Hypolipidemic dosage form and method for preparing it

FIELD: medicine.

SUBSTANCE: invention provides a solid hypolipidemic dosage form containing rosuvastatin or its pharmaceutically acceptable salt in an amount of 3 to 15%, processing additives and a pharmaceutically acceptable excipient containing microcrystalline cellulose, lactose monohydrate, polyvinylpyrrolidone and croscarmellose sodium. The above excipient represents granulate in an amount of 79 to 95 wt % of the dosage form containing absorbed moisture within the range of 0.5% to 1.5%. What is also described is a method for preparing the dosage form.

EFFECT: uniform distribution of the active substance and storage stability of the dosage form of rosuvastatin.

11 cl, 3 tbl

 

The present invention relates to a dosage form of lipid-lowering action containing rosuvastatin or its pharmaceutically acceptable salt, and its manufacturing method.

Cardiovascular diseases rank first among causes of death in Russia and in many other countries. The most important medico-social problem is to find methods of treatment that can reduce the number of complications and, consequently, reducing the number of fatal outcomes. The main pathogenic cause of most cardiovascular disease is atherosclerotic disease of the vascular wall. In this regard, to prevent the development and slow the progression of atherosclerosis is the primary goal of therapy in this large group of patients.

Correction of lipid metabolism disorders in this area occupies a leading position (Diagnosis and correction of lipid metabolism disorders prevention and treatment of atherosclerosis. Russian recommendations // cardiovascular therapy and prevention. - 2007. - No. 6). The first-line drugs in the treatment of dyslipidemia in patients with risk factors for cardiovascular diseases associated with atherosclerosis, are statins (inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme a reductase - HMG-COA reductase). The main purpose of PR�application of statins in all patients is to slow the progression of atherosclerosis, that, in turn, reduces the risk of complications and improve the prognosis.

Currently the public is the use of the six statins - lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin and rosuvastatin. Among these preparations a special place is rosuvastatin, which is associated with the presence of advantages in relation to pharmacological and clinical properties compared with other statins. Rosuvastatin is a synthetic statin that increasingly interacts with HMG-COA-reductase, which is associated with a higher affinity to the active center of this enzyme (R. Rubba, G. Marotta, M. Gentile. Efficacy and safety of rosuvastatin in the management of dyslipidemia // vasc score Health Risk Manag. 2009; 5: 343-352.). Also, this drug has the longest half life among all statins and is the only statin that is minimally metabolized by the system of cytochrome P450 enzymes (CYP 450) without the meaningful involvement of CYP 3A4. The result is clinically significant drug interactions of rosuvastatin and other drugs that inhibit CYP 450 enzymes, practically does not occur (McKenney J. M. Efficacy and safety of rosuvastatin in treatment of dyslipidemia // Am J Health Syst Pharm). This property rosuvastatina facilitates its purpose in the complex therapy of, for example, with inhibitors of angiotensin-Pribram�delivery enzyme nitrates, calcium antagonists, diuretics, β-blockers. As for the safety and tolerability of rosuvastatin, it is comparable to other statins - atorvastatin, simvastatin and pravastatin what was shown on more than 12 thousand patients (R. Rubba, G. Marotta, M. Gentile. Efficacy and safety of rosuvastatin in the management of dyslipidemia // vasc score Health Risk Manag. 2009; 5: 343-352.)

It is known that rosuvastatin {(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methyl-sulfonyl)amino]pyrimidine-5-yl](WR,58)3,5-dihydroxide-6-envoy acid calcium salt} as the active ingredient and a method for its synthesis was first described in the patent EP 521471.

In the prior art is widely known and applicable gipolipidemiceski compositions containing from 5 to 40 mg of rosuvastatin or its pharmaceutically acceptable salt available on the market in the form of tablets film-coated.

In particular, the known formulations of medications Martini® (Registration certificate № LSR-000278/10 registration date: 25.01.2010.), Roxana (Registration certificate № LP-001450 registration date: 24.01.2012 G.), Rookard® (Registration certificate № LP-001704 registration date: 18.05.2012, Devastor (Registration certificate № LP-001357 registration date: 15.12.2011), HSE (Registration certificate № LP-000819 registration date: 07.10.2011,) and others.

The most well known�th drug contains rosuvastatin and widely available on the market, is Crestor® (Registration certificate № N 015644/01 registration date: 24.03.2009 G.), made in the form of tablets film-coated. These tablets contain the following components, mg:

Componentsmg
Rosuvastatin calcium102040
Lactose monohydrate89,50179,00164,72
Microcrystalline cellulose29,8259,6454,92
Calcium phosphate10,9021,8020,00
Polyplasdone7,5015,0015,00
Magnesium stearat1,883,763,76
About�points (lactose monohydrate, polymer, triacetin, titanium dioxide, colorant iron oxide red)4,509,009,00
Total154,1308,2307,4

Tablets with the same composition is presented in the patent RU 2206324, EN 2264210 and EA 014451.

In the prior art it is known that among the inhibitors of HMG-COA reductase inhibitors, in particular statins, some compounds are sensitive to the properties of the microenvironment of the composition, such as light, heat, and humidity. So, the main products of decomposition of rosuvastatin is (3R,5S) lactone (hereinafter referred to as the lactone) and the oxidation product called 5-keto acids. Accordingly, in the manufacture of dosage form of rosuvastatin to specialists in this field is mainly the task of improving the stability of the active principle.

Thus, in the known from the prior art, the patent RU 2264210 stability rosuvastatina increased as a result of the selection of inorganic salts, which are added to the arrangement and which contains one or more polyvalent inorganic cations. In this case, the polyvalent cation of the inorganic salt is selected from the following elements: calcium, magnesium, zinc,aluminum and iron or mixtures thereof.

In the patent RU 2206324 solution stability rosuvastatin was found by the inclusion in the composition of the tribasic phosphate salt in which the cation is multivalent, which can be selected from tribasic calcium phosphate, tribasic magnesium phosphate and tribasic aluminum phosphate.

As stabilizing additives in the composition containing amorphous rosuvastatin calcium, according to the patent EA 014451 used magnesium hydroxide and/or calcium acetate or calcium gluconate or calcium glycerophosphate or aluminum hydroxide.

Thus, at present there remains a need in developing and producing solid dosage forms containing rosuvastatin with high chemical and physical stability during storage for a long time and the ease of fabrication, and also allows you to expand the Arsenal of lipid-lowering drugs of domestic production.

The technical objective of the claimed invention is to provide a solid oral dosage form of rosuvastatin, containing in the composition of alkaline stabilizers having adequate shelf life and high uniformity is obtained in a simple manner, without the use of auxiliary substances special stamps.

As a result of numerous variant�in the manufacture and combinations of substances experimentally by the authors of the present invention unexpectedly found sufficient stability Rosuvastatina can be achieved when using granules containing a low level of adsorbed moisture - less than 1.5%, which is used as filler metered-dose solid dosage forms. To maintain low moisture levels in the dosage form generally requires that the number of such granules (with a moisture content of less than 1.5%) is not less than 70% of the total weight of manufactured dosage forms.

The results of the study on the stability of the composition with the content of the granulate 80% of the total weight of the dosage form are shown in table 1.

Table 1
Example/Humidity of the granulate (%)Storage at 75°C for 7 days
A common degradation product (%)Laktonovye product (%)
Example 1/0,50,30,01
Example 2/1,00,30,01
Example 3/1,20,40,02
Example 4/1,50,5 0,02
Example 5/1,71,80,50
Example 6/1,92,40,60
Example 7/2,27,40,92
Example 8/2,59,10,95

As these results show, when the moisture content of the granules is from 0.5 to 1.5%, the total product degradation and the formation of lactone are relatively stable and within the normal range, however, at a humidity of more than 1.5% these results show a dramatic and significant deviations, indicating current instability onset.

The composition of the granules is selected in such a way that, under different granulation, known to the person skilled in the art, can be obtained with the physical properties sufficient to tech for producing solid dosage forms such as capsules and tablets.

It is known that the use of fillers with low residual moisture difficulties with moldability and fluidity of the product, which may lead to insufficient strength, poor appearance of solid dosage form and not�narodnosti dose distribution in it. The inventors have carried out work on the selection of the composition of the granulate, which allows to solve this problem, even when the content of adsorbed moisture of 0.4-0.5%.

The content of components in granules in wt.%:

Components%
Microcrystalline cellulose5-20
Lactose94-65
Povidone1-5
Disintegrant0-10

The required low residual moisture of the granulate is achieved by drying during granulation process or after it, in any equipment used for such purposes in the pharmaceutical industry, for example in installations with a fluidized bed or in a shelf dryer. Drying parameters - the temperature and volume of air drying time, thickness of the layer, the characteristics of the fluidized bed can vary within wide limits.

Residual moisture of the granulate is determined on an automatic analyzer of humidity, at a temperature of 80-90°C or by drying before the sample to constant mass at 60°C, as described in GF XI.

The most preferred�, but not mandatory, is the following content of components in granules in wt.%:

Components%
Microcrystalline cellulose14,00
Lactose80,00
Povidone3,00
Croscarmellose sodium3,00

The use by the authors of the present invention is the use as a filler of the granules with a moisture content up to 1.5%, which includes these components, solves the problem of stability rosuvastatina without additional introduction of stabilizing additives.

In addition, this dosage form may be coated with a film or placed in capsules in a standard way.

The present invention also relates to a method for producing a pharmaceutical composition, which comprises the following stages: preparation of the granulate filler with a low content of adsorbed moisture, sieving the active substance alone or together with substances external phase mixture, disintegrants, lubricants, Association of the granules and the external phase in a homogeneous mixture, pressing mixture� into tablets, perhaps the coating of tablets or filling the mixture into capsules.

In the prior art to identify such a composition and a method of manufacturing pharmaceutical compositions of rosuvastatin failed.

The invention is additionally illustrated by the following examples.

The most preferred, but not required, is the following content of components in the solid unit dosage form, wt.%:

Table 2
ComponentsWt.%
Active substance15,0-3,0
Rosuvastatin calcium
Pet:79,0 and 95.0
including microcrystalline Cellulose13,0-11,0

Lactose monohydrate60,0-81,0
Povidone3,0-2,0
Croscarmellose sodium3,0-1,0
External phase:6,0-2,0
including Magnesium stearate1,5-0,5
Colloidal silicon dioxide1,5-0,5
Croscarmellose sodium3,0-1,0
Total:100%

Table 3 shows the specific versions of the formulations of the claimed composition in mg per unit dosage form.

A specific method of manufacturing the above formulations can be carried out as follows. Weighed in the estimated amount of lactose, microcrystalline cellulose and part of croscarmellose sodium granulated in a fluidized bed by spraying through a nozzle of an aqueous solution of povidone, then dried to a moisture content of less than 1.5%. The dry granulate is calibrated, the pellet mill or by passing through a sieve to eliminate large agglomerates. At the same time preparing external phase by co-mixing and sieving of rosuvastatin calcium, silicon dioxide colloidal, magnesium stearate and the rest of croscarmellose sodium. Combine the granulated material and the external phase. The resulting mixture is compressed into tablets.

In one of possible embodiments of a specified dosage form is covered with a film cover normal for this process on standardized equipment for mixing ratio�Oia film coating. Possible the shell is usually applicable for this kind of coatings and may, for example, consist of the following components: hydroxypropyl methylcellulose, macrogol 4000, titanium dioxide.

The uniqueness and advantage of this method is that the active substance is introduced into the mixture by simple mixing, thus avoiding technological factors, which could negatively affect its stability. The storage stability of rosuvastatin calcium in the form of solid dosage forms is achieved due to the low content of residual moisture. Required for manufacturability mechanical properties of the product and the uniformity of distribution of active ingredient is achieved through selection of the components of the granulate. Thus, this method allows to solve the problem.

Table 3
ComponentsOption 1Option 2Option 3Option 4
mg%mgmg%mg%
Rosuvastatin calcium5,210levels lower than the 5.3710,420levels lower than the 5.3720,83010,7441,67010,74
Microcrystalline cellulose12,30712,6924,61512,6923,15711,9446,31311,94
Lactose monohydrate70,328RUR 72.50140,656RUR 72.50132,32868,21264,64868,21
Povidone (polyvinylpyrrolidone)2,6372,725,2752,724,9622,569,924 2,56
Croscarmellose sodium4,5774,729,1554,728,842to 4.5617,684to 4.56
Magnesium stearate0,9701,001,9401,001,9401,003,8801,00
Colloidal silicon dioxide0,9701,001,9401,001,9401,003,8801,00
The weight of the unit dosage forms97,0100,0194,0100,0194,0100,0388,0100,0

ComponentsOption 6Option 7Option 8
mg%mg%mg%mg%
Rosuvastatin calcium5,213,010,42515,020,8303,041,67015,0
Microcrystalline cellulose19,1411,09,03513.086,7512,534,72512,5
Lactose monohydrate140,9581,041,760.0520,4975,0173,62562,5
Povidone (polyvinylpyrrolidone)3,482,02,0853,0of 17.352,55,5562,0
Croscarmellose sodium3,482,04,176,034,705,016,6686,0
Magnesium stearateof 0.870,51,04251,53,470,54,1671,5
Colloidal silicon dioxideof 0.870,51,04251,510,411,51,3890,5
The weight of the unit dosage forms174,00100,0 69,5100,0694,00100,0277,8100,0

1. Dosage form lipid-lowering action, containing as active ingredient rosuvastatin or its pharmaceutically acceptable salt in an amount of from 3 to 15%, processing AIDS, and a pharmaceutically acceptable excipient comprising microcrystalline cellulose, lactose monohydrate, polyvinylpyrrolidon (povidone) and croscarmellose sodium, where the filler is a granulate in an amount of from 79 to 95% by weight of the dosage form with the adsorbed moisture content in the range from 0.5% to 1.5%.

2. Pharmaceutical form according to claim 1, where the specified microcrystalline cellulose is contained in the range of 11 to 13% by weight of the dosage form.

3. Pharmaceutical form according to claim 1, where the specified lactose monohydrate contained in the interval from 60 to 81% by weight of the dosage form.

4. Pharmaceutical form according to claim 1, where the specified povidone is contained in the interval from 2 to 3% by weight of the dosage form.

5. Pharmaceutical form according to claim 1, where the specified croscarmellose sodium is contained in the interval from 1 to 3% by weight of the dosage form.

6. Pharmaceutical form according to claim 1, where the composition of the dosage form contains an external f�for.

7. Pharmaceutical form according to claim 6, where the specified external phase is from 2 to 6% by weight of the dosage form.

8. Pharmaceutical form according to claim 6, where the composition of the external phase contains magnesium stearate in the range from 0.5 to 1.5% by weight of the dosage form.

9. Pharmaceutical form according to claim 6, where the composition of the external phase contains colloidal silicon dioxide in the range from 0.5 to 1.5% by weight of the dosage form.

10. Pharmaceutical form according to claim 6, where the composition of the external phase contains croscarmellose sodium in the range of 1 to 3% by weight of the dosage form.

11. A method of manufacturing a dosage form hypolipidemic actions in accordance with claim 1, wherein the weighted lactose, microcrystalline cellulose, povidone and part of croscarmellose sodium granulated, then dried to a moisture content of less than 1.5%, the obtained granulate is calibrated, external phase, prepared by mixing and sieving of rosuvastatin calcium, silicon dioxide colloidal, magnesium stearate and the rest of croscarmellose sodium combine with the granules, the resulting mixture was tableted (Packed, enter into a capsule may apply the coating.



 

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6 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substance - 2-ethyl-6-methyl-3-hydroxypyridine dichloroacetate of formula I its stable crystalline form and method of obtaining thereof. Substance (I) possesses antiatherosclerotic, hypolipidemic, antihypoxic, nootropic, anxiolytic and adaptogenic action with low toxicity (LD50=30000 mg/kg, rats, intragastrically) and absence of hygroscopicity. Substance is obtained with interaction of equimolar quantities of 2-ethyl-6-methyl-3-hydroxypyridine and dichloroacetic acid in presence of solvent.

EFFECT: increase of stability.

9 cl, 8 dwg, 10 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound of formula or to its pharmaceutically acceptable salt, where Alk represents linear C1-6 alkylene group, branched C1-6 alkylene group or C1-6 alkylene group, which has ring structure, where part of carbon atoms, constituting ring structure can be optionally substituted with oxygen atom, in ring X, X1 represents N or CRX1, X2 represents N or CRX2, X3 represents CRX3, X4 represents N or CRX4, where RX1, RX2, RX3 and RX4 each independently represents hydrogen atom; linear or branched C1-6alkyl group; linear or branched C1-6alcoxygroup; or halogen atom, in ring Y, Y1 represents CRY1, Y2 represents N or CRY2, Y3 represents N or CRY3, Y4 represents N or CRY4, RY1, RY2, RY3 and RY4 each independently represents hydrogen atom; linear or branched C1-6alkyl group, which can be substituted with halogen atom(s); C3-7alkyl group, which has ring structure; linear or branched C1-6alkoxygroup; halogen atom or cyanogroup, in ring Z, RZ represents linear or branched C1-6alkyl group, which can be substituted with halogen atom(s), or C3-7alkyl group, which has ring structure, which can be substituted with halogen atom(s). Invention also relates to particular compounds, DGAT1 inhibitor based on formula (I) compound, application of formula (I) compound, method of prevention or treatment of diseases, mediated by DGAT1 inhibition.

EFFECT: obtained are novel compounds, possessing useful biological activity.

19 cl, 19 tbl, 149 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to using the tetrapeptide Arg-Pro-Gly-Pro as an agent for preventing and treating hypercholesteremia and thrombosis.

EFFECT: using the tetrapeptide Arg-Pro-Gly-Pro leads to increasing the effectiveness of preventing and treating hypercholesteremia and thrombosis.

10 cl, 5 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, and concerns using tetrapeptide Pro-Gly-Pro-Val as an agent for preventing or treating lipid storage disease; a method for preventing or treating lipid storage disease involving the intranasal administration of a therapeutic agent containing tetrapeptide Pro-Gly-Pro-Val in an effective amount; to a pharmaceutical composition for preventing or treating lipid storage disease, containing peptide Pro-Gly-Pro-Val with the anticholesteremic and triglyceridemic action as an active substance, and an auxiliary substance as a preserving agent.

EFFECT: group of inventions provides the more effective prevention and treatment of lipid storage disease as compared to natural tripeptide Pro-Gly-Pro.

6 cl, 4 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to phenol derivatives of formula (1), wherein R1 represents C1-C6 alkyl group, C1-C6 alkynyl group, C1-C6 halogen alkyl group, C1-C6 alkyl sulphanyl group or a halogen atom, R2 represents a cyano group or a halogen atom, R3 represents a hydrogen atom, and X represents -S(=O)2. Besides, the invention refers to a drug preparation containing a compound of formula (I) as an active ingredient.

EFFECT: phenol derivatives of formula (1) characterised by the high urine concentration of the permanent compound, and possess the uricosuric action.

11 cl, 1 dwg, 2 tbl, 42 ex

FIELD: chemistry.

SUBSTANCE: as active component pharmaceutical composition contains dihydrochloride of 9-(2-morpholine ethyl)-2-(4-fluorophenyl)imidazo[1,2-α]benzimidasol, and as additional substances - fillers, binding, sliding and film coatings, in quantities, given in the invention formula. Composition can be made in form of solid medication form, mainly in form of tablets and capsules.

EFFECT: obtained solid medication forms satisfy the requirements of the State Pharmacopoeia.

7 cl, 2 dwg, 3 tbl, 14 ex

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