JP6243265B2 - Pharmaceutical preparation containing rosuvastatin - Google Patents

Description

  The present invention relates to a pharmaceutical preparation excellent in stability, containing rosuvastatin, which is an HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt thereof.

Rosuvastatin or a pharmaceutically acceptable salt thereof {(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxyhept-6-enoic acid or pharmaceutically acceptable salt} is an HMG-CoA reductase inhibitor and is useful in the treatment of hypercholesterolemia.
However, many HMG-CoA reductase inhibitors (commonly known as statins) represented by rosuvastatin or a pharmaceutically acceptable salt thereof are known to be unstable to light, heat and humidity. .
In order to solve the above problems, a commercially available pharmaceutical composition (trade name: Crestor) has a ferric oxide photoprotective coating on the outer layer of the tablet.
However, in the case of coating on the outer layer of the tablet, when there is a possibility of dividing or crushing the tablet, exposure due to exposure of rosuvastatin occurs due to exposure of the portion not covered with the light-shielding coating film, and particle level It is necessary to perform light resistance imparting treatment in
Moreover, it is not preferable to coat the outer layer of a tablet in the case of an orally disintegrating tablet or the like that is being developed for the purpose of improving compliance.

As for solid formulation of a drug unstable to light, a method for improving light stability by encapsulating in a capsule or applying a coating is known.
For example, a preparation coated with a light-shielding agent such as talc or barium sulfate (Patent Document 1), a sertindol-containing preparation coated with elementary granules with a coating containing titanium oxide (Patent Document 2) And alanidipine-containing composition (Patent Document 3) characterized by spraying a solid-dispersed preparation with a coating liquid containing a light-shielding agent and a colorant.
There is also known a method for improving light stability by adding a specific substance to the base of a solid preparation instead of applying a coating.
As an example of this, there can be mentioned a photostability improving preparation of a fat-soluble drug which is unstable to light by blending a yellow or red pigment (Patent Document 4).
In addition, preparations for improving light stability of light-unstable drugs by adding a colorant (Patent Documents 5 and 6) can be mentioned, and by further adding titanium oxide, light stability can be further improved. It has been reported.
However, there is no known method for suppressing rosuvastatin photodegradation other than film coating of tablets, and pharmaceutical preparations containing rosuvastatin suitable for split tablets and orally disintegrating tablets, or methods for producing such preparations, are completely known. There is no current situation.
Furthermore, it is known that statins such as rosuvastatin generally generate lactones depending on temperature and humidity.
In order to suppress the production of a lactone form of a statin drug, various methods for defining the pH of a composition containing a statin drug have been proposed (Patent Documents 7 and 8).
On the other hand, for rosuvastatin or a pharmaceutically acceptable salt thereof, a method that is not bound by the concept of the above patent has been proposed, and the technology is described in the patent document specifications (Patent Documents 9 and 10).
Although a technique of combining rosuvastatin or a pharmaceutically acceptable salt thereof with a monovalent cationic inorganic salt has been reported (Patent Document 11), there is no description regarding photostability.
Therefore, at present, there is no known rosuvastatin preparation that is stable to all of light, temperature, and humidity, or a method for producing the preparation.

JP 2002-212104 A WO97 / 37952 pamphlet JP 2003-104887 A JP 2000-7583 A JP 2000-191516 A Japanese Patent No. 5166676 JP-A-5-246844 JP 2002-532409 A Japanese Patent No. 3267960 Japanese Patent No. 4800908 International Publication No. 2008/062476

  An object of this invention is to provide the pharmaceutical formulation which contains rosuvastatin or its pharmaceutically acceptable salt, and was excellent in stability.

It is known that the chemical structure of rosuvastatin or a pharmaceutically acceptable salt thereof changes upon exposure to light, and the following decomposition compound (1) which is a diastereomer is generated.
When the HPLC analysis was actually performed using the preparation sample, the chart shown in FIG. 1 was obtained, and a photodegradation product composed of two peaks that were not observed before exposure could be confirmed.
In the present specification, these two photolysates 1 and 2 are defined as R.P. R. T1.6 and R.I. R. Expressed as T1.7.
When this decomposition product is produced, it becomes impossible to keep the content of rosuvastatin in the preparation constant, and there is a concern that a sufficient therapeutic effect cannot be obtained.
Furthermore, since the influence of this decomposition product on the living body is unknown, generation should be prevented.
Therefore, the present inventors have examined the pharmaceutical composition from the viewpoint of suppressing the production of the above-mentioned two kinds of degradation products, and have reached the present invention.
It has been found that such tablets are effective to contain rosuvastatin or a pharmaceutically acceptable salt thereof, a monovalent cationic inorganic salt, and a photoprotective agent.
In this case, a granule granule containing rosuvastatin or a pharmaceutically acceptable salt thereof, a monovalent cation inorganic salt, and a photoprotective agent, the latter component (photoprotective powder) containing the photoprotective agent It is good also as the tablet which added and tableted.
Moreover, it is good also as a tablet which formed the coating layer in which the granule containing the rosuvastatin or its pharmaceutically acceptable salt, monovalent | monohydric cation inorganic salt, and a photoprotective agent contains a photoprotective agent.
Furthermore, a coating layer containing a photoprotective agent is formed on granulated granules containing rosuvastatin or a pharmaceutically acceptable salt thereof, a monovalent cationic inorganic salt, and a photoprotective agent, and the coated granules Furthermore, it is good also as the tablet which added the latter component (photoprotective powder) containing a photoprotective agent, and was tableted.
The photoprotective agent is preferably any one or more of titanium oxide, iron oxide, and tar dye.
In addition, rosuvastatin is known to produce a lactone that is a decomposition product under warm and humid storage conditions.
Although it is a known fact that it is useful to add a basic substance to suppress the formation of this lactone body, as a result of investigation, it is not a basic substance but a monovalent cationic inorganic salt regardless of pH. It was found that the effect of suppressing lactone formation was higher.
That is, rosuvastatin or a pharmaceutically acceptable salt thereof contains a monovalent cationic inorganic salt, and further contains at least one selected from iron oxide, tar dye, and titanium oxide, so that temperature, humidity, light Therefore, the present invention was completed.
According to the present invention, the photostability of rosuvastatin or a pharmaceutically acceptable salt contained in the preparation is maintained without relying on film coating.
Therefore, in the case where there is a possibility that the tablet may be divided or pulverized, the degradation by exposure of rosuvastatin or a pharmaceutically acceptable salt thereof is suppressed, and the same applies to an orally disintegrating tablet in which film coating is not preferred. Therefore, degradation due to exposure is suppressed, and highly effective treatment for hyperlipidemia and hypercholesterolemia becomes possible.
In addition, monovalent cationic inorganic salts and the like that are blended for the purpose of suppressing lactone formation are often unpleasant tastes (bitterness, astringency).
As proposed in the present invention, a monovalent cationic inorganic salt is blended into the main drug-containing granule, and the main drug and the inorganic salt are in efficient contact with each other, whereby the blending amount of the monovalent cationic inorganic salt can be reduced.
Furthermore, since the elution of the monovalent cationic inorganic salt in the oral cavity can be suppressed by coating the granules, an unpleasant taste can be reduced as compared with the production method in which the monovalent cationic inorganic salt is dispersed throughout the tablet.
In the present invention, the content of titanium oxide as a photoprotective agent is preferably 0.01 to 25% by mass, more preferably 0.1 to 20%, based on the total amount of the preparation, from the viewpoint of preventing the degradation of rosuvastatin. % By mass, particularly preferably 0.5 to 15% by mass.
Examples of the iron oxide used in the present invention include yellow ferric oxide and ferric oxide.
Examples of tar dyes include food yellow No. 5, yellow No. 4, and the like and aluminum lakes thereof.
Among these, yellow iron sesquioxide is particularly preferable.
The content of iron oxide or tar-based pigment in the pharmaceutical preparation of the present invention is preferably 0.001 to 4% by mass, more preferably 0.005 to 4% by mass with respect to the total amount of the preparation from the viewpoint of preventing the degradation of rosuvastatin. It is 2 mass%, Most preferably, it is 0.01-1 mass%.
Known techniques such as dry granulation, fluidized bed granulation, rolling granulation, agitation granulation, spray granulation and the like can be used for granulation.
Fluidized bed granulation is particularly preferred because all of granulation, coating and drying can be performed with the same apparatus.
In the present invention, in addition to the photoprotective agent, orally administrable pharmaceutical additives such as excipients, binders, disintegrants, lubricants, and coating agents can be used.
Examples of the excipient include lactose hydrate, D-mannitol, crystalline cellulose, potato starch, corn starch, light anhydrous silicic acid, hydrous silicon dioxide and the like.
As binders, hydroxypropylcellulose, hypromellose, methylcellulose, polyvinyl alcohol, povidone, ethylcellulose, aminoalkyl methacrylate copolymer RS, vinyl acetate resin, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer S, Examples include promellose phthalate ester, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and the like.
Examples of the disintegrant include crospovidone, low-substituted hydroxypropyl cellulose, carmellose, croscarmellose sodium, sodium starch glycolate, carmellose calcium, and partially pregelatinized starch.
Examples of the lubricant include magnesium stearate, sucrose fatty acid ester, hydrogenated oil, talc and the like.
Examples of the coating agent include hypromellose, hydroxypropyl cellulose, ethyl cellulose, PEG 6000, triacetin, titanium oxide, iron sesquioxide, carnauba wax and the like.
Furthermore, you may mix | blend another component, for example, a sweetener, a corrigent, a coloring agent, a fragrance | flavor, etc. as needed.
The pharmaceutical preparation of the present invention preferably contains a monovalent cationic inorganic salt for the purpose of improving the temporal stability of rosuvastatin under warm and humid storage.
Examples of monovalent cation inorganic salts include sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, disodium citrate, sodium chloride and the like. Can do.

  Since the rosuvastatin-containing pharmaceutical preparation according to the present invention is excellent in light stability without coating the outer layer of the tablet with a photoprotective agent, it can be easily applied to orally disintegrating tablets.

The HPLC analysis chart after 600,000 Luxxhr exposure using the formulation sample which is not mix | blended with the photoprotective agent shown to the comparative example 1 is shown.

Examples and comparative examples will be described below in detail.
However, the present invention is not limited to these.
<Examples 1-5>
Table 1 shows the basic formulation using the photoprotective agents of Examples 1 to 5 shown in Table 2.
In addition, as Comparative Example 1, a composition without a photoprotective agent was formulated.
The basic formulation shown in Table 1 was tableted by the direct tableting method.
Specifically, rosuvastatin Ca, crystalline cellulose, sodium hydrogen carbonate, light anhydrous silicic acid, lactose hydrate, crospovidone, and a photoprotective agent were mixed and then sieved with a 30 mesh sieve.
Magnesium stearate was added to the sieved powder and mixed to obtain a tableting powder.
This tableting powder was tableted with a rotary tableting machine to obtain a tablet having a diameter of 7.0 mm.

<Experimental example 1>
The preparations of Examples 1 to 5 and Comparative Example 1 were stored for 1 week under a temperature of 25 ° C., a relative humidity of 60%, and an irradiation light of 4000 lx.
The amount of the related substance was measured for the stored preparation, and the content ratio of the amount of the related substance to the main drug content was determined.
The results are shown in Table 3.
Compared to Comparative Example 1 without the addition of the photoprotective agent, Examples 1 to 5 had less than half the amount of related substances after 1 week.
In particular, the effect of yellow ferric oxide was high, and the amount of related substances in Example 2 was 1/7 as compared with the comparative example.

<Examples 6 to 9>
The formulation shown in Table 4 was dry-granulated to form a main drug granule, and a tablet was prepared by adding photoprotective powder, light anhydrous silicic acid and magnesium stearate comprising the components shown in Table 5 to the granule.
Specifically, rosuvastatin Ca, crystalline cellulose, sodium hydrogen carbonate, light anhydrous silicic acid, yellow iron sesquioxide, and magnesium stearate were mixed and then sieved with a 30 mesh sieve.
This sieved powder was granulated with a dry granulator, the granulated product was granulated with a granulator, and the entire 18 mesh sieve was passed through to produce dry granulated granules.
Further, lactose hydrate, crystalline cellulose, crospovidone, and sodium bicarbonate were sprayed with a photoprotective solution or suspension to produce a photoprotective powder.
The dry granulated granules, photoprotective powder, light anhydrous silicic acid and magnesium stearate obtained above were mixed to obtain a tableting powder.
This tableting powder was tableted with a rotary tableting machine to obtain a tablet having a diameter of 7.0 mm.

<Experimental example 2>
The preparations of Examples 6 to 9 were stored for 1 week at 25 ° C., a relative humidity of 60%, and an irradiation light of 4000 lx.
The amount of the related substance was measured for the stored preparation, and the content ratio of the amount of the related substance to the main drug content was determined.
The results are shown in Table 7.
Compared to Example 2 which was the most effective in Experimental Example 1, Examples 6 to 11 were further suppressed in the amount of related substances after 1 week.
In particular, in Example 8, 1/10 or less compared to Comparative Example 1, and the amount of related substances was suppressed to about half compared to Example 2.

<Examples 12 and 13>
The formulation shown in Table 4 is dry-granulated, and the granules are coated with the coating base shown in Table 8 with a photomasking coating. The resulting photomasking-coated granules are coated with photoprotective powder, light anhydrous silicic acid, magnesium stearate. To make tablets.
Specifically, the dry granulated granules produced in Examples 6 to 11 were produced by the same formulation and production method, and hypromellose, magrogol, yellow ferric oxide, and titanium oxide solution were fluidized bed granulated into the obtained granules. Sprayed with a machine and applied a light masking coating.
The photomasking powder used in Example 6, light anhydrous silicic acid, and magnesium stearate were added to and mixed with the obtained photomasking-coated granules to obtain a tableting powder.
This tableting powder was tableted with a rotary tableting machine to obtain a tablet having a diameter of 7.0 mm.
The formulation shown in Table 9 was granulated and coated with a fluid bed granulator, and the resulting granulated and coated powder was added with photoprotective powder, light anhydrous silicic acid, and magnesium stearate, and tableted.
Specifically, rosuvastatin Ca, crystalline cellulose, sodium hydrogen carbonate, and light anhydrous silicic acid are prepared by spraying hypromellose, magrogol, yellow iron sesquioxide, and titanium oxide solution (dispersion) in a fluid bed granulator. The granules were coated, and the obtained granules were mixed with the photoprotective powder used in Example 6, light anhydrous silicic acid, and magnesium stearate, to obtain a tableting powder.
This tableting powder was tableted with a rotary tableting machine to obtain a tablet having a diameter of 7.0 mm.

<Experimental example 3>
The preparations of Examples 12 and 13 were stored at 25 ° C., a relative humidity of 60%, and an irradiation light of 4000 lx for 2 weeks.
The amount of the related substance was measured for the stored preparation, and the content ratio of the amount of the related substance to the main drug content was determined.
The results are shown in Table 10.
Compared to Example 8, which was the most effective in Experimental Example 2, Examples 12 and 13 were further suppressed in the amount of related substances after 2 weeks, and surprisingly, the values were similar to Example 8 (storage). The sample was suppressed to about half compared to the sample of 1 week period).

<Examples 14 and 15>
The formulation shown in Table 11 was granulated and coated with a fluidized bed granulator, and the resulting granulation / coating powder was further added with the latter ingredients to make tablets.
Specifically, after spraying rosuvastatin Ca, crystalline cellulose, crospovidone, sodium bicarbonate, light anhydrous silicic acid with hypromellose and yellow ferric oxide solution (dispersion) in a fluid bed granulator, further hypromellose, Eudragit E and titanium oxide solution (dispersion) were sprayed for granulation / coating, and the resulting granules were mixed with the ingredients shown in Table 11 to obtain a tableting powder.
This tableting powder was tableted with a rotary tableting machine to obtain a tablet having a diameter of 7.0 mm.

<Experimental example 4>
The preparations of Examples 14 and 15 were stored for 1 week under a temperature of 25 ° C., a relative humidity of 60%, and an irradiation light of 4000 lx.
The amount of the related substance was measured for the stored preparation, and the content ratio of the amount of the related substance to the main drug content was determined.
The results are shown in Table 12.
Surprisingly, by adding a photoprotective component (titanium oxide, yellow ferric oxide) at the end, the amount of related substances produced was suppressed to about 1/4.

<Examples 16 and 17 and Comparative Examples 2 and 3>
The basic formulation shown in Table 13 was produced by the direct compression method.
Specifically, rosuvastatin Ca, crystalline cellulose, and the stabilizers shown in Table 14 were mixed, and then sieved with a 30 mesh sieve.
Lactose hydrate and crospovidone were added to and mixed with this sieved powder, and further magnesium stearate was added and mixed to obtain a tableting powder.
In addition, since it was not mix | blended with the comparative example 3, in order to match | combine a tablet mass, lactose hydrate equivalent to the stabilizer addition amount was added as a substitute of a stabilizer.
This tableting powder was tableted at 7000 N to obtain a tablet having a diameter of 7.0 mm.
The tablets were coated with the coating composition shown in Table 13 (hypromellose, macrogol 6000, titanium oxide, yellow iron sesquioxide, iron sesquioxide) to obtain film-coated tablets.

<Experimental example 5>
Using the stabilizers of Examples 16 and 17 and Comparative Examples 2 and 3, preparations prepared as shown in Table 13 were stored at 40 ° C. and 75% RH (opened) for 2 weeks.
The amount of the related substance was measured for the stored preparation, and the content ratio of the amount of the related substance to the main drug content was determined.
The results are shown in Table 15.
The trisodium phosphate combination preparation (Example 14) and the sodium bicarbonate combination preparation (Example 15) hardly detect the lactone form, and are extremely stable even under storage under warm and humid conditions.
On the other hand, the tricalcium phosphate combination preparation (Comparative Example 2), which is a divalent cation inorganic salt, and the preparation not containing the cation inorganic salt (Comparative Example 3) have an increased lactone form compared to Examples 16 and 17. It was big.
In the preparation of Example 15, in the same experiment as described above, the lactone form was 0.01% at the start, but 0.02% after storage for 2 weeks.

Claims (5)

Rosuvastatin or a pharmaceutically acceptable salt thereof,
A monovalent cationic inorganic salt , sodium bicarbonate or trisodium phosphate,
Tablets tableted mixture as a light protection agent containing a 0.001 to percent by weight of yellow ferric oxide to a tablet. In the dry granulated granule of the mixture according to claim 1 ,
Tablets added with a powdered ingredient (photoprotective powder) containing yellow ferric oxide as a photoprotective agent. A tablet in which a dry granulated granule of the mixture according to claim 1 is provided with a coating layer containing yellow ferric oxide as a photoprotective agent. In the dry granulated granule of the mixture according to claim 1 ,
Forming a coating layer containing the yellow ferric as light protection agent, the coated granules was as light protective agent and tablets powder component (light protection powder) was added strokes after that contain yellow ferric oxide tablets. An orally disintegrating agent comprising the tablet according to any one of claims 1 to 4 .