Pharmaceutical compositions containing irbesartan

 

The pharmaceutical composition contains irbesartan in combination with a diuretic drug. A diuretic is preferably hydrochlorothiazide. The pharmaceutical composition preferably molded in the form of tablets. The pharmaceutical compositions according to the invention contain the minimum number of additional fillers that can get a small, easy to swallow tablets with a high number taken by the patient matter. The compositions have good properties for forming tablets. Tablets are easy to receive, are characterized by good wettability, disintegration, fast and full selection of medicines. 2 S. and 9 C.p. f-crystals, 3 tables.

This application is isolated from the application for the patent of the Russian Federation 96111030 with Convention priority from 07.06.1995.

This invention relates to pharmaceutical compositions containing irbesartan, along with a diuretic drug, preferably to compositions in the form of tablets. This invention relates to tablets prepared from these compositions.

Irbesartan, 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-serdechno-vascular diseases, such as hypertension and heart failure. Irbesartan has the following structure:and for the first time described in U.S. patent 5270317 authors Bernhart et al. Preferred pharmaceutical compositions of this medication contain as the active(main) ingredient(s) irbesartan without additional medicines or in combination with a diuretic such as hydrochlorothiazide.

Irbesartan may be administered in dosage forms that contain a large amount of the active ingredient (for example, 75-300 mg). But some physical properties of this medication cause impossibility of making compositions, suitable for tablets with the large amount of active agent and at the same time sufficiently small size for easy swallowing.

For example, irbesartan is a friable material with relatively low bulk density and bulk weight. This complicates the introduction of a large number of drugs in the small tablet, uniform in density, hardness and other desirable for tablet properties. In addition, irbesartan has some undesirable flow characteristics, for example,STI stamps, causing problems in forming tablets, especially on high-speed press. Irbesartan is poorly soluble in water, which is also a problem, so as to save a small mass of tablets should only enter a limited number of components that contribute to wetting, disintegration and, ultimately, rapid and complete separation of the drug. Adding diuretics, such as hydrochlorothiazide, which is a lightweight material with poor flow properties and low solubility in water, can lead to additional complications when receiving tablets.

Therefore, there is a need for pharmaceutical compositions containing irbesartan in combination with diuretic possessing good properties for molding of tablets containing such quantity of fillers, in which you can get a small easy to swallow tablets with high content of active ingredient.

This invention relates to pharmaceutical compositions containing irbesartan in combination with a diuretic, which (1) have a minimum number of additional fillers that can get nebe for receiving, (2) have excellent properties for forming tablets and (3) provide for the production of tablets with excellent wetting, disintegration and, ultimately, rapid and complete selection of medicines.

In particular, this invention relates to pharmaceutical compositions which are particularly suitable for obtaining tablets containing from about 20 to about 70 wt.% irbesartan or its pharmaceutically acceptable salts, and pharmaceutically acceptable excipients, characterized in that the tablets obtained from the specified composition, have the capacity to dissolve, at which approximately 80% or more, preferably 85% or more irbesartana or its salts contained in said tablet dissolves within 30 minutes. Data composition also includes from about 2 to about 33% diuretics, and the total number of irbesartan and diuretics does not exceed approximately 85%.

Preferred compositions containing irbesartan and a diuretic, include (based on the total weight, which was taken as 100%): (a) from about 20 to about 70% (preferably about 50%) irbesartan,e than approximately 85%, (C) from about 1 to about 70% filler, (d) from about 2 to about 20% binder, (e) from about 1 to about 10% dezintegriruetsja substances, (f) from about 0.1 to about 5% of antiadhesive, (g) from about 0.2 to about 5% lubricant, and, optionally, (h) up to about 2% (preferably from about 0.1 to about 1%) of the coloring matter.

Presents the composition can contain approximately 85% (weight. /weight. ) irbesartan and diuretics, and, in addition, can be applied in a reproducible large-scale method for industrial preparation of tablets. These compositions can, for example, pressoffice on high-speed machines (especially on high-speed media) to obtain tablets of uniform weight and composition and possessing desirable physical properties, including fine appearance, low brittleness and small time disintegration. Tablets obtained from these compositions, can highlight the active(s) component(s) fast and reproducible manner.

Unless another value, the term "irbesartan" in this description refers to pharmaceutically when is omposite of the present invention, must be pharmaceutically acceptable, in particular, specified in the National list (Ntional Formylary, NF) or USP (United States Pharmacopeia, USP).

The term "ability to dissolve tablets, used in the description regarding irbesartana, means the weight of irbesartan, expressed in % of the accepted 100% of the total weight of irbesartan included in the tablet, which dissolves within 30 minutes under the following conditions: your tablet has a total weight of 150 to 600 mg used USP ratus 2, in which the tablet is placed in 1000 ml of 0.1 G. of hydrochloric acid at 37oWith the speed of mixing of the liquid is 50 rpm and quantification of dissolved irbesartan (in particular, using high-performance liquid chromatography and radiation with a wavelength of 272 nm) spend 30 minutes later. (If necessary, the process of dissolution can also be controlled at various points of the time interval).

The term "ability to dissolve tablets, used in the description in relation to diuretic drugs (preferably of hydrochlorothiazide), mean weight diuretics, expressed in % of the accepted 100% of the total weight of diuretics included in the tablet, to the orenia for diuretics preferably provided in the USP Dissolution Specification diuretics (hydrochlorothiazide over 60% dissolution in 30 minutes). The most preferred characteristic of dissolution of tablets containing hydrochlorothiazide, is a characteristic of dissolution, in which approximately 90% or more of hydrochlorothiazide is dissolved within 30 minutes.

As "diuretics" in the composition of this invention can be applied to any suitable diuretic or a mixture of two or more diuretic tools such as hydrochlorothiazide, bendroflumethiazide, benzthiazide, chlorothiazide, chlorthalidone, cyclothiazide, hydroflumethiazide, methylclothiazide, metolazone, polythiazide, chinease and three-chlorothiazide. The preferred diuretic drug is hydrochlorothiazide.

As a "filler" in the composition of this invention can be used one or more compounds capable of weighing to obtain tablets of the desired mass. It is desirable to apply the filler in a quantity close to the lower limit of interval weight filler. The preferred fillers are inorganic phosphate such as dibasic calcium phosphate, sugars such as lactose aqueous or anhydrous lactose; cellulose or derivatives of cellulose, such as microcrystalline the cellulite, tighten the are compounds, able to facilitate granulation of irbesartan and/or diuretics in more dense and larger and/or more free-flowing particles. Preferred binders are alginic acid (most preferably applied in amounts of 2-5 wt.%) or sodium alginate (most preferably applied in amounts of 2-3 wt.%); cellulose or cellulose derivatives such as sodium carboxymethylcellulose (most preferably used in the amount of 2-6 wt.%), ethylcellulose (most preferably applied in amounts of 2-3 wt.%) hydroxyethylcellulose (most preferably applied in amounts of 2-5 wt.%), hydroxypropylcellulose (most preferably used in the amount of 2-6 wt.%), the hypromellose (most preferably applied in amounts of 2-5 wt.%), or methylcellulose (most preferably used in the amount of 2-6 wt.%); gelatin (most preferably used in the amount of 2-10 wt.%); povidone (polyvinylpyrrolidone, i.e., a homopolymer of 1-ethyl-2-pyrrolidinone (e.g., povidone K-30), (most preferably applied in amounts of 2-20 weight. %); or starch (most preferably applied in naprimer 5-20 wt.%).

As dezintegriruetsja substances in the composition of this invention can be applied one or more connections that can facilitate the dispersion of the tablets obtained from the composition, upon contact of the tablet with water. Preferred binders are alginic acid (most preferably applied in amounts of 2-5 wt.%) or sodium alginate (most preferably applied in amounts of 2.5 to 10 weight. %); cellulose or derivatives of cellulose such as sodium carboxymethyl cellulose (most preferably used in the amount of 2-6 wt.%), microcrystalline cellulose (most preferably used in the amount of 5-15 wt.%), powdered cellulose (most preferably used in the amount of 5-15 wt.%) or nutritionnelles (cross-linked polymer of sodium carboxymethyl cellulose) (most preferably applied in amounts of 2-5 wt.%), crosspovidone (crosslinked homopolymer M-vinyl-2-pyrrolidinone, i.e. stitched 1-ethynyl-2-pyrrolidinone) (most preferably applied in amounts of 2-5 weight. %), pre-gelatinising starch (most preferably used in the amount of 5-10 wt.%), sodium starch glycolate (most ol the ve 3-15 wt.%).

As antiadhesive" in the composition of this invention can be used one or more compounds capable of reducing the buildup of the composition, for example, eliminating adhesion to the metal surface. The preferred antiadhesive are silicon compounds such as silicon dioxide (most preferably applied in amounts of 0.25-5% (for example, 0.5 to 2 or 2.5-3.0 wt.%), trisilicate magnesium (most preferably used in quantities of 0.5-2 wt.%) or talc (most preferably used in the amount of 1-5 wt.%).

As a "lubricant" in the composition of this invention can be used one or more compounds able to resolve the problems associated with the formation of tablets, such as the release of the molding machine manufactured from the composition of the tablets, eliminating buildup on the surface of the upper or lower press to form tablets. The preferred lubricants are fatty acids or derivatives of fatty acids such as calcium stearate (most preferably used in quantities of 0.5-2 wt.%), glycerylmonostearate (most preferably used in quantities of 0.5-2 weight. %), glycerylmonostearate (most pre is the amount of 1-2 wt.%), sodium dodecyl sulfate(most preferably used in the amount of 1-2 wt.%), nutritionalvalue (most preferably used in quantities of 0.5-2 weight. %), zinc stearate (most preferably used in quantities of 0.5-1 wt.%) or stearic acid (most preferably used in the amount of 1-3 wt.%); gidrirovannoe vegetable oil (most preferably used in the amount of 1-5 weight. %); polyalkylene glycols such as polyethylene glycol (most preferably used in the amount of 1-5 wt.%), nitrobenzoate (most preferably applied in amounts of 2-5 wt.%); or talc (most preferably used in the amount of 1-5 wt.%).

As surfactants in the compositions of this invention can be applied one or more compounds able to improve the wetting of tablets and/or to increase the solubility. The preferred surfactants are matricariifolium (most preferably applied in an amount of 0.2-6 weight. %) and poly(oksietilenom), poly(oxypropylene) block copolymers, such as poloxamer, especially poloxamer 188 (most preferably used in the amount of 1-6 wt.%).

In kachestvenni, which give the desired color tablet obtained from the composition. Add the coloring matter may be used, for example, in order to be able to easily distinguish between tablets containing different amounts of the active substance. Preferred coloring agents are iron oxides, which have universal applicability.

As can be seen from the above description, the same substance can perform two or more functions. The calculation of the weight percentage is preferably carried out on the basis of the main functions of the compounds in the composition. These compositions are preferably composed almost of the above components, most preferably of the above components.

Preferred compositions of the Preferred compositions of this invention contain one or more components listed below, the number entered in this field concentrations (in weight. %): irbesartan, 20-60 (for example, from 25 to 60), more preferably 30 to 60, most preferably 30-50, especially about 50%; diuretic drug 2-20, most preferably 2-17, especially 4-9%; filler 1-70, most preferably 1-60, especially 1-40%; binder 5-20, most P5,0% (for example, of 0.25 to 1.5, most preferably 0.7-0.8 percent); lubrication of 0.5 to 1.5, most preferably about 1%; and surfactant - 1-3, most preferably about 3%.

In the following tables presents the preferred compositions of the present invention, which are tablets of high quality with excellent performance. Table A presents the compositions containing irbesartan in mixture with a diuretic.

The composition shown in table A, preferably contains from 0.08 to 0.12 wt.% red iron oxide and from 0.08 to 0.12 wt.% yellow iron oxide as a coloring matter.

Methods of making Tablets can be obtained from the compositions of this invention any suitable method to obtain tablets. Preferably the tablets obtained from the compositions of this invention using wet granulation. One such method includes the following stages: a) obtaining "vnutrigornoj" song (composition of granules containing the active drug(s) tool(a): (i) mixing irbesartana, diuretics, part of the filler (preferably from about 5 to about 80 wt.% the total number of Napo is the amount dezintegriruetsja substances), binders and, optionally, part of antiadhesive (preferably from about 50 to about 80 wt.% the total weight of antiadhesive) to obtain a powder mixture, and optionally sieving the mixture (for example, grinding for grinding units); (ii) re-mixing the mixture; iii) granulating the mixture with a granulation liquid medium, preferably water and/or aqueous solution of a surfactant, to obtain granules (for example, using a high-speed mixer/granulator); (iv) drying the granules (for example, in a furnace or preferably in a fluidized bed dryer); and
v) sieving the dried granules (e.g., grinding or sieving through a sieve);
b) obtaining a mixture of granules of a certain size, obtained in stage (a) (v), with "winegrowing" song (composition, which contribute granules obtained in stage (a) (v)):
i) mixing the rest of the filler, the rest of dezintegriruetsja substance, antiadhesive or the rest of antiadhesive and, optionally, coloring substances (one or more of these components can be pre-mixed and the size of the particles is brought to a desired value (for example, by grinding for grinding agregate mixture; and
ii) mixing the lubricant with granular mixture; and
(C) compressing the mixture obtained in stage (b) (ii), to obtain tablets (for example, with the use of a press for forming tablets).

Solid source materials of these compositions preferably before applying sift through a sieve. The weight ratio of water (preferably purified water (USP) or water for injection (USP)) to the solid materials used in stage (a) (iii) is preferably in the range from approximately 0.25 to approximately 0.6:1.

Tablets can be treated or covered with a sheath in accordance with known methods.

The tablets obtained from the compositions of this invention preferably contain (on a tablet) from about 25 to about 300 mg irbesartan, most preferably from about 75 to 300 mg irbesartan and from about 1 to about 25 mg diuretics, most preferably from about 6,25 to approximately 25 mg of hydrochlorothiazide. The total weight of the resulting tablets preferably ranges from about 50 to about 600 mg. of the Composition of this invention can also be used for producing granulated products, generator or granules. The methods used to obtain such compositions are well known qualified specialists and can be used for the preparation of these dosage forms.

Compositions and tablets of this invention can be used for the treatment or prevention of diseases, such as described in U.S. patent 5270317, which is included as references in this invention. Such diseases include cardiovascular diseases such as hypertension or heart failure, venous insufficiency, as well as glaucoma, diabetic retinopathy, renal failure, and various disorders of the Central nervous system. Song data or tablets preferably introduced orally in an effective amount to a mammal (particularly a human), which need treatment, or prevention of the above diseases. For a person preferred dose is from about 75 mg to about 300 mg irbesartan in combination with a diuretic) and can be entered, for example, 1-2 times a day.

The following examples illustrate preferred embodiments of the invention without limiting the scope of this invention.

Example 1.

On the blecki, contains irbesartan and hydrochlorothiazide, with different content of active drug, the composition presented in table 1: (1) 75 mg irbesartan and 12.5 mg of hydrochlorothiazide with a total weight of 150 mg/tabl.; and 2) 150 mg irbesartan and 12.5 mg of hydrochlorothiazide with a total weight of 300 mg/tab.

Tablets of the above compositions produced by the method of wet granulation according to the following procedure. Mix irbesartan and hydrochlorothiazide used as medicines, lactose, water, Pregelatinised starch and part (4/5 total) nitrocresols. This powder mixture is then milled to break up the agglomerates of medicines. The crushed powder mixture is again mixed, and then granularit with water (which is taken in the amount of approximately 55% of the total weight of solid materials in mixer/granulator. The wet granules are dried in a suitable apparatus (for example in the dryer on a pallet or in a fluidized bed dryer) until such time as the weight loss during drying will not be equal to 2% or less 2%, and then dried granules are milled.

A mixture of iron oxides with part (1/3 total) microcrystalline cellulose gain kr is eskers, nitrocresols mixed with ink mixture and silicon dioxide, after which the mixture is weighed, sieved and mixed with dried crushed granules. At the final stage weighed magnesium stearate is sifted through a sieve and mixed with the obtained pellet mixture. This final mixture is then pressed into tablets using a suitable press for tableting.

Obtaining tablets
For tablets with a content of irbesartan/hydrochlorothiazide equal 75/12 .5 mg per tablet, the total weight of each tablet 150 mg and hardness of the tablets is equal to 10-14 SCU (Strong bb Units). For tablets with a ratio of irbesartan/hydrochlorothiazide equal 150/12 .5,weight of each tablet is 300 mg and hardness of the tablets is 14-18 SCU. For both types of tablets fragility is less than 0.5%, the disintegration time is less than 7 minutes and the coefficient of variation of the weight of the tablet is less than 2%. In addition, the dissolution of these tablets comply with the specifications for dissolution of irbesartan, which is more than 85% within 30 minutes, and fully comply with the specifications of hydrochlorothiazide, which is more than 60% within 30 minutes.

Tablets of this composition was found to have good the software products of free amine and formaldehyde (see D. S. Desai et al. International Journal of harmaceutics, 107 (2), 141-47 (1994)). Selection of fillers can improve the stability of hydrochlorothiazide. Application Pregelatinised starch as binders in the compositions, it is found that improves the stability of hydrochlorothiazide and makes it more stable than, for example, when using povidone (the use of which is formed a number of free amine). It was found also that poloxamer promotes the decomposition of hydrochlorothiazide and therefore, while in the composition without hydrochlorothiazide, poloxamer is a preferred component in the composition with a mixture of irbesartan and hydrochlorothiazide, poloxamer is not the preferred component. Thus, the above preferred composition of this invention containing irbesartan and hydrochlorothiazide, possess some additional advantages, as applied to them components minimize or eliminate the decomposition of hydrochlorothiazide.

Example 2
Obtaining tablets containing irbesartan and hydrochlorothiazide, alternative composition
By the way, is similar to that described in example 1, get tablets compositions 2(A), 2 (B) 2 (C) or 2(D), Praia, characterized in that the said composition comprises from 20 to 70 weight. % irbesartana or its pharmaceutically acceptable salt, from 2 to 33 weight. % diuretic, and the total number of irbesartan or its pharmaceutically acceptable salt and diuretic does not exceed 85 weight. %, from 1 to 70 weight. % filler, from 2 to 20 weight. % binder, 1 to 10 weight. % disintegrator, from 0.1 to 5 weight. % antiadhesive and from 0.2 to 1.5 weight. % lubricating agent.

2. The pharmaceutical composition under item 1, characterized in that it additionally contains up to 2% of dye.

3. The pharmaceutical composition according to any one of p. 1 or 2, wherein the diuretic is one or more compounds selected from the group including hydrochlorothiazide, bendroflumethiazide (benzylhydroxylamine), benzthiazide, chlorothiazide, chlorthalidone, cyclothiazide, hydroflumethiazide, methyclothiazide, metolazone, polythiazide, ginataan and trichlormethiazide.

4. The pharmaceutical composition under item 1, characterized in that it comprises from 20 to 50 weight. % irbesartan, from 2 to 20 weight. % diuretic, from 1 to 70 weight. % filler, from 10 to 20 weight. % binder, from 4 to 6 weight. % disintegrator, from 0.5 to 1.0 weight. % antiadhesive, from 0.5 to 1.5 weight. % lubricating agent.

5. The pharmaceutical composition of the position p. 5, wherein the diuretic is hydrochlorothiazide, the filler is lactose water and microcrystalline cellulose, the binder is Pregelatinised starch, disintegrator is sodium crosscarmellose, antiadhesion is silicon dioxide, and a lubricating agent is magnesium stearate.

7. The pharmaceutical composition according to p. 6, characterized in that it comprises 50 weight. % irbesartan, 8,33 weight. % of hydrochlorothiazide, 4,72 weight. % lactose water, 15.0 weight. % Pregelatinised starch, 5.0 weight. % sodium croscarmelose, 15 weight. % microcrystalline cellulose, 0.75 weight. % silicon dioxide, 1,0 weight. % of magnesium stearate, and 0.1 weight. % iron oxide red and 0.1 weight. % iron oxide yellow.

8. The pharmaceutical composition according to p. 6, characterized in that it comprises 50 weight. % irbesartan, 4,17 weight. % of hydrochlorothiazide, 8,88 weight. % lactose water, 15.0 weight. % Pregelatinised starch, 5.0 weight. % sodium croscarmelose, 15 weight. % microcrystalline cellulose, 0.75 weight. % silicon dioxide, 1,0 weight. % of magnesium stearate, and 0.1 weight. % iron oxide red and 0.1 weight. % iron oxide yellow.

9. The pharmaceutical composition according to any one of paragraphs. 1-8, characterized in that it is molded in the form of tablets.

10. Tablet, distinguish or more irbesartana or its salts, contained in said tablet dissolves within 30 minutes

11. Tablet p. 10, characterized in that its total weight is from 50 to 600 mg

 

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