RU2578432C1 - Method of obtaining a solid form of the drug sedative and antispasmodic action - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to the pharmaceutical industry, namely to a process for preparing a solid form of the drug sedative and antispasmodic action by creating a complex of beta-cyclodextrin with a mixture of ethyl ether of alpha-bromine-isovalerianic acid and peppermint oil (EBR-oil mixture).

EFFECT: drug obtained by the inventive process is stable.

4 cl, 2 tbl, 11 ex

Description

FIELD OF TECHNOLOGY

The invention relates to the pharmaceutical industry, and in particular to a method for producing a solid form of a sedative and antispasmodic drug, and can be used as a sedative for increased nervous irritability, sleep disturbances, insomnia, irritability, and a feeling of internal tension.

BACKGROUND

Sedative and antispasmodic drugs are known that contain, in addition to herbal components, derivatives of barbituric acid (phenobarbital and others). The most famous of these drugs is the drug “Corvalol”, the effect of which is due to the properties of its constituents: ethyl bromisovalerianic acid, phenobarbital, peppermint oil pepper [Mashkovsky M.D. Medicines New Wave, - 2001, v. 1, p. 89]. The drug "Corvalol" is available in the form of a solution and is used according to the instructions attached to it as drops with a small amount of water. The use of the drug “Corvalol” and its analogues may be accompanied by side effects in the form of respiratory depression, as well as xerotomy - dry mouth. The disadvantage of the drug is that in emergency cases it is difficult to use this drug in the form of drops.

In this regard, there is a need to develop a sedative and antispasmodic in the form of solid dosage forms that are convenient for use, have an accurate dosage and persist for a long time and, in addition, the unpleasant taste of the medicinal substances contained in them is less felt.

A known drug of sedative and antispasmodic action and a method for its manufacture, made in solid dosage form [RU 2349334]. According to the invention, a sedative and antispasmodic drug containing ethyl ether bromisovalerianic acid, phenobarbital and peppermint oil additionally contains microcrystalline cellulose, auxiliary substances for creating a solid dosage form in the form of tablets in the following ratio, wt. %:

ethyl ether bromisovalerianic acid 1.37-8.2 phenobarbital 1.25-7.5 peppermint oil 0.16-0.58 microcrystalline cellulose 2.0-15.0 Excipients rest,

moreover, the tablets are coated, which includes cyclodextrin in a dose of up to 10% of the weight of the dry coating.

The known drug may optionally contain - cyclodextrin in a dose of up to 70 wt. %

A method of manufacturing a sedative and antispasmodic drug in the form of a tablet according to the description of the invention [patent RU 2349334] includes, in one embodiment, the following steps:

first, ethyl bromisovalerianic acid ethyl ester (hereinafter referred to as EBK) is mixed with peppermint oil, the amount of the mixture being more than 4.5% of the total weight of the tablet, core tablet or capsule weight,

the mixture is added to moistened beta-cyclodextrin, the amount of which is up to 70% of the mass of the total mass of the tablet core, mixed for 1-2 minutes,

the resulting mixture is dried, granulated, after which the granulate is mixed with phenobarbital, microcrystalline cellulose powders, with excipients - fillers, disintegrants and glidants, tablets are compressed,

and then they are coated with a coating containing beta-cyclodextrin in a dose of up to 10% of the weight of the dry coating.

A method of manufacturing a sedative and antispasmodic drug in the form of a tablet according to the description of the invention [RU 2349334] in another embodiment includes the following steps:

phenobarbital is first mixed with excipient,

separately preparing a mixture of ethyl ester of alpha-bromisovalerianic acid and peppermint oil, the mixture of essential oils being less than 4.5% of the tablet weight,

core tablets or masses of the contents of the capsule, add microcrystalline cellulose (hereinafter - MCC), powders with a developed surface of crystals, excipients, disintegrants and glidants,

the resulting mixture is added to a mixture of phenobarbital with a filler and tablets are compressed,

and then they are coated with a coating containing beta-cyclodextrin in a dose of up to 10% of the weight of the dry coating.

The manufacturing method variants described in patent RU2349334 make it possible to obtain a dosage form containing liquid volatile substances in the form of a tablet. However, if the content of beta-cyclodextrin as an auxiliary substance in a molar ratio is less than the content of volatiles, the tablets obtained in a known manner will be unstable during manufacture and storage.

In addition, it is known that a stable complex of EBA and peppermint oil with beta-dextrin can be created with stirring only in the presence of a certain amount of water, which is a prerequisite for intramolecular encapsulation of volatile substances [KLEPTOSE, betacyclodextrins and hydroxypropyl betacyclodextrins, Roquette Freres S.. - 07/2006].

In the case of obtaining a medicinal product by the method described in patent RU 2349334, when the mixture of essential oils is less than 4.5%, there is no water during the mixing process, while some of the volatile substances will be lost during the manufacture of the mixture, some during tabletting, and most - at the beginning of the coating process, when the tablets are exposed to air during the drying process.

In the case of obtaining a medicinal product by the method described in patent RU 2349334, when the mixture of essential oils is more than 4.5%, in order to obtain a stable composition, it is necessary to select a certain ratio of the amount of water and beta-cyclodextir, the mixing time, and ensure an efficient drying process. Otherwise, when implementing the known method, the formation of a thick viscous paste is inevitable, which is dried to a powder state in several stages and takes a long time, for example [No. 81623] for at least 2-2.5 days.

A significant disadvantage of the method described in patent RU 2349334 is the process of applying to tablets a coating containing up to 10% beta-cyclodextrin as an auxiliary substance. This complicates the technology and leads to the effect on the tablet core of such negative factors as increased humidity and temperature, which affect stability (which is indirectly confirmed by the absence in the description of the invention of information confirming the safety and stability of volatile substances in the dosage form).

From the level there are known methods for producing drugs of sedative and antispasmodic action in solid dosage form, which are more stable during the manufacturing process [EA 201200290, UA 83783U].

By the method described in Eurasian application EA 201200290, water-soluble stable microgranules containing complexes of active substances in the form of microgranules included in the solid dosage form and containing a complex of beta-cyclodextrin separately with ethyl ether bromisovalerianic acid (hereinafter - EBK) can be obtained ) and separately with peppermint oil. According to the description of the invention, in order to obtain separate complexes, a weighed portion of beta-cyclodextrin is dissolved in a 2: 1 ethanol-water mixture, and then EBA or peppermint oil is introduced, a clear solution is obtained, which is placed in a rotary-film evaporator and then dried to form on the surface of the flask crystals. Such a process avoids the formation of a hard-drying paste, but requires a large amount of energy to evaporate the significant amounts of solvents necessary to obtain a true solution of the substances involved in the formation of the complex. In addition, in the known method, a significant amount of ethanol is used as a solvent, which increases the requirements for ensuring fire and explosion safety of the process and significantly increases its cost.

Eurasian application EA 201200290 indicates that the formation of a stable beta-cyclodextrin complex with the introduction of a solution of two active pharmaceutical substances simultaneously - EBA and peppermint oil is difficult, since the ratio of EBA to peppermint oil in the solution is approximately 14: 1.

It should also be noted that the process of obtaining individual complexes of active substances has several disadvantages: it increases the production process of one series at least twice, requires either cleaning equipment between different complexes, or using two separate equipment lines.

Closest to the proposed method is a method for producing a sedative, vasodilator and antispasmodic drug in solid form (tablets, sublingual tablets or capsules), described [UA83783U].

According to the description of the known method provides:

- obtaining separately a complex of beta-cyclodextrin with ethyl ether alpha-bromisovalerianic acid (EBA);

- obtaining separately a complex of beta-cyclodextrin with peppermint oil, both complexes are obtained in the presence of calcium hydrogen phosphate dihydrate and some purified water, the resulting wet complex is calibrated before drying in a fluidized bed,

- two prepared solid complexes are mixed with phenobarbital and excipients;

- the resulting mass is converted into a unit dosage form;

- drying is carried out at an inlet air temperature of 22 ° C for 1-1.5 hours.

The method adopted as a prototype, involving the process of obtaining separate complexes of active substances, has several disadvantages: it increases the production process of one series at least twice, requires either cleaning equipment between the manufacturing processes of different complexes, or using two separate lines of equipment. Also, the method described in UA 83783U increases the number of analyzes and calculations that must be performed to obtain a solid dosage form with the exact dose of all components, since before the last mixing of the mixture, it is necessary to know the actual weight of the obtained complexes and the actual content of the active substance in them. More components are involved in the process of mixing the finished mixture, and, as indicated, the ratio of the two of them is approximately 14: 1, which invariably leads to the difficulty of uniform distribution.

The present invention solves the problem of obtaining a solid dosage form of a medicinal product of sedative and antispasmodic action, stable during production and during long-term storage.

The technical result obtained by using the invention is to obtain a solid dosage form stable during production and during long-term storage by stabilizing the volatile ethyl ester of alpha-bromisovalerianic acid and peppermint oil due to the formation of a beta-cyclodextrin complex with a mixture of ethyl ether-bromisovalerianic peppermint acids and oils with a minimum duration of the technological process (the complex formation time does not exceed 5 minutes). In the process of formation of a stable complex of volatile substances, a mixture of EBA-oil is used, the formation of the complex occurs with stirring in the presence of a strictly defined ratio of beta-cyclodextrin: MCC and MCC: water. The use of EBK-oil mixtures allows to avoid the preparation of two separate complexes of volatile substances, reduces the time of production, cleaning equipment, reduces the number of auxiliary operations.

SUMMARY OF THE INVENTION

To solve the problem and achieve the technical result, a method for producing a sedative and antispasmodic drug in solid dosage form, characterized in that

- from a mixture of ethyl ester of alpha-bromisovalerianic acid and peppermint oil, a complex is prepared with beta-cyclodextrin taken in a molar amount of at least a molar amount of a mixture of ethyl ester of alpha-bromisovalerianic acid and peppermint oil components in the presence of microcrystalline cellulose and water in a weight ratio components of beta-cyclodextrin and microcrystalline cellulose, respectively, from 2: 1 to 1: 6 and a ratio of microcrystalline cellulose and water, respectively, from 2: 1 to 1: 2;

- mix beta-cyclodextrin with microcrystalline cellulose, the resulting mixture is moistened with water, taken in a ratio of from 2: 1 to 1: 2 to microcrystalline cellulose;

- then add a mixture of ethyl ester of alpha-bromisovalerianic acid and peppermint oil and mix to form a complex for 2 to 5 minutes;

- the resulting complex is dried in a fluidized bed of a drying granulator at a temperature of incoming air up to 45 ° C for 10-30 minutes,

- the dried complex is mixed with phenobarbital,

- after which excipients are added and the resulting mass is converted into a unit dosage form of a solid dosage form.

In a further aspect, the method is characterized in that a solid dosage form is obtained in the form of a tablet.

In a further aspect, the method is characterized in that a solid dosage form in the form of a capsule is obtained.

In a further aspect, the method is characterized in that a solid dosage form is obtained in the form of a powder.

It is important to note that the composition of the components and the process of obtaining the pharmaceutical composition is selected in such a way that it allows to obtain a stable solid dosage form by creating a complex of beta-cyclodextrin with a mixture of ethyl ester of alpha-bromisovalerianic acid and peppermint oil (with a mixture of EBA-oil). Moreover, the formation time of the complex does not exceed 5 minutes.

In addition, organic solvents are not used in its manufacture, and no solutions or pastes are formed in the process, which allows the complex to be dried in a fluidized bed equipment immediately after introducing the EBK-oil mixture without calibration. At the same time, the temperature of the incoming drying air can be increased to 45 ° C, which reduces the drying time of the beta-cyclodextrin complex with EBK-oil mixture to 30 minutes. A stable dosage form can be obtained in the form of a tablet without coating on it.

In contrast to the prototype, in the proposed method, a complex with beta-cyclodextrin taken in an amount of not less than 5 8 mg / dose, in the presence of MCC and water in a possible mass ratio of beta-components is prepared from a mixture of ethyl ester of alpha-bromisovalerianic acid and peppermint oil cyclodextrin: MCC from 2: 1 to 1: 6 and a ratio of MCC: water from 2: 1 to 1: 2.

New in the proposed method is that in the process of formation of a stable complex of volatile substances, a mixture of EBA-oil is used, the formation of the complex occurs with stirring in the presence of a strictly defined ratio of beta-cyclodextrin: MCC and MCC: water. The use of EBK-oil mixtures allows to avoid the preparation of two separate complexes of volatile substances, reduces the time of production, cleaning equipment, reduces the number of auxiliary operations.

The ratio of beta-cyclodextrin: MCC from 2: 1 to 1: 6 during the development process is selected so that after the complex is formed in the presence of water, the mixture is in a state of wet powder and can be dried directly in the equipment with a fluidized bed even without preliminary calibration, which provides a reduction in cooking time So, if the ratio of beta-cyclodextrin: MCC is more than 2: 1, this can lead to the formation of a paste after wetting, if less than 1: 6, then this is possible from the point of view of stability of the complex, but is not economically feasible, because increases the weight of the dosage form, requires a large amount of MCC and water, and therefore, increases the energy consumption of excipients and drying of the complex. The ratio of MCC: water from 2: 1 to 1: 2 is selected in such a way as to ensure the complexation process for a time not exceeding 5 minutes, and to prevent over-wetting of the components with the formation of a paste. If there is less than 2: 1 water to the MCC, then for the formation of the complex it will take more than 5 minutes, and with a further decrease in the amount of water, the full complex of all molecules of volatile substances may not form at all. If there is more than 2: 1 water in relation to the MCC, this can lead to the formation of a paste and increases the energy consumption for drying.

During the development process, the minimum required amount of beta-cyclodextrin for the formation of a stable complex with a mixture of EBK-oil was substantiated and experimentally confirmed.

The minimum weight of a stable complex per dose is possible with a ratio of beta-cyclodextrin: MCC = 2: 1 and then the composition per unit solid dosage form:

EBK 8.2 mg Peppermint Oil 0.58 mg Beta-cyclodcstrin 58 mg MCC 2 9 mg

Total: 95.78 mg

Known [Handbook of Pharmaceutical excipients, 7th edition, 2012, p.229-231; Nature reviews / DRUG DISCOVERY, volume 3, December 2004, p.1025-1035] that the molar ratio of the mixture of EBA and peppermint oil components with beta-cyclodextrin in a stable complex should be 1: 1. Peppermint oil consists of a large number of related compounds, the main of which is present in the largest amount in the composition of the oil is menthol (molecular weight 156.3 g / mol). Since menthol has the smallest molecular weight of the remaining components, it can be assumed in the calculations that peppermint oil consists only of this component. The molecular weight of EBA is 209.9 g / mol, and beta-cyclodextrin 1135 g / mol. Then you can find the minimum amount of beta-cyclodextrin needed to form a stable complex with 8.2 mg of EBA and 0.58 mg of peppermint oil: (8.2 / 209.9 + 0.58 / 156.3) * 1135 = 48, 6 mg, given that beta-cyclodextrin powder in accordance with EPh can contain up to 16% water, the minimum required amount should be taken 48.6 / 0.84 = 58 mg.

For the formation of a stable complex of beta-cyclodextrin with a mixture of ethyl ester of alpha-bromisovalerianic acid and peppermint oil, taken in amounts of 8.2 and 0.58 mg per dose, respectively, a minimum of 58 mg per dose of beta-cyclodextrin is required, and to ensure the technological process komplesoobrazovaniya necessary that the mixture was present at least 29/95, 78 * 100% = 30 wt. % microcrystalline cellulose (MCC).

The invention is illustrated in Tables 1 and 2.

Table 1 presents examples of formulations in mg / per dose and in grams per load.

Table 2 shows the ratio of the components of the complexes, the modes of their preparation and the results of the quantitative determination of EBA and menthol in solid dosage forms immediately after their manufacture and after storage at an elevated temperature of 55 ° C in an thermostat for 69 and 138 days.

The invention is illustrated by examples of obtaining the proposed method of solid forms of the drug sedative and antispasmodic action. In all examples, EBA and peppermint oil were mixed with each other in a glass beaker with a glass rod for 2 minutes before being introduced into the complex, to obtain a mixture of EBK-oil. A mixture of beta-cyclodextrin with MCC is carried out in a MIC-DV mixer at a speed of the lower paddle mixer of 100 rpm, a side grinder - 400 rpm, then, without stopping mixing, the amount of water indicated in the table is poured, stirred for another 30 seconds and the mixture is introduced EBK oil.

Description of the essence of the proposed method. In a glass beaker by non-vigorous stirring with a glass rod for 2 minutes, a mixture of ethyl ester of alpha-bromisovalerianic acid and peppermint oil (EBA oil) is prepared. A complex of beta-cyclodextrin with a mixture of EBK-oil is obtained in a high shear granulator, for example MIC-DV, COMASA, Argentina, or beta-cyclodextrin and microcrystalline cellulose (MCC) in a ratio of 2: 1 to 1: 6. To the resulting mixture, through a funnel with stirring turned on, add water taken in a ratio of 2: 1 to 1: 2 to the MCC, then add a mixture of EBA-oil and mix to form a complex for 2-5 minutes.

The resulting wet complex is dried without preliminary calibration in a fluidized bed of a granulator DPL-1, "DDPM", China, at an inlet air temperature of 25 to 45 ° C for 10-30 minutes to a residual moisture content that does not differ from the initial moisture content of the beta-cyclodextrin mixture : MCC more than ± 2%.

The humidity of the mixture before the introduction of water and after drying is measured by drying to constant weight at a temperature of 90 ° C using an automatic moisture analyzer MF-50, "AND", Japan. The dried complex is calibrated through a Comil sieve or cone mill, Quadro, Canada, then mixed with phenobarbital in a MIC-DV mixer until a homogeneous mixture is obtained.

Depending on the particular dosage unit form, appropriate excipients are added by mixing in a mixer.

Pressing of the tablets is carried out on a rotary four-punch press PICCOLA, "RIVA", Argentina, equipped with a mechanical feeder with an independent drive.

Dosing of the mixture into capsules is carried out by the disk method on a single-position automatic machine IN-CAP, "DOTT.BONAPACE", Italy.

Three-layer powder packaging in sachets made of combined material is carried out by a screw method on an automatic machine SP-101-08, "Solpak", Korea.

Tablets and capsules were packaged in a blister of aluminum and PVC foil on a semi-automatic machine FANTASY, O.M.A.R., Italy.

To obtain the complex, peppermint leaf oil was used, produced by Bhagat Aromatics Ltd., in which the menthol content is normalized from 30 to 55%. The actual menthol content was measured by gas chromatography (European Pharmacopoeia, method 2.2.28) and is 43%, then the average expected menthol content in a unit dosage form is: 0.59 mg * 43/100 = 0.254 mg.

Also, to obtain the complex, ethyl bromisovalerianic acid ethyl ester produced by Technopark Center LLC with an active substance content of close to 100% was used, therefore, the average expected content of EBA in a single dosage form is 8.2 mg.

Assessment of the stability of the resulting complex was carried out in accordance with I-42-2-82 "Instructions for the work to determine the shelf life of drugs based on the method of" Accelerated aging "at elevated temperature. For this, tablets and capsules were packaged immediately after production in a blister pack consisting of aluminum foil and a PVC film, and the powder in a sachet was made of packets of a three-layer combined material. Solid forms in the appropriate primary packaging were placed in a thermostat, maintaining a constant temperature of 55 ° C.

The method of gas chromatography was used to determine the quantitative average content of EBA and menthol in a unit of solid dosage form immediately after its manufacture and after storage in primary packaging at an elevated temperature of 55 ° C for 69 and 138 days, which corresponds to an expiration date of 18 and 36 months when stored with temperature up to 25 ° С. To assess the stability of volatile substances in the complex, the obtained values were compared with the theoretical expected quantitative content. In accordance with the requirements of the leading Pharmacopoeias, the average quantitative content in dosage solid dosage forms over the entire shelf life is accepted for EBC 8.2 mg ± 10%, i.e. from 7.38 to 9.02 mg, for menthol at least 0.23 mg.

Example 1

Obtaining a sedative and antispasmodic drug in the form of a solid dosage form - tablets. The composition per tablet is shown in table 1.

Beta-cyclodextrin and MCC are loaded into the MIC-DV mixer-granulator, they are mixed for 30 seconds, the purified water is added, the mixture is stirred for another 30 seconds, immediately the mixture of EBK-oil is added and stirring is continued for another 2 minutes. The wet complex is transferred to a laboratory granulator dryer DPL-1, where it is dried in a fluidized bed at an inlet air temperature of 30 ° C for 20 minutes to obtain the indicator "weight loss by drying" in the range of 8-12%. The dried complex is calibrated to break large agglomerates in a Comil cone mill through a mesh with a hole size of about 1.0 mm.

The calibrated complex in accordance with the composition of example 1 of table 1 is mixed with phenobarbital and anti-friction substance -magnesium stearate in a laboratory mixer - cube for 3 minutes. From the resulting mixture, tablets of a flat cylindrical shape, 6.0 mm in diameter, about 2.7 mm high and an average weight of 104.3 mg, compressive strength 80-100 N are pressed on a PICCOLA press.

Example 2

Obtaining a sedative and antispasmodic drug in the form of a solid dosage form - capsule. The composition per capsule is shown in table 1.

The preparation of the wet complex is carried out similarly to the method described in example 1. The wet complex is transferred to a laboratory granulator dryer DPL-1, where it is dried in a fluidized bed at an inlet air temperature of 40 ° C for 20 minutes to obtain the indicator "weight loss by drying" in the range of 8-12%. The dried complex is calibrated to break large agglomerates in a Comil cone mill through a mesh with a hole size of about 1.0 mm.

The calibrated complex in accordance with the composition of example 2 of table 1 is mixed with phenobarbital, filler - lactose monohydrate and anti-friction substance - magnesium stearate in a laboratory mixer - cube for 3 minutes. The resulting mixture is dosed in hard gelatin capsules (capsule size No. 2) on an automatic IN-CAP machine using a dosing disk 12 mm high, the average weight of the contents of the capsule is 200 mg.

Example 3

Obtaining a sedative and antispasmodic drug in the form of a solid dosage form - a powder.

Obtaining a wet complex is carried out similarly to the described method in examples 1 and 2, only the mixing time in the mixer after introducing the mixture of EBK-oil is 5 minutes, drying in a fluidized bed is carried out at an inlet air temperature of 2 5 ° C for 30 minutes to obtain the indicator "loss mass upon drying "in the range of 5-9%.

The dried complex, in accordance with the composition of Example 3 of Table 1, is mixed with phenobarbital and a filler, which at the same time performs the function of flavor corrector - sugar in a V-shaped mixer - cube for 5 minutes. The resulting mixture is Packed in a sachet - bags on the machine SP-101-08, the average weight of the powder contained in the bag is 2.0 g

Example 4

Obtaining a sedative and antispasmodic drug in the form of a dispersible tablet.

Beta-cyclodextrin and MCC are loaded into the MIC-DV mixer-granulator, they are mixed for 30 seconds, the purified water is added, the mixture is stirred for another 30 seconds, immediately the mixture of EBK-oil is added and stirring is continued for another 2 minutes. The wet complex is transferred to a laboratory granulator dryer DPL-1, where it is dried in a fluidized bed at an inlet air temperature of 45 ° C for 30 minutes to obtain the indicator "weight loss by drying" in the range of 4-8%. The dried complex is calibrated to break large agglomerates at a Comil cone mill through a mesh with a hole size of about 0.45 mm.

The calibrated complex in accordance with the composition of example 4 of table 1 is mixed with phenobarbital, the disintegrant with croscarmellose sodium and anti-friction substance magnesium stearate in a laboratory mixer - cube for 2 minutes. Dispersible tablets of flat cylindrical shape, with a diameter of 12.0 mm, a height of about 4.2 mm and an average weight of 500 mg, compressive strength of 110-140 N, with a disintegration time of 60 to 90 at room temperature in water, are pressed on a PICCOLA press from the resulting mixture. sec

Example 5

Obtaining a sedative and antispasmodic drug in the form of a tablet.

Beta-cyclodextrin and MCC are loaded into the MIC-DV mixer-granulator, mix them for 10 seconds, add purified water, mix for another 30 seconds, immediately add the EBK-oil mixture and continue mixing for another 5 minutes. The wet complex is transferred to a laboratory granulator dryer DPL-1, where it is dried in a fluidized bed at an inlet air temperature of 40 ° C for 10 minutes to obtain the indicator "weight loss by drying" in the range of 7-11%. The dried complex is calibrated to destroy large agglomerates through a laboratory sieve with a hole diameter of about 1.0 mm.

The calibrated complex, in accordance with the composition of Example 5 of Table 1, is mixed with phenobarbital, filler — lactose monohydrate, brand SD, disintegrant — corn starch and anti-friction substance — magnesium stearate in a laboratory mixer — cube for 2 minutes. From the resulting mixture, tablets of a cylindrical shape, with a diameter of 8.0 mm, a height of about 3.1 mm and an average weight of 200 mg, compressive strength 79-88 N, a disintegration time in water at a temperature of 37 ° C from 5 to 6 minutes

Example 6

Obtaining a sedative and antispasmodic drug in the form of a solid drug - powder.

Obtaining a wet complex is carried out similarly to the method described in example 5, only the mixing time in the mixer after introducing the mixture of EBK-oil is 2 minutes, drying is carried out in a fluidized bed at an inlet air temperature of 30C for 10 minutes to obtain the indicator "weight loss by drying" within 4-8%.

The dried complex, in accordance with the composition of Example 6 of Table AAA, is mixed with phenobarbital and a filler, which at the same time performs the function of flavor corrector - sorbitol, disintegrant - crospovidone, glidant - silicon dioxide colloidal in a laboratory mixer - cube for 3 minutes. The resulting mixture is Packed in a sachet on a machine SP-101-08, the average weight of the powder contained in the package, 1.0 g

Example 7

Obtaining a sedative and antispasmodic drug in the form of a biconvex tablet.

Obtaining a wet complex is carried out similarly to the method described in example 5, only drying is carried out in a fluidized bed at an inlet air temperature of 45 ° C for 10 minutes to obtain the indicator "weight loss by drying" within 7-11%.

The dried complex, in accordance with the composition of Example 7 of Table 1, is mixed with phenobarbital, the filler is calcium hydrophosphate, the disintegrant is croscarmellose sodium and the antifriction substance is magnesium stearate in a laboratory mixer - cube for 2 minutes, then passed through a grid of a Comil cone mill. Biconvex oval tablets with an average weight of 350 mg and a height of 4.3 mm, compressive strength 110-120 N are pressed from the resulting mixture.

Example 8

Obtaining a sedative and antispasmodic drug in the form of capsules.

Beta-cyclodextrin and MCC are loaded into the MIC-DV mixer-granulator, they are mixed for 30 seconds, the purified water is added, the mixture is stirred for another 30 seconds, immediately the mixture of EBK-oil is added and stirring is continued for another 2 minutes. The wet complex is transferred to a laboratory granulator dryer DPL-1, where it is dried in a fluidized bed at an inlet air temperature of 30 ° C for 30 minutes to obtain the indicator "weight loss by drying" in the range of 7-11%. The dried complex is calibrated to break large agglomerates in a Comil cone mill through a mesh with a hole size of about 1.0 mm.

The calibrated complex in accordance with the composition of example 8 of table 1 is mixed with phenobarbital, filler - starch corn and anti-friction substance - magnesium stearate in a laboratory mixer - cube for 3 minutes. The resulting mixture is metered into hard gelatin capsules (capsule size No. 2) on an IN-CAP automatic machine using a 9 mm high metering disk, the average weight of the contents of the capsule is 160 mg.

Example 9

Obtaining a sedative and antispasmodic drug in the form of a tablet.

Obtaining a wet complex is carried out similarly to the method described in example 5, only drying is carried out in a fluidized bed at an inlet air temperature of 30 ° C for 10 minutes to obtain the indicator "weight loss by drying" in the range of 7-11%.

The dried complex is calibrated to destroy large agglomerates through a laboratory sieve with a hole diameter of about 1.0 mm.

The calibrated complex in accordance with the composition of Example 9 of Table 1 is mixed with phenobarbital, filler — lactose SD brand monohydrate, disintegrant — corn starch and anti-friction substance — magnesium stearate in a cube laboratory mixer for 2 minutes. From the resulting mixture, tablets of a cylindrical shape, with a diameter of 7.0 mm, a height of about 2.6 mm and an average weight of 120 mg, compressive strength 55-63 N, a disintegration time in water at a temperature of 37 ° C from 3 to 4 minutes.

Example 10

Obtaining a sedative and antispasmodic drug in the form of a tablet.

Obtaining a wet complex is carried out similarly to the described method in example 1, the only difference is that the amount of water is less than 1/3 part, and the mixing time after introducing the mixture EBK0-oil was increased from 2 to 5 minutes. Because less water, the drying air temperature was maintained at 25 ° C, and the drying time was 10 min. Dried to a moisture content of 7-11%, the complex is calibrated to destroy large agglomerates in a Comil cone mill through a mesh with a hole size of about 1.0 mm.

The calibrated complex in accordance with the composition of example 10 of table 1, is mixed with phenobarbital and anti-friction substance - magnesium stearate in a laboratory mixer - cube for 3 minutes. From the resulting mixture, PICCOLA presses compressed tablets of a flat cylindrical shape, 6.0 mm in diameter, about 2.7 mm high and an average weight of 104.3 mg, compressive strength of 75-85 N.

Example 11

Obtaining a sedative and antispasmodic drug in the form of a tablet.

Beta-cyclodextrin and MCC are loaded into the MIC-DV mixer-granulator, they are mixed for 30 seconds, immediately the mixture of EBA-oil is added and stirring is continued for another 5 minutes. Water is not added, therefore, drying is not carried out. Phenobarbital, lactose monohydrate, corn starch and silicon dioxide colloidal in accordance with the composition of example 11 of table 1 are added to the same mixer, mixed for 1 minute. The mixture is passed through a Comil cone mill screen. From the resulting mixture, tablets of a cylindrical shape, with a diameter of 8.0 mm, a height of about 3.1 mm and an average weight of 200 mg, compressive strength 47-55 N, a disintegration time in water at a temperature of 37 ° C from 12 to 14 minutes

Thus, examples 1-8 clearly demonstrate that the complex of volatile substances with betacyclodextrin made by the proposed method is stable during storage. Solid dosage forms manufactured as described in examples 1-8, when stored under the conditions of the “accelerated aging” test, meet the established criteria for the quantitative content for EBC of 8.2 mg ± 10%, i.e. from 7.38 to 9.02 mg, and for menthol at least 0.23 mg.

Moreover, examples 9-11 show that when going beyond the scope of the steps described in the proposed method, it is impossible to obtain a storage stable composition. So, in example 9, the molar amount of beta-cyclodextrin is less than the amount of volatile substances - EBA and mint oil components. Therefore, some of the molecules of volatile substances cannot form a complex and gradually evaporate from the dosage form. In example 10, the quantitative content of EBA and menthol immediately after the manufacture of the tablet is at the lower limit, which is explained by the low rate of complexation in the presence of an insufficient amount of water. According to the results of the analysis of the quantitative content of volatile substances shown in Example 11, we can conclude that in the absence of water introduced into the process, a stable complex is not formed, most of the EBK and menthol are lost even when manufacturing a solid dosage form.

Claims (4)

1. A method of obtaining a sedative and antispasmodic drug in solid dosage form, characterized in that a complex with beta-cyclodextrin taken in a molar amount of at least a molar amount of alpha ethyl ester is prepared from a mixture of ethyl ester of alpha-bromisovalerianic acid and peppermint oil β-bromisovalerianic acid and peppermint oil components in the presence of microcrystalline cellulose and water with a mass ratio of beta-cyclodextrin and microcrystalline components cellulose, respectively, from 2: 1 to 1: 6 and a ratio of microcrystalline cellulose and water, respectively, from 2: 1 to 1: 2; beta-cyclodextrin is mixed with microcrystalline cellulose, the resulting mixture is moistened with water taken in a ratio of 2: 1 to 1: 2 to microcrystalline cellulose; then add a mixture of ethyl ester of alpha-bromisovalerianic acid and peppermint oil and mix to form a complex for 2 to 5 minutes; the resulting complex is dried in a fluidized bed of a drying granulator at a temperature of incoming air up to 45 ° C for 10-30 minutes; the dried complex is mixed with phenobarbital; after which excipients are added and the resulting mass is converted into a unit dosage form of a solid dosage form. 2. The method according to p. 1, characterized in that the solid dosage form is made in the form of tablets. 3. The method according to p. 1, characterized in that the solid dosage form is made in the form of a capsule. 4. The method according to p. 1, characterized in that the solid dosage form is made in the form of a powder.