BG110504A - A compound containing inositolhexaphosphorous acid or its salts, and the method of its derivation - Google Patents

Abstract

The invention refers to a compound for oral application containing as active substance inositol-hexaphosphorous acid or its salts, more specifically its calcium-magnesium salt, and the method for itsderivation. According to the invention the compound contains therapeutic quantity, preferentially over 60% as related to the total mass of the inositol-hexaphosphorous acid or its salts plus ancillary substances, chosen from the group of: starch or starch glicolate, microcrystal cellulose, lactose, magnesium stearate or sodium stearyl fumarate, talc or colloid silicon dioxide. The compound, in conformity with the invention, contains an optimum quantity of ancillary substances and an adequate therapeutic quantity of active substance û over 60 % the mass of the tablet kernel guarantees the necessary degree of dissolution, a steady durability and the necessary therapeutic effect. It is intended for functional feeding, for prevention or therapy of metabolic disorders, for diseases of nervous,cardiovascular and digestive system as an immune modulating agent, an antivirus and anti-tumor remedy with a strong antioxidant effect and as a stimulator.

Description

COMPOSITION CONTAINING INOSITOLHEXAPHOSPHOSPHORIC ACID OR ITS SALTS AND METHOD FOR PREPARING MU

TECHNICAL FIELD

The invention relates to a composition for oral administration containing the active substance inositol hexaphosphoric acid (phytic acid) or its salts, in particular the calcium-magnesium salt of inositol hexaphosphoric acid, and to a method for preparing it. The composition is intended for use in human medicine and functional nutrition for the treatment and prevention of diseases of the nervous, cardiovascular and digestive systems, as well as in disorders of metabolic processes, etc.

BACKGROUND OF THE INVENTION

Inositol hexaphosphoric acid or its salts, incl. and its calcium-magnesium salt, as a donor of inositol and phosphates, influence major metabolism and energy processes in the body, making it particularly valuable for inclusion in compositions for the treatment and prevention of multiple diseases having biological effects such as 20 antioxidant activity , antitumor activity, cell control

functions in the nervous system, an effect close to that of the sedatives, affects high blood pressure, fat metabolism and reduces blood cholesterol levels, positively affects hypoglycaemia and is used in patients with high levels of copper and low levels of zinc in the blood. [EP 1 896 489]

A stabilized oral composition comprising phytic acid is known to eliminate odors from the body. This composition may be in the form of tablets comprising phytic acid, maize starch, microcrystalline cellulose and magnesium stearate or in the form of capsules comprising phytic acid, lactose, maize 30 starch, magnesium stearate. [EP 0 409 494]

An oral composition comprising phytic acid or salts thereof for the treatment of hyperlipidemia, obesity and obesity-related diseases is also known. This composition may be in the form of capsules containing 40mg phytic acid (such as

anhydride), lactose, corn starch, magnesium stearate or in the form of tablets containing 20mg phytic acid, corn starch, crystalline cellulose and magnesium stearate. [EP 0 342 956]

The poor physicochemical performance of the active substance (it is practically insoluble in water) creates problems in the production of solid formulations and therefore adversely affects the solubility, bioavailability and overall effectiveness of the preparation.

SUMMARY OF THE INVENTION

The problem to be solved with the present invention is to provide a novel oral composition comprising an appropriate therapeutic amount of the active substance and an optimum amount of excipients to ensure good decomposition, the required degree of dissolution and, at the same time, high stability. The new composition according to the invention contains a therapeutic amount, preferably more than 60% by weight of the total composition of inositol hexaphosphoric acid or its salts, in particular its calcium-magnesium salt and excipients selected from the group of: starch, in particular wheat or maize or sodium starch glycolate; microcrystalline cellulose;

lactose, in particular anhydrous or monohydrate; magnesium stearate or

sodium stearyl fumarate and talc or colloidal silica. The ratio of inositol hexaphosphoric acid or its salts to the excipients is from 1: 0.5 to 1: 1. The composition is in the form of tablets and capsules, preferably film-coated tablets.

According to the invention, the composition contains the following amounts, represented as a percentage by weight of tablet core / capsule content, respectively: calcium-magnesium salt of inositol hexaphosphoric acid from 60 to 80%, starch or sodium starch glycolate from 3 to 25%, microcrystalline crystalline , lactose from 6 to 10%, talc or colloidal silica from 0.5 to 3.0% and magnesium stearate or sodium stearyl fumarate from 0.5 to 3.0%. In this composition, starch (respectively, sodium starch glycolate) has a two-sided function - a binder (in the form of glue) and a disintegrating excipient, with the amounts used being in the ratio of 1: 2. Talc or colloidal silica powders included; microcrystalline cellulose; starch or sodium starch glycollate and magnesium stearate or sodium stearyl fumarate are, in total, not less than 10% by weight of the tablet core / capsule content, respectively.

The invention also relates to a method for preparing a composition comprising wet granulation, tabletting and subsequent filming of the tablet pellets obtained. The required amounts of inositol hexaphosphoric acid or its salts, lactose and a portion of microcrystalline cellulose in an amount of 3/7 10 to 6/7 are placed in the appropriate granulation apparatus and after homogenization moistened with the pre-prepared granulation solution from 2% to 18% of starch. glue or sodium starch glycolate adhesive, depending on the apparatus. The resulting granular mass is dried to a loss of drying 2.5-3.5 percent at temperatures up to 75 ° C. Talc or colloidal silica, starch or sodium starch glycolate, magnesium stearate or sodium stearyl fumarate and the remaining amount of microcrystalline cellulose are added to the calibrated granule mass. It is homogenized, the resulting granular mass is suitable for capsule filling or, if necessary, tableted and the resulting tablet cores are subjected to filming. In a preferred embodiment, the tablet cores may be coated with an aqueous film prepared on the basis of hydroxypropyl methylcellulose or

polyvinyl alcohol or hydroxypropyl cellulose and the like.

The resulting composition of the present invention contains an optimum amount of excipients and a therapeutic amount of active substance over 60% by weight of the tablet core. The selected excipients microcrystalline cellulose and starch further contribute to the decomposition of the form. The excipients thus selected and the ratios thereof, as well as the ratios between the excipients and the active substance, improve the rheological properties of the mixture and at the same time provide the necessary degree of dissolution and long-term stability of the pharmaceutical composition. Essential for the good qualities of the tablet core (low abrasion and good appearance) is the described method of preparing the composition. The resulting composition achieves the required physicomechanical performance of the tablet core / capsule contents, respectively,

which are a prerequisite for providing good therapeutic effect.

An additional technological advantage is that the composition allows for both encapsulation and tableting. The composition of the invention is intended to influence major processes of metabolism and energy in the body when used as a functional food, in the prevention or treatment of diseases of the nervous, cardiovascular and digestive systems. It is designed to help overcome physical and mental fatigue, help manage stress, improve memory and concentration, favorably affect the function of the gastrointestinal tract through the contained in the active substance

dietary fiber. It is used in neuroses; in functional sexual disorders; in haematopoietic diseases (anemia) in combination therapy with iron-containing preparations; for bone diseases (rickets, osteomalacia, fractures) in combination therapy is calcium products and for severe diseases in the convalescent period. Helps suppress re-formation of kidney stones, has useful functions in neuropsychiatric disorders, liver disease, diabetes and more. It is also recommended as an immunomodulator, as an antiviral and antitumor agent with a strong antioxidant effect.

EXAMPLE IMPLEMENTATIONS:

The exemplary embodiments and variations described are for illustration only and do not limit the inventive idea, the scope of which is determined by the scope of

the patent claims.

Example 1 Example 2 Calcium Magnesium Salt of 250,0 mg 250,0 mg inositol hexaphosphoric acid Wheat starch 64,0 mg 80,0 mg Microcrystalline cellulose 45,0 mg 28,0 mg Lactose monohydrate 30.0 mg 35,0 mg Talc 6.0 mg 3,0 mg Magnesium stearate 5.0 mg 4.0 mg Film coverage 12,0 mg 12,0 mg

The required amounts of the calcium-magnesium salt of inositol hexaphosphoric acid, lactose monohydrate and 4/7 parts of microcrystalline cellulose are placed in the appropriate granulation apparatus and after homogenization, moistened with the pre-prepared granular solution - 12% auxiliary granulation solution. The resulting granular mass was dried to dryness by drying about 3.0 percent (at 75 ° C). Talc, wheat starch, magnesium stearate and the rest of the microcrystalline cellulose are added to the calibrated pellet mass. It is homogenized, tableted and the tablet cores are coated with an aqueous film prepared on the basis of hydroxypropylmethylcellulose.

Example 3

Example 4

Calcium Magnesium Salt of

250.0 mg 250.0 mg inositol hexaphosphoric acid

Sodium starch glycolate 12,0 mg 28,0 mg Microcrystalline cellulose 80,0 mg 75,0 mg Anhydrous lactose 40,0 mg 36,0 mg Colloidal silica 6.0 mg 3,0 mg Sodium stearyl fumarate 12,0 mg 8.0 mg Film coverage 12,0 mg 12,0 mg

The required amounts of calcium-magnesium salt of inositol hexaphosphoric acid, anhydrous lactose and 4/7 parts of microcrystalline cellulose are placed in the appropriate granulation apparatus and after homogenization, moistened with the pre-prepared granular solution of 5% nitrate alumina. The resulting granular mass was dried to dryness by drying about 3.0 percent (at 75 ° C). Colloidal silica, sodium starch glycollate, sodium stearyl fumarate and the rest of the microcrystalline cellulose are added to the calibrated pellet mass. It is homogenized, tableted and the tablet cores are coated with an aqueous film prepared on the basis of hydroxypropylmethylcellulose.

• · · ·

Example 5

Calcium Magnesium Salt of 500.0 mg inositol hexaphosphoric acid

Wheat starch 140.0 mg

Microcrystalline cellulose 80,0mg

Lactose monohydrate 62.0mg

Talc 10.0mg

Magnesium stearate 8.0mg

Film coating 20.0mg

The required amounts of the calcium-magnesium salt of inositol hexaphosphoric acid, lactose monohydrate and 6/7 parts of microcrystalline cellulose are placed in the appropriate granulation apparatus and after homogenisation moistened with the previously prepared granular solution - 8% dry oil level. The resulting granular mass was dried to dryness by drying about 3.0 percent (at 75 ° C). Talc, wheat starch, magnesium stearate and the rest of the microcrystalline cellulose are added to the calibrated pellet mass. It is homogenized, tableted and the tablet cores are coated with an aqueous film made on the basis of hydroxypropylcellulose.

Example 6 Calcium Magnesium Salt of 320,0 mg inositol hexaphosphoric acid Sodium starch glycolate 22,0 mg Microcrystalline cellulose 31,0 mg

Anhydrous lactose

20,0 mg

Talc

4.0 mg

Magnesium stearate

Film coverage

3,0 mg

12,0 mg

Obtained according to the method described in Examples 3 and 4 above.

· ♦: 7 • ·

Investigation of the physicochemical properties of uncoated tablets obtained according to Example 1 (lot 50209) and Example 5 (lots 60209 and 70209). The statistically processed results are given in Table 1.

Table 1

INDICATORS NORMS RESULTS Batch No. 50209 Batch No. 60209 Batch No. 70209 Crumbling Under 15 m chess 9t max 8m max 8m min 7m min 7 m min 7m Mechanical strength From 80 to 130 N 124 N 112N 107 N 121 N 92 N 104 N 111 N 107 N 116N 104 N 98 N 100 N 116 N 103 N 100 N 119N 100 N 107 N 115 N 110N 99 N 104 N 106 N 112N 115 N 106 N 107 N 115 N 105 N 97 N Xcp.ll4N Xcp.lO4N Xcp, 105N S = 7N S = 6N S = 6N RSD 5,74% RSD 5,69% RSD 5,80%

Investigation of the physicochemical properties of a pellet containing the active substance calcium magnesium salt of inositol hexaphosphoric acid from batches 50209, 60209 and 70209. The results are given in Table 2.

Table 2

INDICATORS NORMS THE RESULT Batch No. 50209 Batch No. 60209 Batch № 70209 Loss on drying 75 C From 2.5 to 3.5 3.37% 3,14% 3.39% Bulk density of dry granule 0.57 to 0.63 g / ml 0.61 g / ml 0.59 g / ml 0.59 g / ml Density after shaking of dry granule 0.71 g / ml 0.70 g / ml 0.6 9 g / ml * Carr Index <20%, 14.1% 15.7% 14.5%

* Carr Index at <20% guarantees good flowability of the granules.

The resulting film-coated tablets according to Example 1 (batch No. 50209) were observed for stability according to Table 3. The composition was stable at 15 (25 ± 2) ° C for a period of 12 months and under accelerated aging conditions at (40 ± 2). ° C for 6 months (studies continue).

· · · · · ·:: $ • ·

Table 3

INDICATORS NORMS RESULTS Part. Room t ° 25 C76O% RH Accelerated aging 40 ° C / 75% RH 12 months 3 months 6 months Calcium Magnesium Salt content of inositol hexaphosphoric acid calculated as phosphoric anhydride in one table. No less than 92.6 mg 132.2 mg 107.9 mg 132.7 mg Breakdown of a movie. tab. Not more than 30 min 3 min 5 min 6 min

Claims (6)

Patent Claims: A composition comprising inositol hexaphosphoric acid or its salts and excipients - starch, microcrystalline cellulose and magnesium stearate, characterized in that it contains starch or sodium starch glycolate, magnesium stearate or sodium stearyl fumarate, and lactose silica or silica dioxide, the ratio of inositol hexaphosphoric acid or its salts to the excipients being from 1: 0.5 to 1: 1. Composition according to claim 1, characterized in that Inositol hexaphosphoric acid is in the form of a calcium-magnesium salt in a therapeutic amount of more than 60% by weight of the total weight of the composition. A composition according to any one of the preceding claims, 20, characterized in that it is intended for oral administration in the form of tablets and capsules. Composition according to claim 3, characterized in that the tablets are film-coated. 5. Composition according to claim 1, characterized in that it contains the following amounts, expressed as a percentage by weight of tablet core / capsule content, respectively: calcium-magnesium salt of inositol hexaphosphoric acid from 60 to 80%, starch or sodium 30 starch glycolate from 3 to 25%, microcrystalline cellulose from 5 to 20%, lactose from 6 to 10%, talc or colloidal silica from 0.5 to 3.0% and magnesium stearate or sodium stearyl fumarate from 0.5 to 3.0%. • r 6. Composition according to claim 1, characterized in that the starch can be corn or wheat, lactose can be anhydrous or monohydrate. 5 7. A process for preparing a composition according to claim 1, comprising wet 10 granulation, tabletting and subsequent filming of the resulting tablet cores, characterized in that the required amounts of inositol hexaphosphoric acid or its salts, lactose and a portion of microcrystalline cellulose in an amount of 3/7 to 6/7 ^ / are placed in the appropriate granulation apparatus and after homogenizing it 15 moistened with the pre-prepared granulation solution; the resulting granular mass is dried to a drying loss of 2.5-3.5 percent at temperatures up to 75 ° C; then talc or colloidal silica, starch or sodium starch glycolate, magnesium stearate or sodium stearyl fumarate are added to the calibrated granule mass and 20 8. the rest of the microcrystalline cellulose; it is homogenized, the granules obtained are filled into capsules or optionally tableted and the resulting tablet cores are filtered. $ A process for the preparation of a composition according to claim 7, characterized 0 25 9. is that the homogenized granulation mixture is moistened with a starch solution of 2 to 18% starch or sodium starch glycolate, depending on the apparatus. Use of a composition according to claims 1 to 6 for the preparation of 30 product intended for functional nutrition, for the prevention or treatment of metabolic disorders, diseases of the nervous, cardiovascular and digestive systems, such as an immunomodulatory agent, an antiviral agent, an antitumor agent with a strong antioxidant effect and as a tonic. • · · ·