RU2314812C2 - Diosmin solid medicinal formulation - Google Patents

Abstract

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to diosmin solid medicinal formulation possessing the vein-tonic and angioprotective activity. Invention proposes the diosmin solid medicinal formulation comprising an active substance, red grape leaves extract as a special additive and accessory substances. Tablet consists of a core and envelope. Therapeutic effect in using tablet exceeds that of the known diosmin formulations as 95-97% of active substance is released from tablet for 45 minutes.

EFFECT: improved and valuable pharmaceutical properties of formulation.

2 cl, 1 ex

Description

The invention relates to the field of the pharmaceutical industry, in particular to a solid dosage form of diosmin having venotonic and angioprotective activity, intended for the treatment of chronic venous insufficiency of the lower extremities, as well as hemorrhoids.

In the early stages, chronic venous insufficiency of the lower extremities is manifested by a feeling of heaviness in the legs, swelling and pain. In the absence or insufficiency of treatment, varicose disease can develop up to the formation of trophic ulcers. The pharmacological effect of diosmin is manifested in increased venous tone, capillary resistance, decreased venous stasis, capillary permeability, and improved microcirculation (Russian Drug Register. Encyclopedia of Medicines. M.: RLS-2002, p.305).

In French patent FR 6967M, 1969, the possibility of using diosmin (7 - [[6-O - (- deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranosyl] oxy] -5-hydroxy-2- ( 3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4-one) obtained by dehydrogenation of hesperidin (3 ', 5,7-trihydroxy-4'-methoxyflavonone-7-rhamnoglucoside), as well as a pharmaceutical composition containing diosmin as an active substance alone and in combination with hesperidin and citroflavonoids for the treatment of pathologies associated with capillary fragility. Known pharmaceutical composition can be performed in various dosage forms: capsules, tablets, granules, suspensions, creams, suppositories. The ratio of diosmin: hesperidin: citroflavonoids in the composition is 1: 1: 0.5 (in wt. Parts).

Tablets according to the known invention contain:

Diosmin 100 mg Hesperidin 100 mg Citroflavonoids 50 mg Rice Starch 40 mg Talc rest

The disadvantage of this dosage form is an insignificant amount of the active substance, since it is known that the vasoconstrictor effect of diosmin on veins is dose-dependent in nature (Russian Drug Register. Encyclopedia of Medicines. M: “RLS-2002”, p.305).

In European patent EP 0541874, 1993, diosmin-based pharmaceutical compositions in the form of a powder, tablets or granules with a diosmin content of 100 to 500 mg are disclosed. The proposed tablets have the following composition:

Micronized Diosmin (100 μm) 300 mg Casein brand Capillact 45 mg Polyvidone 12 mg Palatinitis 420 mg Glycine 25 mg

The disadvantages of this dosage form include a significant amount of sweetener (palatinitis), which can be undesirable and even dangerous, especially for patients with diabetes mellitus.

Closest to the claimed invention is the drug "Detralex" (Servier Laboratory, France), which includes a micronized flavonoid fraction: 1 coated tablet contains 450 mg of diosmin and 50 mg of hesperidin (Vidal Handbook. Medications in Russia: Handbook M.: AstraPharmService, 2005, p. B-403). As auxiliary ingredients, a known agent includes sodium carboxymethyl starch, microcrystalline cellulose, gelatin, magnesium stearate, talc, white wax, glycerol, hypromellose, macrogol 6000, sodium lauryl sulfate, yellow iron oxide, titanium dioxide. The quantitative composition of this drug is not disclosed. The well-known dosage form in its composition has scarce, expensive ingredients, which significantly increases the cost of the drug.

The objective of the present invention is to expand the raw material base for the production of solid dosage forms of diosmin.

The technical result of the invention is the use of more affordable and less expensive auxiliary components for the production of domestic solid dosage forms containing diosmin as an active substance that meets all the requirements of the State Pharmacopoeia.

The specified technical result is achieved in that the solid dosage form of diosmin containing the active substance and target additives, such as microcrystalline cellulose, additionally contains an extract of red grape leaves, calcium phosphate, polyvinylpyrrolidone, molecular weight sodium, croscarmellose, sodium stearyl fumarate in the following ratio of components in wt.% :

Diosmin 50-70 Leaf extract red grape 10-25 Calcium phosphate 1-20 Polyvinylpyrrolidone molecular weight 1-20 Croscarmellose Sodium 0.5-5 Sodium Stearyl Fumarate 0.5-1.5 Cellulose microcrystalline rest

The preferred solid dosage form for the claimed invention are tablets. For tablets, the choice of excipients is especially important. These fillers should provide quick dissolution and, on the other hand, proper strength and sufficient hardness. In addition, fillers should be convenient for the industrial production of tablets.

Tablets should have sufficient hardness and strength, mainly because under industrial conditions they are obtained on presses at high speed. With insufficient strength, the tablets may crumble, which is unacceptable, since the patient will not be sure about taking the necessary dose of the drug.

The selection of auxiliary target additives for the inventive solid dosage form was carried out experimentally. Some excipients in the composition of the claimed dosage form perform several functions simultaneously.

It is known that red grape leaf extract contains pharmacologically active flavonoids, the main of which are quercetin-glucuronide and isoquercetin, and can be used for the prevention and treatment of chronic venous insufficiency (FR 2466989, 1981).

It was unexpectedly found that the introduction into the composition of the dosage form as excipients of a red grape leaf extract having venotonic activity, in combination with calcium phosphate and microcrystalline cellulose, allows to obtain a well-flowing mass with a high uniformity of distribution of the active substance, which allows to reduce the dispersion of the content of the active substance in pills. Thus, the extract of red grape leaves, introduced into the composition of the inventive solid dosage form as a target additive, can exhibit venotonic properties along with diosmin. Microcrystalline cellulose, in addition, is a filler that has the ability to give tablets the necessary hardness and the properties of a disintegrant, since cellulose fibers swell upon contact with water.

The content of the extract of leaves of red grapes may be from 10 to 25 wt.%, Preferably from 15 to 20 wt.%. The content of calcium phosphate can vary from 1 to 20 wt.%, Preferably from 5 to 10 wt.%.

Medium molecular weight polyvinylpyrrolidone is used as a binding agent according to the invention. The average molecular weight polyvinylpyrrolidone content may be from 1 to 20 wt.%, Preferably from 3 to 10 wt.%.

Good release of the active substance is due to the presence of croscarmellose sodium, which contributes to the disintegration of the tablet, as well as the optimal ratio of the remaining target additives. The sodium content of croscarmellose in the composition of the dosage form can be from 0.5 to 5 wt.%.

As a sliding agent in the composition of the proposed dosage form, sodium stearyl fumarate is used with a content of from 0.5 to 1.5 wt.%.

A preferred embodiment of the pharmaceutical composition is a film-coated tablet. The shell significantly improves the appearance of the tablet, increases its mechanical strength, as well as the stability of the drug during storage.

However, it should be noted that the tablets of the claimed composition, uncovered with a film coating, are also quite strong and stable.

According to the present invention, the optimal composition of the film membrane is as follows (in wt.%):

Hydroxypropyl methylcellulose 50-80 Polyethylene glycol 5-20 Talc 1-10 Titanium dioxide 5-20 Iron (III) oxide yellow 0.1-1

Most of the components of the dosage form used in the present invention are inexpensive and affordable products of domestic production and provide good quality of the claimed solid dosage form.

The following example illustrates a preferred method for preparing the inventive pharmaceutical composition.

Sifted powders of diosmin, calcium phosphate and microcrystalline cellulose are loaded into the mixer. The mixture is stirred for 5-7 minutes, moistened with a 10% solution of Kollidon 30 (medium molecular weight polyvinylpyrrolidone brand), mixed again until the moisture is evenly distributed. An extract of red grape leaves is added to the moistened mass, the mass is mixed for 3-5 minutes, then granulated through a sieve with a hole diameter of 1.5-2 mm. Wet granulate is dried at a temperature of 50-55 ° C to a residual moisture content of not more than 4.0 wt.%. The dried granules are sieved through a sieve with a hole diameter of 0.8-1.0 mm The resulting dry granulate is dusted with a mixture of primellose (croscarmellose sodium) and stearyl fumarate sodium. The resulting mass is tabletted. The core tablets are film-coated using a nebulizer using a homogenized suspension prepared from hydroxypropyl methylcellulose, talc, titanium dioxide, iron oxide (III) yellow powders, and also purified water and polyethylene glycol (PEG 6000). The process of drying wet granules in a fluidized bed apparatus also contributes to the production of tablets of high strength.

The following formulations of the solid dosage form of diosmin can be given as an example.

Example 1

Tablet core:

Diosmin 0.424 g Red grape leaf extract 0.100 g Calcium phosphate 0.060 g Collidon 25 0.035 g Croscarmellose Sodium 0.008 g Microcrystalline cellulose 0.027 g Sodium Stearyl Fumarate 0.006 g

The average weight of the tablet core is 0.66 g.

Shell:

Hydroxypropyl methylcellulose 0.0170 g Polyethylene glycol (PEG 6000) 0.0040 g Talc 0.0015 g Titanium dioxide 0.0018 g Iron (III) oxide yellow 0,00025 g

The total weight of the tablet is 0.685 g.

Example 2

Tablet core:

Diosmin 0.5 g Red grape leaf extract 0.100 g Calcium phosphate 0.068 g Collidon 25 0.035 g Croscarmellose Sodium 0.008 g Microcrystalline cellulose 0.055 g Sodium Stearyl Fumarate 0.004 g

The average weight of the tablet core is 0.77 g.

Shell:

Hydroxypropyl methylcellulose 0.0190 g Polyethylene glycol (PEG 6000) 0.0048 g Talc 0.0015 g Titanium dioxide 0.0060 g Iron (III) oxide yellow 0,0003 g

The total weight of the tablet is 0.802 g.

The resulting film-coated tablets satisfy all the requirements of the State Pharmacopoeia. The disintegration of the dosage form is 10 minutes (the norm for coated tablets is 30 minutes), the strength is 110 N. In 45 minutes, 95-97% of the active substance is released from the tablet and passes into a solution.

Thanks to the described formulation of the solid dosage form (tablets) of diosmin, the claimed technical result is achieved - obtaining a more affordable solid dosage form of diosmin hydrochloride that meets the requirements of the State Pharmacopoeia, and simplification of the production technology of these dosage forms.

Claims (2)

1. The solid dosage form of diosmin, made in the form of a tablet, the core of which is coated, characterized in that it additionally contains an extract of red grape leaves, calcium phosphate, medium molecular weight polyvinylpyrrolidone, croscarmellose sodium, sodium stearyl fumarate in the following ratio of components, wt.%: diosmin 50-70 leaf extract red grape 10-25 calcium phosphate 1-20 polyvinylpyrrolidone molecular weight 1-20 croscarmellose sodium 0.5-5 sodium stearyl fumarate 0.5-1.5 cellulose microcrystalline rest the shell includes hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, iron oxide (III) oxide yellow in the following ratio, wt.%: hydroxypropyl methylcellulose 50-80 polyethylene glycol 5-20 talc 1-10 titanium dioxide 5-20 iron oxide (III) oxide yellow 0.1-1 2. The solid dosage form according to claim 1, characterized in that as polyvinylpyrrolidone contains Collidone 30.