RU2482846C2 - Pharmaceutical antidiabetic composition and method of obtaining antidiabetic composition - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely, to antidiabetic composition. Method of obtaining antidiabetic pharmaceutical composition includes preparation of trituracio mixture of active substance repaglinide, taken in therapeutically efficient quantity, with complex-forming substance, solubiliser and colloid silicon dioxide, further addition of filling agent, disintegrant and lubricant, and tabletting by method of direct pressing.

EFFECT: pharmaceutical composition in form of tablet, obtained by claimed method, is characterised by high degree of active substance release, satisfactory strength and has storage term longer than 2 years.

10 cl, 1 tbl

Description

The invention relates to medicine, in particular to an agent that can be used to treat diabetes.

Repaglinide is widely used in medical practice as a hypoglycemic agent.

International application WO 2007/111933 describes a pharmaceutical composition comprising, as active ingredient, repaglinide and as excipients, a filler / diluent, a solvent / solubilizer and, optionally, other excipients. The known composition is intended for nasal administration and cannot be performed in solid form.

Patent Document CN 101695491 describes a repaglinide composition which contains, as excipients, a filler, a binder, for example hydroxypropyl methylcellulose, a lubricant, for example stearic acid and other excipients, which prolong the release of repaglinide. The composition is characterized by a slow release of the active substance, which is not always acceptable.

In patent application US 2009/0209587 a pharmaceutical composition is described comprising repaglinide and a complexing agent, for example meglumine. In a preferred embodiment, the composition also includes a binder (polyvinylpyrrolidone), a solubilizer / solvent (poloxamer 188, glycerol), a filler (microcrystalline cellulose, starch, anhydrous dicalcium phosphate), a disintegrant (potassium polyacrylin), a lubricant (magnesium stearate). The disadvantages of the known composition include the need to use micronized repaglinide to achieve acceptable indicators of the release of repaglinide and an excessively large scatter of their values (83-100%). In addition, the known composition can be obtained in the form of tablets only by wet granulation.

The objective of the invention is to provide an antidiabetic preparation based on repaglinide in the form of a solid dosage form having a shelf life of 2 years, with a high degree of release of the active substance and a method for producing an antidiabetic composition.

To solve this problem, the proposed method for producing an antidiabetic composition includes preliminary preparation of a mixture of the active substance - repaglinide with a complexing substance, a solubilizer and silicon dioxide, the subsequent addition of the remaining ingredients - filler, disintegrant and lubricant and tabletting by direct compression, while the ingredients are taken in the following ratio, wt .h .:

Repaglinide - 0.50-2.00 Complexing substance - 1.50-30.00 Solubilizer - 0.50-10.00 Colloidal silicon dioxide - 0.05-2.00

and tableting. Preferably, a mixture of repaglinide with a complexing agent, a solubilizer and silica is rubbed through a sieve, more preferably through a sieve with a mesh diameter of not more than 450 μm.

In another aspect of the invention, there is provided an antidiabetic pharmaceutical composition in the form of a tablet comprising the active ingredient repaglinide in a therapeutically effective amount in the form of a trituration mixture with a complexing substance, a solubilizer and colloidal silicon dioxide, as well as an excipient, disintegrant and lubricant in the following ratio of ingredients, parts by weight :

Repaglinide - 0.50-2.00 Complexing substance - 1.50-30.00 Solubilizer - 0.50-10.00 Colloidal silicon dioxide - 0.05-2.00,

and obtained by the claimed method.

The active substance in the proposed composition is repaglinide. Repaglinide is a hypoglycemic agent that quickly reduces blood glucose by stimulating the release of insulin from functioning pancreatic β-cells. It is used in the treatment of type 2 diabetes mellitus (non-insulin-dependent). The inventive composition may also contain a dye.

The preferred ratio of the ingredients of the claimed composition is, parts by weight:

Repaglinide - 0.50-2.00 Complexing substance - 1.50-30.00 Solubilizer - 0.50-10.00 Filler - 13.50-330.00 Disintegrant - 0.50-15.00 Lubricant - 0.05-2.00 Silica - 0.05-2.00 Dye - 0-0.15

The claimed composition is characterized by a high degree and uniformity of the values of the release of the active substance, the stability of the indicators during storage with satisfactory strength without the use of wet granulation. So, the composition releases 99-100% of the active substance into the dissolution medium - Mc Ilvin buffer solution with a pH of 5.0 after 30 minutes (HPLC).

In a comparative example, the composition in the absence of a complexing agent and a solubilizer, the release of repaglinide was 20% for the same time interval.

The introduction of repaglinide tablets obtained by direct compression of a complexing agent and a solubilizer (repaglinide is present in the form of a mechanical mixture with auxiliary substances) increased the release rate by 20%, and for tablets in which repaglinide is present in the form of triturate with a solubilizer and a complexing agent and dioxide silicon, the release rate increased 2.7 times relative to the last comparative example (or 3.25 times relative to the composition, where the complexing substance and a solubilizing agent absent).

During the development of the drug, it was possible to apply the direct compression technology instead of the wet granulation technology used in the preparation of the prototype. The production of tablets by direct compression is scientifically based, since it eliminates the use of a humidifier and subsequent drying, which have an adverse effect on the active substance and are critical factors in the production of tablets that affect the stability of the dosage form.

In a preferred embodiment, the composition comprises as a filler a combination of lactose monohydrate and microcrystalline cellulose, more preferably in a ratio of 0.05-30.0 parts by weight. lactose monohydrate per 1 wt.h. microcrystalline cellulose, which allows to achieve high strength of the obtained tablets without the use of wet granulation.

As a solubilizer, the composition may contain sodium lauryl sulfate, dioctyl sulfosuccinate, dextran, polyoxyethylene alkyl ethers, twins, poloxamers, poloxamines, polyethylene glycol derivatives and other similar substances, preferably poloxamer 188, as a complexing agent, the composition may contain meglumine, diethanolamine, lysethanolamine, preferably N-methyl-D-glucamine.

As a disintegrant, the composition may contain calcium carmellose, carboxymethyl starch sodium, croscarmellose sodium, crospovidones, potassium polacrilin, preferably potassium polacrilin, as a lubricant, stearic acid and its derivatives, such as stearic acid salts, calcium stearate, magnesium, and sodium stearyl fumarate, preferably calcium and / or magnesium stearate is used; iron oxide yellow is preferably used as a dye.

The new pharmaceutical composition is in the form of a solid dosage form, preferably in the form of a tablet.

Examples of the invention are presented in the table.

A typical example (example 1). To achieve uniformity of mixing and to ensure the release of the active substance from the tablets, the sieved substance of repaglinide is mixed with silicon dioxide, colloidal, complexing agent and solubilizer. After mixing, the mixture is rubbed through a sieve with a mesh size of 450 μm.

If it is necessary to use a dye in a 1 mg tablet, to achieve uniform staining of the tablets, a mixture of a part of a filler, for example, lactose monohydrate and a yellow iron oxide dye, is prepared separately. To do this, the dye iron oxide yellow is ground in a mortar with a small amount of lactose monohydrate.

To a mixture of the substance of repaglinide with silicon dioxide, a complexing agent and a solubilizer, a filler, a disintegrant and a salt of stearic acid (magnesium stearate) are added and the finished mass is tableted. Get tablets with an average weight of 0.100 g (for dosages of 0.5 mg and 1 mg) and 0.130 g (for dosages of 2 mg), strength 70 ÷ 90 N (for dosages of 0.5 mg and 1 mg) and 110 ÷ 140 N ( for a dosage of 2 mg).

The resulting tablets satisfy the regulatory requirements for a pharmaceutical agent. Dissolution,% release of repaglinide into the dissolution medium — McIlvin buffer solution with pH 5.0 — after 30 minutes (HPLC) —99, repaglinide content in one tablet (HPLC) —0.5 mg (0.5 mg dosage), 1.0 mg (dosage 1 mg) and 2.0 mg (dosage 2 mg). The resulting tablets have a shelf life of more than 2 years.

Table Ingredients Content, parts by weight Dosage 0.5 mg Dosage 1 mg Dosage 2 mg Examples one 2 3 one 2 3 one 2 3 Repaglinide 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1,000 1.00 Poloxamer 188 6.00 1.00 20.00 3.00 0.50 10.00 1,50 0.250 5.00 N-methyl-D-glucamine 20.00 3.00 60.00 10.00 1,50 30.00 6.50 0.750 15.00 Lactose Monohydrate 95.60 280.00 16.00 47.50 140.00 8.00 30.85 95,000 5.00 Microcrystalline cellulose 67.40 11.20 220.00 33.45 5.50 100.00 22.50 3,500 70.00 Potassium polacryline 8.00 1.00 30.00 4.00 0.50 15.00 2.00 0.250 7.50 Silicon Colloidal Dioxide 1.00 0.10 4.00 0.50 0.05 2.00 0.35 0,025 1.00 Stearic acid salt 1.00 0.10 4.00 0.50 0.05 2.00 0.30 0,025 1.00 Dye Iron Oxide Yellow - - - 0.05 0.01 0.15 - - -

Claims (10)

1. A method of obtaining an antidiabetic pharmaceutical composition, which includes the preliminary preparation of a trituration mixture of the active substance - repaglinide, taken in a therapeutically effective amount, with a complexing substance, a solubilizer and colloidal silicon dioxide, the subsequent addition of filler, disintegrant and lubricant and tabletting by direct compression, with the ingredients take in the following ratio, parts by weight:
Repaglinide 0.50-2.00 Complexing substance 1,50-30,00 Solubilizer 0.50-10.00 Colloidal silicon dioxide 0.05-2.00 2. The method according to claim 1, wherein the mixture of repaglinide with a complexing substance, a solubilizer and colloidal silicon dioxide is wiped through a sieve. 3. The method according to claim 2, in which the sieve has a cell diameter of not more than 450 microns. 4. The method according to any one of claims 1 to 3, characterized in that the dye is additionally used. 5. The method according to any one of claims 1 to 3, characterized in that a combination of lactose monohydrate and microcrystalline cellulose is used as filler. 6. The method according to any one of claims 1 to 3, characterized in that they take lactose monohydrate and microcrystalline cellulose in the following ratio, parts by weight:
Lactose 0.05-30.0 Microcrystalline cellulose one 7. An antidiabetic pharmaceutical composition in the form of a tablet that contains the active substance repaglinide in a therapeutically effective amount in the form of a trituration mixture with a suitable substance, a solubilizer and colloidal silicon dioxide, as well as an excipient, disintegrant and lubricant in the following ratio of ingredients, parts by weight:
Repaglinide 0.50-2.00 Complexing substance 1,50-30,00 Solubilizer 0.50-10.00 Colloidal silicon dioxide 0.05-2.00,
and obtained by the method according to any one of claims 1 to 6. 8. The antidiabetic pharmaceutical composition according to claim 7, characterized in that it contains 0.5 mg repaglinide in one tablet. 9. The antidiabetic pharmaceutical composition according to claim 7, characterized in that it contains 1 mg repaglinide in one tablet. 10. The antidiabetic pharmaceutical composition according to claim 7, characterized in that it contains repaglinide in an amount of 2 mg in one tablet.