TW200416034A - Medicinal composition - Google Patents

Abstract

A medicinal composition which contains 2-amino-6-(4-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester as an active ingredient and in which the 2-amino-6-(4-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester is substantially inhibited from forming a dimer and/or hydrolyzate thereof.

Description

200416034 (υ 玖, description of the invention [Technical field to which the invention belongs] The present invention relates to a pharmaceutical preparation composition, and more specifically relates to 2-amino-6- (4-methoxyphenylthio) _9- [ 2- (phosphomethoxy) ethyl] purine bis (252,2-trifluoroethyl) ester as an active ingredient of a pharmaceutical preparation composition.

[Prior art]

As a method for preventing the appearance change of the original medicine from being inhibited by photodegradation of the original drug and the light of the tablet, a known light-shielding coating for light-shielding of the bare tablets itself or a light-shielding package for light-shielding by packaging is known. Among them, the method of light-shielding by packaging cannot guarantee the stability of the package after opening. Therefore, it is expected that the light-shielding method of the entire preparation itself will be performed. In addition, the shading of tablets is generally the shading of thin film coating and the shading of sugar coating. Among the coating ingredients, those who use light-shielding ingredients usually use titanium oxide, while those used in pharmaceuticals have the purity specified in the national regulations, and those with impurities are usually required to use high-purity, low-content Impure. 2-Amino-6- (4-methoxyphenylthio) -9- [2- (phosphomethoxy) ethyl] ester (hereinafter referred to as "Compound A") is described in Patent Document 1 For the known compounds of anti-HBV agents, the formulation of this compound so far has been directed to the general formulation technology described in Patent Document 1. [Patent Document 1] Japanese Patent Application Laid-Open No. 9-2 5 5 6 9 [Summary of the Invention] -4- (2) (2) 200416034 The bare ingot formed by the aforementioned compound A usually causes yellowing after appearance change caused by light. In addition, when a bare ingot is coated with a light-shielding coating film containing a general hydrophilic substance and thorium oxide, the compound A2 molecules react with each other after light to produce a dimmer. In addition, when a thin film-coated ingot containing no titanium oxide has insufficient light-shielding energy, the appearance of the tablet changes. In addition, when the sugar-coated tablets without titanium oxide have sufficient light-shielding properties, the moisture content of the core of the sugar-coated tablets cannot be reduced, and therefore, the tablets are likely to cause decomposition. The storage stability is insufficient. In order to solve the above-mentioned problems, the present invention provides a variety of precise investigations and found that the bare ingot of Compound A contains traces of metal blunt substances with a trivalent or lower valence, and is used as the purity of titanium oxide to meet the specifications of each bureau After the thin film coating of titanium oxide having a purity of 99% or more, it is possible to suppress the appearance change of the lozenge and the generation of the light quantifier. The lozenge can easily adjust the water content in the lozenge, and by reducing the moisture content of the lozenge, after inhibiting the hydrolysis of the compound A in the lozenge, it is determined that the preservation stability is also excellent, and the present invention is completed. That is, the gist of the present invention is as follows. (1) 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphomethoxy) ethyl] purinebis (2,2,2-trifluoroethyl ) Ester as the active ingredient'The 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphomethoxy) ethyl] purinebis (2,2,2- A pharmaceutical preparation composition in which the formation of a difluoroethyl) ester diluent and / or a hydrolysate is substantially suppressed. (2) The dimer is a compound contained in (1), which is a compound represented by the following formula (1). 200416034

(5) The composition contained in any one of (1) to (4) having a coating layer. (6) The coating layer is a composition contained in the above (5), which contains metallic impurities of a trivalent or less value and contains titanium oxide having a purity of 99% or more. (7) The coating layer is the composition (4) (4) (2004) 200416034 (8) which is composed of the impurities contained in the metal (3) and impure metals, and contains titanium oxide with a purity of 99% or more and a hydrophilic compound (4) The concentration of the hydrophilic compound in the layer is about 200% or less of the composition contained in (6) or (7). (9) The composition contained in any one of (6) to (8), wherein the concentration of the hydrophilic compound in the coating layer is about 6% or more. (10) The hydrophilic compound is selected from the group consisting of polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and hydroxyethyl cellulose. The composition of any one of (6) to (9). (1 1) The composition according to any one of (6) to (9), wherein the hydrophilic compound is hydroxypropylmethyl cellulose. (1 2) The composition according to any one of (1) to (1 1), wherein the water content is about 3% or less based on the total weight of the pharmaceutical preparation composition. (13) The composition according to any one of (1) to (1 1), wherein the water content is about 2.8% or less of the total weight of the pharmaceutical preparation composition. (1 4) The composition according to any one of (1) to (1 3), wherein the water content is about 1% or more based on the total weight of the pharmaceutical preparation composition. (1 5) The composition of any one of (4) to (1 4), which contains a main additive having a moisture content of about 2% or less in a bare ingot. (16) The composition according to any one of (1) to (15), containing D-mannitol in a naked tablet. (17) The composition according to any one of (1) to (16) containing 2.5 mg, 5 mg, 10 mg, or 20 mg of an active ingredient. (18) The composition of any one of (1) to (17) used as an antiviral agent. -7- (5) (5) 200416034 (1 9) The virus is a composition of Hepatitis B virus or Varicella zoster virus. [Embodiment] (Best Mode for Implementing Invention) The present invention will be described in detail below. This invention uses 2-amino-6- (4-methoxyphenylthio) _9_ [2_ (phosphomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester It is a medicinal preparation composition with active ingredients. 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphomethoxy) ethyl] purinebis (2,2,2-trifluoroethyl) A known compound described in Kaiping 9-2 5 5 69 5 can be appropriately produced by the method described in the publication or based on the method. The present invention provides 2-amino-6- (4-methoxyphenylthio) _9_ [2_ (phosphomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester A pharmaceutical preparation composition in which the formation of a dimmer and a hydrolysate is substantially suppressed. One of the systems refers to the compound represented by the formula (1), and the hydrolysate refers to the compound represented by the formula (2). In the present invention, the production of these compounds may be suppressed as long as it is pharmaceutically acceptable, and the amount of inhibition is not particularly limited. As shown in the storage stability test described in Example i described later, the production of the compound represented by the formula (2) is about 3% or less (40 ° C 7 5% RH). In addition, the production of the compound represented by the formula (i) is about 2% or less, preferably about 1% or less, and more preferably about 0.5% in the light stability test carried out in Example 1 described later. As examples of the pharmaceutical preparation composition of the present invention, such as: lozenges, powders (including granules (6) (6) 200416034 granules, fine granules) and the like, and the preferred ones are lozenges. Among the tablets of the present invention, a film-coated tablet in which a film is coated on a bare tablet is a preferred example. If the main additive used in the bare tablets is to consider those whose compound A is prone to hydrolysis, the moisture content should be less than 2%, and D-mannitol and the like are ideal examples. In the pharmaceutical preparation composition of the present invention, it is preferable to have a coating layer. As the coating layer, it is preferable to contain a trace amount of metallic impurities below 3 valence, and it is preferable to contain titanium oxide with a purity of 99% or more. As mentioned above, the titanium oxide having a purity of 99% or more refers to a titanium oxide having a purity of 99% or more that meets the specifications of each bureau. The coating layer contains a hydrophilic compound in addition to the titanium oxide. Here, the hydrophilic compound refers to a hydrophilic compound used for a film coating of a general pharmaceutical preparation, and is not particularly limited. Examples include polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and hydroxyethyl cellulose. Those with hydroxypropyl methylcellulose. The coating layer contains a trace amount of metal impurities below 3 valence, and the titanium oxide containing 99% or more purity is based on the concentration of water-soluble compounds in the coating layer. The upper limit is determined without affecting the rough skin and color of the tablet surface ( Graying), etc., should be less than about 200%, and the lower limit of about 6% is ideal. The pharmaceutical preparation composition provided by the present invention can easily adjust the water content in the agent. As a result, it is possible to provide a pharmaceutical preparation composition having a reduced water content, and to provide an inhibitor of 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphomethoxy) ethyl] purine. Hydrolysate of bis (2,2,2-trifluoroethyl) ester The production of a compound represented by the formula (200416034 2) and the preservation of a pharmaceutical preparation composition with good stability. Specifically, it is preferable that the water content is a pharmaceutical preparation composition of less than about 3% of the total weight of the pharmaceutical preparation composition. The more ideal water content is about 2.8% or less as an example, and the lower limit of the water content is About 1% is appropriate. [Examples] Hereinafter, the present invention will be described in more detail through examples. However, the present invention is not limited to the following examples without departing from the scope of the present invention. In addition, the 2-amino-6- (4-methoxyphenylthio) _phosphomethoxy) ethyl] purinebis (2,2,2-trifluoroethyl) used in the following examples The ester (hereinafter also referred to as "compound A") was manufactured based on the method described in JP-A No. 9 _ 2 5 5 6 9 5. .

[Example 1] Production of bare ingots

Compound A and D-mannitol (with a water content of 2 ° /. Or less) were mixed at a weight ratio of 1:20, and then manufactured in a tablet molding machine to obtain pellets i. After replacing d_mannitol with lactose (water content about 4 ~ 6%), granule tablets 2 were obtained in the same way. Table 1 below shows the results of the storage stability test of granules 1 and 2 (stored at 40 ° C 75% RH for 3 months at 50 t). The stability comparison is shown by the original color difference Δ of the granules and the production% of the compound (hydrolysate) represented by the formula (7). From this result, it was proved that D-mannitol represented by the main additive with less water content had a more stable color change and a hydrolysate formation%. -10- (8) (8) 200416034 Table 1 Storage stability test color difference (△ E) of granule ingots 1 and 2 4 0 ° C 75% RH 5 0 ° C granule ingot 2 6.95 2.42 granule ingot 1 1.27 1.04 (2) Production of the indicated compound (%) 40 ° C 7 5% RH 5 0 ° C Granule ingot 2 4.77 1.55 Granule ingot 1 2.34 1. .74 or less, Use this to obtain granule ingot and perform light stability test, also That is, the raw color difference (△ E) of the tablets was measured under the conditions of bare light and naked light ingots with tin wheels under the conditions of D 6 5 light and 200 Lu x. . The results are shown in Fig. 1. From this result, it was proved that the color difference (Δ E) that causes the appearance change (coloring) is increased when the ingot is bare, and is colored by light. After referring to this Example 1, each bare ingot having the composition shown in Table 2 below was produced. [Example 2] 100 g of Compound A and 3,700 g of D-mannitol were put into a high-speed mixer (manufactured by Fukang Industry Co., Ltd., FS-GS-25J). , And 924g corn starch, and mix them. The obtained mixture was put into a flow coater (Floint Industries, FL0-5M), and 124 g of hydroxypropyl cellulose dissolved in 270 g of purified water (-11-(9) (9) 200416034 hereinafter referred to as "HPC") Spray granulation as a binder. After the granulated product was dried and sieved, 5 2 g of low-substitution hydroxypropyl cellulose (hereinafter also referred to as "LHPC") and 100 g of magnesium stearate (vegetable from Taiping Chemical Industry) were simultaneously charged into V. Type mixer (MEIWA Industrial Co., Ltd., SVM-50), and after mixing, the tablets were prepared using a rotary tableting machine (AQUARIUS by Kikusui Seisakusho). [Example 3] 2,000 g of compound A, 3,580 g of D-mannitol and 986 g of corn starch were mixed in a high-speed mixer (FS-GS-25J, manufactured by Fukae Industry Co., Ltd.). The obtained mixture was put into a flow coater (manufactured by f 1 io int, ρ 10-5 M) 'and spray-granulated by using I24 g of hydroxypropyl cellulose dissolved in 207 g of purified water as a binder. After drying and sieving this granulated product, 100 g of a low degree of substitution was passed through propyl cellulose and 100 g of magnesium stearate (plant-made by Taiping Chemicals) into a V-type mixer (Mingwa Industrial) After mixing with SvM-5), the mixture was adjusted with a rotary beater (AQUA RIU S manufactured by Kikusui Seisakusho, Ltd.). [Example 4] 400 σ § Compound A, 3,380 g of D-mannitol, and 8 44 g of corn starch were added to a high-speed mixer (manufactured by Fukae Industrial Co., Ltd., FS-GS-25J) and mixed. . The obtained mixture was put into a flow coater (FLO-5M manufactured by Fl (Int Industries, Ltd., FLO-5M), and spray-granulated with 124 g of hydroxypropyl cellulose dissolved in 270 g of purified water as a binder. After the granulated product was dried and sieved, -12- (10) 200416034 1 5 2 g of a low-substitution degree hydroxypropyl plant) was simultaneously injected) and mixed, and then cellulose was prepared with AQUARIUS), 100g magnesium stearate (Taihe Chemical Co., Ltd. V-type mixer (manufactured by Meiwa Industrial Co., Ltd., SVMdC rotary tableting machine (manufactured by Kikusui Seisakusho, tablet). [Example 5] In a local-speed mixer (manufactured by Fukae Industries, FS-GS- 25J) Put 800 g of compound A, 2,980 g of D-mannitol, and 74.4 g of corn starch and mix them. Put the obtained mixture into a flow coater (Floint Industrial Co., FL Ο- 5 Μ), spraying granulation with 1 2 4 g of hydroxypropyl cellulose dissolved in 270 g of purified water as a binding agent. After drying and sieving the granulated material, a low of 2 5 2 g Degree of substitution: hydroxypropyl cellulose, 1000 g of magnesium stearate (plant-made by Taiping Chemicals) are simultaneously put into a V-type mixer (manufactured by Meiwa Industrial Co., Ltd., sV Μ-50), and then mixed with a rotary tablet. Machine (manufactured by Kikusui, AQUARIUS) to prepare lozenges. Table_2 Prescriptions for bare ingots 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 2 1.1 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 Total weight of bare tablets (mg) 125 125 125 125 • 13- (11) 200416034 [Example 6] Production of coated ingots Regarding 700 g of the bare ingots obtained in Example 2 were prepared from 4 3 9 g of purified water and 35 g of hydroxypropyl methylcellulose (Hereinafter also referred to as "HpMC") 29 10, 7g propylene glycol, 5g talc, and 105g high-purity titanium oxide (Toho titanium coating, NA-61) A coating solution made by Ishihara Sangyo Co., Ltd .. This coating solution is spray-dried with a bare coater (fl01nt Industrial Co., Ltd., hct_3 裸), and then one coating film is 5 mg. Here, a small amount of hardened oil is powder-added and coated to form a coated ingot. In addition, the 'light stability test was performed according to the method set out in Example 1. Table 4 proves that when high-purity thorium oxide is used, although no appearance change occurs, However, a large amount of the compound (dual body) represented by the formula (1) is produced. Surface coating formulation mg HP MC 2910 Total Propylene Glycol Titanium Talc Hardening Oil (mg .04 .6 1 • 9 1 0.43 .125 -14-(12) (12) 200416034 Table 4 Titanium oxide contains 3 > two or less impurities Volume formation% High purity titanium oxide 2.04 Trace impurities contain 0.68 titanium oxide [Example 7] In a bare ingot prepared in the same manner as in Example 2, titanium oxide containing a trace amount of impurities below 3 valence was used as a sunscreen. Table 5 The coating formulation shown is coated. After the coating was performed in the same manner as in Example 6, three coating ingots having a titanium oxide content of 6.7 to 20.0% in the coating film were prepared. Table 6 shows the results of a light stability test performed on the prepared coated ingot in the same manner as in Example 1. The results show that the coating ingot having a titanium oxide content of 6.6% in the coating film has a small color difference (AE), and the production amount of the compound (diaster) represented by the formula (1) is also small and stable. Table 5 Formulation of titanium oxide content in coatings (%) 6.6% 1 2.4% 2 0.0% Ingredients mg mg Mg HPMC 29 10 ο ο 勹 J. JJ 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 Hardened oil 0.06 0.06 0.06 1 Total weight (mg) 5 5 5 -15- (13) 200416034 Table 6 Relationship between titanium oxide content and stability in coating film Titanium oxide content (%) 6.6% 12.4% 2 0.0% Color difference (△ E) 0.40 0.60 0.68% of doublings 0.38 0.95 1.26 [Examples 8, 9, 10 and 1 1]

The bare ingots obtained in Examples 2, 3, 4, and 5 were coated in the same manner as in Example 6 using the coating formulations in Table 7. That is, 1,8 20 g of purified water, 120 g of hydroxypropyl methyl cellulose 2910, 28 g of propylene glycol, 20 g of talc, and 12 g of titanium oxide having a purity of 99% or less (purified by Ishihara Industries, A- 1 0 0). This coating solution was spray-dried on a bare tablet using a base coater (manufactured by Poulec, DRC-500), and the coating film of each tablet was 5 mg. Here, a small amount of hardened oil is powder-coated, and a coated ingot is prepared.

Table 8 shows the results of the light stability test of the prepared tablets of Example 8 and Example 11 (the light stability test of the same method as in Example 1). As a result, it was proved that the color difference (ΔE) is extremely small in a sufficiently tolerable range, and the formation of a dimorph is also very small and stable. -16-(14) 200416034 Table 7 Bare and coated tablets Example 8 Example 9 Example 1 〇 Example 1 1 Compound A 2.5 5 10 20 D-Mannitol 92.5 89.5 84.5 74.5 Corn starch 23.1 22.4 2 1.1 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 25 25. Bare ingot m (mg) 125 1 25 125 125 Coating prescription HPMC 29 10 3.3 5 ο nr J JJ ο or J. JJ η oc J. J 3 Propanediol 0.77 0.7 7 0.77 0.77 Titanium oxide 0.3 3 0.33 0.33 0.33 Talc 0.55 0.55 0.55 0.55 Hardened oil 0.0625 0.625 0.625 0.625 Coating weight (mg) 5.06 5 .. 0 6 5.06 5.06 Total weight of revolving agent (mg) 130 130 13 0 13 0

-17- (15) (15) 200416034 Table 8 Results of light stability test Color difference (△ E) Binary body formation% The coating obtained in Example 1.1.7 '1' '————. 0.45 layer ingot obtained in Example 1 1 2.2 1 0.05 Coated tablets [Example 1 2] After the film coated tablets obtained in Example 9 were stored under various relative humidity for 3 days, the water content in the tablets was adjusted. These tablets were placed in airtight containers (glass bottles) and stored at 25 ° C 60% RH to compare the stability. The results are shown in Fig. 2. It is proved from FIG. 2 that the more the water content, the more the compound represented by the formula (2) increases. (Industrial Applicability) The present invention can provide 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphomethoxy) ethyl] purinebis ( After using 2,2,2-trifluoroethyl) ester as the active ingredient, the 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphomethoxy) Ethyl] purine bis (252,2-trifluoroethyl) ester is used as a stable pharmaceutical preparation composition as an active ingredient. The present invention will be described in detail in a specific form. Without departing from the spirit of the present invention, various appropriate changes and modifications can be made to those skilled in the art. In addition, this application is based on the Japanese Patent Application No. 18- (16) (16) 200416034 (Japanese Patent Application No. 2002-332162), which was filed on November 15, 2002, and is incorporated by reference in its entirety. Of it. [Brief Description of the Drawings] FIG. 1 is a view showing a result of a light stability test in Example 1. FIG. Fig. 2 is a graph showing the stability test results of Example 12;

-19-

Claims (1)

200416034 范围 The scope of application and patent application 丨 A kind of medicinal preparation composition'characterized by 2_amino group_6- (4-methoxymethoxythio) _9_ [2 · (phosphomethoxy) ethyl]嚷 Ling bis (2,2,2-trifluoroethyl) vinegar as the active ingredient, the amino group -6 · (4_methoxyphenylthio (phosphomethoxy) ethyl] ㈣bis (2 , 2,2_ Trifluoroethyl) esters in which the production of the diploid and / or hydrolysate is substantially inhibited. -2. For example, a pharmaceutical preparation composition in the scope of item B i of the patent application, wherein the dual system is of the following formula (1) For the compounds shown, MeO f3ch2go, Bu 3 2 0 3. As claimed in the composition of item 1 or item 2 of the patent scope, wherein the hydrolysate is a compound represented by the following formula (2), -20 · 200416034 4. The composition according to any one of claims 1 to 3 in the scope of patent application, wherein the composition is a lozenge. 5. The composition according to any one of claims 1 to 4 in the scope of patent application, wherein the composition is a one having a coating layer. 6. The composition according to item 5 of the scope of the patent application, wherein the coating layer contains impurities of a metal having a valence of 3 or less and contains titanium oxide having a purity of 99% or more. 7. The composition according to item 5 of the scope of the patent application, wherein the coating layer is made of a metal impurity having a trivalent or lower valence, and contains titanium oxide having a purity of 99% or more, and a hydrophilic compound. 8. The composition of claim 6 or claim 7, wherein the concentration of the titanium oxide to the hydrophilic compound in the coating layer is about 200% or less. 9. The composition according to any one of claims 6 to 8 in the scope of the patent application, wherein the concentration of the titanium oxide to the hydrophilic compound in the coating layer is about 6% or more. 1 0 · If the composition of any one of items 6 to 9 of the scope of the applied patent is-21-(3) (3) 200416034, where the hydrophilic compound is selected from polyvinyl alcohol, polyethylene glycol, ^ Vinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, residual methyl cellulose, and hydroxyethyl cellulose. 11. The composition according to any one of claims 6 to 9 of the scope of the patent application, wherein the hydrophilic compound is hydroxypropyl methylcellulose. 12. As for the composition of any one of the items 1 to n in the scope of the patent application, wherein the water content is less than about 3% of the total weight of the pharmaceutical preparation composition. 13. As described in any one of claims 1 to 11 of the scope of patent application, the composition 'is one in which the water content is less than about 2.8% of the total weight of the pharmaceutical preparation composition. 14. The composition according to any one of the items 1 to 13 of the scope of the patent application, wherein the water content is about 1% or more of the total weight of the pharmaceutical preparation composition. 1 5 · If the $ composition in any of the items 4 to 14 of the scope of patent application, the bare ingot contains the main additive with a moisture content of less than 2%. 16. The composition according to any one of items 1 to 15 of the scope of patent application, wherein the naked tablet contains D-mannitol. 1 7 · If the composition of any one of items 1 to 16 of the scope of patent application ', wherein the composition contains 2.5 mg, 5 mg, 10 mg, or 20 mg of an effective ingredient. 1 8. If any one of the items 1 to 17 of the scope of patent application & _, the composition is used as a user of the antiviral agent. 19. The composition according to item 18 of the scope of patent application, wherein the diseased stomach -22- (4) 200416034 is a person with hepatitis B virus or varicella-zoster virus. -twenty three-