MXPA99008344A - Stable solid preparation containing vitamin d3 and tricalcium phosphate - Google Patents

Abstract

The invention relates to a stable solid preparation containing vitamin D3 and tricalcium phosphate in the treatment of osteoporosis and fractures of the femoral neck, vitamin D3 and/or calcium deficiencies as well as Paget's disease.

Description

SOLID STABLE PREPARATION CONTAINING VITAMIN D3 AND TRICALCICO PHOSPHATE DESCRIPTION OF THE INVENTION The invention relates to a new pharmaceutical preparation containing an active form of vitamin D3 and tricalcium phosphate, and which is free of traces of organic solvents. This new preparation has an improved stability and can be used, for example, to prevent osteoporosis, to treat conditions that result from vitamin D3 and / or calcium deficiency, to prevent fractures of the femur and Paget's disease. Another object of the invention is a pharmaceutical preparation characterized in that 100 to 1400 IU of an active form of vitamin D3 and 1000 to 4500 mg of tricalcium phosphate are used. 1000 to 4500 mg of tricalcium phosphate correspond to 360 to 1640 mg of calcium. It is preferred to employ from 200 to 1200 IU, in particular from 400 to 1000 IU of an active form of vitamin D3. It is also preferred to use from 1300 to 4000 mg, in particular from 1600 to 3500 mg of tricalcium phosphate. REF .: 30969 Another object of the invention is a pharmaceutical preparation characterized in that it is a solid preparation in the form of powder or granules. Another object of the invention is a pharmaceutical preparation characterized in that it is a solid preparation which is administered orally in a daily and once-only form, and which is packaged in sachets or tablets. Another object of the invention is a pharmaceutical preparation characterized in that it is a suspension prepared before its ingestion from powders. The objective of the invention was to provide new drugs in the form of pharmaceutical preparations that have better properties than those already known and used for the same purposes. This objective was achieved through the discovery of this new preparation. It was surprisingly discovered that tricalcium phosphate can be combined with an active form of vitamin D3 to form a preparation. Tricalcium phosphate has the formula Ca-, (P0) 2. As active forms of vitamin D3, particularly those in which the active form carries a hydroxyl group at the la position are preferred, for example, la-hydroxycholecalciferol, la, 25-dihydroxycholecalciferol, la, 24-dihydroxycholecalciferol, , 24, 25-trihydroxycholecalciferol, la-hydroxy-24-oxocholecalciferol, la, 25-dihydroxy-24-oxo-colecalciferol, la, 25-dihydroxycholecalciferol-26, 23-lactone, la, 25-dihydroxy-colecalciferol-26, 23 -peroxylactone or 26, 26, 26, 27, 27, 27-hexafluoro-la, 25-dihydroxycholecalciferol. Also preferred is, for example, 25-hydroxycholecalciferol, 24-hydroxycholecalciferol, 24-oxocolecalciferol, 24,25-dihydroxycholecalciferol, 25-hydroxy-24-oxo-colecalciferol, 25-hydroxycholecalciferol-26, 23-lactone or -hydroxycholecalciferol-26, 23-peroxylactone. The particularly preferred compound is la-hydroxycholecalciferol which is also commonly referred to simply as vitamin D0 or cholecalciferol-. European patents Nos. 0 413 828 and 0 702 954 mention pharmaceutical preparations containing combinations of vitamin D and calcium salts. European Patent No. 0 413 828 claims a solid pharmaceutical preparation of an active form of vitamin D 1 comprising an active form of vitamin D. dispersed in an excipient readily soluble in an organic solvent and containing a basic substance . Among the basic substances, tricalcium phosphate is not mentioned. The basic substance serves to stabilize vitamin D3. European Patent No. 0 702 954 discloses a pharmaceutical preparation containing a calcium salt, vitamin D and at least one compound of boron, copper or magnesium. The composition that is suitable for the treatment of osteoporosis may contain from 1000 to 2500 mg of calcium salt corresponding to 400 to 1000 mg of calcium. As a calcium salt, tricalcium phosphate is not mentioned. The mentioned compounds of boron and copper can produce undesired side effects in long-term applications. Japanese document No. 05255095 discloses a composition containing a microcrystalline powder of calcium phosphate (hydroxyapatite or calcium triphosphate) and, for example, vitamin D¿. However, the object of the invention is intended for the application i.v. and to use in blood vessels. As a source of calcium, the compounds known from the state of the art and familiar to the person skilled in the art are used, including calcium gluconate, calcium lactate, calcium citrate, calcium dibasic phosphate or, preferably, carbonate. of calcium. The preparation of the invention exhibits surprising stability compared to the preparations of the state of the art. The stability test data are indicated in Table I and are representative of a batch. In the European patent No. 0 413 828 the results of the stability tests are published on page 5, table I. The preparation of the invention can be obtained surprisingly, and contrary to the European patent No. 0 413 828, without the use of organic solvents whose purpose is to dissolve sticky auxiliary substances. If compared with the vitamin D5 content of 91% which is measured in the European patent No. 0 413 828 after 30 days, at 40 ° C and 75 ° or relative humidity, the composition of the invention presents under the same conditions and even after 13 weeks a vitamin D3 content of 97%.

Table I Stability of lot 41/95 prepared according to example 2 corresp .: corresponds d.l .: below the limit determinable Te: transcolecalcí ferol Ts. : tachisterol UI: international unit Another object of the invention is a process for obtaining a pharmaceutical preparation, characterized in that an active form of vitamin D3 and tricalcium phosphate is brought into a suitable dosage form by mixing both components with at least one vehicle or product solid auxiliary The active form of vitamin D3 is preferably used in the form of a solid concentrate. As a concentrate of cholecalciferol, it is preferred, for example, Duphasol D3-1000 dry stable or Vita in D3 Typ 100 CWS®. As vehicles and auxiliary products (excipients and / or substances which increase viscosity) are suitable, for example, for mannitol, hydroxypropylcellulose, lactose, polyvinylpyrrolidone, polyvinylalcohol, gelatin, starch, crystalline cellulose, hydroxypropylmethylcellulose, ethylcellulose, carboxymethylcellulose , dextrin, lactose, sorbitol, sucrose, talcum (hydrate of magnesium silicate), kaolin, precipitated calcium carbonate, sodium chloride, titanium oxide, gum arabic and / or gum of xanthan. As the fluidizing agent, the aerosil is suitable, for example. Other vehicles or auxiliary substances can also be added such as, for example, excipients, antioxidants, colorants, lubricants, sweeteners and / or flavors. Among the antioxidants, for example, butylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), lecithin, α-tocopherol, hydroquinone, octyl gallate, dodecyl gallate, aluminum gallate, etc. are preferred. isoamyl, nordihydroguaracetic acid, guaiac resin, α-naphthylamine, ethyl protocatechuate, ascorbic-stearic acid ester, ascorbyl palmitate, cysteine hydrochloride, sodium salt of ascorbyl stearate, thioglycerol or thiosorbitol. Among the lubricants, for example, talc, starch, magnesium and calcium stearate, boric acid, paraffin, cocoa butter, macrogol, leucine or sodium benzoate are preferred. As the sweetener, for example, Aspartame or the sodium salt of saccharin is preferred. As aroma, the aroma of lemon or orange is preferred. As indicated in example 1 and despite the great demands regarding the uniformity in the distribution of the active substance (see example 2, 20 ug of colecalciferol in 4.1 g of powder per sachet), the manufacturing process was 'characterized by simple mixing and without granulation by spraying which is very expensive and impairs stability. The new pharmaceutical preparation can be obtained by taking an active form of vitamin D. and tricalcium phosphate to a suitable dosage form, together with at least one vehicle or solid auxiliary product. The preparations thus obtained can be used in medicine or veterinary medicine as a medicament, in particular, to prevent osteoporosis and femur fractures, to treat vitamin D3 and / or calcium deficiency states and to prevent the disease from developing. Paget. As carriers, organic and inorganic substances which are suitable for oral administration and which do not react with the compounds can be used, for example, gelatine, soy lecithin, carbohydrates such as lactose, mannitol or starch, magnesium stearate, talc, cellulose. For oral administration, they are adequate, in particular, tablets, dragees, capsules, suspensions or granules, and also powders packed in sachets for use in suspensions. The preparations may contain auxiliary agents such as preservatives, stabilizing agents and / or wetting agents, emulsifiers, colorants and / or flavors. The dose of vitamin D3 and tricalcium phosphate that is ingested daily and at one time is preferably between approximately 200 and 1200 IU of vitamin D3 and between 1200 and 4000 mg of tricalcium phosphate, preferably between approximately 400 to 1000 IU of vitamin D3 and between 1600 and 3500 mg of tricalcium phosphate, more preferably between about 700 and 900 IU of vitamin D and between 3200 and 3500 mg of tricalcium phosphate. Oral administration is preferred. Particularly preferred doses contain 400 IU of vitamin D3 and 1650 mg of tricalcium phosphate, or they contain twice that amount, ie 800 IU of vitamin D3 and 3300 mg of tricalcium phosphate. The components of this new pharmaceutical preparation are preferably administered in combined form. However, they can also be administered individually, either simultaneously or successively. The following examples illustrate the preparation and composition of the pharmaceutical preparation of the invention.

EXAMPLE 1 The concentrate of colecalciferol and sorbitol is sieved and both are mixed in a drum mixer for 30 minutes (mixture a). The tricalcium phosphate, the colloidal anhydrous silica, the hydroxypropylmethylcellulose, the gum arabic, the gelatin, the Aspartame and the lemon aroma are sifted. Then all these components are mixed together with the mixture a in a drum mixer for 30 minutes. The mixture is sifted and mixed once more. The mixing of all the components can also be carried out alternately in a rapid mixer.

EXAMPLE 2 The concentrate of colecalciferol and lactose is sieved and both are mixed in a drum mixer for 30 minutes (mixture a). The tricalcium phosphate, the colloidal anhydrous silica, the hydroxypropylmethylcellulose, the gum arabic, the gelatin, the Aspartame and the orange flavor are sifted. Then all these components are mixed together with the mixture a in a drum mixer for 30 minutes. The mixture is sifted and mixed once more. The mixing of all the components can also be carried out alternately in a rapid mixer.

Example 3 Composition of a powder for an oral suspension, which contains 1.2 g of calcium and 20 ug of vitamin D3 and is packaged in a sachet: Concentrate of colecalciferol * 8, 0 mg Sorbitol 227 mg Tricalcium phosphate ** 3300, 0 mg Colloidal anhydrous silica 130, 0 mg Hydroxypropylmethylcellulose 150, 0 mg Gum arabic 175, 0 mg Sodium salt of saccharin 10.0 mg Natural lemon flavor 100.0 g 4100.0 mg * corresponds to 800 IU of colecalciferol ** corresponds to 1.2 g of calcium Example 4 • Composition of a powder for an oral suspension, which contains 0.6 g of calcium and 10 ug of vitamin D and is packaged in a sachet: Concentrate of colecalciferol * 4, 0 mg Sorbitol 114.0 mg Tricalcium phosphate ** 1650, 0 mg Colloidal anhydrous silica 65.0 mg Hydroxypropylmethylcellulose 75.0 mg Xanthan gum 87.0 mg Sodium salt of saccharin 5, 0 mg Natural lemon aroma 50, 0 mg 2050, 0 mg * corresponds to 400 IU of colecalciferol ** corresponds to 0.6 g of calcium Example 5 Composition of a suspension containing 1.2 g of calcium and 20 ug of vitamin D3: Concentrate of colecalciferol * 8, 0 mg Sorbitol 227 mg Tricalcium Phosphate ** 3300.0 mg Colloidal anhydrous silica 130, 0 ig Hydroxypropylmethylcellulose 150, 0 mg Gum arabic 175, 0 mg Sodium salt of saccharin 10.0 mg Natural lemon aroma 100.0 mg purified water 10 ml * corresponds to 800 IU of colecalciferol ** corresponds to 1.2 g of calcium.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (8)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Pharmaceutical preparation that contains an active form of vitamin D3 and tricalcium phosphate and that is free of traces of organic solvents.

2. Pharmaceutical preparation according to claim 1, characterized in that 100 to 1400 IU of an active form of vitamin D3 and 1000 to 4500 mg of tricalcium phosphate are added.

3. Pharmaceutical preparation according to claim 1 or 2, characterized in that it is a solid preparation in the form of powder, tablets or granules.

4. Pharmaceutical preparation according to claim 1, 2 or 3, characterized in that it is a solid preparation that is administered orally in a daily and one-time form and that is packaged in sachets or tablets.

5. Pharmaceutical preparation according to claim 1 or 2, characterized in that it is a suspension prepared before the engestion from powders.

6. Process for obtaining a pharmaceutical preparation, characterized in that an active form of vitamin D3 and tricalcium phosphate is brought into a suitable dosage form by mixing both components with at least one vehicle or solid auxiliary product.

7. Use of an active form of vitamin D3 and tricalcium phosphate to prepare a medicine to prevent osteoporosis, to treat vitamin D3 and / or calcium deficiency states and to prevent Paget's disease.

8. Pharmaceutical preparation that contains an active form of vitamin D3 and tricalcium phosphate and is used to fight diseases.