JP5506415B2 - Oral solid preparation containing HMG-CoA reductase inhibitor - Google Patents

Description

The present invention relates to a stabilized oral solid formulation containing an HMG-CoA reductase inhibitor. The HMG-CoA reductase inhibitor is an effective drug for the treatment of hypercholesterolemia and is selected from the group consisting of pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin and their salts. The HMG-CoA reductase inhibitor as used herein includes pharmaceutically acceptable salts and hydrates thereof, and may be collectively referred to as a free form unless it means a specific salt.

HMG-CoA reductase inhibitors are generally unstable to heat, moisture and acid. Since these have a hydroxy acid in common and easily produce a lactone form which is a related substance in an acidic environment, various stabilization patents have been filed.

Patent Document 1 mentions the use of an alkaline earth metal salt such as calcium carbonate, calcium hydroxide, or magnesium carbonate as a stabilizing metal salt additive for atorvastatin.
Patent Document 2 shows that the amount of use should be kept as small as possible because alkaline earth metal salts affect atorvastatin bioavailability. Since these alkaline earth metal salts cause moisture absorption, in the case of an oral solid preparation such as a tablet, there is a concern about a decrease in hardness under high humidity conditions.
Patent Document 3 describes a pharmaceutical composition characterized in that it contains an HMG-CoA reductase inhibitor having a ring-opened hydroxy acid structure as an active ingredient, and the aqueous dispersion or aqueous solution has a pH of less than 9. Basic amino acids are mentioned as stabilizers. In addition, based on the knowledge that stability is impaired by contact with a compound containing a metal in the structure, formulation examples are disclosed in which any metal compound is excluded. However, comparing the structures of each HMG-CoA reductase inhibitor, for example, there are those that have a heterocyclic ring and those that do not, and this difference affects fat solubility, and naturally it also causes differences in properties. Conceivable. However, in this example, only pravastatin sodium has been studied, and in view of the report of Patent Document 1, it is unclear whether the present invention is applicable to all HMG-CoA reductase inhibitors.
In Patent Document 4, there is a preparation in which a tablet containing pravastatin is coated with a coating solution in which hydroxypropylmethylcellulose is dissolved and further coated with hydroxypropylmethylcellulose acetate maleate or hydroxypropylmethylcellulose trimellitate.
Similarly, Patent Document 5 discloses a preparation in which an outer layer is coated with hydroxypropylmethylcellulose acetate succinate. Since these outer layer coating agents have a carboxyl group, they cannot be directly coated with an acid-labile HMG-CoA reductase inhibitor, so a subbing is required, and the process is complicated.
Patent Document 6 discloses that granules are prepared by spray-coating a mixture of pravastatin sodium and D-mannitol with a solution of aminoalkyl methacrylate copolymer or ethyl cellulose in ethanol.
In Patent Document 7, in order to obtain a solid dispersion containing amorphous atorvastatin, a melt-processable polymer is softened or melted to disperse atorvastatin in a polymer carrier. Therefore, the mixing temperature is as high as 130 to 180 ° C., and it is considered difficult to control the production conditions.
In Patent Document 8, a drug powder or a mixed powder of the drug and an additive is granulated in order to solve the tableting trouble, and the surface of the granulated product is coated with a polymer film agent. In Example 11, a granulated product of atorvastatin calcium and light anhydrous silicic acid is coated with an aqueous solution of polyvinyl alcohol. In this invention, only the examples in which polyvinyl alcohol is combined with atorvastatin calcium and the sticking occurrence level score of the preparation are shown, and it is not clear whether a stable preparation can be obtained by this method.
The present inventors have found that when an HMG-CoA reductase inhibitor such as atorvastatin comes into contact with a high-temperature environment or a water-rich excipient, undesirable events such as an increase in lactone form occur. The present inventors tried to apply the technique described in Patent Document 6 to atorvastatin, but did not satisfy the stability required for pharmaceuticals.

Japanese National Patent Publication No. 08-505640 JP-T-2006-527260 JP 2003-055217 A JP 2000-159692 A JP 2000-264846 A JP 2004-339072 A Special table 2008-521878 gazette JP 2009-099882 A

The problem to be solved by the present invention is to provide a preparation having excellent temporal stability in an oral solid preparation containing an HMG-CoA reductase inhibitor.

As a result of diligent studies to solve these problems, the inventors of the present invention, when granulating a HMG-CoA reductase inhibitor alone or a mixture of the drug and a basic amino acid with a gastric polymer, is effective against the heat and humidity of the drug. It was found that stability is increased. It has also been found that the effect is further increased when a gastric polymer powder is added to the granulated product and granulated.

The HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin and salts thereof. Those having a heterocyclic ring in the structure are particularly preferred, and include fluvastatin, atorvastatin, pitavastatin, rosuvastatin and salts thereof.

A basic amino acid refers to an amino acid having a basic residue in addition to the α-amino group. The aqueous solution or dispersion is basic, for example, a 5% aqueous solution with a pH> 7. The basic amino acid referred to in the present invention includes D-form, L-form and DL-form. Examples include arginine, lysine, and histidine, and L-arginine is particularly suitable for maintaining the stability of the present formulation in a humid environment. The method of mixing these basic amino acids with the drug is not limited as long as the basic amino acid powder or granulated product is directly mixed with the drug, such as by mixing it with the drug. As an example, mixed pulverization is suitable for the above purpose, and a ball mill, a sample mill, a jet mill or the like is used as a pulverizer. There is an advantage that the particle size of the drug and the basic amino acid is made uniform by mixing and grinding, and the subsequent granulation step becomes easy.

The HMG-CoA reductase inhibitor or a mixture of the drug and a basic amino acid is granulated with a gastric soluble polymer. As the gastric polymer, aminoalkyl methacrylate copolymer and polyvinyl acetal diethylaminoacetate are preferable, and aminoalkyl methacrylate copolymer (trade name Eudragit E, EPO) is particularly preferable. These polymers may be used alone or mixed at an appropriate ratio according to the purpose and used for granulation.

In consideration of drug stability, granulation is preferably performed in an organic solvent system, particularly preferably based on ethanol or hydrous ethanol that is harmless to the environment and the human body. Although the granulation method is arbitrary, stirring granulation or fluidized bed granulation is preferable. In the case of stirring granulation, the drug mixed with the basic amino acid is stirred, and the polymer solution is dropped or sprayed on the flowing powder layer, and granulated by granulation with a stirring blade and pulverization granulation with a chopper. The In the case of fluidized bed granulation, a drug mixed with a basic amino acid is fluidized in a powder form, sprayed with the polymer solution, and dried to obtain a granulated product. Alternatively, the whole amount or a part of the polymer may be put in powder form into a mixture of a basic amino acid and a drug and allowed to flow, and then an organic solvent or a solution composed of the organic solvent and the remaining polymer may be sprayed. These polymers may be used alone or may be mixed in an appropriate ratio depending on the purpose. The ratio of gastric soluble polymer to drug is suitably in the range of 0.03: 1 to 2: 1 by weight.

In addition, granulation should be performed so that the resulting granulated product converges to a certain particle size distribution. For example, when “volume average particle diameter (D50)” is used as an index, the obtained granulated product is preferably D50 = 0.5 to 20 (μm), more preferably D50 = 1 to 10 (μm). If it deviates from this range, it will affect the obstacles and dissolution during tableting. The “volume average particle size (D50)” can be determined using, for example, Aerotrac SPR (manufactured by Nikkiso Co., Ltd.) which is a spray particle size distribution measuring device.

In the case of obtaining a tablet, it is produced by mixing the granulated product obtained above with a desired excipient and lubricant in an appropriate ratio, and tableting. In another embodiment, a powdery polymer, excipient and disintegrant are mixed with this granulated product, and then a secondary granulated product is obtained by a conventional method, and an appropriate excipient, disintegrant and A lubricant can be mixed and compressed into tablets. This process can further enhance the stability of the tablet against heat and humidity. These polymers may be used alone, or several kinds may be mixed in an appropriate ratio according to the purpose.

In addition to excipients and lubricants, tablets can contain light stabilizers (titanium oxide, iron sesquioxide, etc.), sweeteners, and coloring agents.

The invention is illustrated by the following non-limiting examples using atorvastatin calcium as the HMG-CoA reductase inhibitor. However, Examples 1-3 are reference examples.

Example 1
131.4 g of atorvastatin calcium hydrate was put into a high-speed stirring granulator (high speed mixer LFS-GS-2J), and polysorbate 80 5.5 g and Eudragit E 4.6 g were mixed with absolute ethanol (99.5 v / v%) 38 mL. The solution dissolved in was sprayed and further dried to obtain a granulated product. D50 of this granulated product was 13 μm.

11.8 g of this granulated product is mixed with 62.8 g of lactose, 46 g of crystalline cellulose, 14 g of croscarmellose sodium and 4 g of hydroxypropylcellulose SL, and further mixed with 1.4 g of magnesium stearate, and a rotary tableting machine is prepared. Tablet was obtained by using the tablet.

Film coating process The coating solution was adjusted so that the coating amount per tablet of this tablet was as shown below, and the tablets were film-coated sequentially by a conventional method.
Hydroxypropyl methylcellulose (TC-5R): 2.9 mg
Titanium oxide: 0.2mg
Talc: 0.4mg
Polyethylene glycol 6000: 0.5mg

Example 2
After 130.2 g of atorvastatin calcium hydrate was put into a high speed stirring granulator (high speed mixer LFS-GS-2J), polysorbate 80 5.5 g and Eudragit E 4.6 g were added to absolute ethanol (99.5 v / v%). A solution dissolved in 16 mL was sprayed and further dried to obtain a granulated product. D50 of this granulated product was 2.6 μm.

Secondary granulation step 185.1 g of lactose, 138.0 g of crystalline cellulose, 21.0 g of croscarmellose sodium, and 9.9 g of hydroxypropylcellulose SL were added to 35.1 g of this granulated product at a high speed stirring granulator (high speed mixer LFS- GS-2J) was mixed after mixing, and a solution obtained by dissolving 2.1 g of hydroxypropylcellulose SL in 32 mL of absolute ethanol (99.5 v / v%) was sprayed and further dried to obtain a secondary granulated product. 13.2 g of croscarmellose sodium and 3.9 g of magnesium stearate were added to and mixed with 363.2 g of this secondary granulated product, and tableted using a rotary tableting machine to obtain tablets.

Example 3
Using the tablets obtained in Example 2, film-coated tablets were obtained in the same manner as in Example 1.

Example 4
1300.8 g of atorvastatin calcium hydrate and 120.0 g of L-arginine were charged into a hammer type fine pulverizer (Sample Mill KIIW-2) and pulverized for 60 minutes. After 142.2 g of this mixed pulverized powder was put into a high speed agitation granulator (high speed mixer LFS-GS-2J), polysorbate 80 5.5 g and Eudragit E 4.6 g were mixed with absolute ethanol (99.5 v / v%) 16 mL. The solution dissolved in was sprayed and further dried to obtain a granulated product. D50 of this granulated product was 2.5 μm. Hereafter, according to the secondary granulation process and the film coating process according to Example 1, 2, the film coating tablet was obtained.

Example 5
1300.8 g of atorvastatin calcium hydrate and 240.0 g of L-arginine were charged into a hammer type fine grinder (Sample Mill KIIW-2) and ground for 60 minutes. After 154.0 g of this mixed pulverized powder was put into a high speed agitation granulator (high speed mixer LFS-GS-2J), polysorbate 80 5.5 g and Eudragit E 4.6 g were mixed with absolute ethanol (99.5 v / v%) 16 mL. The solution dissolved in was sprayed and further dried to obtain a granulated product. D50 of this granulated product was 2.6 μm. Hereafter, according to the secondary granulation process and the film coating process according to Example 1, 2, the film coating tablet was obtained.

Example 6
1300.8 g of atorvastatin calcium and 120.0 g of L-arginine were charged into a hammer type fine grinder (Sample Mill KIIW-2) and ground for 60 minutes. After 130.2 g of this mixed pulverized powder and 6 g of Eudragit EPO were put into a high speed stirring granulator (High Speed Mixer LFS-GS-2J), 5.5 g of polysorbate 80 and 4.6 g of Eudragit E were added to absolute ethanol (99.5 v). / V%) A solution dissolved in 16 mL was sprayed and further dried to obtain a granulated product. D50 of this granulated product was 2.5 μm. Hereafter, according to the secondary granulation process and the film coating process according to Example 1, 2, the film coating tablet was obtained.

Comparative Example 1
A solution obtained by charging 130.2 g of atorvastatin calcium hydrate into a high-speed stirring granulator (high speed mixer LFS-GS-2J) and dissolving 5.6 g of polysorbate 80 in 16 mL of absolute ethanol (99.5 v / v%) Spraying and further drying gave a granulated product. D50 of this granulated product was 4.9 μm. Hereinafter, film-coated tablets were obtained according to the secondary granulation step and the film coating step.

Stability test 1
The tablets of Examples 1 to 6 and Comparative Example 1 were stored under open conditions (40 ° C. and 75% RH), and the amounts of lactone formed after 1 week and 2 weeks were measured by liquid chromatography under the following conditions. . The results are shown in Table 1.

Stability test 2
The tablets of Example 5 and Comparative Example 1 were stored under sealed conditions (70 ° C.), and the amount of lactone formed after 1 week and 2 weeks was measured by liquid chromatography under the following conditions. The results are shown in Table 2.

Lactone measurement condition detector: UV absorption photometer (measurement wavelength: 245 nm)
Column: ODS
Flow rate: 0.4 mL / min
Mobile phase A: aqueous ammonium acetate + methanol + formic acid mobile phase B: acetonitrile

Claims (4)

A secondary granulated product obtained by granulating a primary granulated product obtained by granulating a mixture of atorvastatin calcium and a basic amino acid with a gastric polymer and adding at least an excipient and a disintegrant. The secondary granulated product according to claim 1, wherein the gastric soluble polymer is selected from polyvinyl acetal diethylaminoacetate or aminoalkyl methacrylate copolymer. The secondary granulated product according to claim 1, wherein a gastric soluble polymer in powder form is added during the secondary granulation. A tablet obtained by tableting by adding at least a lubricant to the secondary granulated product according to any one of claims 1 to 3.