KR20040042896A - Pharmaceutical composition - Google Patents

Abstract

PURPOSE: A medicinal preparation composition containing 2-amino-6-(4-methoxyphenylthio)-9-(2-(phosphonomethoxy)ethyl)purine bis(2,2,2-trifluoroethyl) ester as an active ingredient is provided. It enables the production of a tablet which has storage stability and is capable of inhibiting the change in the external appearance and formation of dimers caused by light by film coating using titanium oxide having a purity of 99% or higher. CONSTITUTION: The medicinal preparation composition contains 2-amino-6-(4-methoxyphenylthio)-9-(2-(phosphonomethoxy)ethyl)purine bis(2,2,2-trifluoroethyl) ester as an active ingredient and is characterized in that the 2-amino-6-(4-methoxyphenylthio)-9-(2-(phosphonomethoxy)ethyl)purine bis(2,2,2-trifluoroethyl) ester is substantially inhibited from the formation of a dimer of the formula 1 and/or hydrolysate thereof. The composition is a tablet and has a coating layer containing metal impurities of trivalents or lower, titanium oxide having a purity of 99% or higher and a hydrophilic compound. The composition has a moisture content of about 3% or less.

Description

Pharmaceutical formulation composition {PHARMACEUTICAL COMPOSITION}

The present invention relates to a pharmaceutical formulation composition, specifically 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2- A pharmaceutical formulation composition comprising trifluoroethyl) ester as an active ingredient.

As a method for suppressing photolysis of raw medicine and preventing changes in appearance due to light from tablets, shading coatings for shading predetermined cells or shading packages for shading by packaging This is known. Among these methods, the method of shielding the bulk of the formulation is preferable because the method of shielding by packaging cannot guarantee the stability after opening the package. In the shading of tablets, shading by film coating and shading by sugar coating are generally used. Among the coating components, titanium oxide is commonly used as a light shielding component.However, the titanium oxide used in medicines has a purity and impurity content specified in the procedures of each country, and is generally high purity. The use of the thing with low impurity content is calculated | required.

2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester (hereinafter referred to as "Compound A Is a compound known as an anti-HBV agent described in Patent Document 1 (Japanese Patent Application Laid-Open No. 9-255695). As for the formulation of this compound, Only general formulation techniques are known.

Predetermined compound A described above is yellow in color due to light change. In a coated tablet coated with one or more layers by a light-shielding coating film containing a general hydrophilic substance and titanium oxide, two molecules of Compound A react with light to generate a dimer. . On the other hand, in the film coating tablet which does not contain titanium oxide, light shielding ability is not enough, and a tablet produces an appearance change. Moreover, in the coating of sugars containing no titanium oxide, the light-shielding performance is sufficient, but since the water content of the nuclei in the sugar-coated tablets cannot be reduced, the tablets are liable to be hydrolyzed and insufficient in storage stability.

As a result of various studies to solve the above problems, the present invention contains a small amount of trivalent or less metal impurities in a predetermined amount of Compound A, and the purity of titanium oxide is the standard of each country's procedures. It has been found that the film coating using titanium oxide having a purity of 99% or more that satisfies can provide a tablet which suppresses the appearance change of the tablet and the generation of the dimer by light. Furthermore, since this tablet can easily control the water content in the tablet, the purification of the reduced water content suppresses the hydrolysis of Compound A in the tablet, confirming that the storage stability is also excellent and completed the present invention.

That is, the gist of the present invention is as follows.

(1) 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester as an active ingredient A dimer of this 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; A pharmaceutical formulation composition wherein the production of hydrolyzate is substantially inhibited.

(2) The composition according to the above (1), wherein the dimer is a compound represented by the following formula (1).

(3) The composition according to the above (1) or (2), wherein the hydrolyzate is a compound represented by the following formula (2).

(4) The composition according to any one of (1) to (3), which is a tablet.

(5) The composition according to any one of (1) to (4), having a coating layer.

(6) The composition according to the above (5), wherein the coating layer contains a trivalent or less metal impurity and contains titanium oxide having a purity of 99% or more.

(7) The composition according to the above (5), wherein the coating layer contains a trivalent or less metal impurity and contains titanium oxide and a hydrophilic compound having a purity of 99% or more.

(8) The composition according to the above (6) or (7), wherein the titanium oxide is about 200% or less relative to the concentration of the hydrophilic compound in the coating layer.

(9) The composition according to any one of (6) to (8), wherein the titanium oxide is at least about 6% relative to the concentration of the hydrophilic compound in the coating layer.

(10) The hydrophilic compound according to any one of (6) to (9), wherein the hydrophilic compound is selected from polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose. And hydroxyethyl cellulose.

(11) The composition according to any one of (6) to (9), wherein the hydrophilic compound is hydroxypropyl methylcellulose.

(12) The composition according to any one of (1) to (11), wherein the water content is about 3% or less based on the total weight of the pharmaceutical formulation composition.

(13) The composition according to any one of (1) to (11), wherein the water content is about 2.8% or less based on the total weight of the pharmaceutical formulation composition.

(14) The composition according to any one of (1) to (13), wherein the water content is about 1% or more based on the total weight of the pharmaceutical formulation composition.

(15) The composition according to any one of (4) to (14), wherein the composition contains a main additive having a water content of about 2% or less in a predetermined amount.

(16) The composition according to any one of (1) to (15), wherein the composition contains D-mannitol.

(17) The composition according to any one of (1) to (16), which contains 2.5 mg, 5 mg, 10 mg or 20 mg of the active ingredient.

(18) The composition according to any one of (1) to (17), which is used as an antiviral agent.

(19) The composition according to the above (18), wherein the virus is hepatitis B virus or varicella zoster virus.

1 is a view showing a light stability test results of Example 1.

2 is a view showing a light stability test result of Example 12.

Hereinafter, the present invention will be described in detail.

The present invention uses 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester as an active ingredient. It is a pharmaceutical formulation composition. 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester is disclosed in Japanese Patent Laid-Open No. 9-255695 It is a well-known compound as described in a publication, and can be suitably manufactured by the method as described in this publication, or the method according to it.

In the present invention, a dimer of 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester and A pharmaceutical formulation composition is provided in which production of hydrolyzate is substantially inhibited. Dimer here is a compound represented by said formula (1), A hydrolyzate is a compound represented by said formula (2).

In the present invention, the production of these compounds may be suppressed within a pharmaceutically acceptable range, but the amount of inhibition is not particularly limited. As an example, the generation | occurrence | production of the compound represented by said formula (2) in the storage stability test of Example 1 demonstrated below is about 3% or less (40 degreeC and 75% RH). The production of the compound represented by the above formula (1) is about 2% or less, preferably about 1% or less, and more preferably about 0.5% or less in the light stability test described in Example 1 described below. Can be.

The pharmaceutical formulation composition of the present invention includes tablets, powders (including granules, fine granules), and the like, and preferably tablets.

In this invention, the film coating tablet which carried out the film coating about predetermined | prescribed among the tablets is a preferable example.

In consideration of the fact that the compound A is liable to cause hydrolysis, the main additive used in the predetermined is preferably about 2% or less of water content, and D-mannitol and the like are preferable.

And in the pharmaceutical formulation composition of this invention, it is preferable to have a coating layer. It is preferable that the coating layer contains a trace amount of trivalent or less metal impurities and contains titanium oxide having a purity of 99% or more. Titanium oxide with a purity of 99% or higher as described above means titanium oxide with a purity of 99% or higher that satisfies the standards of each country's process. Furthermore, the coating layer contains a hydrophilic compound in addition to the titanium oxide described above. The hydrophilic compound is not particularly limited as long as it is a hydrophilic compound that is usually used for film coating of a pharmaceutical formulation. For example, polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, etc. are mentioned, Preferably it is hydroxypropyl methyl cellulose.

In the coating layer, titanium oxide containing a trace amount of trivalent or less metal impurities, and having a purity of 99% or more, the upper limit for the concentration of the water-soluble compound in the coating layer is the roughness and color of the shell of the tablet surface (graying Although it is determined in the range that does not affect, etc., it is preferable that it is about 200% or less, and the minimum is about 6% as a preferable example.

The pharmaceutical formulation composition provided by the present invention can easily control the water content during manufacture. As a result, a pharmaceutical formulation composition having reduced water content can be provided, and 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2, The production | generation of the pharmaceutical formulation composition excellent in storage stability can be provided by suppressing production | generation of the compound represented by said Formula (2) which is a hydrolyzate of 2-trifluoroethyl) ester. Specifically, a pharmaceutical formulation composition having a water content of about 3% or less based on the total weight of the pharmaceutical formulation composition is preferable, and more preferably, a case where the moisture content is about 2.8% or less, and a lower limit of the moisture content is preferably about 1% or less. .

EXAMPLE

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples without departing from the gist of the present invention. And 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester used in the examples below [Hereinafter, sometimes referred to simply as "Compound A"] is manufactured according to the method of Unexamined-Japanese-Patent No. 9-255695.

Example 1 Preparation of Predetermined

Compound A and D-mannitol (content 2% or less) were mixed at a ratio of 1:20 by weight ratio, and the pellet tablet (1) was obtained by a tablet molding machine. Similarly, instead of D-mannitol, lactose [lactose; Water content of about 4-6%] to obtain pellet tablets (2). The results of the storage stability tests (40 ° C. and 75% RH, 3 months storage at 50 ° C.) of the pellet tablets (1) and (2) are shown in Table 1 below. The comparison of the stability was expressed by the color difference ΔE from the beginning of the pellet definition and the% production of the compound (hydrolyzate) represented by the formula (2). From these results, it can be seen that D-mannitol, which is a representative of a small water-containing main additive, is stable in comparison of the color change and the percentage of hydrolyzate produced.

TABLE 1 Preservation stability test of pellet tablets (1) and (2)

Color difference △ E

40 ° C. and 75% RH 50 ℃ Pellet tablet (2) 6.95 2.42 Pellet Tablet (1) 1.27 1.04

Production (%) of the compound represented by the formula (2)

40 ° C. and 75% RH 50 ℃ Pellet tablet (2) 4.77 1.55 Pellet Tablet (1) 2.34 1.74

Subsequently, the light stability test was done using the pellet tablet (1) obtained above. That is, predetermined | prescribed and predetermined | prescribed light was shielded with aluminum foil, and the light was irradiated to 1.2 million Lux.hr in 2000 Lux conditions with the D65 lamp, and the color difference ((DELTA) E) from the beginning of a tablet was measured. The result is shown in FIG. From these results, it was found that the appearance caused a change in appearance (coloring), the color difference (ΔE) increased, and coloring by light.

Each predetermined with the composition shown in Table 2 below was prepared with reference to the above examples.

Example 2

100 g of compound A, 3,700 g of D-mannitol and 924 g of corn starch were added to a high speed mixer (manufactured by Deep River Industries, Ltd., FS-GS-25J) and mixed. The resulting mixture was poured into a flow coater (FLO-5M, manufactured by Freund Industries, Inc.) and sprayed with 124 g of hydroxypropylcellulose (hereinafter sometimes referred to simply as "HPC") dissolved in 2070 g of purified water as a binder. It was assembled. After drying the granulated material and passing through a sieve, 52 g of low-substituted hydroxypropyl cellulose (hereinafter sometimes referred to simply as "LHPC"), magnesium stearate (vegetable plant made in Japan) The mixture was added to a V-type mixer (SVM-50, manufactured by Nihon Kogyo Co., Ltd., Japan), and mixed, and tablets were prepared by a rotary tablet press (Aquarius, Japan).

Example 3

200 g of Compound A, 3,580 g of D-mannitol and 896 g of corn starch were added to a high speed mixer (manufactured by Deep Industries Co., Ltd., FS-GS-25J) and mixed. The obtained mixture was poured into a flow coater (FLO-5M, manufactured by Freund Industries, Inc.) and spray granulated using 124 g of hydroxypropyl cellulose dissolved in 2070 g of purified water as a binder. After drying the granulated material and passing through a sieve, a V-type mixer (made in Japan, SVM, together with 100 g of low-substituted hydroxypropyl cellulose and 100 g of magnesium stearate (vegetable vegetable made in Japan) -50), and then mixed, tablets were prepared in a rotary tablet press (AQUARIUS, Japan).

Example 4

400 g of Compound A, 3,380 g of D-mannitol and 844 g of corn starch were added to a high speed mixer (manufactured by Deep River Industries, Ltd., FS-GS-25J) and mixed. The obtained mixture was poured into a flow coater (FLO-5M, manufactured by Freund Industries, Inc.) and spray granulated using 124 g of hydroxypropyl cellulose dissolved in 2070 g of purified water as a binder. After drying the granulated material and passing through a sieve, a V-type mixer (SVM made in Japan, SVM) together with 152 g of low-substituted hydroxypropyl cellulose and 100 g of magnesium stearate (vegetable vegetable made in Japan) -50), and then mixed, tablets were prepared in a rotary tablet press (AQUARIUS, Japan).

Example 5

800 g of compound A, 2,980 g of D-mannitol and 744 g of corn starch were added to a high speed mixer (manufactured by Deep Industries, Ltd., FS-GS-25J) and mixed. The obtained mixture was poured into a flow coater (FLO-5M, manufactured by Freund Industries, Inc.) and spray granulated using 124 g of hydroxypropyl cellulose dissolved in 2070 g of purified water as a binder. After drying the granulated material and passing through a sieve, V-type mixer (made in Japan, SVM, together with 252 g of low-substituted hydroxypropyl cellulose and 100 g of magnesium stearate (vegetable vegetable made in Japan) -50), and then mixed, tablets were prepared in a rotary tablet press (AQUARIUS, Japan).

TABLE 2 Prescription of Prescription

Example 2 Example 3 Example 4 Example 5 Compound A 2.5 5 10 20 D-mannitol 92.5 89.5 84.5 74.5 Corn starch 23.1 22.4 21.1 18.6 LHPC 1.3 2.5 3.8 6.3 HPC 3.1 3.1 3.1 3.1 Magnesium stearate 2.5 2.5 2.5 2.5 Predetermined total weight (mg) 125 125 125 125

Example 6: Preparation of Coated Tablets

439 g of purified water, hydroxypropyl methylcellulose (hereinafter sometimes referred to simply as "HPMC") 2910 35 g, propylene glycol 7 g, talc 5 g, and high purity titanium oxide, for a given 700 g obtained in Example 2 above. A coating liquid of 10.5 g of (titanium titanium made in Japan, NA-61) or titanium oxide having a purity of 99% or more containing trivalent or less impurities (A-100 made by Japan, A-100) was prepared. This coating solution was spray-dried in a pan-type coating machine (manufactured by Freund Industrial Co., Ltd., HCT-30) at predetermined time to coat the coating film so that the coating film per tablet was 5 mg. Coated tablets were prepared by powder addition coating a small amount of cured oil thereto. Table 4 shows the results of the light stability test of the prepared tablets. And the light stability test was done by the method of Example 1.

From Table 4, when a high purity titanium oxide is used, the appearance change does not appear, but it can be seen that many compounds (dimers) represented by the formula (1) are produced.

Table 3 Coated Prescription

Coating prescription mg HPMC 2910 3.04 Propylene glycol 0.61 Titanium oxide 0.91 Talc 0.43 Cured oil 0.125 Total weight (mg) 5

TABLE 4 Effect of containing trivalent or less impurity ions in titanium oxide

Dimer Generation% High purity titanium oxide 2.04 Titanium oxide with trace impurities 0.68

Example 7

Coating prescribed | regulated as a coating formulation as shown in Table 5 using the titanium oxide containing a trace amount trivalent or less impurity as a light-shielding agent by predetermined | prescribed by the method similar to Example 2 as a light-shielding agent. Coating was carried out in the same manner as in Example 6, to prepare three coating tablets with a titanium oxide content in the coating film up to 6.7 to 20.0%. Table 6 shows the results of the same photostability test as in Example 1 on the prepared coated tablets. It can be seen that the coating tablet having a titanium oxide content of 6.6% in the coating film has a small color difference (ΔE) and a small amount of the compound (dimer) represented by the formula (1).

[Table 5] Coating prescription

Titanium oxide content (%) 6.6% 12.4% 20.0% ingredient mg mg mg HPMC 2910 3.33 3.13 2.86 Propylene glycol 0.78 0.73 0.67 Titanium oxide 0.33 0.62 1.00 Talc 0.56 0.52 0.48 Cured oil 0.06 0.06 0.06 Total weight (mg) 5 5 5

[Table 6] Relationship between titanium oxide content and stability in coating film

Titanium Oxide Content (%) 6.6% 12.4% 20.0% Color difference (△ E) 0.40 0.60 0.68 Dimer Generation% 0.38 0.95 1.26

Examples 8, 9, 10 and 11

Coating prescribed | regulated in Example 2, 3, 4, and 5 by the same method as Example 6 with the coating prescription as shown in Table 7 was carried out. That is, titanium oxide having a purity of 99% or more containing 1,820 g of purified water, 120 g of hydroxypropyl methylcellulose, 28 g of propylene glycol, 28 g of talc, 20 g of talc, or less than trivalent impurities (A-100, Japan). Prepare a coating solution of 12 g. The coating liquid is spray-dried in a pan-type coating machine (Paureg, DRC-500) at a predetermined time and coated so that the coating film per tablet is 5 mg. Coated tablets are prepared by powder addition coating a small amount of hardened oil thereto.

Table 8 shows the results of the light stability test of Example 8 and Example 11 of the prepared tablet (the same light stability test as in Example 1). It is understood that the color difference (ΔE) is also small in a sufficient permissible range, and the amount of dimers produced is also small and stable.

TABLE 7 Prescription and Coating

Example 8 Example 9 Example 10 Example 11 Compound A 2.5 5 10 20 D-mannitol 92.5 89.5 84.5 74.5 Corn starch 23.1 22.4 21.1 18.6 LHPC 1.3 2.5 3.8 6.3 HPC 3.1 3.1 3.1 3.1 Magnesium stearate 2.5 2.5 2.5 2.5 Predetermined total weight (mg) 125 125 125 125 Coating prescription HPMC 2910 3.35 3.35 3.35 3.35 Propylene glycol 0.77 0.77 0.77 0.77 Titanium oxide 0.33 0.33 0.33 0.33 Talc 0.55 0.55 0.55 0.55 Cured oil 0.0625 0.625 0.625 0.625 Coating layer weight (mg) 5.06 5.06 5.06 5.06 Tablet total weight (mg) 130 130 130 130

[Table 8] Light Stability Test Results

Color difference (△ E) Dimer Generation% Coated Tablets Obtained in Example 8 1.77 0.45 Coated Tablets Obtained in Example 11 2.21 0.05

Example 12

The film coated tablets obtained in Example 9 were stored for 3 days under various relative humidity to control the water content in the tablets. These tablets were placed in airtight containers (glass bottles) and stored at 25 ° C. and 60% RH to compare stability. The result is shown in FIG. It can be seen from FIG. 2 that as the water content increases, the compound represented by Formula (2) increases.

According to the present invention, 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester is effective. As a component, this 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester is effective. A stable pharmaceutical formulation composition comprising the components can be provided.

While the invention has been described in detail with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the invention.

In addition, this application is based on the JP Patent application (Japanese Patent Application No. 2002-332162) for which it applied to Japan on November 15, 2002, The whole is taken in into consideration.

Claims (19)

2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester is used as an active ingredient, and Dimer and / or valence of 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester A pharmaceutical formulation composition wherein the production of degradation products is substantially inhibited. The composition according to claim 1, wherein the dimer is a compound represented by the following formula (1). The composition of Claim 1 or 2 whose hydrolyzate is a compound represented by following formula (2). The composition according to any one of claims 1 to 3, which is a tablet. The composition of claim 1 having a coating layer. The composition according to claim 5, wherein the coating layer contains a trivalent or less metal impurity and contains titanium oxide having a purity of 99% or more. The composition according to claim 5, wherein the coating layer contains a trivalent or less metal impurity and contains titanium oxide and a hydrophilic compound having a purity of 99% or more. 8. The composition of claim 6 or 7, wherein the titanium oxide is about 200% or less relative to the concentration of hydrophilic compound in the coating layer. The composition of claim 6, wherein the titanium oxide is at least about 6% relative to the concentration of hydrophilic compound in the coating layer. The hydrophilic compound according to claim 6, wherein the hydrophilic compound is selected from polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose and hydroxyethyl cellulose. Composition selected. 10. The composition of any one of claims 6-9, wherein the hydrophilic compound is hydroxypropyl methylcellulose. The composition of claim 1, wherein the water content is about 3% or less based on the total weight of the pharmaceutical formulation composition. The composition of claim 1, wherein the water content is about 2.8% or less based on the total weight of the pharmaceutical formulation composition. The composition according to claim 1, wherein the water content is at least about 1% by weight of the total weight of the pharmaceutical formulation composition. The composition according to any one of claims 4 to 14, wherein the composition contains a main additive having a water content of about 2% or less in a predetermined amount. The composition according to any one of claims 1 to 15, wherein the composition contains D-mannitol. The composition according to any one of claims 1 to 16, which contains 2.5 mg, 5 mg, 10 mg or 20 mg of the active ingredient. The composition according to any one of claims 1 to 17, which is used as an antiviral agent. 19. The composition of claim 18, wherein the virus is hepatitis B virus or varicella zoster virus.