrant, moving substances in the following ratio of ingredients , wt.%:

Betahistine hydrochloride  4-16 Microcrystalline cellulose  25-70 Acid Stabilizer  1-3 Aerosil  1-10 Disintegrant  2-10 Glidants  1,2-5 Milk sugar  Rest.

As disintegrant substances, i.e. substances that improve the penetration of the aqueous medium into the dosage form and lead to rapid swelling and disintegration, which leads to an acceleration of the release of the active substance, substances such as pregelatinized starch, hydroxypropyl methylcellulose (HPMC), croscarmellose, crospovidone, alginic acid in the form of salt or mixtures.

Talc or magnesium and / or calcium stearate, or mixtures thereof, are used as glidants, the total content is from 1.2 to 5%. It is preferable to use a mixture of magnesium and / or calcium stearate and talc, with magnesium and / or calcium stearate 0.2-1.0% and talc 1.0-3.0%.

An acid stabilizer (citric acid, its hydrated forms, their mixture or ascorbic acid) acts as a stabilizer of betahistine due to the additional binding of the lone electron pair of nitrogen, which is part of the betahistine molecule, which leads to a decrease in its reactivity, and as a result, greater resistance to air components in the presence of moisture.

Aerosil (colloidal silicon oxide) is a component that improves the distribution of components in the mass of technological mix.

Milk sugar (lactose) is the most optimal filler for compositions with betahistine. The introduction of it in the declared amount does not irritate the gastrointestinal tract and contributes to better disintegration of the finished dosage form.

Microcrystalline cellulose (MCC) is a multi-purpose component that provides the necessary strength characteristics of the finished dosage form and increases the bioavailability of betahistine.

The technical result of the claimed invention is to obtain a domestic dosage form of a histamine-like drug for the treatment of dizziness and hearing loss of various origins, simplification of the production of HFs by optimizing the composition and sequence of operations and technological parameters, strength characteristics, time stability, cheapening of the finished product while ensuring guaranteed for patients values of bioavailability assessment indicators (rast digestion, disintegration), ensuring a more rapid onset of therapeutic effect compared with the analogue drug.

The claimed proportion of ingredients is optimal, found experimentally and provides the necessary quality of the composition, its compliance with the requirements of the Global Fund XI and shelf life of more than 3 years.

Example 1

1. Betahistine hydrochloride - from 4 to 16%

2. MCC - from 55.2 to 66.2%

3. Mannitol - 20%

4. Citric acid - 2%

5. Aerosil - 2%

6. Talc - 4.8%

Components 1–3 and 5 (1/2 part) are mixed, moistened with a solution of component 4, granulated, dried using calorifer drying at a temperature of (45 ± 10) ° С to a residual moisture content of not more than 6%. The granulate obtained is dusted with a mixture of components 5 (1/2 part) and 6 and tableted.

Conclusions: the resulting preparation has a high heterogeneity in the distribution of the active substance by the weight of the tablets. Appearance - does not satisfy the requirement due to the presence of marbling and painted spots.

Example 2

1. Betahistine hydrochloride - from 5 to 16%

2. MCC - from 55.2 to 66.2%

3. Mannitol - 20%

4. Citric acid - 2%

5. Aerosil - 2%

6. Talc - 4.8%

Components 1 and 4 are dissolved in a small amount of water. Components 2, 3 and 5 are mixed, the resulting mixture is moistened with a prepared solution of components 1 and 4, wet granulation is carried out, and the granulate is dried in a calorific dryer at a temperature of (45 ± 10) ° С to a residual moisture content of not more than 6%. The dried granulate is dusted with a mixture of components 5 and 6 and tableted. The average tablet weight is 0.25 g.

Conclusions: the drug meets the requirements.

Example 3

Replacing mannitol with lactose as a more common and cheaper ingredient.

1. Betahistine hydrochloride - from 5 to 16%

2. MCC - from 55.2 to 66.2%

3. Lactose - 20%

4. Citric acid - 2%

5. Aerosil - 2%

6. Talc - 4.8%

Components 1 and 4 are dissolved in a small amount of water. Components 2, 3 and 5 are mixed, the resulting mixture is moistened with a prepared solution of components 1 and 4, wet granulation is carried out, and the granulate is dried in a calorific dryer at a temperature of (45 ± 10) ° С to a residual moisture content of not more than 6%. The dried granulate is dusted with a mixture of components 5 and 6 and tableted. The average tablet weight is 0.25 g.

Conclusions: the drug meets the requirements.

Example 4

Changing the composition in order to reduce consumption rates while maintaining quality.

1. Betahistine hydrochloride - from 6 to 16%

2. MCC - from 55 to 65%

3. Lactose - from 15 to 25%

4. Citric acid - 2%

5. Aerosil - 2%

6. Talc - 4.8%

Components 1 and 4 are dissolved in a small amount of water. Components 2, 3 and 5 are mixed, the resulting mixture is moistened with a prepared solution of components 1 and 4, wet granulation is carried out, and the granulate is dried in a calorific dryer at a temperature of (45 ± 10) ° С to a residual moisture content of not more than 6%. The dried granulate is dusted with a mixture of components 5, 6 and tabletted. The average tablet weight is 0.20 g.

Conclusions: Reduced component costs by 20%. The drug meets the requirements, however, bioavailability indicators are reduced compared to example 3 (disintegration - up to 15 min, dissolution - at least 80%). To maintain the required tablet height, the pressing pressure is selected so that the final strength of the obtained tablets meets the requirements. The latter adversely affects the operation of the press tool and increases its wear.

Example 5

1. Betahistine hydrochloride - from 4 to 16%

2. MCC - from 30 to 65%

3. Lactose - from 10 to 45%

4. Citric acid - from 1 to 5%

5. Crospovidone - from 2 to 10%

6. Aerosil - from 1.5 to 10%

7. Talc - from 1 to 6%

Components 1 and 4 are pre-dissolved in water. Components 2, 3, 5, and 6 are mixed, the resulting mixture is moistened with the prepared solution of components 1 and 4, wet granulation is carried out, and the granulate is dried in a calorifer drying at a temperature of (45 ± 10) ° С to a residual moisture content of not more than 6%. The dried granulate is dusted with a mixture of components 5, 6 and 7 and tabletted. The average tablet weight is 0.20 g.

Talc (component 7) is replaced partially or completely by magnesium stearate or calcium stearate or a mixture thereof.

Conclusions: The drug meets the requirements.

Various options for the combination of the composition in accordance with example 5 are presented in table 1. The data on the quality indicators of the bioavailability of the drug (disintegration, dissolution, time to reach 90% dissolution) are also given.

Table 1.

Component Name Percentage Betahistine hydrochloride four 8 8 10 fourteen 16 four 8 16 MCC 51.9 54 49 63.5 52,5 36.7 36 35,4 31.6 Lactose 31 25.8 25.5 10.5 fifteen thirty 40.5 42.1 26.1 Citric Acid 2 2.2 1.9 2,5 2 4,5 1,6 3 3.8 Crospovidone 4.7 3.2 10 8 3 2.6 6.1 2,4 10 Aerosil 3 3.8 3.6 4,5 10 8 10 4.1 6.8 Talc 2,5 1,5 one 0 one 1,5 one 2 4,5 Magnesium stearate 0.9 one one 0.5 one 0.5 0 1,5 0.2 Calcium stearate 0 0.5 0 0.5 1,5 0.2 0.8 1,5 one Disintegration, min (not more than 15 min) from 1 to 6 1 to 4 from 1 to 5 from 1 to 6 from 1 to 7 from 1 to 3 from 2 to 8 2 to 4 from 2 to 7 Dissolution,% (not less than 75%) 99,4 99.36 99,99 99.1 98.44 99.64 95.64 96.46 98.4 The time to reach 90% level of dissolution, min less than 5 less than 10 less than 5 less than 5 less than 10 less than 10 less than 5 less than 10 less than 5 Appearance sat. sat. sat. sat. sat. sat. sat. sat. sat. Average weight 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Expiration date, years more than 2.5 more than 3 more than 3 3,5 more than 2.5 more than 2 more than 3 3,5 more than 2.5

To compare experiment 5 (second column, with a disintegrant content of 3.2%), the kinetics of the release of the active ingredient from the finished dosage form was studied in comparison with the analogue drug (Betaserk, manufactured by Solvey Pharma) at the end of the observation period of 3 years.

Comparative data show that the curve for the release of the active pharmaceutical ingredient from the claimed drug is characterized by a higher speed - the time to reach the release level of more than 95% is reached in about 8 minutes, while from the analogue preparation the achievement of the set value is achieved in about 20 minutes

The concentration curve is characterized by rapid growth and reaching a stable concentration level already at the 10th minute, while the analogue drug shows an initial concentration jump and its further gradual increase without reaching a plateau. The scatter of values is significantly reduced for the claimed drug in comparison with the analogue drug, which shows a decrease in the variability of the active concentration of betahistine in the blood plasma (estimated - not less than three times) and the stabilization of pharmacokinetic parameters.

This is shown in the graphs of the dynamics of the release of betahistine from the developed drug (figure 1) and the dynamics of the release of betahistine from the drug "Bataserk" (figure 2).

Example 6

1. Betahistine hydrochloride - from 6 to 16%

2. MCC - from 55 to 65%

3. Lactose - from 15 to 25%

4. Citric acid - 2%

5. Aerosil - 2%

6. Talc - 4.8%

Components 1 and 4 are dissolved in a small amount of water. Components 2, 3 and 5 are mixed, the resulting mixture is moistened with a prepared solution of components 1 and 4, wet granulation is carried out, and the granulate is dried in a calorific dryer at a temperature of (45 ± 10) ° С to a residual moisture content of not more than 6%. The dried granulate is dusted with a mixture of components 5, 6 and sprinkled into capsules.

The drug is equivalent in stability to that in tablet form for at least 3 years. Unlike tablets, capsules belong to a dosage form that has greater bioavailability and ease of use compared to tablets.

Example 7

The same as in example 4. The humidification process and the drying process of the granulate is carried out in fluidized bed plants, then they are dusted and tabletted or sprinkled in hard gelatin capsules.

Conclusions: the drug meets the requirements for a shelf life of at least 3 years.

Example 8

As a disintegrant, crospovidone is replaced by HPMC or pregelatinized starch or croscarmellose or alginic acid (in the form of a sodium or potassium salt).

Talc is replaced partially or completely with magnesium stearate or calcium stearate or a mixture thereof.

Table 2.

Betahistine hydrochloride 8 8 8 8 8 8 8 8 MCC 31.5 33,4 34.5 35.9 39,4 44.35 52 32,5 Lactose 41 37.6 34.5 36.1 37.6 30.65 27.8 44.5 Citric Acid 3 3 3 3 3 3 3 3 GPMC 10 0 0 0 four 0 0 0 Pregelatinized starch 0 10 0 0 0 5 0 0 Crosscarmelose 0 0 10 0 0 0 2 0 Alginic acid in the form of salt 0 0 0 10 0 0 0 one Aerosil 1,5 3 5 2 3 four 6 6 Talc 3 0 0 0 2 2 1,2 2 Calcium stearate 2 2 0 3 3 0 0 1,5 Magnesium stearate 0 3 5 2 0 3 0 1,5 Disintegration at the end of the shelf life, min (not more than 15 min) no more than 8 no more than 8 no more than 8 no more than 7 no more than 9 no more than 9 no more than 10 no more than 13 Dissolution at the end of the shelf life,% (not less than 75%) not less than 90 not less than 95 not less than 90 not less than 90 not less than 95 not less than 90 not less than 90 not less than 90 The time to reach 90% level of dissolution, min less than 10 less than 10 less than 10 less than 10 less than 10 less than 10 less than 10 less than 10 Appearance sat. sat. sat. sat. sat. sat. sat. sat. Average weight 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2

Literature

1. Mashkovsky M.D. Medicines In two volumes. - Ed. 13th, new- Kharkov: Torsing, 1997. Volume 1, p.275.

2. Encyclopedia of medicines. - 12th issue / Ch. ed. G.L. Vyshkovsky. - M .: RLS-2005. S.168-169, 1086.

3.Http: //www.solvay-pharma.ru from 04/28/2006

4. The Merck Index, 12-edition, MERCK & CO., Inc., Whetehouse Station, NJ, 1996, p .97.

5. Report on the experimental study of the toxicity of the drug “Betagistin” manufactured by JSC “Moscow Production Chemical-Pharmaceutical Association named after N.A. Semashko ”and the registered drug-analogue“ Betaserk ^® ”, Institute of Toxicology, St. Petersburg, 2006

6.Http: //www.compendium.com.ua from 04/28/2006

7. Afanasyeva S.A., Gorbatseva F.E., Natyazhkina G.M. Nevrol. journal 2003; 4 (8): 38-42.

8. http://solvav-pharma.com.ua/lekarze/psycho/Chekman2.pdf dated 04/28/2006. AGONISTS / ANTAGONISTS OF HISTAMIN RECEPTORS: CLINICAL PHARMACOLOGY BETASERKU. I. Chekman, National Medical University im. O.O.Bogomoltsya, Kuiв.

Claims (8)

1. A solid dosage form for the treatment of dizziness and hearing loss, containing betahistine and target additives as an active pharmaceutical ingredient, characterized in that it contains microcrystalline cellulose (MCC), lactose (milk sugar), an acid stabilizer, aerosil, as target additives a disintegrant, a sliding substance selected from the group consisting of talc, magnesium stearate, calcium stearate or a mixture thereof in the following ratio of ingredients, wt.%: Betahistine hydrochloride 4-16 Microcrystalline cellulose 25-70 Acid Stabilizer 1-3 Aerosil 1-10 Disintegrant 2-10 Glidants 1,2-5 Milk sugar rest 2. The dosage form according to claim 1, characterized in that as a stabilizer of acidity contains citric acid or ascorbic acid. 3. The dosage form according to claim 1, characterized in that the disintegrant contains pregelatinized starch, hydroxypropyl methylcellulose (HPMC), crosscarmellose, crospovidone, alginic acid in the form of a salt or a mixture thereof. 4. The dosage form according to claim 1, characterized in that as a sliding contains talc in an amount of 1-3%. 5. The dosage form according to claim 1, characterized in that it is a hard gelatin capsule in which the active pharmaceutical ingredient and the desired additives are placed. 6. A method of obtaining a solid dosage form of a drug for treating dizziness and hearing loss according to claim 1, containing betahistine and target additives as an active pharmaceutical ingredient, including mixing, granulating and molding a mixture, characterized in that the powder is mixed with MCC, lactose and aerosil and parts of the disintegrant substance, moisten the mixture with a solution containing betahistine, an acid stabilizer, part of the disintegrant substance, wet granulation of the mixture, drying and dusting of the granulate are sliding m selected from the group consisting of talc, magnesium stearate, calcium stearate, or mixtures thereof. 7. The method according to claim 6, characterized in that the process of moistening and drying the granulate is carried out in a fluidized bed installation. 8. The method according to claim 6, characterized in that when dusting, an additional 3-6% of the disintegrant of the total amount of the disintegrant is added.

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