Oral administrable pharmaceutical composition

Abstract

An orally administrable pharmaceutical composition containing α,α,α-trifluorothymidine and 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4 (1H,3H)-pyrimidinedione hydrochloride as active ingredients and sugar having a critical relative humidity of 85% or more at 25°C as an excipient, and containing partially pregelatinized starch as a disintegrating agent, where the content of the disintegrating agent is from 2 to 16% by weight of the total amount of the pharmaceutical composition. The application also contains 7 patent claims.

Description

Description [Technical field]

[0001] The present invention relates to an orally administrable pharmaceutical composition comprising α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidine dione hydrochloride (TPI). [Prior Art]

[0002] A combination drug containing α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidine dione hydrochloride (TPI) is an anti-tumor agent in which FTD, which has an effect of inhibiting thymidylate formation and an effect of inhibiting DNA synthesis by incorporation into DNA to exert an anti-tumor effect, is combined with TPI, which has an effect of inhibiting thymidine phosphorylase, thereby suppressing the degradation of FTD in vivo and enhancing the anti-tumor effect (Patent Literature 1).

[0003] An anti-tumor agent "TAS-102" in which FTD and TPI are combined in a molar ratio of 1:0.5 is currently being developed as an orally administrable formulation (Non-patent Literatures 1 and 2). As for the orally-applicable TAS-102 formulation, tablets, granules, capsules, and the like have been known so far (Patent Literatures 1 and 2). However, the quality, especially the storage stability of the formulation, has not been sufficiently investigated.

[0004] In the case of formulation, in order to facilitate oral administration of drugs, excipients, binders, disintegrants, lubricants, taste masking agents, and the like are usually allowed to be present in addition to the active ingredient. Of these, excipients are added to increase the bulk to thereby adjust the size and weight of oral drugs to a size and weight that are convenient for handling and ingestion. The weight fraction of excipients often becomes large relative to the amount of drugs. Therefore, excipients among the formulation additives have a great influence on the stability of the formulations, and must be selected with due care.

[0005] Meanwhile, in medical settings, in order to prevent accidental ingestion and to improve drug compliance, single-dose packaging is preferred for packaging various drugs in a single-dose form, and therefore, stable and high-quality formulations are desirable even without moisture-resistant packaging. Also, if moisture-resistant packaging becomes unnecessary, advantages are realized, such as eliminating the problem of opening the package and eliminating packaging waste. [List of references] [Patent Literature]

[0006] [Patent Literature 1] International publication No. WO 96 / 30346 [Patent Literature 2] International publication No. WO 2006 / 80327 [Non-Patent Literature]

[0007] [Non-Patent Literature 1] International Journal of Oncology 25: 571-578, 2004 [Non-Patent Literature 2] Invest New Drugs 26(5): 445-54, Oct 2008. [Summary of the invention] [Technical problem]

[0008] The present inventor added various formulation additives to the above-mentioned FTD and TPI, and examined the storage stability of the resulting compositions under various conditions. Furthermore, it was demonstrated that the amount of substances associated with FTD and TPI increased when stored, especially under high humidity conditions, depending on the type of formulation additives added.

[0009] Accordingly, the object of the present invention is to provide an orally applicable pharmaceutical composition containing FTD and TPI which can be orally administered and whose active ingredients are stable even under high humidity conditions. [Problem Solving]

[0010] Therefore, the present inventor added various additives to FTD and TPI and evaluated the storage stability, and found that a stable pharmaceutical composition that can be orally administered in which the mass of the associated substances is not substantially increased even upon storage in the case of using sugar that has a high critical relative humidity, completing the present invention.

[0011] That is, the present invention provides an orally administrable pharmaceutical composition containing FTD and TPI as active ingredients and a sugar having a critical relative humidity of 85% or more at 25°C as an excipient.

[0012] Also, the present invention provides an orally administrable pharmaceutical formulation comprising the above-described orally administrable pharmaceutical composition, which is coated. [Beneficial effects of the invention]

[0013] According to the present invention, high quality formulations that have ensured formulation stability even under high humidity conditions can be provided to patients and medical personnel. [Description of technical solutions]

[0014] The active ingredients of the orally administrable pharmaceutical composition of the present invention are FTD and TPI. The molar ratio of FTD to TPI present in the composition is preferably 1:0.5. Also, the content of FTD per dosage unit of the orally administrable pharmaceutical composition is preferably from 5 to 35 mg and more preferably from 15 to 20 mg.

[0015] easily the contents of FTD and TPI, which are the active ingredients of the oral pharmaceutical composition of the present invention, depend on the formulation forms and regimens, and can be selected without special limitation and if necessary, the amount of each active ingredient in the pharmaceutical composition is preferably from 1 to 40% by weight.

[0016] The orally administrable pharmaceutical composition of the present invention, to which sugars having a critical relative humidity of 85% or more at 25°C are added as excipients, suppresses the increase in FTD and TPI of the related substances even when stored under high humidity conditions. "Critical relative humidity" herein means a well-known indicator representing hygroscopicity, and refers to the relative humidity at which a rapid increase in the amount of moisture absorbed in the sample is observed in the case where the relative humidity is increased. The critical relative humidity can be checked by measuring the change in the mass of the sample at 25°C and a relative humidity of 10 to 95% using, for example, a moisture sorption analyzer (DVS-1, Surface Measurement Systems Ltd.). "Critical relative humidity at 25°C is 85% or more" means that moisture is not significantly absorbed when the relative humidity at 25°C is less than 85%. Also, "no critical relative humidity" means that moisture is absorbed at low humidity depending on the humidity, and a rapid increase in the amount of moisture absorbed associated with an increase in relative humidity is not observed.

[0017] The sugar having a critical relative humidity of 85% or more at 25°C in the oral pharmaceutical composition of the present invention is not particularly limited as long as it has a critical relative humidity of 85% or more at 25°C, and examples of the sugar include monosaccharides, oligosaccharides, and sugar alcohols.

[0018] Of these sugars, from the viewpoint of the stability of the aforementioned FTD and TPI, disaccharides or sugar alcohols having a critical relative humidity of 85% or more at 25°C are preferred, disaccharides or sugar alcohols having a critical relative humidity of 90% or more at 25°C are more preferred, and disaccharides or sugar alcohols having a critical relative humidity of 95% or more at 25°C are particularly preferred. Specifically, lactose (including anhydrous and hydrate), sucrose, mannitol, trehalose, maltose, maltitol, or erythritol are preferred, lactose, sucrose, mannitol, trehalose, or maltose are more preferred, lactose, sucrose, or mannitol are more preferred, and lactose or mannitol is particularly preferred. It should be noted that these sugars may be used singly or in combination of two or more.

[0019] The content of sugar having a critical relative humidity of 85% or more in the orally administrable pharmaceutical composition of the present invention is, from the viewpoint of stability of FTD and TPI and function as an excipient, preferably 3.6 parts by weight or more, more preferably 3.6 to 50 parts by weight, even more preferably 3.7 to 25 parts by weight, and particularly preferably 3.7 to 10 parts by weight, based on 1 part by weight of FTD.

[0020] Also, disintegrants are added to the orally administrable pharmaceutical composition of the present invention to ensure good disintegrability during oral administration. However, most disintegrants do not have a critical relative humidity, and may reduce the stability of FTD and TPI depending on the types. The disintegrant in the orally administrable pharmaceutical composition of the present invention is partially pregelatinized starch. The content of the disintegrant is, from the viewpoint of combining the stability of FTD and TPI in the pharmaceutical composition of the present invention and the disintegrability of the pharmaceutical composition, preferably from 2 to 16% by weight, more preferably from 3 to 13% by weight, even more preferably from 3 to 10% by weight, and particularly preferably from 3 to 7% by weight in the total amount of the pharmaceutical composition.

[0021] Although the contents of FTD and TPI, which are active ingredients of the orally applicable pharmaceutical composition of the present invention, depend on the formulation forms and regimens, and can be selected without particular limitation and as needed, the amount of each active ingredient in the total amount of the pharmaceutical composition is preferably in the range of 1 to 40% by weight. Of the additives for the pharmaceutical composition, the proportion of sugar having a critical relative humidity of 85% or more at 25°C in the present invention is, from the viewpoint of the stability of the active ingredients, preferably in the range of 50 to 100% by weight, more preferably in the range of 70 to 100% by weight, and particularly preferably in the range of 70 to 98% by weight, in the total amount of the additives.

[0022] Alternatively, excipients other than sugars having a critical relative humidity of 85% or more at 25°C may be added to the orally applicable pharmaceutical composition of the present invention. From the viewpoint of stability of the active ingredients, the proportion of sugars having a critical relative humidity of 85% or more at 25°C is preferably 50% by weight or more, more preferably 70% by weight or more, more preferably 90% by weight or more, and particularly preferably 100% by weight in the total excipient.

[0023] The orally administrable pharmaceutical composition of the present invention may further contain various additives generally used, to the extent that the effects of the present invention are not inhibited. Examples of additives include, but are not particularly limited to, as long as the additive is one that is generally used, excipients other than the aforementioned sugar having a critical relative humidity of 85% or more at 25°C, binders, lubricants, flavor enhancers, coloring agents, and taste masking agents.

[0024] Examples of binders include hydroxypropyl cellulose, hypromellose, and polyvinyl alcohol. Examples of lubricants include hydrogenated oils, sucrose fatty acid esters, and stearic acid. Examples of coloring agents include food color yellow No. 5, food color blue No. 2, color pigment, ferric oxide, yellow ferric oxide, and titanium oxide. Examples of flavor enhancers include various orange and lemon flavors. Examples of flavor masking agents include 1-menthol, camphor, and mint. These may be used singly or in combination of two or more.

[0025] The content of the binder here is preferably from 0.001 to 5% by weight and more preferably from 0.01 to 3% by weight in the total composition. The lubricant content is preferably from 0.001 to 3% by mass and more preferably from 0.01 to 2% by mass in the total composition.

[0026] Examples of orally administrable forms of the pharmaceutical composition of the present invention include granules, compression molded products (e.g., uncoated tablets), and mixtures.

[0027] Also, the orally administrable pharmaceutical composition of the present invention, from the viewpoint of ensuring storage stability of the active ingredients, is preferably substantially free of metal salts, such as alkali metal salts and alkaline earth metal salts. "is substantially free" herein refers to from 0 to 0.1 parts by weight, preferably from 0 to 0.05 parts by weight, more preferably from 0 to 0.01 parts by weight, and even more preferably 0 parts by weight, based on 1 part by weight of FTD.

[0028] Although the orally administrable pharmaceutical composition of the present invention can be used as a pharmaceutical formulation as such, the formulation may be further coated on its surface to be an orally administrable pharmaceutical formulation that is stable and easy to take. The coating herein includes film coating and sugar coating. Examples of coating bases include hypromellose, ethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, and sucrose. It should be noted that, in the case of coating an orally administrable pharmaceutical composition containing FTD and TPI, the coating layer may contain the above-mentioned additives having a critical relative humidity of less than 85% or no critical relative humidity to the extent that the stability of FTD and TPI is not substantially affected.Also, in the case of coating an orally administrable pharmaceutical composition containing FTD and TPI, the coating layer may contain a small amount of plasticizers, coloring agents, flavor enhancers, taste masking agents, and lubricants to the extent that the stability of FTD and TPI is not substantially affected. Examples of plasticizers include polyethylene glycol. Examples of coloring agents include food tar dyes, food tar dye pigments, iron oxide, yellow iron oxide, and titanium oxide. Examples of flavor enhancers include various orange and lemon flavors. Examples of flavor masking agents include 1-menthol, camphor, and mint, which may be used singly or in combination of two or more. The total amount of the coating layer herein is preferably from 1 to 5% by weight and more preferably from 2 to 4% by weight in the total formulation.

[0029] Examples of the pharmaceutical formulation of the present invention that can be administered orally include tablets, granules, powders, and fine granules. Examples of tablets include chewable tablets, lozenges, beads, and compositions that rapidly dissolve or disintegrate in in the oral cavity and can be taken even without water, and also include effervescent tablets that dissolve for use at the time of administration. Examples of granules, powders, and fine granules include dry syrups that dissolve for use at the time of administration, and also include powder particles that dissolve quickly in the oral cavity and can be taken without water.

[0030] The orally administrable pharmaceutical composition and the pharmaceutical formulation of the present invention can be produced according to a known method for producing orally administrable formulations. Examples of granulation methods include fluidized bed granulation methods, mixing granulation methods, fluidized bed tumbling granulation methods, extrusion granulation methods, spray granulation methods, and crushing granulation methods, which can be used to produce granules or uncoated tablets. Also, from the viewpoint of granulation principles, granulation methods are largely divided into dry granulation methods and wet granulation methods. From the viewpoint of FTD and TPI stability, dry granulation methods are preferable.

[0031] According to the present invention, the addition of sugar can suppress the increase in the formation of related substances of FTD and TPI which are potentially formed when orally administrable pharmaceutical compositions and pharmaceutical formulations containing FTD and TPI as active ingredients are produced. The corresponding related substances herein mean components other than FTD, TPI, and additives, and generally refer to structurally related compounds of the corresponding two active ingredients. Specifically, the related substances are substances other than FTD, TPI, and additives which are detected when measured according to the Liquid Chromatography described in the Japanese Pharmacopoeia, General Tests, Physical Tests (the Japanese Pharmacopoeia, General Tests, Physical tests) after storing the orally administrable pharmaceutical composition and pharmaceutical formulations of the present invention under certain constant conditions.

[0032] Next, aspects and preferred technical solutions of the present invention are shown below. [1] An orally administrable pharmaceutical composition comprising a,a,a-trifluorothymidine (FTD) and 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4 (1H,3H)-pyrimidine dione hydrochloride (TPI) as active ingredients and a sugar having a critical relative humidity of 85% or more at 25°C as an excipient. [2] The orally administrable pharmaceutical composition according to [1], wherein the content of the sugar having a critical relative humidity of 85% or more at 25°C is 3.6 parts by weight or more, preferably from 3.6 to 50 parts by weight, more preferably from 3.7 to 25 parts by weight, and even more preferably from 3.7 to 10 parts by weight, based on 1 part by weight of FTD. [3] The orally administrable pharmaceutical composition according to [1] or [2], wherein the sugar having a critical relative humidity of 85% or more at 25°C is a disaccharide or a sugar alcohol. [4] The orally administrable pharmaceutical composition according to any one of [1] to [3], wherein the sugar having a critical relative humidity of 85% or more at 25°C is one or more selected from lactose, sucrose, mannitol, and erythritol, and preferably one or more selected from lactose, sucrose, and mannitol. [5] An orally administrable pharmaceutical composition according to any one of [1] to [4], comprising FTD and TPI in a molar ratio of 1:0.5. [6] The orally administrable pharmaceutical composition according to any one of [1] to [5], further comprising, as a disintegrating agent, one or more selected from low-substituted hydroxypropyl cellulose, carmellose, corn starch, partially pregelatinized starch, and crospovidone, preferably one or more selected from low-substituted hydroxypropyl cellulose, carmellose, corn starch, and partially pregelatinized starch, and more preferably one or more selected from low-substituted hydroxypropyl cellulose, corn starch, and partially pregelatinized starch. [7] Oral pharmaceutical composition according to [6], where the disintegrating agent content is preferably from 2 to 16% by weight, preferably from 3 to 13% by weight, more preferably from 3 to 10% by weight, and especially preferably from 3 to 7% by weight, in the total amount of the pharmaceutical composition. [8] The oral pharmaceutical composition according to any one of [1] to [7], wherein the pharmaceutical composition is in the formulation form of a granule, a compression molded product, or a mixture. [9] An orally administrable pharmaceutical formulation comprising an orally administrable composition according to any one of [1] to [8], wherein the composition is coated. [Examples]

[0033] Although the present invention is described in more detail hereinafter with reference to Examples, Comparative Examples, Reference Examples, and Test Examples, the present invention should not be limited solely by these Examples. Example 1

[0034] In a mortar, 40 g of FTD and 18.84 g of TPI were mixed. In a mortar, 1.6 g of this mixture and 8 g of lactose hydrate "Lactochem DOMO" (manufactured by DMV-Fonterra Excipients GmbH & Co) were mixed to obtain a mixture (see Table 1). It should be noted that the proportion of the respective sugars in the additives is 100% in this composition. Example 2

[0035] The mixture was prepared according to the same method as in Example 1, except that sucrose "Granulated sugar EA" (manufactured by ENSUIKO Sugar Refining Co., Ltd.) was used instead of lactose hydrate. Example 3

[0036] In a plastic bag, 105 g of FTD and 49.5 g of TPI were mixed. In a tablet crusher (manufactured by Konishi-Seisakusho Co., Ltd.), 6.0 g of this mixture and 24 g of lactose hydrate "Lactochem DOMO" (manufactured by DMV-Fonterra Excipients GmbH & Co.) were mixed. Purified water was further added to this mixture, which was granulated, and then dried in a Mini Jet Oven (manufactured by TOYAMA SANGYO CO., LTD.) at 70°C for two hours to thereby obtain granules (see Table 2). It should be noted that the proportion of the respective sugars in the additives is 100% in this composition. Example 4

[0037] The granule was prepared according to the same method as in Example 3, except that D-mannitol (manufactured by KYOWA HAKKO BIO CO., LTD.) was used instead of lactose hydrate (see Table 2). Comparative example 1

[0038] The mixture was prepared according to the same method as in Example 1, except that crystalline cellulose "Ceolus" (manufactured by Asahi Kasei Corporation) was used instead of lactose hydrate (see Table 1). Comparative example 2

[0039] The granule was prepared according to the same method as in Example 3, except that D-sorbitol (manufactured by Towa Chemical Industry Co., Ltd.) was used instead of lactose hydrate (see Table 2). Comparative example 3

[0040] The granule was prepared according to the same method as in Example 3, except that xylitol (manufactured by Towa Chemical Industry Co., Ltd.) was used instead of lactose hydrate (see Table 2). Reference Example 1

[0041] In a mortar, 40 g of FTD and 18.84 g of TPI were mixed to obtain a mixture (see Table 1). Test Example 1

[0042] The critical relative humidity of the additives at 25°C shown in Tables 1 and 2 was measured using a moisture sorption analyzer (DVS-1, Surface Measurement Systems Ltd.). The results are shown in Tables 1 and 2. Test Example 2

[0043] The mixtures obtained in Examples 1 and 2, Comparative Example 1, and Reference Example 1 were stored at 40°C / 75% relative humidity for one month, and then, the mass of the related substances formed was measured in accordance with the Liquid Chromatography described in the Japanese Pharmacopoeia, General Tests, Physical Tests. The results are shown in Table 1. It should be noted that peaks other than those of FTD, TPI, and additives are called related substance peaks and that the total mass of related substances refers to the sum of the mass of related substances calculated based on the area under the peak of the active ingredients from the area of ​​the peak of related substances. Test Example 3

[0044] According to the method described in Test Example 2, the granules obtained in Examples 3 and 4, and Comparative Examples 2 and 3 were stored at 40°C / 75% relative humidity for one week, and then, the mass of the related substances formed was measured in accordance with the Liquid Chromatography described in the Japanese Pharmacopoeia, General Tests, Physical Tests. The results are shown in Table 2. [Table 1] Unit: parts by mass Example |1 2 i Compare vni ^Example [1 ^Reference ^Example [1 FTD I 10 10 I 10 [10 TPI [4.71 4.71 [4.71 [4.71 Lactose hydrate [73.55 - b Sucrose 73.55 b = Crystalline cellulose - 73.55 b Critical relative humidity (%, [95 or 85 or Nijc applicable s _ ; at 25°C) Šviš viš § ; Total mass of related |0.19 0.36 [1.64 b.i5 1 substances (%) S : [Table 2] Unit: parts by mass Example § Comparative Example 3 4 I 2 3 FTD 10 10 [10 10 TPI 4.71 4.71 [4.71 4.71 Hidrat lactose 58.84 - s- - D-mannitol - 58.84 - D-sorbitol - - [58.84 - Xylitol - k 58.84 Critical relative humidity (%, at 25°C) 95 ili vise 95 ili vise ^50-60 75-85 Total mass of associated substances (%) 0.08 0.00 |0.81 0.63

[0045] As is clearly seen from Table 1, the total mass of the related substances of Examples 1 and 2, in which sugar having a critical relative humidity of 85% or more at 25°C was used as an excipient, showed practically no difference compared with Reference Example 1, and was very stable compared with Comparative Example 1. Also, from Table 2, the total mass of the related substances of Examples 3 and 4 in which sugar having a critical relative humidity of 85% or more at 25°C was used as an excipient was obviously smaller than that in Comparative Examples 2 and 3 in which sugar having a critical relative humidity of less than 85% at 25°C was used as an excipient, and was very stable.

[0046] From the results described above, it was found that formulations containing FTD and TPI which have high stability even under severe conditions such as 40°C / 75% relative humidity can be obtained by using sugar having a critical relative humidity of 85% or more at 25°C as an excipient. Since the formation of related substances is suppressed, it is possible to provide higher quality formulations to patients and medical personnel. Example 5

[0047] In a plastic bag, 400 g of FTD, 188.4 g of TPI, 1511.6 g of lactose hydrate, 300 g of carmellose "NS-300" (manufactured by GOTOKU CHEMICAL COMPANY LTD), and 40 g of stearic acid were mixed. This mixture was tableted with a rotary tableting machine into tablets having a diameter of 15 mm and a weight of 800 mg. Then, the tablets were crushed with a crusher to thereby obtain granules. To 122 parts of these granules, 1 part of stearic acid was further added and mixed in a plastic bag. Uncoated tablets having a diameter of 7 mm and a weight of 123 mg were obtained using the rotary tableting machine (see Table 3). Example 6

[0048] In a mortar, 1 g of a mixture of 1 part FTD and 0.471 parts TPI, 6 g of lactose hydrate, and 1 g of carmellose were mixed. From this mixture, uncoated tablets having a mass of 235.36 mg were obtained using a hydraulic press (see Table 3). Example 7

[0049] In a plastic bag, 1200 g of FTD, 565.2 g of TPI, 7258.8 g of lactose hydrate, 480 g of partially pregelatinized starch "PCS(PC-IO)" (manufactured by Asahi Kasei Chemicals Corporation), and 96 g of stearic acid were mixed. From this mixture, uncoated tablets having a diameter of 7 mm and a weight of 120 mg were obtained using a rotary tabletting machine (see Table 3). Example 8

[0050] According to the method described in Example 7, 100 g of FTD, 47.1 g of TPI, 371.9 g of lactose hydrate, 100 g of partially pregelatinized starch, and 6 g of stearic acid were mixed in a plastic bag. From this mixture, uncoated tablets having a diameter of 7 mm and a weight of 125 mg were obtained using a rotary tabletting machine (see Table 4). Example 9

[0051] According to the method described in Example 7, 100 g of FTD, 47.1 g of TPI, 371.9 g of lactose hydrate, 25 g of partially pregelatinized starch, and 6 g of stearic acid were mixed in a plastic bag. From this mixture, uncoated tablets having a diameter of 7 mm and a mass of 110 mg were obtained using a rotary tabletting machine (see Table 4). Example 10

[0052] According to the method described in Example 7, 100 g of FTD, 47.1 g of TPI, 371.9 g of lactose hydrate, 50 g of partially pregelatinized starch, and 6 g of stearic acid were mixed in a plastic bag. From this mixture, uncoated tablets having a diameter of 7 mm and a mass of 115 mg were obtained using a rotary tabletting machine (see Table 4). Example 11

[0053] According to the method described in Example 7, 100 g of FTD, 47.1 g of TPI, 521.9 g of lactose hydrate, 75 g of partially pregelatinized starch, and 6 g of stearic acid were mixed in a plastic bag. From this mixture, uncoated tablets having a diameter of 7 mm and a mass of 150 mg were obtained using a rotary tabletting machine (see Table 4). Example 12

[0054] According to the method described in Example 7, 100 g of FTD, 47.1 g of TPI, 671.9 g of lactose hydrate, 75 g of partially pregelatinized starch, and 6 g of stearic acid were mixed in a plastic bag. From this mixture, uncoated tablets having a diameter of 7 mm and a mass of 150 mg were obtained using a rotary tabletting machine (see Table 4). [Table 3] Unit: parts by mass Example 5 [6 I 7 FTD 1 |1 [1 TPI 0.47 [0.47 |0.47 Lactose hydrate 3.78 [8.83 [6.05 Carmellose 0.75 11.47 Partially pregelatinized starch - s [0.4 Stearic acid 0.15 s- [0.08 Total 6.15 111.77 [8 [Table 4] Unit: parts by mass [Example I 8 And 9 And 10 And 11 12 FTD [1 [1 [1 [1 1 TPI 10.471 10.471 [0.471 [0.471 0.471 Lactose hydrate [3.719 [3.719 Ј3.719 [5.219 6.719 Partially pregelatinized starch [1 [0.25 [0.5 [0.75 0.75 Stearic acid [0.06 [0.06 [0.06 [0.06 0.06 Total |b.25 |5.5 [5.75 [7.5 Example 13

[0055] In a mortar, 1 g FTD, 0.471 g TPI, 3.779 g lactose hydrate, and 0.15 g stearic acid were mixed. From this mixture, uncoated tablets having a mass of 108 mg were obtained using a hydraulic press (see Table 5). Example 14

[0056] In a plastic bag, 1 g FTD, 0.471 g TPI, 3.779 g lactose hydrate, 0.75 g carmellose as a disintegrating agent, and 0.15 g stearic acid were mixed. From this mixture, uncoated tablets having a mass of 123 mg were obtained using a hydraulic press (see

[0057] Table 5). Comparative example 4

[0058] According to the method described in Example 14, 0.75 g of carmellose calcium "ECG-505" (manufactured by GOTOKU CHEMICAL COMPANY LTD.) was used as a disintegrating agent instead of carmellose to thereby obtain uncoated tablets having a mass of 123 mg (see Table 5). Comparative example 5

[0059] According to the method described in Example 14, 0.75 g of croscarmellose sodium "Ac-Di-Sol" (manufactured by Asahi Kasei Corporation) was used as a disintegrating agent instead of carmellose to thereby obtain uncoated tablets having a mass of 123 mg (see Table 5). Test Example 4

[0060] According to the method described in Test Example 2, the tablets obtained in Examples 13 and 14 and Comparative Examples 4 and 5 were stored at 40°C / 75% relative humidity under ambient conditions for one month, and then the total mass of the related substances was measured (see Table 5).

[0061] As a result, even if carmellose, which is a disintegrating agent that does not have a critical relative humidity, was present, it was found that disintegrability as an orally administrable tablet was sufficiently ensured, significant increases in related substances were not observed, and storage stability was ensured. In contrast, if carmellose calcium or croscarmellose sodium were present as disintegrating agents, the mass of the associated substances increased significantly, and storage stability was not ensured. [Table 5] — § Example Unit: parts by mass § Comparative Example § I 13 14 4 I 51 FTD |1 1 1 |1 i TPI 10.471 0.471 0.471 Ј0.471 | Lactose hydrate 13.779 3.779 3.779 13.779 | Carmellose s- 0.75 - s- s Carmellose calcium s- - 0.75 s- s Croscarmellose sodium s- - - Ј0.75 | Stearic acid jo. 15 0.15 0.15 Ј0.15 | Total [5.4 6.15 6.15 ,6.15 | Total mass of related substances (%) Ј0.286 0.404 1.194 Ј2.529 | Example 15

[0062] According to the method described in Example 7, 50 g FTD, 23.55 g TPI, 226.45 g lactose hydrate, and 3 g stearic acid were mixed in a plastic bag. From this mixture, uncoated tablets having a mass of 121.2 mg were obtained using a rotary tabletting machine (see Table 6). Example 16

[0063] According to the method described in Example 7, 50 g of FTD, 23.55 g of TPI, 211.45 g of lactose hydrate, 15 g of disintegrating agent (any of corn starch "corn starch W" (manufactured by NIHON SHOKUHIN KAKO CO., LTD.), partially pregelatinized starch, or low-substituted hydroxypropyl cellulose), and 3 g of stearic acid were mixed in a plastic bag. From this mixture, uncoated tablets having a mass of 121.2 mg were obtained using a rotary tabletting machine (see Table 6). Example 17

[0064] According to the method described in Example 16, 50 g FTD, 23.55 g TPI, 196.45 g lactose hydrate, 30 g disintegrant (either corn starch, partially pregelatinized starch or low-substituted hydroxypropyl cellulose), and 3 g stearic acid were mixed in a plastic bag. From this mixture, uncoated tablets having a mass of 121.2 mg were obtained using a rotary tabletting machine (see Table 6). Test Example 5

[0065] According to the method described in Test Example 2, the tablets obtained in Examples 15, 16, and 17 were stored at 40°C / 75% relative humidity under ambient conditions for two weeks, and then, the total mass of the associated substances was measured (see Table 6).

[0066] As a result, no noticeable increases in related substances were observed in any of the disintegrating agents or their amounts. [Table 6] Unit: parts per mass Example 15 [16 [17 FTD 1 And 1 1 And 1 b 1 And 1 TPI 0.47110.471 0.471 [0.471 [o.471 0.47110.471 Lactose hydrate 4.529 [4.229 4.229 [4.229 [3.929 3.929 [3.929 Corn starch |o.3 |- [0.6 [- |- Partially pregelatinized starch s- 0.3 [- I- 0.6 1- Low-substituted hydroxypropyl cellulose s- |o.3 1- |0.6 Stearic acid Total Total mass of associated substances I 0.06 |o.O6 0.06 |0.06 |0.06 0.06 [0.06 6.06 [6.06 6.06 |b.O6 |b.O6 6.06 [6.06 [%) 0.188 |0.2 0.266 [0.332 [0.282 0.334 |0.391

Claims

Patent claims 1. An orally administrable pharmaceutical composition comprising α,α,α-trifluorothymidine and 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4 (1H,3H)-pyrimidine dione hydrochloride as active ingredients and a sugar having a critical relative humidity of 85% or more at 25°C as an excipient, and comprising partially pregelatinized starch as a disintegrating agent, wherein the disintegrating agent content is from 2 to 16% by weight in the total amount of the pharmaceutical composition.

2. The orally administrable pharmaceutical composition according to claim 1, wherein the content of the sugar having a critical relative humidity of 85% or more at 25°C is 3.6 parts by weight or more based on 1 part by weight of α,α,α-trifluorothymidine.

3. An orally administrable pharmaceutical composition according to any one of claims 1 to 2, wherein the sugar having a critical relative humidity of 85% or more at 25°C is a disaccharide or a sugar alcohol.

4. An orally administrable pharmaceutical composition according to any one of claims 1 to 3, wherein the sugar having a critical relative humidity of 85% or more at 25°C is one or more selected from lactose, sucrose, mannitol, and erythritol.

5. An orally administrable pharmaceutical composition according to any one of claims 1 to 4, comprising α,α,α-trifluorothymidine and 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidine dione hydrochloride at a molar ratio of 1:0.

5.

6. An orally administrable pharmaceutical composition according to any one of claims 1 to 5, wherein the proportion of sugar having a critical relative humidity of 85% or more at 25°C is 100% by weight of the total amount of excipients.

7. An oral pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition is formulated as a granule, a compression molded product, or a mixture.

8. An orally administrable pharmaceutical formulation comprising an orally administrable composition according to any one of claims 1 to 7, wherein the composition is coated. Published and printed by: Intellectual Property Office, Belgrade, Kneginje Ljubice 5 20