RU2033160C1 - Process for manufacture of 'videin' d3-protein vitamin preparation - Google Patents

Abstract

FIELD: chemical-pharmaceutical industry. SUBSTANCE: this process prescribes carrying out such steps as purifying casein by dissolving it in alkali, precipitating it in acetic acid, granulating and drying, using videhol as D₃ vitamin-containing preparation, admixing it with vitamin E in 1:1 ratio, dissolving it in alcohol, drying, granulating D₃ vitamin protein complex with sugar granulate wetted by polyvinylpyrrolidone taken in ratio of (18.6 to 22.0): 0.11 and calcium stearate taken in ratio of (5.0 to 2.0): (18.6 to 22.0):0.24, respectively, and finally making tablets from resulting desired product. EFFECT: higher activity, stability and quality of preparation effective for prevention and treatment of infantile D-hypovitaminosis and rickets. 2 tbl

Description

 The invention relates to the pharmaceutical industry, in particular to the production of vitamin preparations in tablet form. The preparation obtained according to the invention is used for the prevention and treatment of D-hypovitaminosis and rickets in children and various forms of bone pathologies.

A known laboratory method for producing a complex based on fat-soluble vitamins and protein, where casein is dissolved in alkali, and vitamins (for example, D ₂ , D ₃ , A, E) in an organic solvent into which glacial acetic acid is previously introduced. After mixing the resulting solutions, the precipitated precipitate, which is a vitamin-protein complex, is centrifuged, dried, and ground. The resulting complexes contain up to 2% of vitamins D ₂ and D ₃ , up to 6% of vitamin A and up to 8% of vitamin E.

A known production method for producing vitamin D-protein preparation vidin for agriculture, where casein dissolved in an alkaline solution is mixed with an alcoholic concentrate of vitamin D ₃ . The resulting complex is precipitated with acetic acid, filtered, crushed and dried. The yield of vitamin D ₃ is 87.8%; the activity of 200,000 IU per 1 g is maintained for 0.5 year. However, the known method has several disadvantages: as an active principle, an alcoholic concentrate of vitamin D _{3 is used} , which contains about 12% of impurities in the form of intermediate products for producing vitamin D ₃ , for example 7-dehydrocholesterol, lumisterin and a number of oxidation products. The resulting preparation can only be used as a feed additive for agriculture.

 The aim of the invention is to increase the activity and stability of the drug by improving its purification.

To achieve the goal in the production method of vitamin D ₃ -protein preparation, where casein is dissolved in alkali, and vitamin D ₃ -containing preparation in alcohol, both solutions are mixed, precipitated with acetic acid, centrifuged, granulated and dried, additionally carry out the following operations: casein previously purified by dissolution in alkali, precipitation with acetic acid, granulation and drying;
as a vitamin D ₃ -containing drug, videhol is used (pharmacopeia article FS-42-20-5383), which is a mixture of vitamin D ₃ and cholesterol;
videhol and vitamin E in a ratio of 1: 1 are dissolved in ethyl alcohol;
sugar granules are prepared by moistening sugar with polyvinylpyrrolidone in the ratio (18.6-22.0): 0.11;
tabletting mass is obtained by mixing vitamin D ₃ protein complex, sugar granules and calcium stearic acid in the ratio, respectively (5-2) :( 18.6-22.0): 0.24;
the resulting mixture is tabletted under pressure.

The yield of vitamin D _{3 is} 98.6-99.0%. One tablet of the obtained preparation (20 or 50 mg of substance) contains 2 or 5 thousand IU of vitamin D ₃ (based on 100 thousand IU per 1 g). The drug retains 100% activity for 2.5 years and 95-90% activity for 3-4 years.

 The proposed technological scheme, conditions and modes of operations make it possible to obtain a highly purified preparation for use in medicine.

The method is illustrated by examples of specific performance. The general scheme of the method includes three main stages: preliminary purification of casein; obtaining vitamin D ₃ protein complex; obtaining a tablet form of the drug "Videin".

 Specification of the qualitative and quantitative composition for the phased implementation of the method is shown in table 1 in examples 1-6.

 I. Preliminary purification of casein.

The reactor with stirrer, heater and filled with distilled water ^at 40 ° C and sodium hydroxide was added to a final concentration of 0.2 ± 0.05% casein was then introduced to a concentration of 3-3.5% is stirred until dissolution is complete within 20-30 minutes at 40 ^about C. Filter through two layers of cotton. Casein is precipitated in the reactor with the stirrer operating for 1-2 minutes with glacial acetic acid until a pH of 4.5-4.6 is reached. After settling for 10 minutes, the precipitate is filtered, washed 2-3 times with distilled water. Liquid again centrifuged, the precipitate obtained is passed through a 1.0-2.0 mm and dried in a vacuum oven at a temperature of 45 ± 1 ^{° C} for 4 hours.

II. Getting vitamin D ₃ protein complex.

In the reactor, purified casein is dissolved in sodium hydroxide to a final concentration of 3-3.5%. Casein yield is 98 ± 2%. It is filtered through two layers of cotton cloth. Videchol is taken at the rate of 0.0025 kg of vitamin D ₃ per 1 kg of casein. Alpha-tocopherol acetate (vitamin E) is taken in an equal amount of 0.0025 kg. In a measuring device with alcohol, the corresponding weights of vitamin preparations are dissolved and mixed with acetic acid. The obtained mixture was introduced into the vitamin in a thin stream to the reactor and mixed with the purified casein for 1-2 minutes at a temperature not higher than 40 ° ^C. The mixture is settled filtered. The precipitate is washed with distilled water, centrifuged to dehydrate the resulting vitamin D ₃ protein complex. The complex was granulated through a sieve of 1.2 mm mesh width and dried at a temperature not higher than 45 ° ^C under stirring. The dried preparation is crushed, sieved through a sieve with a hole diameter of 0.3 mm

 III. Getting the tablet form of the drug "Videin".

Sugar granulate is obtained by mixing crushed sugar with 10% polyvinylpyrrolidone, sieved through a sieve (cells with a diameter of 1 mm), dried in air to a residual moisture of 0.15%. Dry granulate is sieved again through this sieve. Sugar granulate (particle diameter 1 mm), vitamin D ₃ protein complex, calcium stearate are loaded into the mixer and mixed until a homogeneous mass is obtained for 15-20 minutes. Tableting is carried out on a RTM-12 rotary tablet press machine. The resulting tablets have a cylindrical shape with a diameter of 8 ± 0.2 mm and an average weight of 0.24 ± 0.01 g. Ready-made tablets of the drug "Videin" are packaged in blister packs of 10 mg. The activity of the drug according to vitamin D _{3 is} 2000 IU (substance weighing 20 mg) or 5000 IU (substance weighing 50 mg). The yield of vitamin D ₃ 98.6 ± 0.2%
PRI me R 7. The biological activity of the drug "Videin" is studied on rats weaning weighing 30-40 g, which are divided into 5 groups of 5 animals and contain for 30 days on a vitamin D-deficient diet. A negative control (group I) is a group of animals that receives only a vitamin D-deficient diet (rickets); The II group of animals receives 10 IU of vitamin D ₃ in oil; Group III receives 10 IU of vitamin D ₂ in alcohol. Animals of groups IV and V receive Vidin in doses of 10 IU and 5 IU of vitamin D _3, respectively. Vitamin D preparations are administered orally with a probe.

Considering that the biological and therapeutic efficacy of vitamin D drugs is associated with the presence of biologically active metabolites in the body: 25-hydroxycholecalciferol (25-ONE), 24,25-dioxocholecalciferol (24,25-OND), 1,25-dioxocholecalciferol (1 , 25- (OH) ₂ D), the content of the indicated vitamin D metabolites, as well as the level of mineral components and the activity of alkaline phosphatase are determined in all serum groups in the blood serum. The results obtained are presented in table.2.

A comparison of the data shows that a high level of active vitamin D metabolites in serum is observed in animals treated with the new drug Videin. These data correlate with the level of mineral components in the blood serum of these animals. The results obtained indicate that Videin has a high biological activity that exceeds the activity of the commercial preparation of vitamin D ₂ in alcohol, vitamin D ₃ in oil, which is the result of better transport of this form of vitamin through the gastrointestinal tract and a decrease in its oxidation in the body. Moreover, in the V group of animals that received 1/2 dose of videin, they are comparable with indicators of groups II and III. Therefore, due to the high biological activity of the new drug, the estimated dose can be halved.

 An analysis of preclinical trials showed that this form of the drug ensures the accuracy of dosing of vitamin D, which in the light of recent data on its physiological role in the body and the dose dependence of these processes is very significant, namely overdosing causes the phenomenon of D-hypervitaminosis (hypercalcemia), impaired synthesis of proteins, lipids , since vitamin D belongs to the group of prohormones.

 In addition, the tablet form provides the possibility of using the drug for gastrointestinal diseases and eliminates the harmful effects of vitamin D solvents (alcohol and vegetable oil) on the body of newborn children.

 The results of clinical trials of the use of the tablet drug "Videin" in the treatment of rickets and rickets-like diseases in children, D-hypovitaminosis in pregnant women and a number of diseases of the skeletal system indicate a high therapeutic efficacy of the drug, which is expressed in a reduction in the time of recovery, complete normalization of pathological changes.

Claims (2)

1. A method of producing vitamin D _z -protein preparation, including dissolving casein in alkali, and vitamin D _z- containing preparation in alcohol, mixing both solutions, precipitating the vitamin D-protein complex with acetic acid, followed by centrifugation, granulation and drying, characterized in that, in order to increase the activity and stability of the formulation by improving the quality of cleaning, pre-casein purified by dissolution in alkalis, acetic acid deposition, granulation and drying, as vitamin D _z -containing Reparata videhol used, which is mixed with vitamin E in a 1: 1 is dissolved in an alcohol, after drying, _of a vitamin D -belkovy complex is mixed with sugar granules and calcium stearate in a ratio of respectively (5 2) (18.6 22.0) 0 , 24 and the resulting mass is tabletted.  2. The method according to claim 1, characterized in that the sugar granulate is obtained by wetting the sugar with polyvinylpyrrolidone in the ratio of (18.6 to 22.0) 0.11.

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