Pharmaceutical composition having antihypertensive and a diuretic, and how you can get

 

(57) Abstract:

The pharmaceutical composition is made in the form of coated cores. The core contains as active ingredient an effective amount indapamide. As pharmaceutically acceptable target supplements the core comprises, by weight. including 1 wt.h. indapamide: polyvinylpyrrolidone with an average molecular weight of more than 19 000 0,3-2,4, saccharide 15,0-33,0, starch 4.2 and 12.0, nitrilotriacetate 0,001-0,5, stearic acid and/or its salt, and/or talc 0,1-2,1. Preferably the core comprises compressed powdered granules. The method of obtaining the pharmaceutical composition comprises wet granulating a mixture of indapamide with saccharide, starch, polyvinylpyrrolidone, nitrilotriacetates and, optionally, talc, and subsequent drying, adding outrivaled agent, forming the mixture into the kernel and application of the obtained kernel shell. The composition has a stability during storage and has a shelf life of over 2 years, dissolves easily, which provides a high degree of release of indapamide. The sequence of operations and technological parameters of the method provide the dosage form with satisfactory strength. 2 C. and 12 C.p. f-crystals.

e active ingredient indapamide, and can find application in the treatment of hypertension and to prevent the delay of sodium and water in the body in chronic heart failure.

Indapamide (or 3-(aminosulfonyl)-4-chloro-N-(2,3-dihydro-2-methyl-1H-indol-1-yl)benzamide) was first described in the application of UK 1203691, publ. 1969 Marked diuretic and antihypertensive activity of new compounds.

In modern medical practice, the drug is prescribed mainly for hypertension stage I-II, and also as an effective diuretic [Mashkovsky M. D. Medicines, T. 1, ed. 13th, Kharkov: Torsing, 1997, S. 489]. therapeutic dose is 2.5 mg, and with the lack of expressiveness of hypotensive effect increased to 5-7,5 mg Indapamide almost completely absorbed from the gastrointestinal tract and slowly excreted from the body. As a consequence, the drug is administered once a day and, subject to smoothing fluctuations in the concentrations of active substance in the blood after repeated taking, the dosage form indapamide slow release does not have significant advantages over traditional (nezametchennym release).

D. the quality of light, which imposes additional difficulties when creating pharmaceutical compositions based on it.

In the European patent 0519820, 1992 proposed matrix tablets indapamide, which include from 1.0 to 2.5 mg of the active substance, oxyalkylation, preferably oksipropilmetiltselljuloza, polyvinylpyrrolidone and other auxiliary ingredients. For example, m h 1 m h active ingredient:

Indapamide is Therapeutically effective amount

Lactose - 45,2 - 46,2

Oxyalkylation - 23,6 - 29,6

Polyvinylpyrrolidone - 2,48 - 3,44

Magnesium stearate - 0,8

Colloidal silicon dioxide - 0,16

The method of producing tablets includes hydration mixture indapamide, polyvinylpyrrolidone and other excipients (lactose, colloidal silicon dioxide) water alcohol, granulating, mixing the granulate with oxyalkylation, adding magnesium stearate and compressing the final mixture.

The disadvantages of the known compositions include the presence of silicon dioxide, which has an irritant effect, which may increase the likelihood of adverse reactions from the gastrointestinal tract after administration of the drug (nausea and other release indapamide from dosage forms. Use as auxiliary substances only lactose and/or microcrystalline cellulose and lubricants to facilitate the production technology of solid dosage forms significantly impairs the release of the active substance (and, consequently, its bioavailability) due to the interaction of the latter with the appropriate excipients. To reduce such interaction in the international application WO 96/18386, 1996 prompted the composition of the inhibitor in the required amount. As inhibitors can be applied starch, its derivatives, derivatives of cellulose or cross-linked polyvinylpyrrolidone (crosspovidone) in an amount of 0.02 to 4.0 m H. 1 m H. the active substance. Additionally, the composition may include lubricants, m h 1 m h active ingredient:

Indapamide - 1

Lactose brand DC - 33,1

Carboximetilkrahmal - 1,6

Magnesium stearate - 0,3

The method of obtaining the composition includes a mixture of active ingredient and auxiliary ingredients and then tableting the mixture.

Known composition easily releases the active ingredient, however, is characterized by low stability and, consequently, low shelf life, and BBB requires the creation of a pharmaceutical composition on the basis of indapamide, stable during storage and at the same time characterized by a high degree of release of the active substance.

The technical result obtained by implementing the present invention is that the proposed pharmaceutical composition reduced side effects due to the exclusion of silicon dioxide (Aerosil), it has the stability during storage and has a shelf life of more than 2 years and dissolves easily, which provides a high degree of release of the active substance and, consequently, its high bioavailability, as well as the sequence of operations and their technological options that allow you to produce a dosage form with satisfactory strength.

This technical result is achieved by the fact that the claimed pharmaceutical composition with antihypertensive and a diuretic includes coated core containing active ingredient: indapamide, polyvinylpyrrolidone with an average molecular weight of about 19000 and other pharmaceutically acceptable additives target, which are used saccharide, starch, nitrilotriacetate, stearic acid and/or its salt and/or talc when following the th number

Polyvinylpyrrolidone with an average molecular weight of more than 19000 - 0,3 - 2,4

Saccharide - 15,0 - 33,0

Starch - 4.2 and 12.0

Nitrilotriacetate - 0,001 - 0,5

Stearic acid and/or its salt and/or talc - 0,1 - 2,1

The claimed ratio of ingredients found experimentally and is optimal.

Use as a part of the claimed compositions of polyvinylpyrrolidone with an average molecular weight of more than 19000 unexpectedly improved the stability of indicators of the quality of the pharmaceutical composition compared to samples in which this kind of polyvinylpyrrolidone replaced by low molecular weight polyvinylpyrrolidone (molecular weight less than 16000), probably by reducing the destructive changes of the active substance. It also gives you the opportunity to enter the active substance at the initial stage of manufacture of the finished dosage form without further comprise stabilizers/antioxidants.

The amount of starch in the composition is between 4.2 and 12.0 m H. per unit mass of the active substance, together with the use of polyvinylpyrrolidone with an average molecular weight of more than 19000, nitrilotriacetate the above and other auxiliary th stability of the inventive pharmaceutical composition disintegrates within 6-9 min (Gasfurnace XI edition of no more than 30 minutes), that provides a high degree of release of the active substance and the composition is reduced adverse effects resulting from the removal of the composition of silicon dioxide (Aerosil).

Preferably as polyvinylpyrrolidone with an average molecular weight of more than 19000 to apply weight polyvinylpyrrolidone (molecular weight in the range of 30,000 to 40,000). The average molecular weight of polyvinylpyrrolidone determined on the basis of values of the characteristic viscosity, which, in turn, is calculated on the basis of measurements of the viscosity of its aqueous solutions.

The proposed pharmaceutical composition is in the form of solid dosage forms. A single dose of active ingredient is determined by therapeutic appropriateness and may be from 0.5 to 7.5 mg, preferably from 2.25 to 2.75 mg

The preferred implementation of the composition are compressed powdered granules having a membrane and containing active ingredient: indapamide, mixed with filler, nitrilotriacetate and the carrier matrix of polyvinylpyrrolidone with an average molecular weight of more than 19,000, with which the active substance is in contact. In kachestva are lactose, glucose, xylitol, sorbitol, sucrose, mannitol, or a mixture of these sugars, preferably lactose and/or mannitol.

The applicable starch can be potato and/or corn and/or rice and/or modified, as nitroglycerol, preferably potato and/or corn.

As a salt of stearic acid can be used stearates of calcium, magnesium, zinc or other metals, preferably magnesium and/or calcium salt.

The presence of shell improves the appearance of the dosage form, protects it from mechanical damage, and also increases the stability of the drug during storage. Preferably the shell is performed based on the derived cellulose is methyl cellulose and/or oxyalkylation, more preferably - oksipropilmetiltselljulozy. Additionally, the shell may include a filler, such as titanium dioxide and, optionally, talc, and a plasticizer, such as polyethylene glycol, glycerol, tween 80, or a combination of these compounds. The optimal ratio of these ingredients in the shell is, wt.%:

The methylcellulose or oksipropilmetiltselljuloza - 41,5 - 83,5

Glycerin and/or polietilene the inventive pharmaceutical composition comprises granulating a mixture of indapamide with saccharide, starch, polyvinylpyrrolidone with an average molecular weight of more than 19000, nitrilotriacetates and, optionally, talc, and subsequent drying, adding outrivaled agent is stearic acid and/or its salts, and/or talc powder, molding the mixture into the kernel and application of the obtained kernel shell.

Getting the granulate intermediate during the manufacture of finished dosage forms, it is advisable to wet granulation. As the humidifier you can use distilled water, solution of polyvinylpyrrolidone with an average molecular weight of more than 19,000, or starch paste, preferably a solution of polyvinylpyrrolidone and, optionally, nitrilotriacetate. The result could be a combination of all operations of the cooking process of dry granules in a single unit machine, fluidized bed, thereby reducing the loss of active substance and other ingredients.

It is advisable as a solution of the polyvinylpyrrolidone to apply an aqueous solution in which the optimal concentration of the polyvinylpyrrolidone is from 3 to 20%, more preferably from 12 to 20%. Introduction to the solution of nitrilotriacetate allows str is CLASS="ptx2">

The preferred drying temperature of the granulate is 35-40oC. To improve the homogeneity of the tableting mixture optimouse agent is added to the dry granules, may optionally contain starch in the amount of 1-35% of the total starch in the composition.

Obtained after molding core has a tensile strength of at least 4.5-5 kg With the purpose of further improvement of technological parameters of the final mixture for forming nuclei (flowability, compressibility) of the granules after drying may be subjected to additional granulation, but this operation is not required.

The following examples illustrate the invention.

Example 1. The wet granules obtained from 5,15 g indapamide (5.0 g, calculated on the dry matter), 100.0 g of lactose, 30.0 g of dry potato starch and 41.7 g of a 12% solution of medium molecular polyvinylpyrrolidone (average molecular weight of 35,000), which contains 0.5 g of nitrilotriacetate, dried at 35-40oC. To the dry granulate type of 3.45 g of talc and 1.0 g of magnesium stearate. All are thoroughly mixed to obtain a homogeneous mass, then tabletirujut. The obtained kernel with an average weight 0.09 g and the strength of 10 kg nanosonics 6000, 1.2 wt.% titanium dioxide and 0.8 wt.% talc. Layering is produced to obtain a satisfactory film thickness. The obtained tablets with an average weight 0,0934 g satisfy regulatory requirements in the pharmaceutical agent. The content of indapamide in one pill - 0,00248 g, uniformity of dosage - meets the requirements of the global Fund XI, raspadaemost - 6 min, dissolved in 0.1 M Hcl - 99.2%, and impurities (% by weight active substance, method HPLC) - 0,22, including a maximum of 0.11. The resulting tablets have a shelf life of more than 2 years.

Example 2. Obtaining tablets indapamide carried out as in example 1 starting from 5 g indapamide (on dry matter), 165 g of lactose, 12 g of polyvinylpyrrolidone (in the form of a 20% aqueous solution; average molecular weight 57000), 2.50 g of nitrilotriacetate and 60 g of starch, of which 3.5 g (starch brand Primogel) is injected together with the 7.65 g of talc and 2.75 g of calcium stearate. Tablets-engine cover film-coated, containing of 41.5 wt.% methylcellulose, 30.0 wt.% titanium dioxide and 28.5 wt.% tween-80. The resulting tablets have a shelf life of more than 2 years.

Example 3. Obtaining tablets indapamide film-coated, carried out analogously to example 1, starting from 5 g indapamide (SOHO, 0.05 g of nitrilotriacetate and 0.5 g of a mixture of stearic acid and stearate, with the difference that the humidifier is used distrurbance water, after drying conduct dry granulation and the wrapper has to 83.5 wt. % oksipropilmetiltselljulozy, 13.5 wt.% titanium dioxide and 3.0 wt.% polyethylene glycol. The resulting tablets have a shelf life of more than 2 years.

Example 4. On cores obtained in example 1, with the difference that the number of nitrilotriacetate is 0.001 m h 1 m h indapamide and part of talc powder (1 g) was injected together with the lactose and starch, layered membrane that contains the 75.5 wt.% oksipropilmetiltselljulozy, 12.8% glycerol, 2.2 wt.% tween 80, 7.0 wt.% titanium dioxide and 2.5 wt.% polyethylene glycol. The resulting tablets have a shelf life of more than 2 years.

1. Pharmaceutical composition with antihypertensive and a diuretic, made in the form of coated core containing as active ingredient indapamide and as a pharmaceutically acceptable target additives polyvinylpyrrolidone with an average molecular weight of more than 19000, saccharide, starch, nitrilotriacetate, stearic acid and/or its salt and/or talc in the following ratio and the STV

Polyvinylpyrrolidone with an average molecular weight of more than 19000 - 0,3-2,4

Saccharide - 15,0-33,0

Starch - 4.2 and 12.0

Nitrilotriacetate - 0,001-0,5

Stearic acid and/or its salt, and/or talc - 0,1-2,1

2. The composition according to p. 1, containing as specified polyvinylpyrrolidone polyvinylpyrrolidone with an average molecular weight of 30,000 to 40,000.

3. Composition under item 1 or 2, containing as potato starch and/or corn starch.

4. Composition according to any one of paragraphs.1-3, containing a salt of stearic acid magnesium and/or calcium salt.

5. Composition according to any one of paragraphs.1-4, made in the form of coated cores, including compressed powdered granules containing a mixture of indapamide with filler, the combination of a saccharide, starch and, optionally, talc, nitrilotriacetate and the carrier matrix, made of polyvinylpyrrolidone with an average molecular weight of more than 19,000.

6. The composition according to p. 5, made in the form of tablets.

7. Composition according to any one of paragraphs.1-6, in which shell has the following composition of ingredients, wt.%:

The methylcellulose or oksipropilmetiltselljuloza - 41,5-83,5

Glycerin, and/or farmacevticheskoi composition with antihypertensive and a diuretic, described in any of paragraphs.1-7, comprising wet granulation of a mixture of indapamide with saccharide, starch, polyvinylpyrrolidone with an average molecular weight of more than 19000, nitrilotriacetates and, optionally, talc, and subsequent drying, adding outrivaled agent is stearic acid and/or its salts, and/or talc powder, molding the mixture into the kernel and application of the obtained kernel shell.

9. The method according to p. 8, in which the humidifier is used an aqueous solution of polyvinylpyrrolidone with an average molecular weight of more than 19,000.

10. The method according to p. 9, which uses the solution of the polyvinylpyrrolidone, optionally containing nitrilotriacetic.

11. The method according to p. 9 or 10, in which use a solution of polyvinylpyrrolidone with a concentration of 12-20%.

12. The method according to any of paragraphs.8-10, in which the drying of the granules is carried out at 35-40oC.

13. The method according to any of paragraphs.8-12, in which, after drying spend additional granulation.

14. The method according to any of paragraphs. 8-13, in which use optimouse agent, optionally containing starch in an amount of 1-35 wt.% from the total amount of starch in the composition.

 

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