Form of prolonged venlafaxine hydrochloride liberation

FIELD: medicine; pharmacology.

SUBSTANCE: minitablets have a kernel and an external cover which makes 2-15% of gross weight of minitablets, the kernel of the specified minitablets, includes a venlafaxine hydrochloride, microcrystallic cellulose and a polyvinylpyrolidone, and the specified cover includes polymer, insoluble in water, and a polymer, soluble in water.

EFFECT: provision of levels of concentration in a blood plasma above the minimum therapeutic concentration during the long period of time.

10 cl, 1 dwg, 1 tbl, 5 ex

 

The scope of the invention

This invention relates to pharmaceutical compositions prolonged release form, including hard gelatin capsule containing a therapeutically effective amount of mini-tablets, each mini-tablet contains venlafaxine hydrochloride, microcrystalline cellulose, binder and optional conventional excipients.

Background and prior art

The use of hydrophobic polymers to obtain pharmaceutical compositions prolonged or controlled release known in this field. For prolonging the release solid dosage form of mini-tablets comprises a drug coated with a hydrophobic polymer and a porous forming agent. Once the solid dosage form comes into contact with the environment, the formed pores and drug diffusive through these pores. Regulation of the speed of release therapy helps, producing constant levels of the active ingredient in the blood plasma and reducing the frequency of administration, thus, promotes patient compliance with the dosage regimen. This invention provides a pharmaceutical composition capsule extended release, which contains a mini-tablets of venlafaxine hydrochloride, when mlemos for a single daily administration entities.

The invention relates to a pharmaceutical form prolonged release for a single daily administration, in particular to the pharmaceutical form of the controlled release of venlafaxine hydrochloride.

In the prior art there are several delivery systems drug extended release, adapted for delivery of venlafaxine hydrochloride.

U.S. patent No. 4535186 describes the class of hydroxycyclophosphamide, which are used as antidepressants, and represents the connection, currently known as venlafaxine hydrochloride, as one of the acceptable types.

Chemical name venlafaxine - (R/S)-1-[2-(dimethylamine)-1-(4-methoxyphenyl)ethyl]cyclohexanol. Currently hydrochloride venlafaxine introduces adults as conventional immediate-release tablets or capsules release multicystic within 24 hours. Hydrochloride venlafaxine is approved for sale in various countries, including the United States of America, under the registered brand name EFFEXOR.RTM. (Wyeth Ayerst). It is available as a traditional tablet immediate release and as capsule extended release under the registered brand name EFFEXOR.RTM. (Wyeth Ayerst) and EFFEXOR XRRTM. (Wyeth Ayerst), respectively.

Hydrochloride is venlafaxine it is soluble in water. It is known that it is very difficult to develop a pharmaceutical form with a very small rate of dissolution of readily soluble drugs.

U.S. patent No. 6274171 and related European patent 0797991 reveal a capsulated form extended release of venlafaxine hydrochloride. Describes daily disposable encapsulated dosage form extended release, which aligns the content of the drug in the plasma and reduces adverse side effects. Encapsulated dosage form involves the incorporation of spherical particles of venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropylmethylcellulose (receiver array). These spherical particles coated with a mixture of ethyl cellulose and a receiver array. The desired profile of blood plasma can be obtained through the appropriate number of the shell.

U.S. patent No. 6274171 and European patent 0797991 also claim that the formation of the dosage form extended release of venlafaxine hydrochloride was complicated, in particular, the high water solubility of the hydrochloride salt. In fact, these patents show that "many attempts to obtain slow release tablets using technology hydrogel proved to be fruitless because of pressovanne the e tablets were or physically unstable (low spressovannost or problems with the floor), or dissolve too quickly in the study of dissolution". Unlike capsulated form prolonged release are described in these patents, hydrogel tablet extended release of venlafaxine hydrochloride corresponds to the typical representation of the dissolution profile, where 40-50% are released within 2 hours, 60-70% are released within 4 hours and 85-100% is released within 8 hours.

WO 99/22724 also discloses encapsulated dosage form extended release of venlafaxine hydrochloride. These forms are different from those stated in U.S. patent No. 6274171 and European patent 0797991, in which a spherical particle is not generally includes a receiver array.

Although there was obtained a capsule extended release venlafaxine, be advantageous to develop a less complex dosage form, which, however, provides extended release of venlafaxine.

WO 94/27589 and WO 01/37815 describe osmotic dosage forms containing venlafaxine hydrochloride.

U.S. patent 20030190354 reveals the prolonged release composition comprising as active compound venlafaxine hydrochloride in dosage form matrix tablets, in which the venlafaxine hydrochloride is mixed with a combination of hydrophilic and hydrophobic components forming the matrix. Matrix components are acceptable to the minciu of high and low viscosity hydroxypropylmethylcellulose, ethyl cellulose, glyceryl of behenate and methylcellulose. For the manufacture of tablets used two granulation: the first was the standard method with a single step granulation, in which all the fillers were mixed together with active, then grained wet with Kollidon SR, dried, crushed and extruded into pellets oval shape with a groove. The second method of granulation took place in two stages, the first is wet granulation of the active material, which was mixed with hydrophobic components selected from Ethocel or Compritol. Later milled granulate was mixed with hydrophilic components, methylcellulose and lubricating components, syloid 244 and magnesium stearate.

WO 03/55475 offers the concept of controlled release form of venlafaxine. Pharmaceutical form of the present invention includes, for example, the core containing the active drug, which may be useful in amorphous form, polyvinylpyrrolidone, a combination of two hydrophilic polymers having different viscosity, and optionally other traditionally used ingredients for solid dosage forms. The core is covered with a polymer shell comprising a combination of two polymers having different permeability. Optional can be added plasticizer and other traditionally used ingredients for film pokr is ment. The combination of media, i.e. water-soluble polymer polyvinylpyrrolidone and low-viscosity hydrophilic polymer, has a double effect and advantage, which stabilizes the amorphous form of the active ingredient and simultaneously modifies the release of an amorphous active ingredient in such a way that it is long lasting, repeatable and independent of the amorphous or polymorphic forms of the active ingredient, the size of its particles and the specific surface area.

WO 03/53402 and related U.S. patent 2004133982 reveal dosage forms continuous release of zero order. Solid dosage form comprising a matrix core containing vnutrikoronarnogo ethylcellulose and water-soluble active agent, was granulated and extruded together with extraglandular ethylcellulose and film coating comprising hydrophobic polymer, where the film coating completely covers the matrix core. This invention also concerns a method for obtaining tablets of continuous release zero order containing water-soluble active agent, including the steps: (a) preparing a first mixture comprising the active agent and vnutrikoronarnogo ethylcellulose; (b) granulating the first mixture to obtain a granulated product; (C) preparing a second mixture comprising extraglandular the th ethylcellulose; (d) preparing a third mixture comprising a granulated product and the second mixture.

WO 04/12699 and related U.S. patent 20040096501 offer dual time-lapse technology to effectively control the speed of the modified release of the released active ingredient, using a small number of agents that control the release. Thus, this dual delayed technology significantly reduces the size of the dosage form that is convenient for swallowing. Dosage form includes: a) micrometric particles containing highly soluble active ingredient and one or more hydrophobic agents that control the release, (b) coating micrometric particles of one or more hydrophobic agents that control the release.

The drug prolonged release of drugs it is convenient to use because of their reduced frequency of dosing. The frequency can be reduced by maintaining a constant concentration of the drug in plasma for a long period, to ensure the long-term effect of the active ingredient.

The purpose of the invention

The purpose of this invention is to provide sustained release of active ingredient from the pharmaceutical composition in which the concentration in plasma is Rove above the minimum therapeutic concentration for a long period of time.

Another purpose of this invention is to provide prolonged release pharmaceutical composition for single daily dosage form.

Another purpose of this invention is the provision of a pharmaceutical composition sustained release, which releases the active ingredient in the required form.

The next objective of this invention is the creation of forms in the traditional way, in order to reduce processing time.

Another purpose of this invention is to develop forms of extended release of venlafaxine hydrochloride, which is bioequivalent to Effexor XR, in the traditional way, including extrusion and coating.

Brief description of the invention

This invention relates to a pharmaceutical form prolonged release, including venlafaxine hydrochloride, thinner, water-soluble component and a water-insoluble polymer, and other pharmaceutically acceptable excipients.

Components are selected in such a way to get a prolonged release of venlafaxine hydrochloride in the required form.

The invention relates to compositions prolonged release in the form of mini-tablets, which are included in hard gelatin capsules containing a therapeutically EF the objective number of mini-tablets, contains venlafaxine hydrochloride, microcrystalline cellulose, polyvinylpyrrolidone, and optional conventional excipients, in addition, the coating of mini-tablets, including ethylcellulose and plasdone S-630 copolyvidone (ISP international standardized profile) technology). Tablets of this invention show profiles dissolution, especially with venlafaxine HCl.

Preferably, the invention concerns the form prolonged release which includes from about 40% to about 80% by weight of venlafaxine hydrochloride; from about 25% to about 45% microcrystalline cellulose and from about 0.5% to about 10% of polyvinylpyrolidone total weight of the composition. Coated mini-tablet comprises from about 2 to 15% of the total weight of the composition. The coating composition includes from about 50% to about 95% ethyl cellulose and from about 3% to about 50% plasdone S-630 copolyvidone (ISP technologies) total weight of the coating layer.

More preferably, the invention concerns the form prolonged release which includes from about 48% to about 68% by weight of venlafaxine hydrochloride; from about 26% to about 38% of microcrystalline cellulose and from about 2% to approx the positive 9% polyvinylpyrrolidone total weight of the composition. Coated mini-tablet comprises from about 4 to 14% of the total weight of the composition. Coated mini-tablet comprises from about 65% to about 95% ethyl cellulose and from about 5% to about 40% plasdone S-630 copolyvidone total weight of the coating layer.

Even more preferably, the invention concerns the form prolonged release which includes from about 57% to about 62% by weight of venlafaxine hydrochloride; from about 27% to about 32% of microcrystalline cellulose and from about 2.5% to about 5.5% of polyvinylpyrrolidone total weight of the composition. Coated mini-tablet comprises from about 6 to 12% of the total weight of the composition. Coated mini-tablet comprises from about 70% to about 80% ethyl cellulose and from about 20% to about 30% plasdone S-630 copolyvidone total weight of the coating layer.

Form prolonged release according to this invention is produced by extrusion, followed by the functional method of covering, the said method comprises the following stages:

i. mixing venlafaxine hydrochloride and diluent;

ii. granulating the mixed mixture in an aqueous or nonaqueous solution of a binder, and drying it;

iii. lubricating the dried granules and pressed into pellets with testwuide form (3-6 mm in diameter);

iv. coating of tablets in water or non-aqueous dispersion of water-insoluble and water-soluble polymer;

v. filling capsules of appropriate size coated mini-tablets obtained in step (IV).

Pharmaceutically acceptable capsule was filled with 12, 6, 3 mini-tablets to get the content of venlafaxine 150 mg, 75 mg and 37.5 mg, respectively.

A detailed description of the invention

In the embodiment of the present invention hard gelatin capsule contains film-coated mini-tablets. These mini tablets contain the active ingredient, a binder component and a component that is soluble in water, and optional conventional excipients. These mini-tablets were coated with a combination of water-soluble and water-insoluble polymer.

The pharmaceutical composition according to this invention contains venlafaxine hydrochloride as the active ingredient. Venlafaxine hydrochloride can be present in an amount from about 40% to about 80%, preferably from about 48% to about 68% by weight, more preferably from about 57% to about 62% of the total weight of the composition sustained release.

In addition, venlafaxine hydrochloride can be present in an amount of from 12.5 to 400 mg per capsule.

Version of this image is the shadow of a mini-tablet contains microcrystalline cellulose as a diluent. Microcrystalline cellulose may be present in an amount from about 25% to about 45%, preferably from about 26% to about 38% by weight, more preferably from about 27% to about 32% of the total weight of the composition sustained release.

According to the variant of implementation of the present invention, a mini-tablet contains polyvinylpyrrolidone as a binder component. The polyvinylpyrrolidone may be present in an amount from about 0.5% to about 10%, preferably from about 2% to about 9% by weight, more preferably from about 2.5% to about 5.5% of the total weight of the composition sustained release.

In addition to the above ingredients mini-tablet contains magnesium stearate/stearic acid pharmaceutical grade as a substance promoting sliding, talc as a parting agent and colloidal silicon dioxide as a lubricant. Preferably magnesium stearate/stearic acid, talc and colloidal silicon dioxide are present in quantities of from 1 to 6% by weight, separately or in combination.

According to a variant implementation of the invention, the coated mini-tablets comprises water-insoluble polymer and a water-soluble polymer. Water-insoluble polymer is chosen from the group consisting of a simple cellulose ether, such as ethylcellulose, complex ester of cellulose such as cellulose acetate, methacrylic derivatives, supplied by Rohm Pharma under the trade name "Eudragit.RTM." RL, RS and NE, etc. In a preferred embodiment, water-insoluble polymer - ethylcellulose is present in amount from about 50% to about 95% by weight of the functional content of the coating composition sustained release.

According to a variant implementation of the invention, the floor of the mini-pill also contains a water-soluble polymer. Water-soluble polymer selected from the group comprising Plasdone S-630 copolyvidone (ISP technologies), gidratirovannuyu colloidal silica, sucrose, mannitol, or any other substance capable of fulfilling the same role. In a preferred embodiment, the water-soluble polymer is Plasdone S-630 copolyvidone (ISP technologies), which is present in amount from about 3% to about 50% by weight of the functional content of the coating composition sustained release.

Ethylcellulose, ethyl ester of cellulose is a long chain polymer b-anhydroglucose units connected together acetaline links. It is without taste, loose, white - light brown powder. Is the battle sustainable, slightly hygroscopic material. It is practically insoluble in glycerin, propylene glycol and water. Ethylcellulose, which contains less than 46.5% of ethoxyline groups, easily soluble in chloroform, methyl acetate and tetrahydrofuran and mixtures of aromatic hydrocarbons with ethyl alcohol (95%). Ethylcellulose, which contains not less than 46.5% of ethoxyline groups, easily soluble in chloroform, ethanol (95%), ethyl acetate, methanol and toluene. They are chemically resistant to alkalis, both diluted and concentrated salt solutions, although they are more sensitive to acid than esters of cellulose. The ethyl cellulose polymers exhibit good stability within the range of pH 3-11, so that they can be used with both acidic and alkaline ingredients.

The viscosity of the ethyl cellulose is measured typically at 25°C using 5% of ethyl cellulose solution in a solvent mixture of 80% toluene and 20% ethanol (V/V). Various grades of ethyl cellulose - ethylcellulose standard 4 premium, ethylcellulose standard 7 FP premium, ethylcellulose standard 7 premium, ethylcellulose standard 10 FP premium, ethylcellulose standard 10 R premium, ethylcellulose standard 20-R premium, ethylcellulose standard 45 R premium, ethylcellulose standard 100 FP premium, ethylcellulose 100 R - have a viscosity in the range of the e 3-5,5 SP, 6-8 SP, 9-11 JV, 18-22 JV, 41-49 SP, 90 -110 JV, respectively. The viscosity of the ethyl cellulose solution increases with increasing concentration of ethyl cellulose. The viscosity of such solutions is almost entirely dependent on alcohol content and is not dependent on toluene. Also available non-pharmaceutical brands ethyl cellulose, which differ in content ethoxyline groups and the degree of polymerization. Ethylcellulose obtained by treating purified cellulose with an alkaline solution followed by transfer of alkali cellulose with chlorethane.

Plasdone S-630 copolyvidone (ISP technologies) is a synthetic water-soluble copolymer consisting of N-vinyl-2-pyrrolidone and vinyl acetate in a random ratio of 60:40. Plasdone S-630 copolyvidonum has a low hygroscopicity. When RH (relative humidity) 50 wt% Plasdone S-630 copolyvidone increases less than 10% and easily gives the resulting moisture. He is the filler of choice for moisture sensitive drugs.

The value of K for Plasdone S-630 copolyvidone is 25.4-34,2. Is To rely on kinematic viscosity of 1% aqueous solution and, therefore, associated with an average molecular weight of the polymer.

Plasdone S-630 copolyvidone is a highly effective film forming adhesive. It is used primarily as a binder component of the tablet, although unique properties make it climbed the output in the form and coverage of a number of pharmaceutical dosage forms.

Plasdone S-630 copolyvidone soluble in many solvents and can be used in non-aqueous granulation or coating. It comes as a granular, spray dried powder, to ensure maximum efficacy of the treatment. The spray drying gives spherical particles with well-controlled particle size distribution. The morphology of the particles responsible for the excellent powder flow properties, which contribute to mixing with other fillers.

According to the method of manufacturing the compositions of this invention venlafaxine hydrochloride was mixed with microcrystalline cellulose and granulated using a solution of a binder. These granules are then compressed into mini-tablets. Received mini-tablets are then coated polymer sustained release.

According to a variant implementation of the invention, the functional coating is prepared by dissolving ethyl cellulose and plasdone S-630 copolyvidone in a solvent such as ethyl alcohol. The resulting solution is sprayed on the core mini-tablets using covering the cell or perforated turbine or a fluidized bed apparatus.

According to the variant of implementation of the present invention the weight ratio of the functional coating/tablet is, for example, from 0.02 to 0.15, preferably from 0.04 to 0.14, bol is e preferably from 0.06 to 0.12.

The size of the mini-pill is in the range of 3-6 mm in diameter.

Preferably venlafaxine hydrochloride and thinner sieved through a screen with an acceptable number, sifted mass is mixed using a mixer with a high shear mixed mass was granulated with an aqueous or non-aqueous solution of a binder, granulated mass was dried until the moisture has not reached less than 4% V/V, and the dried mass pass through a screen with an acceptable number, these granules were lubricated with lubricants, chemicals, promoting sliding, antiadhesive. The lubricated granules were compressed into mini-tablets of appropriate size (3-6 mm in diameter). Next mini-tablets were covered with a coating of water-soluble and water-insoluble polymer. These film-coated mini-tablets were filled in hard gelatin capsule.

The invention is illustrated by the following examples.

Examples

General procedure for preparation of prolonged release capsules, containing mini-tablets

Venlafaxine hydrochloride and microcrystalline cellulose were sifted through a screen with an acceptable number, sifted mass is mixed in a mixer with high shear, and the mixed mass was granulated with an aqueous solution of polyvinylpyrrolidone, granulated mass was dried until the content of the logs is less than 4% V/V, the dried mass is missed through the screen with an acceptable number, and these granules were lubricated with magnesium stearate, colloidal silicon dioxide and talc, and the lubricated granules were compressed into mini-tablets.

These mini-tablets were coated with an aqueous or non-aqueous dispersion of functional coatings water-soluble and water-insoluble polymer. The diameter of the film-coated mini-tablets is in the range of 3-6 mm, Then these mini tablets filled in hard gelatin capsule.

Pharmaceutically acceptable capsule was filled with 12, 6, 3 mini-tablets to get the content of venlafaxine hydrochloride 150 mg, 75 mg and 37.5 mg, respectively.

Method of dissolution

In all examples, the capsule containing tablets were tested for dissolution of venlafaxine hydrochloride in 900 ml of water as the solvent medium, at 37°and in the sieve with 40 holes per inch (USP (U.S. Pharmacopoeia) type 1), rotating at 100 rpm

In the following examples, the composition and the dissolution profiles are shown in tabular form.

Example 1

Composition

IngredientWeight (mg/tablet)
Venlafaxine HCl14,27
Microcrystalline cellulose7,13
Povidone1,10
Adilov the y alcohol D.K. (enough)
Talc0,25
Colloidal silicon dioxide0,25
Magnesium stearate0,50
Ethylcellulose1,22
Copolyvidone0,37
EthanolD.K.
Total weight25,09

The dissolution profile

Time (hours)The percentage of released venlafaxine HCl
10
213
438
862
1275
2492

EXAMPLE 2

Composition

IngredientWeight (mg/tablet)
Venlafaxine HCl14,27
Microcrystalline cellulose7,13
Povidone1,10
Purified waterD.K.
Talc0,25
Colloidal silicon dioxide0,25
Magnesium stearate0,50
Ethylcellulose1,59
Copolyvidone0,48
EthanolD.K.
Total weight25,57

The dissolution profile

Time (hours)The percentage of released venlafaxine HCl
10,2
27,7
423,2
846,2
1260
2481,9

EXAMPLE 3

Composition

IngredientWeight (mg/tablet)
Venlafaxine HCl14,27
Microcrystalline cellulose7,13
Povidone1,10
Purified waterD.K.
Talc0,25
Colloidal silicon dioxide0,25
Magnesium stearate0,50
Ethylcellulose1,08
Copolyvidone0,32
EthanolD.K.
Total weight24,9

The dissolution profile

Time (hours)About the UNT released venlafaxine HCl
16,2
222,7
448,8
877,5
1292,2
24102,7

EXAMPLE 4

Composition

IngredientWeight (mg/tablet)
Venlafaxine HCl14,27
Microcrystalline cellulose7,13
Povidone1,10
Purified waterD.K.
Talc0,25
Colloidal silicon dioxide0,25
Magnesium stearate0,50
Euredit RS 30D3,15
Talc0,16
Triethylcitrate0,19
Clean waterD.K.
Total weight27,00

The dissolution profile

Time (hours)The percentage of released venlafaxine HCl
18
29
412
885
12104
24 ---

In addition, when the composition of this invention was extrudible, led in the form of spherical particles and dried for forming spherical particles instead of mini-tablets, as provided by this invention, the dissolution profile was higher, which is not suitable for single daily injection, as shown in the following example.

EXAMPLE 5

Composition:

No.IngredientQuantity/Capsule (150 mg)
CORE
1Venlafaxine HCl171,24
2Microcrystalline cellulose85,56
3Povidone13,20
4WaterD.K.
The SHELL270,00
8Ethylcellulose19,500
9Copolyvidone5,86
10EthanolD.K.
TOTAL WEIGHT295,36

Uniformly mixed mixture of venlafaxine hydrochloride (171,24 g) and microcrystalline cellulose (85,56 g) was granulated to a wet paste with a solution surface is don (13,2 g) in water. The plastic mass was extrudible, led in the form of spherical particles and dried to obtain unpainted spherical particles. Cylindrical extrude compositions were very sticky and fragile with variable length of extruded cylinders, which were transformed into spheroids different forms within spheronization. Extruder shaped spheroid particles. Formed spherical particles have different shapes and overly sticky by nature that led to the formation of aggregates. Aggregates were removed by sieving after drying of spherical particles. Then spherical particles coated in the coating, fluidized bed booster type solution of 19.5 g of ethyl cellulose and 5,86 g copolyvidone in ethyl alcohol. The fragile nature of spherical particles led to the formation of a large number of small particles on the floor. We observed formation of related aggregates multiple particles at the time of covering. Film-coated spherical particles were sieved to remove these units, and then they filled in a pharmaceutically acceptable capsule.

Study of in vitro dissolution of the drug was carried out on the formed spherical particles using USP I at 37°C and 100 rpm in 900 ml of water. The release of drug was as follows:

Time (hours)
The percentage of released venlafaxine HCl
121
284
499

The dissolution profile shows that the prepared spherical particles of the compositions of this invention have a more rapid release characteristics of the medicinal product, unacceptable for a single daily injection. Thus, the invention is feasible only for mini-tablets with diameter greater than 3 mm and not for spherical particles with a diameter of less than 2 mm.

Biopharmaceuticals

Randomized, double-treatment, two period, two sequence, single dose crossover study potential capsules Venlafaxine 150 mg slow release (Example 1) compared with the capsule Venlafaxine hydrochloride 50 mg extended release (Effexor XR™)issued by Wyeth Ayerst laboratories, USA, was carried out on 12 healthy adult males under conditions of starvation. The average concentration of drug in plasma is shown on the drawing, and the pharmacokinetic parameters are shown in the table.

SourceThe Metabo is it
UnitExample 1Effexor XRExample 1Effexor XR
Cmaxng/ml101,28106,183162,33166,025
TMhourto 7.678,500at 11.2512,17
AUC(0->t)ng hour/ml1560,621669,104119,863949,95
AUC(0->inf)ng hour/ml1635,481823,6164740,364494,14

1. Form extended release of venlafaxine hydrochloride in the form of mini-tablets, which are filled hard gelatin capsule, with these mini tablets have the core and outer shell, which is 2-15% of the total weight of mini-tablets, the core of these mini-tablets contains venlafaxine hydrochloride, microcrystalline cellulose and polyvinylpyrrolidone, and the said sheath comprises a polymer that is insoluble in water, and the polymer soluble in water.

2. Form extended release of venlafaxine hydrochloride according to claim 1, comprising 40-80% venlafaxine hydrochloride by weight of each mini-tablet, 25-45% of microcrystalline cellulose by weight of each mini-tablet, 0.5 to 10% polyvinylpyrrolidone by weight of each of the th mini-pill these mini-coated tablets comprising 2-15% of the total weight of mini-tablets, where the shell comprises 50-95% of the polymer, insoluble in water, and 3-50% of the polymer soluble in water.

3. Form extended release of venlafaxine hydrochloride according to claim 2, comprising about 48-68% venlafaxine hydrochloride by weight of each mini-tablet, approximately 26-38% of microcrystalline cellulose by weight of each mini-tablet and approximately 2-9% of polyvinylpyrrolidone by weight of each mini-tablets; these mini-coated tablets, including 5-14% of the total weight of mini-tablets, where the shell includes 65-95% of the polymer, insoluble in water, and 5-40% of a polymer, soluble in water.

4. Form extended release of venlafaxine hydrochloride according to claim 3, comprising about 57-62% venlafaxine hydrochloride by weight of each mini-tablet, approximately 27-32% of microcrystalline cellulose by weight of each mini-tablet and approximately 2.5 to 5.5% of polyvinylpyrrolidone by weight of each mini-tablets; these mini-coated tablets, containing 6-12% of the total weight of mini-tablets, where the shell comprises 70-80% of the polymer, insoluble in water, and 20-30% of the polymer soluble in water.

5. Form extended release of venlafaxine hydrochloride according to any one of the previous pun is tov, where used, the polymer is insoluble in water, selected from ethyl cellulose and Eudragit.

6. Form extended release of venlafaxine hydrochloride according to claim 5, where the used polymer, insoluble in water, is ethylcellulose.

7. Form extended release of venlafaxine hydrochloride according to claim 1, where the used water-soluble component is copolyvidone.

8. Form extended release of venlafaxine hydrochloride according to claim 1, where the diameter of the mini-pill is 3-6 mm

9. Form extended release of venlafaxine hydrochloride according to claim 1, which is injected once a day.

10. The method of obtaining the form prolonged release according to claim 1, in which:

(i) mix hydrochloride venlafaxine and thinner,

(ii) granularit mixed mixture in an aqueous or nonaqueous solution of a binder and dried her,

(iii) grease dried granules and compressed into tablets,

(iv) cover tablet aqueous or non-aqueous dispersion of water-insoluble and water-soluble component,

(v) fill capsules coated mini-tablets that get on stage (iv).

Priority items:

04.02.2004 of claim 10;

13.09.2004 according to claims 1-9.



 

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54 cl, 7 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with the general formula (I) in the racemic, enantiomeric form or in any combination of these forms and in which: A represents -CH2-, -C(O)-, -C(O)-C(Ra)(Rb)-; X represents -CH-; Ra and Rb independently represent the hydrogen atom or a radical (C1-C6)alkyl; Rj represents the atom of hydrogen; a radical (C1-C8)alkyl, not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1; R2 represents a radical (C1-C8)alkyl not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1; each X1 independently represents (C1-C6)alkoxy, (C3-C7)cycloalkyl or heteroaryl, and radicals (C3-C7)cycloalkyl, aryl and heteroaryl are not necessarily replaced by one or more either identical or various assistants chosen from: -(CH2)n'-V1-Y1, halogen and; V1 represents -O-, -S- or a covalent bond; Y1 represents a radical (C1-C6)alkyl, not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; n represents an integer from 0 up to 6 and n ' - an integer from 0 up to 2 that if n is equal 0 then X1 does not represent a radical alkoxy); or R1 and R2 form together with the atom of nitrogen to which they are attached, heterobicycloalkyl or heterocycloalkyl, are not necessarily replaced by one or more either identical or various substitutes chosen from: hydroxy, (C1-C6)alkyl, not necessarily substituted by hydroxy, (C1-C6)alkoxycarbonyl, heterocycloalkyl and-C(O)NV1'Y1', in which V1' and Y1' independently represent the atom of hydrogen or (C1-C6)alkyl; or R1 and R2 together form a radical of the formula: R3 represents-Z3, -C(RZ3)(R'Z3)-Z3, -C(RZ3)(R'Z3)-(CH2)p-Z3 or -C(O)Z'3; RZ3 and R'Z3 independently represent atom of hydrogen or a radical (C1-C6)alkyl; Z3 represents Z3b, Z3c, Z3d or Z3e; Z3b represents (C1-C6)alkoxy, (C1-C6)alkythio, (C1-C6)alkylamino, or a radical di((C1-C6)alkyl) amino; Z3c represents aryl or a radical heteroaryl; Z3d represents C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, di((C1-C6)alkyl) aminocarbonyl, (C1-C6)alkyl-C(O)NH-, (C3-C7) cycloalkyl, heterocycloalkyl; and radicals (C3-C7) cycloalkyl and heterocycloalkyl are not necessarily replaced by one or more either identical or various substitutes chosen from: (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl and oxy, radicals aryl and heteroaryl are not necessarily replaced by one or more either identical or various substitutes chosen from: halogen, cyanogen, nitro, azide, oxy, (C1-C6)alkylcarbonyl-(C1-C6)alkenyl, (C1-C6)alkylaminocarbonyl-(C1-C6)alkenyl, -SO2-NR31R32, heterocycloalkyl, heteroaryl or -(CH2)P'-V3-Y3; R31 and R32 form together with atom of nitrogen to which they are attached, heterocycloalkyl, V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -O-C(O)-, -SO2-, -SO2NH-, -NR'3-SO2-, -NR'3-, -NR'3-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR'3- or covalent bonds; Y3 represents the atom of hydrogen; radical (C1-C6)alkyl, not necessarily replaced by one or more either identical or different radicals of halogens; radical aryl or a radical aryl-(C1-C6)alkyl; Z3e represents a radical of the formula

, Z'3 represents a radical aryl, not necessarily replaced by one or more oreither identical or various substitutes chosen from: halogen, nitro and -(CH2)P"-V'3-Y'3; V'3 represents -O-, -C(O)-, -C(O)-O, -C(O)-NR'3-,-NH-C(O)-NR'3- or covalent bonds; Y'3 represents the atom of hydrogen or a radical (C1-C6)alkyl, not necessarily replaced by one or more either identical or different radicals of halogens; R'3 represents the atom of hydrogen (C1-C6)alkyl or a radical (C1-C6)alkoxy; p represents an integer from 1 up to 4; p' and p" independently represent an integer from 0 up to 4; R4 represents a radical of the formula -(CH2)S-R'4; R'4 represents a radical guanidine; heterocycloalkyl containing, at least, one atom of nitrogen and not necessarily substituted (C1-C6)alkyl or aralkyl; heteroaryl containing, at least, one atom of nitrogen and not necessarily substituted (C1-C6)alkyl or a radical of the formula -NW4W'4; W4 represents an atom of hydrogen or (C1-C8) alkyl; W'4 represents a radical of the formula -(CH2)S-Z4; Z4 represents an atom of hydrogen (C1-C8) alkyl, (C3-C7)cycloalkyl, heteroaryl and aryl; s and s' independently represent an integer from 0 up to 6; and i) if R3 represents -C(O)-Z'3 and R4 represents a radical of the formula -(CH2)S-NW4W'4, and W4 and W'4 independently represent an atom of hydrogen or a radical C1-C6)alkyl, then -(CH2)s represents neither radical ethylene nor radical -(CH2)-CH((C1-C4)alkyl) and ii), if R3 represents -Z3c and Z3c represents phenyl or naphthyl, then phenyl and naphthyl are not substituted by cyanogen; also note that if R3 represents -Z3d, then Z3d, represents only one (C3-C7)cycloalkyl or heterocycloalkyl; or to their pharmaceutically acceptable salts. The invention also relates to the method of obtaining the compounds of the formula (I), to a pharmaceutical composition, and to the application of compounds of the formula (I) and (I ').

EFFECT: obtaining new biologically active compounds on their basis, possessing activity with respect to receptors MC4.

41 cl, 535 ex

FIELD: medicine; pharmacology.

SUBSTANCE: touch-and-heal herb (Hypericum perforatum L.) is extracted. Ethyl alcohol concentrated within 60...90% is used as extracting agent. Raw material and extracting agents are taken in proportion as follows 1:11 ÷ 1:13.

EFFECT: invention enables to carry out specified value and increase flavonoid yield.

8 ex, 2 tbl

FIELD: medicine; veterinary science.

SUBSTANCE: invention refers to application of compounds with common structural formula

R1=-H, -NH2, -Br, -Cl, -ОН, -СООН,

B=-N=, -CH=, Z=-CH=, -N=,

A=-CH- at B=-N=, Z=-CH-,

A=-CH- at В=-СН=, Z=-CH=,

A=-N= at B=-N=, Z=-CH-,

A=-CH- at B=-N=, Z=-N=,

A=-CH= at В=-СН=, Z=-N=.

Structures of specified formula are active for nitrergic and dopaminergic systems of mammal body including human body. These compounds can be applied as neuroprotectors, to improve cognitive function and to normalise psychophysiologic state, to treat consequences of substance abuse, as well as to treat wide range of diseases including neuropsychic, cardiovascular, immune, inflammatory and gastro-intestinal disorders.

EFFECT: application of new and well-known compound to effect nitrergic and dopaminergic systems for treatment purposes.

4 ex, 3 tbl, 8 dwg

FIELD: chemistry.

SUBSTANCE: invention pertains to compounds with formula I or to its pharmaceutically accepted salts: where R1 is chosen from phenyl, thienyl, furanyl and thyazolyl; and R2, R3, R4 and R5 are independently chosen from hydrogen and C1-6alkyl. The invention also relates to the use and methods of obtaining compounds of formula I, as well as to compounds of formula III.

EFFECT: obtaining new biologically active compounds.

12 cl, 5 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2- pyrrolidine-2-yl-[1, 3, 4]oxadiazole with common formula I where R1 is aryl or heteroaryl, aryl here being phenyl unsubstituted or substituted with F, Cl, O-alkyl or phenyl, whereas heteroaryl is pyridinyl or thyenyl, R2 designates H, SO2R3 or COR4 where R3 and R4 independently designate C1-C10alkyl, C3-C10cycloalkyl, (C1-C6alkyl)-C3-C10cycloalkyl, aryl, (C1- C6alkyl)aryl, heterocyclyl, carboxylate residues with 3-10 C-atoms, dimethylamide or NR5R6, C1-C10alkyl at that being methyl, propyl, butyl, butenyl, isobutyl, amyl, pent-3-yl, hept-3-yl, hept-4-yl, 2,2-dimethylpropyl, CH2OCH3, CH2O(CH2)2OCH3 or CH(benzyl)MSO2C6H4CH3, C3-C10cycloalkyl is cyclopropyl, cyclobutyl, cycloamyl, adamantane-1-yl, 2-phenylcyclopropyl or 4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-on-1-yl, (C1-C6alkyl)-C3-C10cycloalkyl is CH2-cycloamyl, (CH2)2-cycloamyl or 7,7-dimethyl-1-methylbicyclo[2.2.1]heptane-2-on, aryl is phenyl, benzyl or naphthyl unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: phenyl, NO2, C1-C6alkyl, O-alkyl, CO2-alkyl, C(=O)C1-C6alkyl, CH2OC(=O)C6H5, F, Cl, Br, N(CH3)2, OCF3, CF3 or (C=O)CH3, (C1-C6alkyl)aryl is 3,4-dimethoxyphenyl-CH2, 4-chlorophenoxy-CH2, phenyl-CH=CH, benzyl-OCH2, phenyl-(CH2)2, 2-bromphenyl-CH2, 1-phenylpropyl, 2-chlorophenyl-CH=CH, 3-trifluorinemethylhenyl-CH=CH, phenoxy-CH2, phenoxy-(CH2)3 or phenoxy-CH(CH3), heterocyclyl is pyridinyl, isoxazole, thienyl, furanyl, triazole, benzoxadiazole, thiadiazole, pyrazole or isoquinoline unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: Cl, C1-C6alkyl, phenyl, in their turn unsubstituted or mono- or polysubstituted with identical or different substitutes, namely: Cl or C1-C6alkyl, CF3, carboxylate residues with 3-10 C-atoms are CH3OC(=O)CH2, CH3OC(=O)(CH2)3, CH3CH2OC(=O)CH2, CH3CH2OC(=O)(CH2)2, CH3C(=O)OCH2, CH3C(=O)OC(CH3)2 or CH3C(=O)OCH(C6H5), and R5 and R6 independently designate H or aryl, aryl at that being benzyl or phenyl respectively mono- or polysubstituted with identical or different substitutes, namely: F, C1, O-alkyl, CN, CF3. Invention also relates to method of obtaining, to medicament and to use of compounds with common formula I.

EFFECT: obtaining of new biologically active compounds and medicinal agents based on the above formulas.

9 cl, 248 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention covers new compounds of formula I or its salts suitable for pharmacology: , where R1 is selected from phenyl, pyridyl, thienyl, difurylglyoxal, imidazolyl, pyrrolyl and thiazolyl; R2, R3 and R4 independently are d-zalkyl or halogenated C1-zalkyl; and R5 is hydrogen. And also new intermediate compounds formula III: , where R2, R3 and R4 independently are C1-3alkyl or halogenated C1-6alkyl; and R5 is hydrogen. Invention also covers method of production of compound formula I and their applications.

EFFECT: production of new biologically active compounds.

12 cl, 9 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: bioactive complex with anti-tumor, antidepressant and wound-healing activities is invented; it contains the secretion of renal tubules of spawning male of thornback - 640-690 mg of solid, and secretion of gills of Atlantic salmon of activated by symbiotic larvae of pearl oyster life cycle - 320-480 mg of solid per 1000 mL of finished product, and five-year-old brandy - the rest. The invented method for treatment of oncology diseases consists in oral administration of the bioactive complex 10-30 mL on an empty stomach 10-40 min before meal not less than twice a day for 2-8 weeks. The invented method for treatment of depressive disorders consists in oral administration of bioactive complex 10-30 mL on an empty stomach 10-40 min before meal not less than twice a day for 2-8 weeks.

EFFECT: invention provides multipurpose ichthyocomplex with powerful anti-inflammatory and antitumor activity and minimal side effects.

6 cl, 6 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of aniline of the general formula (I): and their pharmaceutically acceptable salts and isomeric forms possessing properties of phosphodiesterase-4 inhibitors. Compounds can be used, fore example, for enhancing cognitive ability. In compounds of the general formula (I) R1 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more halogen atoms; R2 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkoxy or their combinations, (C3-C10)-cycloalkyl, (C4-C16)-cycloalkylalkyl wherein alkyl fragment comprises from 1 to 4 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and alkyl fragment that can be linear or branched and comprises from 1 to 5 carbon atoms and wherein radical arylalkyl can be unsubstituted or substituted in aryl fragment with one or more substitutes of the following order: halogen atom, alkoxy group comprising from 1 to 4 carbon atoms or their combinations, and in alkyl fragment one group -CH2CH2- is optionally replaced for group -CH=CH-, and one group -CH2- is optionally replaced for -O- for -NH-, partially unsaturated carbocyclic group comprising from 5 to 9 carbon atoms that can comprise condensed benzene ring, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including one atom chosen from oxygen (O), or heterocyclylalkyl group wherein heterocyclic fragment can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including 1-2 atoms chosen from nitrogen (N) or sulfur (S) atoms, and alkyl fragment that can be linear or branched comprises from 1 to 5 carbon atoms; R3 means partially unsaturated carbocyclylalkyl group wherein carbocyclic fragment comprises from 5 to 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein arylalkyl radical can be linear or substituted in aryl fragment with one or more substitutes of the following group: trifluoromethyl, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations, heterocyclylalkyl group wherein heterocyclic fragment can be aromatic, partially or completely saturated and comprises from 5 to 10 atoms in cycle including 1-2 atoms chosen from N, O or S, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein heterocyclylalkyl group can be linear or substituted in heterocyclic fragment with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations; R4 means (C6-C12)-aryl that can be linear or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C2-C4)-alkenyl, hydroxy, (C1-C4)-alkoxy, (C2-C4)-alkoxyalkoxy, nitro, trifluoromethyl, -OCF3, amino group, aminoalkyl, aminoalkoxy, hydroxy-(C1-C4)-alkyl, hydroxamic acid, tetrazol-5-yl, 2-(heterocyclyl)-tetrazol-5-yl, carboxy, alkoxycarbonyl, cyano, acyl, alkylsulfonyl, phenoxy, trialkyloxy, R5-L or their combinations, or heteroaryl comprising from 5 to 10 atoms in cycle including 1-2 atoms chosen from N wherein heteroaryl can be linear or substituted with one or more substitutes of the following order: (C1-C4)-alkyl, (C1-C4)-alkoxy, carboxy, alkoxycarbonyl or their combinations; R5 means hydrogen atom, (C1-C8)-alkyl, (C3-C10)-cycloalkyl, C6-aryl, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 10 atoms in cycle from which at least atom means N or O, and wherein heterocyclic group can be linear or substituted with one or more (C1-C4)-alkyls, or group heterocyclylalkyl, and others. Also, invention relates to intermediates compounds and to a method for enhancing the cognitive ability.

EFFECT: valuable biological and biochemical property of compounds.

49 cl, 8 sch, 26 ex

FIELD: medicine.

SUBSTANCE: invention discovers improved composition for profile control of active compound release through the digestive tract, including particles, especially granules, containing the active compounds. They are covered with coating material, solution of which depends on pH value, or polymethacrylate material, solution of which, for preference, depends on pH value, the definite thickness, desirable place and speed of the active compound release. In preferable compositions two or more particles, in which particles of each multitude are covered with the coating material, the solution which depends on pH value, or polymethacrylate material, of different thickness in comparison with the particles of each other multitude, are contained in capsules with enterosoluble coating and provide the active substance release in different desirable places of the digestive tract.

EFFECT: provision of active substance release in desirable places of digestive tract.

28 cl, 7 dwg, 9 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to sustained-release medicinal formulation composition comprising venlafaxin hydrochloride as an active component. In this formulation venlafaxin hydrochloride in common with a binding agent is applied on inert core as lozenge form (nonpareil) followed applying with a cover-insulating polymeric layer for providing stability and additional cover with external polymeric layer providing the sustained-release of venlafaxin hydrochloride.

EFFECT: improved and valuable properties of composition.

18 cl, 1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: the [present innovation deals with manufacturing intestinally soluble capsular forms of medicinal preparations, particularly, to the technology for creating capsular membranes of improved protective properties. The innovation deals with the method for obtaining capsular membrane out of calcium alginate due to successive keeping capsular nuclei in solutions of sodium alginate and calcium chloride, in which sodium alginate solution at concentration of 1.5-2.0% (weight/volume) should be pre-treated with ultrasound for about 8-10 at the power of 400-450 W/sq. cm. Calcium chloride solution should be applied at concentration of 2.0-2.5%, moreover, the terms for keeping capsular nuclei in solutions of sodium alginate and calcium chloride corresponds to 5 min in every solution.

EFFECT: higher efficiency.

1 dwg, 3 ex, 1 tbl

The invention relates to medicine and can be used for the treatment of venous leg ulcers
The invention relates to soft gelatin capsules filled with granules that contain at least one beneficial agent

The invention relates to pharmaceutical facilities intended for use orally, in particular to the pharmaceutical agent in the form of microcapsules and method thereof

FIELD: medicine.

SUBSTANCE: invention describes pharmaceutical and dosage band of sustained release for peroral ingestion. It contains effective quantity of tramadol or its pharmaceutically acceptable sal, dispersed in the matrix, that comprises xanthan gum. Method of peroral dosage band preparation is also described. This invention gives possibility of controlled tramadol release during long-lasting periods of time, without rises and falls in its scheme.

EFFECT: provision of tramadol controlled release.

11 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes solid dispersed measured drug including a core with pharmacological agent dispersed in the first matrix for controlled liberation at relatively low speed; and coating covering the core and including the agent dispersed in the second matrix for controlled liberation at relatively high speed. The first matrix can be represented by cross-linked starch with high amylose content, and the second matrix can be represented by polyvinylacetate and polyvinylpyrrolidone mix. Solid measured drug is preferably a pill.

EFFECT: reduced administration frequency, relatively stable medicine concentration in organism for a given time period and reduced undesired side effect frequency and intensity due to reduction of high concentrations in plasma.

19 cl, 5 dwg, 4 tbl, 4 ex

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