KR101302243B1 - Pharmaceutical composition comprising Rosuvastatin or the salt thereof - Google Patents

Abstract

The present invention provides a pharmaceutical composition comprising anhydrous calcium hydrogen phosphate as rosuvastatin or a pharmaceutically acceptable salt thereof and a stabilizer. The composition of the present invention has excellent storage stability.

Description

Pharmaceutical composition comprising Rosuvastatin or a pharmaceutically acceptable salt thereof

The present invention relates to a stabilized pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to a rosuvastatin calcium salt oral preparation having improved stability including anhydrous calcium hydrogen phosphate as a stabilizer. It is about.

Rosuvastatin is described in European Patent Publication No. 0521471 and Bioorganic and Medicinal Chemistry, (1997), 5 (2), 437-444, with 3-hydroxy-3-methylglutaryl CoA reductase (HMG). CoA reductase) inhibitors and are used in the treatment of hypercholesterolemia, hyperlipidproteinemia and atherosclerosis.

On the other hand, rosuvastatin calcium salt-containing formulations have a problem of being prone to degradation under specific conditions. The main decomposition products formed are the products (B2) in which the corresponding (3R, 5R) lactones and hydroxy groups adjacent to the carbon-carbon double bonds are oxidized to ketone functional groups, which have the following structure.

[Structural formula 1]

In this regard, British Patent 2262229 discloses pharmaceutical preparations of 7-substituted-3,5-dihydroxy-6-heptenoic acid salts which are inhibitors of HMG CoA reductase, which preparations of aqueous solutions or dispersions of compositions It is disclosed that an alkali medium (e.g., carbonate or bicarbonate) that can have a pH of 8 or more is required. In addition, the article Determination of Rosuvastatin in the presence of Its Degradation Products by a Stability-Indicating LC Method (Journal of AOAC International Vol. 88, No.4,2005) has also reported that rosuvastatin calcium salts have acidic pH, oxidation, It has been reported that granules, which are easily decomposed by light and temperature, and which have a large exposure area to the environment, are unstable and stable, and film coated tablets are more stable.

Therefore, it is important to prepare a pharmaceutical composition of rosuvastatin calcium salt that is stable for a long time. Such a composition has a good flow rate and is easily processed into a unit dosage form for oral administration such as a tablet, and when processed into a tablet for oral administration, it is preferable that the dosage strength of the tablet may vary due to good disintegration and solubility. Preferably, the tablet is about 150 mg, the size of which is easy to administer.

Accordingly, Korean Patent 0698333 discloses a method for stabilizing rosuvastatin through a pharmaceutical composition in which an inorganic salt with a cation is multivalent, especially an inorganic salt is not hydrotalcite or synthetic hydrotalcite, and the counter anion for the inorganic salt is not phosphate. It is describing.

In addition, Korean Patent 0388713 reports that tribasic phosphate stabilizes the structure of Rochevastatin or a pharmaceutically acceptable salt thereof, and stabilizes it against oxidation and lactonation.

It is therefore an object of the present invention to provide a stabilized formulation containing rosuvastatin or a pharmaceutically acceptable salt thereof.

The present invention provides a pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, and anhydrous calcium hydrogen phosphate as a stabilizer.

The rosuvastatin or rosuvastatin pharmaceutically acceptable salt in the composition of the present invention may contain about 1 to 20 mg, more preferably about 5 to 12 mg.

In the composition of the present invention, the pharmaceutically acceptable salt is an inorganic ion salt prepared with calcium, potassium, sodium, magnesium, etc., an inorganic acid salt prepared with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid and sulfuric acid, Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, Organic acid salts, glycine, arginine, lysine made with lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. Amino acid salts prepared from and the like, and amine salts made from trimethylamine, triethylamine, ammonia, pyridine, picoline and the like, and the like, but the salts of the present invention The meaning of the salt is not limited. In the composition of the present invention, calcium salts are more preferred.

In the present invention, the stabilizer means an excipient which maintains or improves physical stability such as storage stability or hygroscopicity of a pharmaceutical composition including rosuvastatin or a pharmaceutically acceptable salt thereof.

In the pharmaceutical composition of the present invention, the anhydrous calcium hydrogen phosphate is preferably in the form of granules (granule type) or powder (powder type), for example, the granule type of calcium hydrogen phosphate anhydrous has the trade name DCP A-Tab, powder type There is a trade name DCP A, and look at their particle shape and physical properties as shown in Table 1 below, but the present invention is not limited to this example.

[Table 1]

In the composition of the present invention, anhydrous calcium hydrogen phosphate is an acid labile rosuvastatin or rosuva in a pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt of rosuvastatin. Stabilizes statin pharmaceutically acceptable salts.

Therefore, in the composition of the present invention, the granular calcium anhydrous phosphate is preferably a pharmaceutical composition having a pH of 5.0 to 6.0 in an aqueous dispersion of 20%, and the powdered calcium anhydrous phosphate is in an aqueous acidic state of 20%. Preference is given to pharmaceutical compositions having a pH of 6.6 to 7.4.

In the compositions of the present invention, the weight ratio of rosuvastatin or pharmaceutically acceptable salt (active ingredient) to anhydrous calcium hydrogen phosphate may vary. It is preferably in the range of 1: 1 to 1: 3.5, and preferably 1: 1 to 1: 1.1.

The compositions of the invention are preferably formulated in oral formulations, for example tablets. Thus, the pharmaceutical compositions of the present invention may contain one or more diluents, binders, disintegrants or glidants in addition to rosuvastatin or a pharmaceutically acceptable salt thereof, and anhydrous calcium hydrogen phosphate. Diluents include, for example, lactose, sucrose, starch, modified starch (stabilized starch), mannitol, sorbitol, inorganic salts, cellulose derivatives (eg microcrystalline cellulose, cellulose), calcium sulfate, xylitol and lactitol .

The binder is, for example, polyvinylpyrrolidone, lactose, starch, modified starch, sucrose, acacia rubber, tragacanth rubber, guar rubber, pectin, wax binder, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, Hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatin and sodium alginate.

Disintegrants include, for example, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycolate, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose.

Glidants include, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycol, and sodium stearyl fumarate.

Additional conventional excipients that may be added in addition to those discussed above include preservatives, stabilizers, antioxidants, silica flow regulators, antiadhesives or glidants.

In the composition of the present invention, the content of anhydrous calcium hydrogen phosphate may be 1 to 30% by weight relative to the total weight in the formulation.

In the compositions of the present invention, the content of at least one diluent may be 30 to 90% by weight relative to the total weight in the formulation.

In the compositions of the present invention, the content of at least one binder may be from 2 to 90% by weight relative to the total weight in the formulation.

In the composition of the present invention, the content of at least one disintegrant may be 2 to 10% by weight, and may be 4 to 6% by weight relative to the total weight of the formulation.

In addition, in the compositions of the present invention, excipients may be used as binders and / or fillers, or may act as binders, fillers and / or disintegrants, depending on the type of excipient.

In the compositions of the present invention, the content of fillers, binders and disintegrants can vary widely, for example, can be contained in 70 to 90% by weight relative to the total weight of the formulation of the composition of the present invention.

In addition, the content of the at least one lubricant in the composition of the present invention may be 0.5 to 3% by weight, and may be 1 to 2% by weight relative to the total weight of the formulation.

The compositions of the present invention can be prepared by standard techniques and methods of preparation generally known in the art (eg, Remington's Pharmaceutical Science, Merck Publishing Company, Easton PA). For example, it can be prepared using a dry mixing method of the components, specifically described as follows. Rosuvastatin calcium salt and anhydrous calcium hydrogen phosphate, one or more diluents, one or more binders and one or more disintegrants as well as any other additional excipients are mixed together. The components of the mixture, or the mixture itself, can be passed through a mesh screen, for example a 400-700 μm mesh sieve, before mixing. Lubricants can also be sieved and mixing continued until a homogeneous mixture is added to the mixture. The mixture is then compressed into tablets. In addition, the pharmaceutical composition of the present invention may be prepared using a wet granulation method. For example, rosuvastatin calcium salt, anhydrous calcium hydrogen phosphate, one or more diluents, one or more binders and a portion of a disintegrant, as well as some other additional excipient, are mixed together and the powder mixture is granulated with a small amount of purified water. . The granules are dried and sized. Residues of excipients, disintegrants and lubricants are added to the milled granules and the resulting homogeneous mixture is compressed into tablets. It will be appreciated that dry mixing and wet granulation methods can be modified in accordance with principles known in the art, including the order of addition of ingredients and mixing prior to their screening and compression into tablets.

If the composition of the present invention is a tablet, it may be tablet coated, and the tablet coating may be applied, for example, by spray coating with an aqueous film coating formulation. The coating may include, for example, lactose, hydroxypropyl methylcellulose, triacetin, titanium dioxide and ferric oxide. Coating component formulations are commercially available as described in the Examples herein. The coating may for example constitute 0.5 to 10% by weight, in particular 1 to 6% by weight, preferably 2 to 3% by weight of the total weight of the tablet composition. Coating of tablets is particularly preferred for light sensitive rosuvastatin calcium salt formulations.

The composition of the present invention has an effect of improving the storage stability in the preparation of rosuvastatin or rosuvastatin pharmaceutically acceptable salt by containing anhydrous calcium hydrogen phosphate as a stabilizer.

Hereinafter, the present invention will be described in detail by way of examples. However, the scope of the present invention is not limited by the following examples. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

[Comparative Example 1]

(1) Preparation of Tablet

As a control of the present invention, a tablet of Comparative Example 1 was prepared by using the calcium triphosphate as a stabilizer, which is used as a stabilizer, which is a commercially available rosuvastatin calcium salt-containing preparation, as a stabilizer. .

As shown in Table 2, rosuvastatin calcium salt and lactose monohydrate (48.7 mg), and calcium triphosphate as a stabilizer were mixed at room temperature, and then granulated with purified water (16 mg), followed by 1 atm and 55% relative. Dry at humidity and 60 ° C. for 2 hours. The granules thus obtained were sieved to 25 mesh, mixed with the remaining lactohydrate (40.8 mg), microcrystalline cellulose, crospovidone, and magnesium stearate and compressed to prepare white tablets of 150 mg per tablet.

(2) Coating liquid preparation and coating

The tablets prepared above were filled in a coating pan (Hi-coater, Freund), and the exhaust air temperature was maintained at about 30 ~ 40 ℃. Opadry 03B64650 (62.5% Hydroxypropylmethylcellulose 2910, Titanium Oxide 30.79%, Polyethylene Glycol 400 6.25%, Yellow Iron Oxide 0.27%, Red Iron Oxide 0.18%, Indigocarmine Aluminate 0.01%) After preparing a coating solution by spraying to the tablet prepared in the step (1) with a spray device operated by pneumatic pressure, the air supply was continued to dry for about 10 minutes. The coating amount of the tablets obtained was 4.5 mg with respect to the tablets, and the total weight of the tablets prepared was 154.5 mg per tablet.

[Table 2]

Examples 1 to 3 Preparation of rosuvastatin-containing tablets according to the present invention

Example 1 was used in about 1: 1 weight ratio of rosuvastatin calcium and granule type anhydrous calcium hydrogen phosphate (trade name: DCP A-Tab) as described in Table 3, the tablet and tablet coating method Comparative Example 1 was prepared in the same manner as in Comparative Example 1 except that anhydrous calcium hydrogen phosphate was used instead of calcium triphosphate.

Examples 2 and 3 were prepared using the powder type anhydrous calcium hydrogen phosphate in the composition ratio of [Table 3]. Example 2 was prepared using an amount of anhydrous calcium hydrogen phosphate relative to rosuvastatin calcium salt in a weight ratio of about 1: 1, and Example 3 was used in a weight ratio of anhydrous calcium hydrogen phosphate to about 1: 3 weight ratio of rosuvastatin calcium salt. Prepared using. Tablets and tablet coating method of Examples 2 and 3 was carried out in the same manner as in Comparative Example 1 except for using calcium hydrogen phosphate anhydrous instead of calcium triphosphate in the production method of Comparative Example 1.

[Table 3]

Examples 4-5 Rosuvastatin Tablet Preparation-Binder Addition According to the Present Invention

Examples 4 and 5 are tablets prepared by adding hydroxypropylmethylcellulose as a binder when granulating in Examples 1 and 2, as shown in [Table 4]. The preparation method is first mixed with rosuvastatin calcium salt and some lactose hydrate (48.7mg), anhydrous calcium hydrogen phosphate, and hydroxypropylmethylcellulose, and then granulated by adding purified water (16mg), then atat, 55% relative humidity. And dried at 60 ° C. for 2 hours. The granules thus obtained were sieved to 25 mesh, mixed with the remaining lactohydrate (40.8 mg), microcrystalline cellulose, crospovidone, and magnesium stearate and compressed to prepare white tablets of 150 mg per tablet. Coating of the tablet was carried out in the same manner as prepared in Comparative Example 1.

[Table 4]

Test Example 1 Stability Test

To ascertain the effects of the present invention, the content of lactone analog (%), ZD4522 B2 analog (%) and total analog (%) were determined in the harsh conditions of temperature and humidity for the final formulation. It was confirmed using the same method. At this time, the content of lactone analog and ZD4522 B2 analog in the rosuvastatin-containing formulation is 1.5% or less, and the total analog content is 3.0% or less.

The film coated tablets prepared in Comparative Example 1 and Examples 1 to 5 were packaged in Alu-Alu and then stored for 4 weeks in harsh (60 ° C., 80% RH) conditions and the content (%) of each flexible substance was measured. It was.

Ten tablets of each tablet were taken as a sample solution, placed in a 100 mL flask, and 50 mL of water was added thereto, followed by shaking and mixing for about 30 minutes. 25 mL of acetonitrile was added again, followed by shaking mixing for about 30 minutes. Water was added to the mark and mixed and filtered. Separately, take 100 mg of rosuvastatin calcium salt as a standard solution, make a 100 mL flask, and add 50 mL of water to dissolve it. 25 mL of acetonitrile was added thereto, water was added to the mark, and the mixture was filtered.

HPLC analysis was carried out under the chromatographic conditions as shown in the following [Table 5], and the results are shown in [Table 6] to [Table 8].

[Table 5] Severity stability test result

[Table 6] Lactone Lead Content

[Table 7] ZD4522 B2 Lead Content

[Table 8] Total Lead Compound Content

As shown in the above table, the pharmaceutical composition of the present invention satisfies the content range of the lactone analog and ZD4522 B2 after the harsh experiments required in the rosuvastatin-containing formulation.

In particular, it is confirmed that the formulation of the present invention exhibits excellent storage stability in the production of lactone analogues compared to the comparative example.

Claims (13)

A pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, and anhydrous calcium hydrogen phosphate in the form of granules having a pH of 5.0-6.0 in an aqueous dispersion of 20% as a stabilizer. A pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, and anhydrous calcium hydrogen phosphate in powder form having a pH of 6.6 to 7.4 in an aqueous dispersion of 20% as a stabilizer. delete delete delete delete The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of rosuvastatin or a pharmaceutically acceptable salt thereof to anhydrous calcium hydrogen phosphate is in the range of 1: 1 to 1: 3.5. The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of rosuvastatin or a pharmaceutically acceptable salt thereof to anhydrous calcium hydrogen phosphate is 1: 1 to 1: 1.1. The pharmaceutical composition of claim 1 or 2 further comprising at least one diluent, binder, disintegrant or glidant. The pharmaceutical composition according to claim 1 or 2, wherein the rosuvastatin or a pharmaceutically acceptable salt thereof is prepared through partial granulation with stabilizers and other excipients. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt is calcium. The method according to claim 1 or 2, further comprising lactose monohydrate, microcrystalline cellulose, crospovidone, magnesium stearate, and Opadry 03B64650. Pharmaceutical composition comprising. 13. The pharmaceutical composition of claim 12, further comprising hydroxypropylmethylcellulose.