RU2314797C2 - Solid medicinal formulation of hepatoprotective effect - Google Patents

Abstract

FIELD: chemical-pharmaceutical industry, medicine, pharmacy.

SUBSTANCE: invention relates to a solid medicinal formulation of hepatoprotective effect that comprises combination of flavanolignan with phopholipids as active components and special additive - colloidal silicon dioxide, polyvinylpyrrolidone, trehalose, sodium stearylfumarate, calcium phosphate and/or mannitol. Method for preparing this medicinal formulation involves a wetting step of mixture of phospholipid with colloidal silicon dioxide with small amount of water in the mass ratio about 2:1, respectively, addition of flavanolignan, calcium phosphate and/or mannitol, trehalose followed by wetting the mixture with 15% polyvinylpyrrolidone aqueous solution, wet and dry granulation and powdering dry granulate with sodium stearylfumarate. Agent is prepared in form of capsule preferably. Invention provides simplifying technology and enhancing stability of agent and expands assortment of agents of hepatoprotective effect.

EFFECT: improved and valuable medicinal properties of formulation.

4 cl, 1 tbl

Description

The invention relates to the pharmaceutical industry, and more particularly to a solid dosage form of hepatoprotective action containing flavanolignans and essential phospholipids as active substances.

The hepatoprotective properties of various flavanolignans, in particular silymarin, are well known. Silymarin, which contains three main components: silibinin, silidianin and silikristin, the most active of which is silibinin, exhibits a stabilizing effect on the cell membrane of the liver against the effect of intoxication with some harmful agents and is widely used to treat liver diseases of various nature (Russian Drug Register. Encyclopedia of drugs M.: "Radar-2006", p.725).

Phospholipids (especially phosphatidylcholine, which is the main component of all endogenous phospholipids) are necessary for the normal structure and functioning of liver cells, smoothness and permeability of cell walls. Essential phospholipids include diglyceride esters of cholinophosphoric acid of natural origin, soy bean extract with a high content of unsaturated fatty acids, mainly linoleic (about 70%), linolenic and oleic. Essential phospholipids ideally combine with endogenous phospholipids in chemical structure, penetrate into liver cells, invading their membranes. Essential phospholipids normalize liver function and enzyme activity of liver cells, reduce liver energy expenditures, promote liver cell regeneration, transform neutral fats and cholesterol into forms that facilitate their metabolism, stabilize the physicochemical properties of bile (Medications in Russia: Vidal Handbook. M ., 2005, p. 1077).

In European patent EP 0209037, 1987, it was shown that the combination of two active components used to treat liver diseases, flavanolignans and phospholipids has a greater hepatoprotective activity than the individual components. The activity of this combination is manifested at lower dosages of these components than those usually used in monotherapy.

In a known pharmaceutical composition, it is shown that silymarin is preferred as flavanolignan and soya bean phosphatidylcholine as phospholipid.

According to the known invention, the weight ratio of flavanolignans; phospholipids in the composition may vary from 1: 0.5 to 1: 5, compositions containing silymarin and unsaturated phospholipids in a weight ratio of 1: 1 to 1: 3 are preferred. It is particularly preferred that the pharmaceutical composition contains 1 part silymarin comprising 80 weight% flavanolignans, with a weight ratio of silibinin: silidianin: silicristine of 3: 1: 1, and as an unsaturated phospholipid, 2 parts of phosphatidylcholine having a high content of polyunsaturated acyl groups.

The pharmaceutical compositions of the known invention may be in the form of chewable tablets and granules for aqueous suspension. The disadvantages of the known pharmaceutical compositions include a significant amount of auxiliary components (more than 76 wt.% Calculated on the whole composition), including sweeteners (fructose, dextrose, etc.), which, of course, is undesirable and even dangerous, especially for patients with diabetes.

The objective of the present invention is to expand the arsenal of drugs with hepatoprotective effects.

The technical result of the invention lies in the implementation of this purpose.

The specified technical result is achieved in that a solid dosage form of hepatoprotective action, containing as active substances a combination of flavanolignans and phospholipids and target additives, such as colloidal silicon dioxide, additionally contains polyvinylpyrrolidone, sodium stearyl fumarate, trialose, calcium phosphate and / or mannitol in the following ratio components, wt.%:

Phospholipids 5-65 Flavanolignans 5-65 Colloidal silicon dioxide 10-20 Polyvinylpyrrolidone 1-5 Sodium Stearyl Fumarate 0.25-1.5 Trehalose 1-5 Calcium Phosphate and / or Mannitol rest

The specified technical result is also achieved by the method of obtaining a solid dosage form of the claimed composition.

As an active component containing flavanolignans, it is preferable to use C-limar in the composition of the claimed dosage form, and as a phospholipid, soya bean phosphatidylcholine "Lipoid S 100" having a minimum content of phosphatidylcholine of 90 weight% and over 60 weight% of the acyl groups of linoleic acid .

Silymar is a dry purified extract obtained from the cake of milk thistle fruit Silybum Marianum (L.) Gaerth. Astrov family - Asteraceae. Milk thistle is a medicinal plant that has been used in medical practice for more than 2000 years and is known for its high content of valuable medicinal and nutritional compounds, including flavanolignans: silymarin, proteins, fatty acids, essential oils, vitamins, biogenic amines, etc.

Known hepatoprotective agent Silymar® tablets, which contains 0.1 g of milk thistle extract (active substance) (Russian Drug Register. Encyclopedia of drugs. M .: "RLS-2006", p.726).

Silymar has a number of valuable pharmacological properties. It has a positive effect on the functional and biochemical state of the liver: it inhibits the processes of cytolysis, reduces the activity of "liver" transaminases; prevents the development of cholestasis, reduces the activity of gamma-glutamintransferase and alkaline phosphatase. It has a positive effect on bile excretion (for example, the dissolution of bile sediment in the biliary tract) and detoxification function of the liver, and has antioxidant, weak anti-inflammatory and antispasmodic activity. Thus, Silimar, introduced as an active substance in the composition of the inventive solid dosage form of hepatoprotective action, may exhibit other of its valuable pharmacological properties described above.

When creating a solid dosage form, the selection of targeted additives is very important. Targeted additives should provide rapid dissolution of the solid dosage form, as well as be technologically convenient for industrial production.

In addition, some physical properties of a mixture of flavanolignans with phospholipids cause certain difficulties in creating compositions suitable for preparing a solid dosage form containing a large amount of active substances and having good molding properties. For example, a mixture of silymarin (like Silymar) with phospholipids is sticky and can adhere to metal surfaces, causing molding problems. In this regard, the choice of target additives that are part of the composition, presents certain difficulties.

All auxiliary target additives (stabilizers, fillers, binders, release agents, dusting agents) should be pharmaceutically acceptable. Their choice for the inventive solid dosage form was carried out experimentally.

To eliminate the manifestation of the stickiness of the composition, in particular, the problem of the composition sticking to the metal surfaces of the molds, the composition of the claimed composition uses release agent - colloidal silicon dioxide in an amount of from 10 to 20 wt.%.

As the binder component of the present invention, polyvinylpyrrolidone is used in an amount of from 1 to 5 wt.%.

As a dusting agent in the composition of the claimed dosage form is used sodium stearyl fumarate in an amount of from 0.25 to 1.5 wt.%.

An important role of the carrier and at the same time the stabilizer in the composition of the inventive solid dosage form is given to trialose.

Trehalose is a naturally occurring disaccharide that serves as a source of energy for yeast, lobster, mushrooms, and various insects and plants that can survive at extreme temperatures. Trehalose is used to protect cell membranes during drying and freezing.

The advantages of trialose over other stabilizers (starch, various saccharides and others) are:

1. Unrecoverable. Trehalose does not react with the active components of the dosage form, while lactose, maltose and other saccharides are reducible and can enter into such a reaction.

2. Low hygroscopicity. Unlike lactose, maltose and other low molecular weight saccharides, trialose does not absorb moisture (absorption begins at a relative humidity of more than 95%) and is less sticky.

3. Simplification of the formulation. Since maltose and lactose are reducing saccharides, when they are used as fillers, stabilizers, it is necessary to include other substances in the formulation to stabilize the saccharides themselves. This greatly complicates the formulation, complicates the control of maintaining a balance between all components, while trialose can greatly simplify this process.

4. Disguise the bitter taste. Trehalose is able to mask the bitter taste of the drug. Other substances that perform this function, such as cyclodextrins, are quite expensive.

5. Color stabilization. Trehalose allows you to preserve the color of the dosage form over time (Millard reaction is negative). Lactose and many other stabilizers do not perform this function.

The amount of trialose in the composition of the inventive solid dosage form is from 1 to 5 wt.%.

As the second filler in the claimed dosage form, calcium phosphate and / or mannitol is used. It is advisable to use the filler in an amount close to the lower limit of the mass range of the filler.

Most of the components of the dosage form used in the present invention are inexpensive and affordable domestic products and provide good quality of the claimed pharmaceutical composition. According to the invention, the solid dosage form is preferably in the form of capsules.

Table 1 shows examples of formulations of the inventive solid dosage form. Kollidon F-90 and Plasdon K-90 are various brands of polyvinylpyrrolidone.

Table 1 The composition of the solid dosage form Component Content example 1 example 2 (mg) (wt.%) Lipoid S 100 200 thirty Silimar 70 40 Colloidal silicon dioxide 60 fifteen Collidon F-90 12 - Placedon K-90 - 3 Sodium Stearyl Fumarate 3 1,0 Trehalose 10 3 Calcium phosphate 45 - Mannitol - 8

A method of obtaining the inventive solid dosage form of hepatoprotective action of the specified composition in the form of capsules includes the following stages:

a) moistening a mixture of phospholipid with colloidal silicon dioxide with a small amount of water in a mass ratio of about 2: 1, respectively;

b) adding to the resulting mixture of flavanolignans, calcium phosphate and / or mannitol and trialose, mixing;

c) moistening with a 15% aqueous solution of polyvinylpyrrolidone;

g) drying the moistened mixture to a residual moisture content of 2-3% at a temperature of 30-35 ° C;

e) granulation, drying and dry granulation;

e) dusting the granulate with sodium stearyl fumarate;

g) encapsulation.

The inventive method of performing a solid dosage form of the specified composition in capsules eliminates the problems associated with the stickiness of the mixture of active substances, and to obtain a mixture for encapsulation with good flowability from 0.7 to 1.0 g / s and bulk density from 0.480 to 0.520 g / ml .

The capsules obtained by the claimed method satisfy the requirements of the State Pharmacopoeia (dissolution in 45 minutes, 76-80%, at a rate of at least 75%). Studies using accelerated aging have shown that the shelf life of the claimed solid dosage form is more than 3 years.

Claims (4)

1. A solid dosage form of hepatoprotective action containing a combination of flavanolignans with phospholipids and target additives, such as colloidal silicon dioxide, characterized in that it further comprises polyvinylpyrrolidone, trialose, sodium stearyl fumarate and calcium phosphate and / or mannitol in the following ratio of components, in wt. %: Phospholipids 5-65 Flavanolignans 5-65 Colloidal silicon dioxide 10-20 Polyvinylpyrrolidone 1-5 Sodium Stearyl Fumarate 0.25-1.5 Trehalose 1-5 Calcium Phosphate and / or Mannitol rest 2. The solid dosage form according to claim 1, characterized in that Silimar is used as a component containing flavanolignans. 3. The solid dosage form according to claim 1, characterized in that as polyvinylpyrrolidone contains Collidone F-90 or Plasdon K-90. 4. The method of producing a solid dosage form according to claim 1 in capsules, which comprises the steps of moistening a mixture of phospholipid with colloidal silicon dioxide with a small amount of water at a weight ratio of approximately 2: 1, respectively adding flavanolignan, calcium phosphate and / or mannitol, trialose, moistening the mixture 15 % aqueous solution of polyvinylpyrrolidone, wet and dry granulation, dusting the dry granulate with sodium stearyl fumarate.