Pharmaceutical solid preparation containing benzazepin and method for preparing it

FIELD: medicine.

SUBSTANCE: what is described is a new pharmaceutically solid preparation of a vasopressin antagonist which contains: (a) 7-chlor-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro- 1H-benzoazepine and/or its salt; (b) hydroxypropylcellulose containing a hydroxypropoxyl group in the amount of 50% or more; and (c) at least one of the ingredients specified in a group consisting of carmellose, sodium carboxymethyl starch, crospovidone and hydroxypropylcellulose with a lower degree of substitution with an average diameter of particles 30 to 70 mcm and 90% of the cumulative diameter of 100 to 200 mcm.

EFFECT: pharmaceutical solid preparation shows excellent desintegration properties and solubility leading to adequate gastrointestinal absorbability of the active ingredients.

17 cl, 4 tbl, 21 ex

 

The technical FIELD TO WHICH the INVENTION RELATES

The present invention relates to solid pharmaceutical preparation and method of its production.

PRIOR art

As disclosed in not held the substantive examination of the patent application of Japan publication No. 1992-154765, 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin or its salt (hereinafter in this description and on the occasion referred to as connection benzazepine)represented by General Formula (1), is used as an antagonist of vasopressin.

However, despite the fact that the connection benzazepine has excellent pharmacological activity, its poor solubility leads to a problematic lack of absorption in the gastrointestinal tract.

To solve this problem in not held the substantive examination of the patent application of Japan publication No. 1999-21241 proposed technology to improve the solubility of the compounds benzazepine through a combination of compounds benzazepine with hydroxypropylcellulose with the formation of the amorphous composite. This technology improves the solubility of the compounds benzazepine; however, when the amorphous composite containing compound benzazepine pressed directly into the tablet, the tablet owls who do not eat disintegrates in the gastrointestinal tract. For this reason, the drug does not show pharmacological activity.

Amorphous composite, thus, has a variable dezintegriruetsja properties, especially in the form of tablets, and significantly changing the degree of disintegration. This leads to unstable pharmacological activity and is impossible to get medical products with constant pharmacological activity.

DISCLOSURE of INVENTION

The object of the present invention is to provide a new pharmaceutical solid preparation with a higher dezinfeciruyuhimi properties and excellent solubility and absorbability of the active ingredients in the gastrointestinal tract. The present invention also provides a method of obtaining a pharmaceutical solid preparation.

As a result of intensive studies to solve the above problems, the authors of the present invention have found that mixing the amorphous composite obtained from benzazepine and hydroxypropylcellulose, especially hydroxypropylcellulose with a low degree of substitution, allows to obtain a solid pharmaceutical preparation with a higher dezinfeciruyuhimi properties and excellent solubility, leading to sufficient absorbability of the active ingredients in the gastrointestinal tract.

Authors who are also detected, the mixing of the amorphous composite obtained from benzazepine and hydroxypropylcellulose with any of carmellose carboxymethyl amylum of sodium and crosspovidone, allows you to get such solid pharmaceutical preparation.

The present invention is made taking into account these findings and provides a solid pharmaceutical preparation and method thereof, as defined in the following Paragraphs 1 through 30.

Paragraph 1: the Pharmaceutical solid preparation containing:

(a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt;

(b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more; and

(C) at least one component selected from the group comprising carmellose, carboximetilkrahmal sodium, crosspovidone and hydroxypropylcellulose with a low degree of substitution with an average particle diameter of from 30 to 70 μm and a 90% cumulative particle diameter of from 100 to 200 microns.

Paragraph 2: the Pharmaceutical solid preparation containing:

(a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt;

(b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more; and

(C-1) hydroxypropylcellulose with a low degree of substitution with an average on what amerom particles from 30 to 70 μm and a 90% cumulative particle diameter of from 100 to 200 microns.

(This pharmaceutical solid preparation is hereinafter referred to as “Hard drug A”)

Item 3: the Pharmaceutical solid preparation according to Item 2, where hydroxypropylcellulose with a low degree of substitution has an average particle diameter of from 45 to 65 μm and a 90% cumulative particle diameter of 100 to 200 microns.

Item 4: the Pharmaceutical solid preparation according to Item 2, where hydroxypropylcellulose with a low degree of substitution has an average particle diameter of from 45 to 65 μm and a 90% cumulative particle diameter of 150 to 200 microns.

Item 5: the Pharmaceutical solid preparation according to any of Items 2 through 4, where the solid pharmaceutical preparation is presented in tablet form.

Item 6: the Pharmaceutical solid preparation according to item 2, obtained by a method that includes:

Stage 1 for amorphous composite of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine and/or its salts and hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more;

Stage 2 mixing of the amorphous compound obtained in Stage 1 with hydroxypropylcellulose with a low degree of substitution with an average particle diameter of from 30 to 70 μm and a 90% cumulative particle diameter of from 100 to 200 μm and

Stage 3 processing is MESI, obtained in Stage 2, in the solid preparation.

Item 7: the Pharmaceutical solid preparation according to Item 6, obtained by the method additionally includes between Stage 1 and Stage 2 stage processing of the amorphous compound obtained in Stage 1 into pellets, using granulation.

Item 8: the Pharmaceutical solid preparation according to Item 6, obtained by the method additionally includes between Stage 2 and Stage 3 stage processing the mixture obtained in Stage 2 into pellets, using granulation.

Item 9: a method of obtaining a solid pharmaceutical preparation in accordance with Paragraph 2, and the method includes:

Stage 1 for amorphous composite of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine and/or its salts and hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more;

Stage 2 mixing of the amorphous compound obtained in Stage 1 with hydroxypropylcellulose with a low degree of substitution with an average particle diameter of from 30 to 70 μm and a 90% cumulative particle diameter of from 100 to 200 μm and

Stage 3 processing the mixture obtained in Stage 2, in the solid preparation.

Item 10: the Method according to Paragraph 9, where stage 3 of Westlaw by processing the mixture, obtained in Stage 2, tablets.

Item 11: the Method according to PP or 10, further comprising between Stage 1 and Stage 2 stage processing of the amorphous compound obtained in Stage 1, in granules, using the granulation technique.

Item 12: the Method according to PP or 10, further comprising between Stage 2 and Stage 3 stage processing the mixture obtained in Stage 2, in granules, using the granulation technique.

Item 13: the Pharmaceutical solid preparation containing:

(a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt;

(b)hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more; and

(C-2) carmellose.

(This pharmaceutical solid preparation is hereinafter referred to as “Hard drug”)

Item 14: the Pharmaceutical solid preparation according to Item 13, where the content carmellose is from 7 to 15% of the total number of pharmaceutical solid preparation.

Item 15: the Method of obtaining the pharmaceutical solid preparation according to Item 13, and the method includes:

Stage 1 for amorphous composite of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine and/or its salts and hydroxypropylcellulose, containing what she hydroxypropoxy group in the amount of 50 wt.% or more;

Stage 2 mixing of the amorphous compound obtained in Stage 1, with carmellose; and

Stage 3 processing the mixture obtained in Stage 2, in the solid preparation.

Item 16: the Method according to Paragraph 15, where the Stage 3 is implemented by processing the mixture obtained in Stage 2, tablets.

Item 17: the Method according to claims 15 or 16, further comprising between Stage 1 and Stage 2 stage processing of the amorphous compound obtained in Stage 1, in granules, using the granulation technique.

Item 18: the Method according to claims 15 or 16, further comprising between Stage 2 and Stage 3 stage processing the mixture obtained in Stage 2, in granules, using the granulation technique.

Item 19: the Pharmaceutical solid preparation containing:

(a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt;

(b)hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more; and

(C-3) carboximetilkrahmal sodium.

(This pharmaceutical solid preparation is hereinafter referred to as “Hard drug”)

Item 20: the Pharmaceutical solid preparation according to item 19, where the content of sodium carboxymethyl amylum is from 0.5 to 15 wt.%, of the total alicescuriosities.com solid drug.

Item 21: a method of obtaining a solid pharmaceutical preparation in accordance with Paragraph 19, where the method includes:

Stage 1 for amorphous composite of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine and/or its salts and hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more;

Stage 2 mixing of the amorphous compound obtained in Stage 1, with carboximetilkrahmala sodium; and

Stage 3 processing the mixture obtained in Stage 2, in the solid preparation.

Paragraph 22: the Method according to paragraph 21, where the Stage 3 is implemented by processing the mixture obtained in Stage 2, tablets.

Item 23: the Method according to PP or 22, further comprising between Stage 1 and Stage 2 stage processing of the amorphous compound obtained in Stage 1, in granules, using the granulation technique.

Item 24: the Method according to Item 21 or 22, further comprising between Stage 2 and Stage 3 stage processing the mixture obtained in Stage 2, in granules, using the granulation technique.

Paragraph 25: the Pharmaceutical solid preparation containing:

(a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt;

(b) hydroxypropylcellulose, soda is containing hydroxypropoxy group in the amount of 50 wt.% or more; and

(C-4) crosspovidone.

(This pharmaceutical solid preparation is hereinafter referred to as “Hard drug D”)

Item 26: the Pharmaceutical solid preparation according to item 25, where the content of crosspovidone is from 2 to 15 wt.% from the total amount of the pharmaceutical solid preparation.

Paragraph 27: the Method of obtaining a solid pharmaceutical preparation in accordance with Paragraph 25, and the method includes:

Stage 1 for amorphous composite of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine and/or its salts and hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more;

Stage 2 mixing of the amorphous compound obtained in Stage 1, with crosspovidone; and

Stage 3 processing the mixture obtained in Stage 2, in the solid preparation.

Item 28: the Method according to Paragraph 27, where the Stage 3 is implemented by processing the mixture obtained in Stage 2, tablets.

Item 29: the Method in accordance with Clauses 27 or 28, further comprising between Stage 1 and Stage 2 stage processing of the amorphous compound obtained in Stage 1, in granules, using the granulation technique.

Item 30: the Method in accordance with Clauses 27 or 28, further comprising between Stage 2 The Stage 3 stage processing of the mixture, obtained in Stage 2, in granules, using the granulation technique.

The pharmaceutical solid preparation according to the present invention contains:

(a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt;

(b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more; and

(C) at least one component selected from the group comprising carmellose, carboximetilkrahmal sodium, crosspovidone and hydroxypropylcellulose with a low degree of substitution with an average particle diameter of from 30 to 70 μm and a 90% cumulative particle diameter of from 100 to 200 microns.

In the present invention the pharmaceutical solid preparation containing as component (C) hydroxypropylcellulose with a low degree of substitution with an average particle diameter of from 30 to 70 μm and a 90% cumulative particle diameter of from 100 to 200 μm is called a Hard Drug; a solid preparation containing carmellose as an indispensable ingredient of the component (C)is called a Hard Drug; a solid preparation containing carboximetilkrahmal sodium as an essential ingredient of the component (C)is called a Hard Drug; and a solid preparation containing crosspovidone as an indispensable ingredient of the Component (C)is called Solid report D.

The following description explains a Solid Drug As Solid Drug, Solid product With a Solid and Drug D in this order.

Solid Drug And

As described above, the Solid Drug And the present invention contains:

(a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt (compound benzazepine);

(b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more; and

(C-1) hydroxypropylcellulose with a low degree of substitution with an average particle diameter of from 30 to 70 μm and a 90% cumulative particle diameter of 100 to 200 microns.

(a) Compound benzazepine

Connection benzazepine is a 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt represented by the General Formula (1).

Salt benzazepine means, for example, salt, obtained by mixing the acid or basic compound, pharmacologically compatible with benzodazepines represented by the General Formula (1).

Examples of the basic compound which forms a salt with benzodazepines include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide; carbonates of alkali metal, such as the carbonates of sodium; the bicarbonate of an alkali metal such as sodium bicarbonate; and an alcoholate of an alkali metal, such as methylate sodium or utility potassium.

Examples of the acid which forms a salt with benzodazepines include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid or Hydrobromic acid; and organic acids such as acetic acid, p-toluensulfonate, econsultancy acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid or benzoic acid.

Examples of compounds benzazepine include solvate benzazepine, such as hydrates and atonality.

Component (a) in connection benzazepine can be selected from various crystalline polymorphisms. Additionally, there are various stereoisomers and optical isomers of the compounds benzazepine of the present invention. Their is also possible to use as Component (a).

Data of various substances used as connection benzazepine of the present invention can be used individually or in combination. More specifically, the connection benzazepine of the present invention includes at least one component from the group consisting of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-N-benzazepine and/or its salts.

Connection benzazepine of the present invention can be obtained in any known way, for example, by the method described in not held the substantive examination of the patent application of Japan publication No. 1992-154765 or No. 1999-21241.

(b) Hydroxypropylcellulose

Component (b) is a simple water-soluble cellulose ether containing hydroxypropyl group in the amount of about 50 wt.% or more, preferably in the range of from about 53 to 80 wt.%. Component (b) is a compound having a repeating unit represented by the following General Formula (2).

,

where each of R1, R2and R3represent a hydrogen atom or a group:

(m is an integer not smaller than 1).

Hydroxypropylcellulose containing hydroxypropyl group in the amount of 50 wt.% or more may be any compound represented by the above Formula (2). However, in the case of a 2% aqueous solution, it is preferable for the viscosity of the aqueous solution of from 2 to 10 centipoise, and more preferably from 3 to 6 centipoise at 20aboutC.

Hydroxypropylcellulose containing hydroxypropyl group in the amount of 50 wt.% or more used in the present invented and, can be obtained in any well known manner or may be selected from commercially available products. Examples of commercially available hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more include “HPC-L, HPC-SL, and HPC-SSL” (Nippon Soda Co. Ltd.), and “Klucel EF” (Hercules).

(C-1) Hydroxypropylcellulose with a low degree of substitution

Hydroxypropylcellulose with a low degree of substitution is a cellulose containing hydroxypropoxy group in the amount of from about 5 to 16 wt.%, preferably in quantities of from about 10 to 13 wt.%.

The average particle diameter hydroxypropylcellulose with a low degree of substitution is in the range from about 30 to 70 μm, preferably from 45 to 65 microns.

Further, the 90% cumulative particle diameter hydroxypropylcellulose with a low degree of substitution is usually around 100 to 200 microns, and preferably from 150 to 200 microns.

Average particle diameter and the 90% cumulative particle diameter within the above range, retain the disintegration properties of solid drug.

The content of hydroxypropylcellulose with a low degree of substitution can be measured by a method in accordance with, for example, the Pharmacopoeia of Japan.

Further, the distribution of particles and average particle diameter of hydroc is propylethylene with a low degree of substitution can be measured by the dry method, using the analyzer of the distribution of particle size laser diffraction type. The obtained value is used to calculate the 90% cumulative particle diameter.

Hydroxypropylcellulose with a low degree of substitution preferably has a negligible content of water-soluble substances within the conservation disintegration properties. Preferred is a content of water-soluble substances, equal to approximately 3% or less.

Hydroxypropylcellulose with a low degree of substitution used in the present invention can be obtained by a commonly known method or may be selected from commercially available products. Examples of commercially available hydroxypropylcellulose with a low degree of substitution include “LH-11”, “LH-21”, and “LH-B1” (Shin-Etsu Chemical Co. Ltd.).

Hydroxypropylcellulose with a low degree of substitution (c-1) can be used with other dezinfeciruyuhimi substances within the limits that do not cause deterioration in performance of the present invention. In this case hydroxypropylcellulose can be used with many types dezintegriruetsja substances.

Next, (c-1) hydroxypropylcellulose with a low degree of substitution is not only used as dezintegriruetsja substances, but also as other kinds of agents, such as binders, diluents and other is obuvki.

(C-1) hydroxypropylcellulose with a low degree of substitution is preferred because it is combined with other drugs, as well as easy to use.

The content of (a) compounds benzazepine in the Solid Preparation is not particularly limited and can have a wide range. Usually the content is from about 0.01 to 95 wt.%, preferably from about 0.05 to 65 wt.%, and more preferably from about 0.1 to 50 wt.%.

The content of (b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more typically ranges from about 0.01 to 2 parts, preferably from about 0.1 to 1.5 parts, and particularly preferably from approximately 0.2 to 1 part by weight of (a) compounds benzazepine.

The content of (C-1) hydroxypropylcellulose with a low degree of substitution in the Solid Drug And is usually from about 1 to 15 wt.%, preferably from about 2 to 13 wt.% and more preferably from 3 to 12 wt.%. This range of content provides the desired disintegration properties.

The compound (a) benzazepine and (b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more, contained in the Solid Preparation is in the form of amorphous composite.

Other ingredients

The solid Preparation may be presented in the form of powder, granules, tablets, pills, capsules, etc.

Including, the present invention provides a form of powder, granules, capsules or tablets from the point of view of easy dispensing. The shape of the tablets is especially preferred.

Method of producing Solid Drug And

A method of obtaining a Solid Preparation And the present invention includes the following Stages 1, 2 and 3.

Stage 1: obtain the amorphous composite of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine and/or its salt (compound benzazepine) and hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more;

Step 2: mixing the amorphous compound obtained in Stage 1, with hydroxypropylcellulose with a low degree of substitution; and

Stage 3: processing the mixture, extracting the Noi Stage 2, in the solid preparation.

In the following description, stage 1, stage 2 and stage 3 details.

Stage 1

Stage 1 represents a method of obtaining amorphous composite connection benzazepine and hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more. Amorphous composite can be obtained in many ways, including the following.

i) Connection benzazepine and hydroxypropylcellulose,

containing hydroxypropoxy group in the amount of 50 wt.% or more, is dissolved in an organic solvent, and then the organic solvent is distilled off in a known manner, receiving a solid material (e.g. powder) amorphous composite.

ii) Amorphous composite can also be obtained via mixing of hot melt; for example, using a twin screw extruder. This method does not use an organic solvent, has advantages such as low risk of environmental pollution and high performance.

iii) Amorphous composite can also be obtained by using an ultrasonic machine for the production of tablets (rotary teletrauma machine, machine for injection molding and so on).

When in Stage 1 using the organic solvent may be any well-known organic rest ritel, which can dissolve hydroxypropylcellulose containing benzazepin and hydroxypropoxy group in the amount of 50 wt.% or more. Examples of the organic solvent include lower alcohols such as methanol, ethanol or isopropanol; ketones, such as acetone, methyl ethyl ketone; halogenated hydrides of carbon, such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; and mixtures of these solvents. Among them, particularly preferred from the viewpoint of solubility, distillation, etc. solvent mixture of a lower alcohol and a halogenated carbon hydride. The solvent from a mixture of dichloromethane and methanol and/or ethanol is preferable.

When using a mixed solution of a lower alcohol and a halogenated carbon hydride, lower alcohol and halogenated carbon hydride are mixed in a mass ratio of from about 99:1 to 1:99, preferably from 10:90 to 40:60. The organic solvent may be added from 0.01 to 5 wt.% water.

When Stage 1 is used, an organic solvent, an organic solvent may Athanasia by way of evaporation, spray drying method, a method of drying fluidized bed or similar. The method of spray drying is preferred.

The amorphous form of the composite of the present and the gain is not specifically limited. Amorphous composite may be in the form of powder or round, or square solids of a certain size.

Stage 2

Stage 2 represents a method of mixing an amorphous composite, obtained from the Component (a) and Component (b) in Stage 1 with (s-1) hydroxypropylcellulose with a low degree of substitution. The method of mixing is not specifically limited. For example, can be used in a diffusion blender (type of container rotation), convection mixer (type machine with stirring), samelevel mixer with air flow and the like.

After mixing the amorphous composite with Component (C-1) can be added to a lubricating substance. Adding lubricants gives some effects, including noise reduction in the subsequent Stage 3 processing of solid drug tablets.

Examples of lubricants include poroshkoobraznuju Arabian gum, Carnauba wax, carmellose calcium, carmellose sodium, hydrated silicon dioxide, dried gel of aluminum hydroxide, esters of fatty acids with glycerine, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, magnesium oxide, wheat starch, bleached beeswax, heavy anhydrous silicic to the slot, esters of fatty acids with sucrose stearyl alcohol, stearic acid, aluminum stearate, calcium stearate, polyoxyl 40 stearate, cetanol, gelatin, talc, magnesium carbonate, precipitated calcium carbonate, corn starch, lactose, sucrose, solid fat, potato starch, fumaric acid, sodium fumarate, polyoxyethylene (160), polyoxypropylene (30) glycol, Polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, yellow beeswax, alumosilicate magnesium, methylcellulose, glycerol monostearate, sodium lauryl sulfate, sulfate calcium and magnesium sulfate.

The method of obtaining of the present invention preferably includes between Stage 1 and Stage 2 Stage 1' processing of amorphous composite pellets using granulation method, or, between Stage 2 and Stage 3, Stage 2' processing the mixture obtained in Stage 2, into granules using granulation method.

In granulation method in Stage 1 or Stage 2 javljaetsja preferred to use a diluent and binder.

Examples of the diluent used in the granulation method include L-aspartic acid powder, maltose syrup, gum Arabic, powdered gum Arabic, alginic acid, sodium alginate, pregelatinized starch, Inositol, ethylcellulose, with the polymer of ethylene and vinyl acetate, erythritol, sodium chloride, kaolin, casein, sodium Caseinate, fructose, carboximetilkrahmal sodium, carmellose, carmellose calcium, carmellose sodium, hydrated silicon dioxide, amorphous hydrate of silicon oxide, agar, powdered agar, xylitol, citric acid, glycine, esters of fatty acids and of glycerol, croscarmellose sodium, crosspovidone, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose and carmellose sodium, hydrogenated oil, wheat starch, potassium acetate, calcium acetate, phthalate cellulose acetate, titanium oxide, magnesium oxide, β-cyclodextrin, heavy anhydrous silicic acid, tartaric acid, esters of fatty acids with sucrose, coprecipitate aluminum hydroxide-magnesium hydroxide, aluminum hydroxide, stearyl alcohol, stearyl acid and calcium stearate, polyxystra 40, magnesium stearate, purified gelatin, purified shellac, purified urea, sucrose, servicesecurity, cetanol, cetosteatil alcohol, gelatin, D-sorbitol, rejonowy calcium phosphate, hydrogenated soybean oil, soy lecithin, talc, ammonium carbonate, calcium carbonate, magnesium carbonate, carboximetilkrahmal sodium with a low degree of substitution, hydroxypropylcellulose with a low degree of the substitution, dextrin, corn starch, silicon dioxide, aluminum lactate, calcium lactate, lactose monohydrate, white shellac, white soft sugar, potato starch, crystalline cellulose, hydroxypropylmethyl, hydroxypropylcellulose, hypromellose 2208, hypromellose 2906, hypromellose 2910, phthalate-free hypromellose, partially pregelatinized starch, pullulan, powdered sucrose, powdered hydrogenated maltose syrup, starch, pectin, povidone, polyoxyethylenesorbitan castor oil 60, polystyrenesulfonate sodium, Polysorbate 80, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, ▫ maltitol, maltose, monohydrate, maltose, D-mannitol, starch molasses, anhydrous citric acid, anhydrous silicic acid hydrate, anhydrous lactose, anhydrous sodium sulfate, anhydrous dibasic calcium phosphate, copolymer LD, methacrylic acid, alumosilicate magnesium, a copolymer of methyl acrylate and methacrylic acid, methylcellulose, aluminum monostearate, glycerol monostearate, carpetmuncher, sodium lauryl sulfate, aluminum sulfate, calcium sulfate, DL-malic acid, monohydratefast calcium, dibasic calcium phosphate, dibasic sodium phosphate, dibasic potassium phosphate, monobasic calcium phosphate and the dihydrate of sodium dihydrophosphate.

Examples of binders include the indicate the dispersion of a copolymer of acrylate and metamyelocyte, copolymer E aminoalkylsilane copolymer RS aminoalkylsilane, amylopectin, powder, maltose syrup, gum Arabic, powdered gum Arabic, sodium alginate, pregelatinized starch, ethylcellulose, powdered hydrolyzed gelatin, sodium Caseinate, fructose, carboxyquinolone, carboximetilzellulozu, carboximetilkrahmal sodium, carmellose, carmellose sodium, hydrated silicon dioxide, agar, hydrogenated fat, powdered agar, guar gum, glycerin, light anhydrous silicic acid, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, poly-[(2-oxo-1-pyrrolidinyl)ethylene], copolyvidone, rice powder, wheat starch, polyvinyl acetate, acetate phthalate cellulose, bleached beeswax, esters of fatty acids and sucrose, stearyl alcohol, stearyl acid, calcium stearate, polyoxyl 40 stearate, purified gelatin, purified shellac, sucrose, servicesecurity, cetanol, shellac, esters of sorbitol, fatty acid, D-sorbitol, soy lecithin, calcium carbonate, hydroxypropylcellulose with a low degree of substitution, dextrin, starch, corn starch, tragakant, powder tragakant, monohydrate lactose, concentrated glycerin, white shellac, potato starch, microcrystalline is ellulose, hydroxyethyl cellulose, hydroxyethylmethylcellulose, hypromellose 2208, hypromellose 2906, hypromellose 2910, acetate succinate of hydroxypropylmethylcellulose, phthalate-free hypromellose, copolymer of vinylpyrrolidone and vinyl acetate, glucose, partially pregelatinized starch, a mixture of fumaric acid, fumaric acid and stearic acid and diethylaminoacetate polyvinylacetal, and hydroxypropylmethylcellulose 2910, pullulan, propylene glycol, pectin, povidone, polyoxyethylene (160), polyoxypropylene (30) glycol, Polysorbate 80, diethylaminoacetate polyvinylacetal, fully hydrolyzed polyvinyl alcohol, sodium polyphosphate, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, D-mannitol, starch syrup, yellow beeswax, copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, methacrylic acid, alumosilicate sodium, metaphosphate sodium, methylcellulose, glycerol monostearate, and sodium lauryl sulfate.

In the method of obtaining respectively the present invention through the implementation of Stage 1' after Stage 1, or Stage 2' after Stage 2, it becomes possible to improve the uniformity of content of the component (a) in solid preparations, which contains a small proportion of the Component (a). Further, improving the burying of solid drug in the mold tablet press machine, as the solid drug is sealed in the granulation. The granulation Stage 1 ili 2 ne specifically limited and may be any method of granulation in accordance with, for example, the target dosage forms. Examples of the granulation methods include methods of dry granulation and how wet granulation (e.g., granulation fluidized bed, the method of granulation by mixing etc).

Stage 3

Stage 3 is a stage of processing the mixture obtained in Stage 2, in the solid preparation.

A method of processing a mixture of a solid drug depends on the target dosage forms. For example, when the target dosage form of solid preparation is a tablet, the mixture can be extruded using teletrauma machine. Examples of tabletting methods include any method of dry tabletting, wet tabletting and method for tableting with external lubrication, etc.

Additionally, the solid preparation may be covered with tape to mask the taste relating to medicine, or to improve the photostability. The solid Preparation may be coated with enteric-soluble film or a film with a slow release for modification of drug release in the gastrointestinal tract.

Solid Drug

Solid Preparation In the present invention contains:

(a) 7-chloro-5-Ki-the Roxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt;

(b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more; and

(C-2) Carmellose.

The following details each of the Components (a), (b) and (C-2).

(a)Connection benzazepine

In hard Drug use In the same connection benzazepine that in the Solid Preparation A.

(b)Hydroxypropylcellulose

Hydroxypropylcellulose used for Solid Drug, represents the same hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more, used for Solid Preparation A.

(C-2) Carmellose

Carmellose can be received by one of the well-known methods. Additionally, industrial products, such as NS-300”manufactured by Nichirin Chemical Co. are readily available.

The solid Preparation can contain other dezintegriruetsja agents along with (2) carmellose within range without disturbing the effect of the present invention. In this case, can be applied to many types dezintegriruetsja agents.

(C-2) carmellose is used not only as disintegrity agent, but also as a binder, thinner or other additive.

The content of (a) compounds benzazepine in the solid composition is not specifically limited and can vary widely, but usually atriplicifolia 0.01 to 95 wt.%, preferably from 0.05 wt.%, and more preferably from 0.1 to 50 wt.%.

The ratio of (b) hydroxypropylcellulose containing at least 50 wt.% hydroxypropylamino group is usually from 0.01 to 2 parts, preferably from 0.1 to 1.5 parts, and particularly preferably from 0.2 to 1 parts (a) connection benzazepine.

The content of (C-2) carmellose in Solid drug is usually from 7 to 15 wt.%, preferably from 9 to 13 wt.%, and more preferably from 10 to 12 wt.%. The content in this range provides the desired disintegration property.

In the Solid preparation In each of (a) compounds benzazepine and (b) hydroxypropylcellulose containing at least 50 wt.% hydroxypropylamino or more of the group is a form of amorphous composite.

Another Ingredient

As a Hard Drug And Solid, the Drug may contain other ingredients used in pharmaceutical solid preparations, in addition to the Components (a), (b) and (C-2). Examples of ingredients include solvents, binders, substances that regulate the pH, nutrients, improves the absorption, lubricants, dyes flavouring agents or perfumes.

The content of these ingredients within a range not to impair effect of the present invention.

As a Hard Drug And Solid P is apart, containing (a) compound benzazepine, (b) hydroxypropylcellulose containing at least 50 wt.% hydroxypropylamino or more of the group, and (C-2) carmellose, can be represented in the form of powder, granules, tablets, pills or capsules. Including, the present invention provides a form of powder, granules, capsules or tablets from the viewpoint of easy preparation and dispensing. The shape of the tablets is especially preferred.

Method of producing solid drug

Solid Preparation get In the same way as solid Preparation A, except that carmellose is used instead of hydroxypropylcellulose with a low degree of substitution.

Solid Drug

Solid Preparation With the present invention contains:

(a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt;

(b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more; and

(C-3) carboximetilkrahmal sodium.

The following details each of the Components (a), (b) and (C-3).

(a) Compound Benzazepine

In the Solid Preparation To use the same connection benzazepine that in the Solid Preparation A.

(b) Hydroxypropylcellulose

Hydroxypropylcellulose used for Solid Preparates, represents the same hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more, used for Solid Preparation A.

(C-3) Carboximetilkrahmal sodium

Carboximetilkrahmal sodium can be easily obtained as an industrial product, for example, “GLYCOLYS LV” (Roquette) “Primojel” (DMV). As the Component (C-3) can also be used partially pregelatinized starch.

Partially pregelatinized starch can be easily obtained as an industrial product, for example, “PCS” (Asahi Kasei Chemicals), “Starch 1500” (use) or “LYCATAB C” (Roquette).

The average particle diameter of the sodium carboxymethyl amylum is, for example, not more than 105 μm, preferably not more than 80 μm, and more preferably from about 20 to 65 μm.

The average diameter of the particles partially pregelatinization starch is, for example, not more than 150 μm, preferably not more than 100 μm, and most preferably from about 15 to 85 microns.

Further, the content of water-soluble partially pregelatinization starch is usually approximately not more than 20 wt.%, preferably approximately not more than 10 wt.%, and further preferably from about 1 to 4 wt.%, in keeping with room temperature water.

In addition, do not contain metal cha is partially pregelatinized starch or similar also show respect to the desired disintegration property, when used in small quantities as disintegrity agent in the solid preparation. Therefore, do not contain metal partially pregelatinized starch can be used for solid preparation of the present invention with a low content dezintegriruetsja agent.

As the content dezintegriruetsja agent increases, containing metal carboximetilkrahmal sodium becomes more appropriate than not containing metal partially pregelatinized starch, from the point of view of the disintegration properties.

On the contrary, in respect of cellulose as dezintegriruetsja agent, such as the aforementioned (1) hydroxypropylcellulose with a low degree of substitution, or (2) carmellose containing metal substance is more appropriate from the standpoint of the disintegration of property, regardless of its content.

The solid Preparation can contain other dezintegriruetsja agents together with (3) carboximetilkrahmala sodium in the range not deteriorating the effects of the present invention. In this case, can be used various kinds dezintegriruetsja agents.

(C-3) carboximetilkrahmal sodium is used not only as disintegrity agent, but also as a binder, thinner or other additive.

The content of (a) compounds benzazepine in solid kompozitsiiu is not specifically limited and can vary widely, but usually from about 0.01 to 95 wt.%, preferably from about 0.05 to 65 wt.%, and most preferably from 0.1 to 50 wt.%.

The ratio of (b) hydroxypropylcellulose containing at least 50 wt.% hydroxypropoxy group is usually from about 0.01 to 2 parts, preferably from 0.1 to 1.5 parts, and particularly preferably from 0.2 to 1 parts (a) connection benzazepine.

The content of (C-3) sodium carboxymethyl amylum in Solid Drug is usually from about 0.5 to 15 wt.%, preferably from about 1 to 10 wt.%, and most preferably from 1 to 5 wt.%. The content in this range improves desirable disintegration properties.

When the component (C-3) is used partly pregelatinized starch, its content is not specifically limited; however, the content is usually from about 1 to 15 wt.%, preferably from about 2 to 10 wt.%, and most preferably from 3 to 7 wt.%, based on the total solid of the drug.

Another Ingredient

As Solid Preparation And a Solid Drug may contain other ingredients for use in pharmaceutical solid preparations, in addition to the Components (a), (b) and (C-3). Examples of ingredients include solvents, binders, washes the VA, substances that regulate the pH, nutrients, improves the absorption, lubricants, dyes flavouring agents or perfumes.

The content of these ingredients within a range not to impair effect of the present invention.

As Solid Preparation And a Solid Drug, containing (a) compound benzazepine, (b) hydroxypropylcellulose containing at least 50 wt.% hydroxypropylamino or more of the group, and (3) carboximetilkrahmal sodium, can be represented in the form of powder, granules, tablets, pills or capsules. Including, the present invention provides a form of powder, granules, capsules or tablets from the viewpoint of the ease of obtaining and dispensing. The shape of the tablets is especially preferred.

Method of producing solid drug

Hard Drug To get the same way as a Solid Preparation A, except that carboximetilkrahmal sodium is used instead of hydroxypropylcellulose with a low degree of substitution.

Solid D Drug

Solid Drug D, respectively, the present invention includes:

(a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt;

(b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more; and

(C-4) crosspovidone

You should detail each of the Components (a), (b) and (C-4).

(a) Compound Benzazepine

Connection benzazepine used in Solid Drug D is the same as the connection benzazepine used in the Solid Preparation A.

(b) Hydroxypropylcellulose

Hydroxypropylcellulose used for Solid Drug D, represents the same hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50 wt.% or more, used for Solid Preparation A.

(C-4) Crosspovidone

The crosspovidone called synthetic cross-linked homopolymer of N-vinyl-2-pyrrolidinone, insoluble in water.

The content of (a) compounds benzazepine in Solid D Drug is not specifically limited and can vary widely, but is usually from about 0.01 to 95 wt.%, preferably from about 0.05 to 65 wt.%, and most preferably from 0.1 to 50 wt.%.

The ratio of (b) hydroxypropylcellulose containing at least 50 wt.% hydroxypropoxy group is usually from about 0.01 to 2 parts, preferably from 0.1 to 1.5 parts, and particularly preferably from 0.2 to 1 parts (a) connection benzazepine.

The content of (C-4) of crospovidon in Solid Drug D is usually from about 2 to 15 wt.%, preferably the t of approximately 3 to 12 wt.%, and most preferably from 3 to 10 wt.%. The content in this range improves desirable disintegration properties.

Solid Drug D can contain another disintegrity agent for use in pharmaceutical solid preparations, in addition to (C-4) crosspovidone. In this case, can be used various kinds dezintegriruetsja agents. (C-4) crosspovidone is used not only as disintegrity agent, but also as a binder, a solvent or other additive.

Other Ingredients

Solid Drug D can contain other ingredients for use in pharmaceutical solid preparations, in addition to the Components (a), (b) and (C-4). Examples of ingredients include diluents, binding agents, substances that regulate the pH, nutrients, improves the absorption, lubricants, dyes flavouring agents or perfumes. The content of these additional ingredients within a range not to impair effect of the present invention.

Solid Drug D containing (a) compound benzazepine, (b) hydroxypropylcellulose containing at least 50 wt.% hydroxypropylamino or more of the group, and (4) crosspovidone, can be represented in the form of powder, granules, tablets, pills or capsules. Including, the present invention provides a form of powder, granules, who Apso or tablets from the viewpoint of the ease of obtaining and dose. Tablets are particularly preferred.

A method of obtaining a solid D drug

Solid Drug D get in the same way as a Solid Preparation A, except that crosspovidone used instead of hydroxypropylcellulose with a low degree of substitution.

Each unit Solid Drugs from a to D of the present invention in a unit dosage form preferably contain (a) compound benzazepine as an active ingredient in an amount of from about 0.1 to 120 mg, preferably from about 1 to 90 mg, and most preferably from about 5 to 60 mg

Dose of Hard Drugs from a to D are determined depending on the use, condition of the patient, including age and gender, degree of disease, etc. Usually the number of (a) compounds benzazepine as the active ingredient per day is from about 0.02 to 2 mg per kilogram of body weight of the patient.

The EFFECT of the INVENTION

The pharmaceutical solid preparation of the present invention shows excellent disintegration properties and excellent solubility, leading to sufficient absorption of the active ingredients in the gastrointestinal tract.

In particular, the Solid Drug And accordingly the present invention provides significantly exceed desintegration the basic properties and excellent solubility, causing sufficient absorption of the active ingredients in the gastrointestinal tract.

Next, in the form of Solid tablets Drug And present invention provides a constant disintegration properties of products, thus reducing the spread of time of disintegration among the products. In the result, it is expected that the Solid Drug And exhibits the best constant pharmacological effect and, thus, is preferable.

The method accordingly the present invention provides the pharmaceutical solid preparation of data favorable characteristics.

BEST mode for carrying out the PRESENT INVENTION

The present invention is described in more detail below, with reference to Reference Examples, Examples, Comparative Examples and Experimental Examples; however, the present invention is not limited to these examples.

Reference Example 1 (Obtaining Amorphous Powder)

100 g of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (hereinafter, “main ingredient”) and 50 g of hydroxypropylcellulose (HPC-HL; Nippon Soda Co. Ltd.), containing from 53 to 78 wt.% hydroxypropoxy group dissolved in the mixed solution 1,390 g of dichloromethane and 350 g of ethanol. The solution is treated with a spray dryer ODT8 (Ohkawara Kakohki Co., Ltd), and then immediately dried by a vacuum dryer LCV-232 (Tabai Espec Corporation), to obtain an amorphous powder.

Reference Example 2 (Obtaining Granulated Substances)

Mix 135 g of an amorphous powder, 222 g of lactose monohydrate, 60 g of corn starch and 60 g of crystalline cellulose and the mixture is placed in a vortex dryer granulation in the fluidized bed Multiplex MP-1 (Powrex Corporation). Granulation in the fluidized bed is carried out with 240 g of 5 m/% aqueous solution of hydroxypropylcellulose (HPC-HL; Nippon Soda Co. Ltd.), containing from 53 to 78 wt.% hydroxypropoxy group, with subsequent drying. So, get a granulating agent.

In the Examples and Comparative Examples below, the resulting product is used as Component (C).

Component (C)

Hydroxypropylcellulose with a low degree of substitution (average particle diameter from 45 to 65 μm and a 90% cumulative particle diameter of 150 to 200 μm; the content of hydroxypropoxy group=10.0 to 12.9 wt.%) (LH-11; Shin-Etsu Chemical Co., Ltd.)

Hydroxypropylcellulose with a low degree of substitution (average particle diameter of 35 to 55 μm and a 90% cumulative particle diameter of 100 to 150 μm; the content of hydroxypropoxy group=10.0 to 12.9 wt.%) (LH-21; Shin-Etsu Chemical Co., Ltd.)

Hydroxypropylcellulose with a low degree of substitution (average particle diameter from 17 to 23 μm and the 90% cumulative diameter is p particles from 40 to 100 μm; content hydroxypropoxy group=10.0 to 12.9 wt.%) (LH-31; Shin-Etsu Chemical Co., Ltd.)

Hydroxypropylcellulose with a low degree of substitution (average particle diameter from 45 to 65 μm and a 90% cumulative particle diameter of 100 to 150 μm; the content of hydroxypropoxy group=10.0 to 12.9 wt.%) (LH-B1; Shin-Etsu Chemical Co., Ltd.)

Carmellose ((carboxymethylcellulose) NS-300; Nichirin Chemical Industries, Ltd.)

Carboximetilkrahmal sodium (Primojel; DMV; After sieving through a sieve with cell 63 microns, or less than 5% of the particles remain on the sieve)

Partly pregelatinized starch (PCS PC-10; Asahi Kasei Chemicals; average particle diameter of 70 μm, the content of water-soluble substances not more than 3 wt.%)

Crosspovidone (Polyplasdone XL; ISP; average particle diameter of 75 μm)

Carmellose calcium carboxymethylcellulose calcium) ECG-505; Nichirin Chemical Industries, Ltd.)

Crosscarmellose sodium (crosscarmellose sodium) Ac-Di-Sol; FMC International)

Example 1

Mix 24.5 g granulated substance obtained in the above Referential Example 2, 0.3 g LH-11 and 0.3 g of magnesium stearate. Using Autograph AG-1 Universal Testing Instrument (Shimadzu Corporation)under a compression speed of 6 kN with a compaction factor of 20 mm/min. and get a flat tablet (6 mm in diameter)having a weight of approximately 84 mg, containing 15 mg the primary ingredient.

The content of LH-11 in the flat tablet was 1.2 wt.%.

Example 2

Mix 24.5 g granulated substance obtained in the above Referential Example 2, 1.4 g LH-11 and 0.3 g of magnesium stearate. A flat tablet having a weight of approximately 87 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of LH-11 in the flat tablet was 5.2 wt.%.

Example 3

Mix 24.5 g granulated substance obtained in the above Referential Example 2, 2.9 g of LH-11 and 0.4 g of magnesium stearate. A flat tablet having a weight of approximately 92 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of LH-11 in the flat tablet amounted to 10.3 wt.%.

Example 4

Mix 24.5 g granulated substance obtained in the above Referential Example 2, 4.4 g LH-11 and 0.3 g of magnesium stearate. A flat tablet having a weight of approximately 97 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of LH-11 in the flat tablet, 14.9 wt.%.

Example 5

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 0.5 g LH-21, and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 87 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of LH-21 in the flat tablet was 5.2 wt.%.

Example 6

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 0.5 g LH-B1 and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 87 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of LH-B1 in the flat tablet was 5.2 wt.%.

Comparative Example 1

Mix 24.5 g granulated substance obtained in the above Referential Example 2 and 0.3 g of magnesium stearate. A flat tablet having a weight of approximately 83 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

Comparative Example 2

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 0.1 g LH-31 and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 87 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of LH-31 in a flat tablet was 1.2 wt.%

Comparative Example 3

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 0.5 g LH-31 and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 87 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of LH-31 in a flat tablet was 5.2 wt.%

uravnitelny Example 4

Mix 24.5 g granulated substance obtained in the above Referential Example 2, 0.3 g of Ac-Di-Sol and 0.3 g of magnesium stearate. A flat tablet having a weight of approximately 84 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of Ac-Di-Sol in the flat tablet was 1.2 wt.%

Comparative Example 5

Mix 24.5 g granulated substance obtained in the above Referential Example 2, 1.3 g of Ac-Di-Sol and 0.3 g of magnesium stearate. A flat tablet having a weight of approximately 87 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of Ac-Di-Sol in the flat tablet was 5.2 wt.%

Comparative Example 6

Mix 24.5 g granulated substance obtained in the above Referential Example 2, 2.9 g of Ac-Di-Sol and 0.3 g of magnesium stearate. A flat tablet having a weight of approximately 92 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of Ac-Di-Sol in the flat tablet amounted to 10.3 wt.%

Comparative Example 7

Mix 24.5 g granulated substance obtained in the above Referential Example 2, 4.4 g of Ac-Di-Sol and 0.3 g of magnesium stearate. A flat tablet having a weight of approximately 97 mg, containing 15 mg the primary ingredient, get in the same way as in the Example is 1.

The content of Ac-Di-Sol in a flat tablet, 14.9 wt.%

Comparative Example 8

Mix 24.5 g granulated substance obtained in the above Referential Example 2, 0.3 g ECG-505 and 0.3 g of magnesium stearate. A flat tablet having a weight of approximately 84 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of ECG-505 in the flat tablet was 1.2 wt.%

Comparative Example 9

Mix 24.5 g granulated substance obtained in the above Referential Example 2, 1.4 g ECG-505 and 0.3 g of magnesium stearate. A flat tablet having a weight of approximately 87 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of ECG-505 in the flat tablet was 5.2 wt.%

Comparative Example 10

Mix 24.5 g granulated substance obtained in the above Referential Example 2, 2.9 g ECG-505 and 0.3 g of magnesium stearate. A flat tablet having a weight of approximately 92 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of ECG-505 in the flat tablet amounted to 10.3 wt.%

Comparative Example 11

Mix 24.5 g granulated substance obtained in the above Referential Example 2, 4.4 g ECG-505 and 0.3 g of magnesium stearate. A flat tablet having a weight of approximately 97 is g, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of ECG-505 in the flat tablet, 14.9 wt.%

Experimental Example 1

Using six tablets in each case corresponding to the tablets obtained in Examples 1 to 6 and Comparative Examples 1 through 11 are tested for disintegration properties, respectively, of the disintegration test method described in the Pharmacopoeia of Japan (test fluid: water, without disk).

Table 1 shows the results of the disintegration test for Examples 1 to 6 and Comparative Examples 1 to 11.

Table 1
Flat tabletDisintegration Time (Seconds, Mean±standard Deviation
Example 1
(LH-11, a 1.2%)
70,8±5,8
Example 2
(LH-11, 5.2 per cent)
63,7±3,9
Example 3
(LH-11, 10,3%)
52,8±2,4

Example 4
(LH-11, 14,9%)
60,5±2,0
Example 5
(LH-21, 5.2 per cent)
79,8±10,7
Example 6
(LH-B1, 5,2%)
75,5±1,9
Comparative Example 1
(Without Dezintegriruetsja Agent)
the 95.8±6,1
Comparative Example 2
(LH-31, 1,2%)
104,7±6,2
Comparative Example 3
(LH-31, 5,2%)
130,3±37,4
Comparative Example 4
(Ac-Di-Sol, 1,2%)
92,3±3,0
Comparative Example 5
(Ac-Di-Sol, 5,2%)
161,3±12,0
Comparative Example 6
(Ac-Di-Sol, 10,3%)
163,8±3,5
Comparative Example 7
(Ac-Di-Sol, 14,9%)
188,0±3,8
Comparative Example 8
(ECG-505, 1,2%)
to 85.5±3,9
Comparative Example 9
(ECG-505, 5,2%)
100,5±5,1
Comparative Example 10
(ECG-505, 10,3%)
130,3±4,5
Comparative Example 11
(ECG-505, 14,9%)
170,0±5,1

Table 1 shows the following.

For tablets of Comparative Examples 2 and 3, which were used LS-31 (hydroxypropyl who cellulose with a low degree of substitution (average particle diameter from 17 to 23 μm and a 90% cumulative particle diameter of 40 to 100 μm), disintegration time was longer than for Comparative Example 1, without dezintegriruetsja agent.

Disintegration time for the tablets of Comparative Example 4, containing 1.2 wt.% Ac-Di-Sol (croscarmellose sodium) tablets of Comparative Example 8, containing 1.2 wt.% ECG-505 (carmellose sodium) was slightly lower than for the tablets of Comparative Example 1 not containing dezintegriruetsja agent. However, by increasing the ratio of Ac-Di-Sol and ECG-505 tablets to 5.2 wt.%, of 10.3 wt.% and 14.9 wt.% (Comparative Examples 5 to 7 and Comparative Examples 9 to 11) disintegration time significantly increased.

Despite the fact that Ac-Di-Sol, used in Comparative Examples 4 through 7 and ECG-505, used in Comparative Examples 8 to 11 known as sverigeinterracial agents, tablets, using data dezintegriruetsja agents instead dezintegriruetsja agents used in the present invention, showed insufficient disintegration properties. Moreover, if their number is increased, the disintegration properties decreased significantly.

On the contrary, as shown in Table 1, the disintegration time was significantly less in Examples 1 to 4 using LH-11 as dezintegriruetsja agent, in comparison with Comparative Examples 1 to 11, and received the desired de the integration properties.

Additionally, the solid preparation of Example 5, which uses LH-21 as dezintegriruetsja agent, a disintegration time was less than in the Comparative Example 1 containing no dezintegriruetsja agent and obtained the desired disintegration properties.

Further, in the solid preparation of Example 6, which uses LH-B1 as dezintegriruetsja agent, a disintegration time was less than in the Comparative Example 1 containing no dezintegriruetsja agent. There were thus obtained the desired disintegration properties.

Experimental Example 2

Table 2 shows the average value and the change in disintegration time among six solid samples (No. 1 to 6) for each of the Examples 2, 5 and 6, and Comparative Example 3, which was measured in the above-mentioned Experimental Example 1.

Table 2
Solid Drug noExample 2Example 5Example 6Comparative Example 3
Disintegration Time
(Seconds)
1 587073106
2607274107
3647375112
4668076121
5668677132
6689878204
The average Disintegration Time
(Seconds)
63,779,875,5130,3
Change (Seconds)a 3.910,71,937,4

As shown in Table 2, the change in disintegration time in Example 2,using LS-11 as dezintegriruetsja agent, 3.9 seconds; change disintegration time in Example 5, using LS-21 as dezintegriruetsja agent, was 10.7 seconds; and the change in disintegration time in Example 6, using LS-B1 as dezintegriruetsja agent, was 1.9 seconds. Thus, the change in disintegration time was small for all tablets of Examples 2, 5 and 6; more specifically tablets these Examples provide a consistent pharmacological effect.

At the same time, the change in disintegration time in Comparative Example 3, using LS-31 as dezintegriruetsja agent, was with 37.4 seconds, which is very large.

Example 7

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 0.5 g NS-300 and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 87 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of the NS-300 in the flat tablet was 5.2 wt.%.

Example 8

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 1.0 g NS-300 and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 92 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of the NS-300 in the flat tabla is ke amounted to 10.3 wt.%.

Experimental Example 3

The test for disintegration was performed for each of the six solid samples in Examples 7 and 8 using test method for disintegration in accordance with the Pharmacopoeia of Japan (liquid medium for the dough: water, without disk).

Table 3 shows the results of the test for disintegration of Examples 7 and 8.

Table 3

The disintegration time (Seconds Average+the standard Deviation
Example 7
(NS-300, 5,2%)
88,8+7,0
Example 7
(NS-300, 10,3%)
55,2+15,1

Table 3 shows the following :

In the solid preparations of Examples 7 and 8, using NS-300 as a disintegration agent, the values of their time disintegration was less than that for Comparative Example 1 (shown in Table 1), in the absence of any disintegration agents, and thus was obtained the desired disintegration properties.

Specifically, the value of the time disintegration in Example 8, which was used to 10.3 wt.% NS-300 in each tablet was significantly less than for the Comparative Examples 1-11. Thus, disintegration properties in Example 8 were excellent.

Note the R 9

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 0.1 g Primojel and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 84 mg, containing 15 mg the primary ingredient, receive the same spoba as in Example 1.

The content of Primojel in the flat tablet was 1.2 wt.%.

Example 10

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 0.5 g Primojel and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 87 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of Primojel in the flat tablet was 5.2 wt.%.

Example 11

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 1.0 g Primojel and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 92 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of Primojel in the flat tablet amounted to 10.3 wt.%.

Example 12

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 0.5 g PCS PC-10 and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 87 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

Contents PCS PC-10 in a flat tablet status is provided to 5.2 wt.%.

Example 13

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 1.0 g PCS PC-10 and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 92 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

Contents PCS PC-10 in a flat tablet amounted to 10.3 wt.%.

Experimental Example 4

The test for disintegration was performed for each of the six solid samples in Examples 9-13 using test method for disintegration in accordance with the Pharmacopoeia of Japan (liquid medium for the dough: water, without disk).

Table 4 shows the results of the test for disintegration for Examples 9-13.

/tr>
Table 4
The disintegration time (Seconds, Mean±standard Deviation
Example 9
(Primojel, 1,2%)
58,8±7,4
Example 10
(Primojel, 5,2%),
65,2±4,2
Example 11
(Primojel, 10,3%)
72,2±7,4
Example 12
(PCS PC-10, 5,2%)
87,2±5,3
Example 13
(PCS PC-10, 10,3%)
of 92.5±2,9

Table 4 shows the following :

In the solid preparations of Examples 9-11, using Primojel (sodium carboxymethyl amylum) as a disintegration agent, the values of their time disintegration was less than that for Comparative Example 1 in the absence of any disintegration agents, and thus was obtained the desired disintegration properties.

Specifically, the value of the time disintegration was significantly less in Example 9, which was used to 1.2 wt.% Primojel as a disintegration agent than for the Comparative Examples 1-11. Thus, disintegration properties in Example 9 were excellent.

In addition, in the solid preparations of Examples 12 and 13 using PCS PC-10 (partially pregelatinization starch as disintegrating agent, the values of their time disintegration was less than that for Comparative Example 1 in the absence of any disintegration agents, and thus was obtained the desired disintegration properties.

Example 14

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 0.1 g of Polyplasdone XL and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 84 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of Polyplasdone XL in a flat t is blade amounted to 1.2 wt.%.

Example 15

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 0.5 g of Polyplasdone XL and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 87 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of Polyplasdone XL in the flat tablet was 5.2 wt.%.

Example 16

Mix of 8.2 g granulated substance obtained in the above Referential Example 2, 1.0 g of Polyplasdone XL and 0.1 g of magnesium stearate. A flat tablet having a weight of approximately 92 mg, containing 15 mg the primary ingredient, receive the same manner as in Example 1.

The content of Polyplasdone XL in the flat tablet amounted to 10.3 wt.%.

Experimental Example 5

The test for disintegration was performed for each of the six solid samples in Examples 14-16 using test method for disintegration in accordance with the Pharmacopoeia of Japan (liquid medium for the dough: water, without disk).

Table 5 shows the results of the test for disintegration of Examples 14-16.

Table 4
The disintegration time (Seconds, Mean±standard Deviation
Example 14
(Polyplasdone XL, 1,2%)
Example 15
(Polyplasdone XL, 5,2%),
73,5±6,6
Example 16
(Polyplasdone XL, 10,3%)
53,8±3,4

Table 5 shows the following :

In the solid preparations of Examples 14-16, using Polyplasdone XL (crosspovidone) as a disintegration agent, the values of their time disintegration was less than that for Comparative Example 1 in the absence of any disintegration agents, and thus was obtained the desired disintegration properties.

Specifically, the value of the time disintegration was significantly less in Example 16, using solid preparation containing of 10.3 wt.% Polyplasdone XL. Thus, disintegration properties in Example 16 were excellent.

Example 17

Mixing 270 g of the amorphous powder obtained in Reference Example 1, and 50.5 g of lactose monohydrate, 60 g of corn starch and 60 g of crystalline cellulose and the mixture is placed in a vortex dryer granulation in the fluidized bed Multiplex MP-01 (Powrex Corporation). Granulation in the fluidized bed is carried out with 240 g of 5 m/% aqueous solution of hydroxypropylcellulose (HPC-HL; Nippon Soda Co. Ltd.), containing from 53 to 78 wt.% hydroxypropoxy group, with subsequent drying. Thus, granulating the substance to receive the same manner as the Reference Example 2. The obtained granulated substance is mixed with 27 g of LH-11, of 0.48 g of aluminum flakes FDC blue No. 2 and 6 g of magnesium stearate to obtain granules for tablets. From the obtained pellets get flat tablets with Rotating Teletrauma Machine 12HUK-AWC (production Kikusui Seisakusho Ltd.) at 40 rpm and when the pressing force of 900 kg. Each tablet was approximately 162 mg by weight, 8 mm in diameter and contains 60 mg the primary ingredient. The content of LH-11 in each tablet was 5.6 wt.%.

Example 18

Mix to 112.5 g of the amorphous powder obtained in Reference Example 1, 184,6 g of lactose monohydrate, 50 g of corn starch and 50 g of crystalline cellulose and the mixture is placed in a vortex dryer granulation in the fluidized bed Multiplex MP-01 (Powrex Corporation). Granulation in the fluidized bed is carried out with 200 g 5 m/% aqueous solution of hydroxypropylcellulose (HPC-HL; Nippon Soda Co. Ltd.), containing from 53 to 78 wt.% hydroxypropoxy group, with subsequent drying. Thus, granulating the substance to receive the same manner as in Reference Example 2. The obtained granulated substance is mixed with 22,5 g LH-11, 0,43 g of aluminum flakes FDC blue No. 2 and 5 g of magnesium stearate to obtain granules for tablets. From the obtained pellets get flat tablets with Rotating Teletrauma Machine 12HUK-AWC (production Kikusui Seisakusho td.) at 40 rpm and when the pressing force of 900 kg Each tablet was approximately 174 mg by weight, 8 mm in diameter and contains 30 mg the primary ingredient. The content of LH-11 in each pill was $ 5.2 wt.%.

Example 19

The granules obtained in Example 18, get a flat tablet with Rotating Teletrauma Machine 12HUK-AWC (production Kikusui Seisakusho Ltd.) at 40 rpm and when the pressing force of 900 kg. Each tablet was approximately 87 mg by weight, 6 mm in diameter and contains 15 mg the primary ingredient. The content of LH-11 in each pill was $ 5.2 wt.%.

Example 20

Mix 56,3 g of the amorphous powder obtained in Reference Example 1, 255,8 g of lactose monohydrate, 50 g of corn starch and 50 g of crystalline cellulose and the mixture is placed in a vortex dryer granulation in the fluidized bed Multiplex MP-01 (Powrex Corporation). Granulation in the fluidized bed is carried out with 200 g 5 m/% aqueous solution of hydroxypropylcellulose (HPC-HL; Nippon Soda Co. Ltd.), containing from 53 to 78 wt.% hydroxypropoxy group, with subsequent drying. Thus, granulating the substance to receive the same manner as in Reference Example 2. The obtained granulated substance is mixed with 22,5 g LH-11, 0.45 g of aluminum flakes FDC blue No. 2 and 5 g of magnesium stearate to obtain granules for tablets. From the obtained pellets get flat tablets with Rotating T is blethisa Machine 12HUK-AWC (production Kikusui Seisakusho Ltd.) at 50 rpm, and when the pressing force of 1000 kg Each tablet was approximately 180 mg by weight, 8 mm in diameter and contains 15 mg the primary ingredient. The content of LH-11 in each tablet was 5.0 wt.%.

Example 21

Mix 33,75 g of the amorphous powder obtained in Reference Example 1, 350,25 g of lactose monohydrate, 60 g of corn starch and 60 g of crystalline cellulose and the mixture is placed in a vortex dryer granulation in the fluidized bed Multiplex MP-01 (Powrex Corporation). Granulation in the fluidized bed is carried out with 240 g of 5 m/% aqueous solution of hydroxypropylcellulose (HPC-HL; Nippon Soda Co. Ltd.), containing from 53 to 78 wt.% hydroxypropoxy group, with subsequent drying. Thus, granulating the substance to receive the same manner as in Reference Example 2. The obtained granulated substance is mixed with 27 g of LH-11 and 6 g of magnesium stearate to obtain granules for tablets. From the obtained pellets get flat tablets with Rotating Teletrauma Machine 12HUK-AWC (production Kikusui Seisakusho Ltd.) at 50 rpm, and when the pressing force of 1000 kg Each tablet was approximately 183 mg by weight, 8 mm in diameter and contains 7.5 mg the primary ingredient. The content of LH-11 in each tablet was 4.9 wt.%.

INDUSTRIAL APPLICABILITY

The pharmaceutical solid preparation of the present invention contains (a) compound benzazepine, (b) the Hydra is xiphopenaeus, containing hydroxypropoxy group in the amount of 50 wt.% or more and disintegrity agent, which is either (1) hydroxypropylcellulose with a low degree of substitution, (2) carmellose, (C-3) carboximetilkrahmal sodium or (C-4) crosspovidone. Using this composition, the pharmaceutical solid preparation of the present invention provides superior disintegration properties and excellent solubility, which leads to sufficient absorbability of the active ingredient through the gastrointestinal tract. The pharmaceutical solid preparation of the present invention, therefore, can be applied in many fields of medicine. The method of obtaining the present invention provides a solid pharmaceutical preparation with such excellent features.

1. The pharmaceutical solid preparation of the antagonist of vasopressin containing:
(a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt;
(b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50% or more; and
(c) at least one component selected from the group comprising carmellose, carboximetilkrahmal sodium, crosspovidone and hydroxypropylcellulose with a low degree of substitution with an average particle diameter of from 30 to 70 μm and 90% cumulativ the th particle diameter of from 100 to 200 microns.

2. The pharmaceutical solid preparation of the antagonist of vasopressin containing:
(a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt;
(b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50% or more; and
(C-1) hydroxypropylcellulose with a low degree of substitution with an average particle diameter of from 30 to 70 μm and a 90% cumulative particle diameter of from 100 to 200 microns.

3. The pharmaceutical solid preparation according to claim 2, where hydroxypropylcellulose with a low degree of substitution has an average particle diameter of from 45 to 65 μm and a 90% cumulative particle diameter of 100 to 200 microns.

4. The pharmaceutical solid preparation according to claim 2, where the pharmaceutical solid preparation is presented in the form of tablets.

5. The pharmaceutical solid preparation according to claim 2, obtained by a method that includes:
stage 1 for amorphous composite of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine and/or its salts and hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50% or more;
stage 2 mixing of the amorphous compound obtained in stage 1 with hydroxypropylcellulose with a low degree of substitution with an average particle diameter of from 30 to 70 μm and a 90% cumulative particle diameter of from 100 to 200 μm and
one hundred is July 3 processing of the mixture, obtained in stage 2 in the solid product.

6. The pharmaceutical solid preparation according to claim 5, obtained by the method additionally includes between stage 1 and stage 2 stage processing of the amorphous compound obtained in stage 1 into pellets, using granulation.

7. The pharmaceutical solid preparation according to claim 5, obtained by the method additionally includes between stage 2 and stage 3 stage processing of the amorphous compound obtained in stage 1 into pellets, using granulation.

8. The method of obtaining the pharmaceutical solid preparation according to claim 2, the method includes:
stage 1 for amorphous composite of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine and/or its salts and hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50% or more;
stage 2 mixing of the amorphous compound obtained in stage 1 with hydroxypropylcellulose with a low degree of substitution with an average particle diameter of from 30 to 70 μm and a 90% cumulative particle diameter of from 100 to 200 μm and
stage 3 processing the mixture obtained in stage 2 in the solid product.

9. The method of claim 8, where the stage 3 is implemented by processing the mixture obtained in stage 2 in tablets.

10. The method according to claim 8 or 9, more is tion includes between stage 1 and stage 2 stage processing of amorphous composite, obtained in stage 1 into pellets, using granulation.

11. The method according to claim 8 or 9, further comprising between stage 2 and stage 3 stage processing the mixture obtained in stage 2 into pellets, using granulation.

12. The pharmaceutical solid preparation of the antagonist of vasopressin containing:
(a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine and/or its salt;
(b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50% or more; and
(C-2) carmellose.

13. The pharmaceutical solid preparation according to item 12, where the content carmellose is from 7 to 15 wt.% from the total amount of the pharmaceutical solid preparation.

14. The pharmaceutical solid preparation of the antagonist of vasopressin containing:
(a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine and/or its salt;
(b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50% or more; and
(C-3) carboximetilkrahmal sodium.

15. The pharmaceutical solid preparation according to 14, where the content of sodium carboxymethyl amylum is from 0.5 to 15 wt.% from the total amount of the pharmaceutical solid preparation.

16. The pharmaceutical solid preparation of the antagonist of vasopressin containing:
(a) -chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepin and/or its salt;
(b) hydroxypropylcellulose containing hydroxypropoxy group in the amount of 50% or more; and
(C-4) crosspovidone.

17. The pharmaceutical solid preparation according to item 16, where the concentration of crosspovidone is from 2 to 15 wt.% from the total amount of the pharmaceutical solid preparation.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

Diuretic // 2456002

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to experimental medicine, namely to pharmacology. The object in view is achieved by the fact that 0.5% humic acids additionally containing magnesium sulphate (II) are applied as a diuretic in the following proportions: 0.5% humic acids - 40 ml; magnesium sulphate - 0.1 g.

EFFECT: higher clinical effectiveness and eliminated side effects.

1 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to therapeutically active chemical compounds which influence uriniparous activity of kidney and specifically a peptide which causes selective increase in release of potassium ions by kidneys.

EFFECT: obtaining a compound for treating hyperkalaemia.

1 cl, 2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to biologically active peptides able to inhibit myosin light chain kinase and thereby regulate the variability of vascular endothelial permeability. What is offered is a cyclic nonapeptide of formula cyclo[-Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys-].

EFFECT: peptide can find application as a decongestant in various fields of medicine.

2 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to surgery and can be used for treatment of distal postmastectomy lymphedema. For this purpose at the background of standard treatment 6 procedures of retrograde lymphotropic introduction of drug mixture are carried out. Lymphotropic introduction is performed in the following way: in area of middle third of forearm applied is cuff, with creating in it pressure of 60 mm Hg, after which in two points on internal surface in area of wrist introduction of mixture of medications is performed. Composition of introduced mixture alternates every second day: 1, 3, 5 days - actovegin 80 mg, ketonal 1 ml, marcaine 0.5% 4 ml; 2, 4, 6 days - chymotrypsin 100 mg, marcaine 0.5% 4 ml.

EFFECT: method ensures efficient treatment of postmastectomy lymphedema due to enhancing of lymphatic drainage of distal parts of extremity.

3 tbl, 2 ex, 1 dwg

Diuretic // 2408367

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered the administration of the preparation Histochrome (echinochrome, 2,3,5,6,8-pentahydroxy-7-ethyl-1,4-nahthochine, formerly known as an antioxidant) as a diuretic.

EFFECT: histochrome exhibits an evident diuretic action equal thiazide-type diuretics in intensity, does not cause associated hypokaliemia, has an absolute advantage over thiazide-type diuretics.

2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to biologically active peptides, able to prevent sharp increase of permeability of vessel endothelium. Claimed is peptide of formula H-(N-Me)-Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys-NH2 and its pharmaceutically acceptable salts.

EFFECT: peptide can be applied as anti-edema medication in various fields of medicine.

1 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to peptides of general formula , and to their cosmetically or dermopharmaceutically acceptable salts, where: X is chosen from the group formed by cysteinyl, seryl, threonyl and aminobutyryl; R1 is chosen from the group formed by H or a saturated linear C2-C24 acyl group; R2 is chosen from the group formed by an amino group optionally substituted with C1-C24 alkyl, or a hydroxy group. Besides the invention covers a method for making said peptides, their cosmetic or dermopharmaceutical compositions intended for reducing or eliminating baggy lower eyelids.

EFFECT: higher effectiveness.

12 cl, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical compound to improve renal function that contains KW-3902 30 mg or its pharmaceutically acceptable salt, ester, amide, and furosemide. Also there are disclosed method to induce diuretic effect, method to improve renal function, method to support renal function and method to recover renal function in a patient.

EFFECT: effective recovery of renal function in patients with congestive heart failure.

13 cl, 2 tbl, 7 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel chemical composition from group quaternary ammonium salts of succinic acid, namely, 1-deoxy-1-N-methyl ammonium-D-glucitole succinate (meglumine succinate) .

EFFECT: obtaining chemical composition which acquires ability to impact on complex of pathological changes accompanying sugar diabetes.

4 cl, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition by invention possesses antagonistic activity with respect to angiotensin II. Pharmaceutical composition contains 30-80 wt % of inrbesartan or its pharmaceutically acceptable salt as active ingredient and more than 10 wt % of loosening agent in terms of complete composition weight. Pharmaceutical composition does not contain silicon-containing antiadhesive. Pharmaceutical composition of irbesartan is made in form of tablet with film coating. Also described is method of irbesartan tablet manufacturing.

EFFECT: irbesartan tablet possesses dissolution profile at which 80 wt % or more of irbesartan dissolve not later than after 30 min.

25 cl, 1 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, and concerns a method for preparing a dosage form of alkali or alkali-earth perindopril salts in the amorphous form wherein perindopril in the form of a free acid is dissolved in alcohol, neutralised by an aqueous solution of an alkali or alkali-earth base; thereafter this solution is sprayed over inert substances for preparing a granulate and dried in a warm air flow at 30-50°C or in vacuum. Before tableting, the granulate is added with substances for improving tableting or additive active substances, such as diurectics, preferentially indapamide.

EFFECT: developing the method for preparing the dosage form of the alkali or alkali-earth perindopril salts in the amorphous form.

7 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely applying a composition of glycine and phenazepam, in psychoneurology, and having therapeutic action on physiological and functional activity of the nervous system in various borderline and pathological conditions of the nervous activity while being safe for application. The combinations in the oral dispersible form having therapeutic action on activating and inhibitory functions of the nervous system contain bromdihydrochlorphenylbenzodiazepine, glycine (aminoacetic acid) and pyridoxine, as well as acceptable excipients.

EFFECT: combinations provide the fast onset of the therapeutic effect and reduced and/or relieved side effects, particularly CNS depression.

7 cl, 4 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and deals with hard pharmaceutical composition, which includes escitalopram or its pharmaceutically acceptable salt and/or solvate.

EFFECT: invention ensures absence of disadvantages as to fluidity and technical characteristics.

12 cl, 8 ex, 1 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a stable pharmaceutical composition for treating cancer containing a water-soluble salt of vinflunine ditartrate and at least one diluent, one binding substance, one aerating agent and one lubricating agent wherein the composition is presented in a solid form for oral application wherein: the content of the water-soluble salt of vinflunine ditartrate makes 5 to 80 wt %, the content of the diluent makes 20 to 80 wt % of total weight of the composition, the content of the binding substance makes 1 to 10 wt % of total weight of the composition, the content of the lubricating agent makes 0.5 to 10 wt % of total weight of the composition, the content of the aerating agent makes 1 to 10 wt % of total weight of the composition.

EFFECT: invention provides storage stability at 5°C for 24 months in a sealed package.

19 cl, 8 ex

FIELD: medicine.

SUBSTANCE: what is described is a method of the one-step introduction of single-dose ibuprofen. The method consists in providing a mammal with an initial dose of 200 mg to 400 mg of immediate release ibuprofen and a second dose of 100 mg to 200 mg of prolonged release ibuprofen. Said prolonged release second dose is delivered for approximately 2 to 10 hours following the immediate release immediate dose. The immediate release immediate dose and the prolonged release second dose ensures pain relief for a 12-hour period.

EFFECT: method for the ibuprofen administration according to the invention provides a higher therapeutic effect as compared to the common dosing regimens.

5 cl, 4 dwg, 6 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a solid dispersion wherein revaprazan particles are surface-modified by a water-soluble polymer, a water-soluble saccharide, a surfactant or their mixture wherein the water-soluble polymer is specified in a group consisting of polyvinylpyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, a water-soluble polyacrylic acid copolymer, polyvinyl alcohol or their mixture, and wherein the water-soluble saccharide is specified in a group consisting of lactose, white sugar, saccharose, mannitol, sorbitol, xylitol, trehalose, maltitol, dulcitol, inositol, dextrin, cyclodextrin and their mixture. The invention also refers to a method for preparing said solid dispersion. The present invention also presents a pharmaceutical composition containing the solid dispersion, and the method for producing the pharmaceutical composition.

EFFECT: invention provides improved solubility of revaprazan and reduced adhesion and agglutination properties.

16 cl, 4 dwg, 7 tbl, 55 ex

FIELD: food industry.

SUBSTANCE: present invention relates to food additives composition. The composition of a poly-vitamin and mineral food additive includes at least one polyvalent metal, at least one oxidable vitamin and waterless dicalcium phosphate; weakly-coupled water is essentially absent from the said composition. One proposes a method for production of the said composition as well as methods for reduction of spots occurrence (caused by oxidation) on the poly-vitamin and mineral pill and stabilisation of decomposition characteristics of pills containing the said composition. Alternatively, one proposes the composition of a poly-vitamin and mineral additive containing the daily dose of at least one vitamin chosen from the group including 15 - 600 mg of vitamin C, 20 - 200 ME of vitamin E, at least one ion of polyvalent metal, chosen from the group including 0 - 400 mg of magnesium, 0 - 50 mg of zinc, 0 -12 mg of manganese, 0 - 4 mg of cuprum, 0 -300 mkg of chrome, 0 - 18 mg of ferrum and 100 - 1500 mg of calcium. In the said additive at least a part of calcium is in the form of waterless dicalcium phosphate; the additive essentially is free of weakly-coupled water.

EFFECT: invention allows to reduce the process of decomposition of vitamin and mineral additives and enhance their stability.

29 cl, 4 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: declared invention refers to an agent for treating ulcer including as an effective ingredient composite hydrotalcite in the form of particles, which contains zinc in the form of a solid solution and presented by formula (MgaZnb)1-xAlx(OH)2(An-1)x/n·H2O, wherein An-1 means CO32-, SO42- or Cl-, n is equal to 1 or 2, and x, a, b and m have the values fulfils the following conditions 0.18≤x≤0.4, 0.1≤a≤1, 0≤b≤0,5, 0≤m<1. Said agent may be presented in the granular or fine-grained form, suspension form or tableted form. The invention also refers to a method of treating peptic ulcer by the oral introduction of an effective amount of said hydrotalcite.

EFFECT: declared invention has an effective effect in treating peptic ulcer in an individual or a mammal, nor damaging a mucous membrane of internal walls of stomach, and possesses low probability of side effects.

17 cl, 6 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared invention refers to chemical-pharmaceutical industry, and concerns orally disintegrating nicotine compositions containing lower levels of buffer agents in comparison with conventional orally disintegrating nicotine tablets. The composition of an orally disintegrating tablet contains a) a basic granular ingredient containing: at least one alkaline buffer agent; at least one dissolution modifier; and at least one excipient; the active substance nicotine; and c) at least one alkaline buffer agent.

EFFECT: compositions provide optimum oral pH and induce nicotine absorption in a smaller more convenient dosage form.

18 cl, 5 ex, 3 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to solid pharmaceutical preparation of matrix type, which contains: (a) enterosoluble polymer based on methacrylic acid; and (b) sugar and/or sugar-alcohol, in which 1 g of sugar and/or sugar-alcohol can be dissolved in not more than 4 g of water at water temperature from 20 to 25°C. Pharmaceutical preparation does not contain softener. Pharmaceutical medicine is produced by extrusion method. Application of sugar and/or sugar-alcohol with specified properties ensures acceptable plasticity of mixture with high content of enterosoluble polymer based on methacrylic acid without addition of softener.

EFFECT: preparation by invention has satisfactory controllability of medicine release, suppressing release in upper part of gastrointestinal tract and insuring immediate release in lower part of gastrointestinal tract.

7 cl, 4 dwg, 31 tbl, 26 ex

Up!