RU2547574C2 - Hypolipidemic dosage form and method for preparing it - Google Patents

Abstract

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

Description

The present invention relates to a hypolipidemic dosage form containing rosuvastatin or a pharmaceutically acceptable salt thereof, and a method for its manufacture.

Cardiovascular diseases take the first place among the causes of mortality both in Russia and in many other countries of the world. The most important medical and social problem is the search for treatment methods that help reduce the number of complications and, as a result, reduce the number of fatal outcomes. The main pathogenetic cause of most cardiovascular diseases is atherosclerotic lesion of the vascular wall. In this regard, preventing the development and slowing the progression of atherosclerosis is the main task of therapy in this vast group of patients.

Correction of lipid metabolism disorders in this area occupies a leading position (Diagnosis and correction of lipid metabolism disorders for the prevention and treatment of atherosclerosis. Russian recommendations // Cardiovascular therapy and prophylaxis. - 2007. - No. 6). The first-line drugs in the treatment of dyslipidemia in patients with risk factors for developing cardiovascular diseases associated with atherosclerosis are statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors - HMG-CoA reductase inhibitors). The main goal of using statins in all patients is to slow the progression of atherosclerosis, which, in turn, reduces the risk of complications and improves the prognosis.

Currently, the use of six statins is widely available - lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin and rosuvastatin. Among these drugs, rosuvastatin occupies a special place, due to the fact that it has undeniable advantages in relation to pharmacological and clinical properties compared to other statins. Rosuvastatin is a synthetic statin that interacts more with HMG-CoA reductase, which is associated with a higher affinity for the active center of this enzyme (P. Rubba, G. Marotta, M. Gentile. Efficacy and safety of rosuvastatin in the management of dyslipidemia // Vasc Health Risk Manag. 2009; 5: 343-352.). This drug also has the longest half-life among all statins and is the only statin that is minimally metabolized by the cytochrome P450 enzyme system (CYP 450) without significant involvement of the 3A4 isoenzyme. As a result of clinically significant drug interactions, rosuvastatin and other drugs that inhibit CYP 450 enzymes practically do not occur (McKenney J.M. Efficacy and safety of rosuvastatin in treatment of dyslipidemia // Am J Health Syst Pharm). This property of rosuvastatin facilitates its appointment as part of complex therapy, for example, with angiotensin-converting enzyme inhibitors, nitrates, calcium antagonists, diuretics, β-blockers. As for the safety and tolerability of rosuvastatin, it is comparable with those for other statins - atorvastatin, simvastatin and pravastatin - which has been shown in more than 12 thousand patients (R. Rubba, G. Marotta, M. Gentile. Efficacy and safety of rosuvastatin in the management of dyslipidemia // Vasc Health Risk Manag. 2009; 5: 343-352.)

It is known that rosuvastatin {(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (ZP, 58) 3,5-dihydroxyhept- 6-enoic acid calcium salt} as an active ingredient and a method for its synthesis are first described in patent EP 521471.

Hypolipidemic formulations containing 5 to 40 mg of rosuvastatin or a pharmaceutically acceptable salt thereof, which are marketed in the form of film-coated tablets, are widely known and applicable in the prior art.

In particular, the compositions of Mertenil® preparations are known (Registration certificate No. LSR-000278/10, registration date 01.25.2010), Roxer (Registration certificate No. LP-001450, registration date 01.24.2012), Rosucard® (Registration certificate No. LP-001704, registration date 05/18/2012), Tevastor (Registration certificate No. LP-001357 registration date 12/15/2011), Akorta (Registration certificate No. LP-000819, registration date 10/07/2011) and others.

The most famous drug containing rosuvastatin and widely available on the market is Krestor® (Registration Certificate No. PN 015644/01, registration date 03.24.2009), made in the form of film-coated tablets. These tablets contain the following components, mg:

Components mg Rosuvastatin Calcium 10 twenty 40 Lactose Monohydrate 89.50 179.00 164.72 Microcrystalline cellulose 29.82 59.64 54.92 Calcium phosphate 10.90 21.80 20.00 Crospovidone 7.50 15.00 15.00 Magnesium stearate 1.88 3.76 3.76 Shell (lactose monohydrate, hypromellose, triacetin, titanium dioxide, dye iron oxide red) 4,50 9.00 9.00 Total 154.1 308.2 307.4

Tablets with a similar composition are presented in patents RU 2206324, RU 2264210 and EA 014451.

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

Thus, in the patent RU 2264210 known from the prior art, the stability of rosuvastatin is enhanced by the selection of an inorganic salt that is added to the composition 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 a mixture thereof.

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

Magnesium hydroxide and / or calcium acetate or calcium gluconate or calcium glycerophosphate or aluminum hydroxide were used as a stabilizing additive in the composition containing amorphous calcium rosuvastatin according to patent EA 014451.

Thus, at present, there is still a need for the development and preparation of solid dosage forms containing rosuvastatin, characterized by high chemical and physical stability during storage for a long time and ease of manufacture, as well as allowing to expand the arsenal of lipid-lowering drugs of domestic production.

The technical task of the invention is the creation of a solid oral dosage form of rosuvastatin that does not contain alkaline stabilizers, has an adequate shelf life and high uniformity obtained in a simple way, without the use of specialty excipients.

As a result of numerous manufacturing options and combinations of substances experimentally, the authors of the present invention unexpectedly found that sufficient stability of rosuvastatin can be achieved by using granules containing a low level of adsorbed moisture - less than 1.5%, which is used as a filler in a solid dosage form. To maintain a low level of moisture in the dosage form as a whole, it is necessary that the amount of such granulate (with a moisture content of less than 1.5%) be at least 70% of the total weight of the manufactured dosage form.

The results of the stability study for a composition with a granulate content of 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 Total degradation product (%) Lactone Product (%) Example 1 / 0.5 0.3 0.01 Example 2 / 1.0 0.3 0.01 Example 3 / 1.2 0.4 0.02 Example 4 / 1.5 0.5 0.02 Example 5 / 1.7 1.8 0.50 Example 6 / 1.9 2,4 0.60 Example 7 / 2.2 7.4 0.92 Example 8 / 2.5 9.1 0.95

As the results show, with a granulate moisture from 0.5 to 1.5%, the total degradation product and the formation of lactone are relatively stable and within normal limits, however, with a moisture content of more than 1.5%, these results show sharp and significant deviations, which indicates about the instability of the current beginning.

The granulate composition is selected in such a way that with different granulation methods known to the person skilled in the art, it can be obtained with physical properties sufficient to technologically produce a solid dosage form, such as capsules and tablets.

It is known that when using fillers with low residual moisture, difficulties arise with compressibility and fluidity of the product, which can lead to insufficient strength, unsatisfactory appearance of the solid dosage form and the heterogeneity of the dose distribution in it. The inventors carried out work on the selection of the composition of the granulate, which allows to solve this problem, even with an adsorbed moisture content of 0.4-0.5%.

The content of components in the granulate in wt.%:

Components % Microcrystalline cellulose 5-20 Lactose 94-65 Povidone 1-5 Disintegrant 0-10

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

The residual moisture of the granulate is determined using an automatic moisture analyzer at a temperature of 80-90 ° C or by drying to a constant mass at a temperature of 60 ° C, described in the Global Fund XI.

Most preferred, but not required, is the following content of components in the granulate in wt.%:

Components % Microcrystalline cellulose 14.00 Lactose 80.00 Povidone 3.00 Croscarmellose sodium 3.00

The use by the authors of the present invention of using granulate with a humidity of up to 1.5% as a filler, including these components, solves the stability problem of rosuvastatin without the addition of stabilizing additives.

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

The present invention also relates to a method for producing a pharmaceutical composition, which consists of the following stages: preparation of a filler granulate with a low content of adsorbed moisture, sieving the active substance separately or together with substances of the external phase of the mixture, disintegrants, lubricants, combining the granulate and the external phase into a uniform mixing the mixture into tablets; optionally coating the tablets or filling the mixture into capsules.

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

The invention is further illustrated by the following examples.

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

table 2 Components Wt% Active active substance 15.0-3.0 Rosuvastatin Calcium Granulate: 79.0-95.0 including Microcrystalline cellulose 13.0-11.0

Lactose Monohydrate 60.0-81.0 Povidone 3.0-2.0 Croscarmellose sodium 3.0-1.0 External phase: 6.0-2.0 including Magnesium stearate 1.5-0.5 Silicon Colloidal Dioxide 1.5-0.5 Croscarmellose sodium 3.0-1.0 Total: one hundred%

Table 3 shows the specific 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 calculated amount of lactose, microcrystalline cellulose and part of croscarmellose sodium are granulated in a fluidized bed by spraying an aqueous solution of povidone through a nozzle, then dried to a moisture content of less than 1.5%. Dry granulate is calibrated, on a granulator or by passing through a sieve, to eliminate large agglomerates. At the same time, the external phase is prepared by co-mixing and sieving rosuvastatin calcium, silicon dioxide colloidal, magnesium stearate and the rest of croscarmellose sodium. Combine the granulate and the external phase. The resulting mixture is compressed into tablets.

In one possible embodiment, said dosage form is coated with a film coating in a manner conventional for a given process using standard film coating equipment. A possible coating composition is also usually applicable for this kind of coating and may consist, for example, of the following components: hydroxypropyl methylcellulose, macrogol 4000, titanium dioxide.

The uniqueness and advantage of this method lies in the fact that the active substance is introduced into the mixture by simple mixing, thereby eliminating technological factors that could adversely affect its stability. The storage stability of rosuvastatin calcium in the form of a solid dosage form is achieved due to the low content of residual moisture in it. The mechanical properties of the product necessary for manufacturability and the uniformity of distribution of the active substance are ensured by the selection of the components of the granulate composition. Thus, this method allows you to solve the problem.

Table 3 Components Option 1 Option 2 Option 3 Option 4 mg % mg % mg % mg % Rosuvastatin Calcium 5,210 5.37 10,420 5.37 20,830 10.74 41,670 10.74 Microcrystalline cellulose 12,307 12.69 24,615 12.69 23,157 11.94 46.313 11.94 Lactose Monohydrate 70,328 72.50 140,656 72.50 132,328 68.21 264,648 68.21 Povidone (polyvinylpyrrolidone) 2,637 2.72 5,275 2.72 4,962 2,56 9,924 2,56 Croscarmellose sodium 4,577 4.72 9,155 4.72 8,842 4,56 17,684 4,56 Magnesium stearate 0.970 1.00 1,940 1.00 1,940 1.00 3,880 1.00 Silicon Colloidal Dioxide 0.970 1.00 1,940 1.00 1,940 1.00 3,880 1.00 Unit Weight 97.0 100.0 194.0 100.0 194.0 100.0 388.0 100.0

Components Option 5 Option 6 Option 7 Option 8 mg % mg % mg % mg % Rosuvastatin Calcium 5.21 3.0 10,425 15.0 20,830 3.0 41,670 15.0 Microcrystalline cellulose 19.14 11.0 9,035 13.0 86.75 12.5 34,725 12.5 Lactose Monohydrate 140.95 81.0 41.7 60.0 520.49 75.0 173.625 62.5 Povidone (polyvinylpyrrolidone) 3.48 2.0 2,085 3.0 17.35 2,5 5,556 2.0 Croscarmellose sodium 3.48 2.0 4.17 6.0 34.70 5,0 16,668 6.0 Magnesium stearate 0.87 0.5 1,0425 1,5 3.47 0.5 4,167 1,5 Silicon Colloidal Dioxide 0.87 0.5 1,0425 1,5 10.41 1,5 1,389 0.5 Unit Weight 174.00 100.0 69.5 100.0 694.00 100.0 277.8 100.0

Claims (11)

1. A dosage form of lipid-lowering action, containing as an active ingredient rosuvastatin or a pharmaceutically acceptable salt thereof in an amount of from 3 to 15%, processing aids and a pharmaceutically acceptable excipient, including microcrystalline cellulose, lactose monohydrate, polyvinylpyrrolidol (povidone) and croscarmellose sodium, the filler is a granulate in an amount of from 79 to 95% by weight of the dosage form with an adsorbed moisture content in the range from 0.5% to 1.5%. 2. The dosage form according to claim 1, where the specified microcrystalline cellulose is contained in the range from 11 to 13% by weight of the dosage form. 3. The dosage form according to claim 1, where the specified lactose monohydrate is in the range from 60 to 81% by weight of the dosage form. 4. The dosage form according to claim 1, where the specified povidone is in the range from 2 to 3% by weight of the dosage form. 5. The dosage form according to claim 1, where the specified croscarmellose sodium is contained in the range from 1 to 3% by weight of the dosage form. 6. The dosage form according to claim 1, where the composition of the dosage form contains an external phase. 7. The dosage form according to claim 6, where the specified external phase is from 2 to 6% by weight of the dosage form. 8. The dosage 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. The dosage form according to claim 6, where the composition of the external phase contains silicon dioxide colloidal in the range from 0.5 to 1.5% by weight of the dosage form. 10. The dosage form according to claim 6, where the composition of the external phase contains croscarmellose sodium in the range from 1 to 3% by weight of the dosage form. 11. A method of manufacturing a hypolipidemic dosage form according to claim 1, wherein the suspended lactose, microcrystalline cellulose, povidone and part of croscarmellose sodium are granulated, then dried to a moisture content of less than 1.5%, the obtained granulate is calibrated, the external phase prepared by mixing and sifting rosuvastatin calcium, colloidal silicon dioxide, magnesium stearate and the rest of croscarmellose sodium are combined with granulate, the resulting mixture is tabletted (packed, encapsulated), possibly applied iat coating.