JP6639368B2 - Solid preparation for treating diabetes - Google Patents

Description

  The present invention relates to a solid preparation comprising a combination of tenerigliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof useful as a therapeutic agent for type 2 diabetes.

  Tenerigliptin [chemical name: {(2S, 4S) -4- [4- (3-Methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidin contained in the solid preparation of the present invention -2-yl} (1,3-thiazolidin-3-yl) methanone] is dipeptidyl peptidase IV (DPP-), an enzyme that degrades glucagon-like peptide-1 (GLP-1), a hormone that increases insulin secretion. 4) and is used clinically as a therapeutic agent for type 2 diabetes (Patent Documents 1 to 3). Similarly, canagliflozin [chemical name: (1S) -1,5-Anhydro-1-C- (3-{[5- (4-fluorophenyl) thiophen-2-yl]) contained in the solid preparation of the present invention methyl} -4-methylphenyl) -D-glucitol] is a new type that inhibits sodium glucose co-transporter 2: SGLT2 and excretes glucose into urine to lower blood glucose levels. It is a therapeutic agent for type 2 diabetes having an action mechanism (Patent Documents 4 to 6).

  Due to its excellent pharmacological action, tenegligliptin is being studied for application in combination with other drugs for treating diabetes. The effects obtained by the combination include, for example, enhancement of the postprandial blood glucose level lowering effect by combining with metformin, and lowering effect of the postprandial blood glucose level without insulin secretion by combining with an α-glucosidase inhibitor (Patent Document 3) Etc. are known. In addition, an effect of enhancing the therapeutic effect on hyperglycemic symptoms by combining teneregliptin and canagliflozin is expected (Patent Document 6).

  As described above, tenegligliptin and canagliflozin are each effective for the treatment of type 2 diabetes, and providing a solid preparation (combination) comprising both active ingredients is extremely clinically useful. high. However, with respect to a formulation containing tenegligliptin, a formulation that improves dissolution stability after storage is known (Patent Document 7), and a formulation containing canagliflozin is known (Patent Document 8). No specific combination preparation containing tenerigliptin and canagliflozin has been reported so far.

International Publication No. WO 02/014271 International Publication No. WO 2006/0888129 WO 2006/129785 International Publication No. 2005/012326 International Publication No. 2008/069327 International Publication No. 2009/091082 International Publication No. 2011/074660 International Publication No. 2011/142478

Until now, there has been no report of a solid preparation containing tenegligliptin or a salt thereof and canagliflozin or a salt thereof in the same preparation. Therefore, it is not known at all how any effect on the storage stability and the like of these active ingredients by mixing tenerigliptin or a salt thereof and canagliflozin or a salt thereof in one solid preparation is not known. Was.
The present inventors have studied the storage stability of a combination preparation containing these active ingredients in order to develop a solid preparation (combination preparation) comprising teneregliptin or a salt thereof and canagliflozin or a salt thereof. However, it has been found that, when tenerigliptin or a salt thereof is mixed with canagliflozin or a salt thereof, an interaction causes an increase in related substances, a change in color tone, an off-odor, etc., which may affect storage stability. . Further, it was confirmed that the degree of the interaction was different depending on the combination of the production lots. This is because even if the drug substance level of a drug product containing a single component has no problem at all for the drug substance level, the difference between the lots that cannot be detected in the quality test etc. is a serious problem for combination drugs. This is an issue in achieving stable supply as a combination drug.
Therefore, an object of the present invention is to contain tenerigliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof, and have excellent storage stability regardless of the production lot of the drug substance. To provide a solid preparation.

  The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, it has been confirmed that tenerigliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof are substantially separated from these active ingredients. It has been found that the interaction between the two components can be suppressed by containing the same component in the same solid preparation in such a manner as not to come into contact with the product, and the present invention has been completed.

That is, the present invention is as follows.
[1] A solid preparation comprising a part containing teneglipliptin or a pharmaceutically acceptable salt thereof, and a part containing canagliflozin or a pharmaceutically acceptable salt thereof,
A solid preparation characterized in that tenegligliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof are independently present in the preparation so as not to substantially contact each other. .
[2] The solid preparation according to the above-mentioned [1], further comprising a portion substantially free of tenegligliptin or a pharmaceutically acceptable salt thereof, and canagliflozin or a pharmaceutically acceptable salt thereof.
[3] The description of the above-mentioned [2], wherein a disintegrating agent and a lubricant are contained in a portion substantially free of tenegligliptin or a pharmaceutically acceptable salt thereof, and canagliflozin or a pharmaceutically acceptable salt thereof. Solid preparation.
[4] The above-mentioned method, wherein the excipient is contained in a portion containing tenegligliptin or a pharmaceutically acceptable salt thereof, and the excipient is contained in a portion containing canagliflozin or a pharmaceutically acceptable salt thereof. The solid preparation according to any one of [1] to [3].
[5] The excipient and the binder are contained in the portion containing tenerigliptin or the pharmaceutically acceptable salt thereof, and the excipient and the binding are contained in the portion containing canagliflozin or the pharmaceutically acceptable salt thereof. The solid preparation according to any one of the above [1] to [4], comprising an agent.
[6] The solid preparation according to any one of [1] to [5] above, wherein the portion containing tenegliptin or a pharmaceutically acceptable salt thereof is a granule produced by fluid bed granulation.
[7] The solid preparation according to any of the above [1] to [6], wherein the portion containing canagliflozin or a pharmaceutically acceptable salt thereof is a granule produced by high-speed stirring granulation.
[8] The above-mentioned [1] to [5], wherein the portion containing teneregliptin or a pharmaceutically acceptable salt thereof is granular, and the portion containing canagliflozin or a pharmaceutically acceptable salt thereof is granular. The solid preparation according to any one of the above.
[9] (A) A solid composition containing teneregliptin or a pharmaceutically acceptable salt thereof and an excipient, and (B) a cannagliflozin or a pharmaceutically acceptable salt thereof and an excipient. A solid preparation comprising a solid composition, wherein tenerigliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof are arranged so as not to be in contact with each other.
[10] The solid preparation according to the above-mentioned [9], wherein the solid composition containing teneregliptin or a pharmaceutically acceptable salt thereof and an excipient is a granule produced by fluid bed granulation.
[11] The solid preparation according to the above [9] or [10], wherein the solid composition containing canagliflozin or a pharmaceutically acceptable salt thereof and an excipient is a granule produced by high-speed stirring granulation. .
[12] The solid preparation according to any one of the above [1] to [11], wherein the dosage form is a capsule, pill, granule, fine granule, powder or tablet.
[13] The solid preparation according to any of the above [1] to [12], which comprises 10 mg to 40 mg as a daily dose of tenegliptin or a pharmaceutically acceptable salt thereof in terms of tenegliptin.
[14] The solid preparation according to any of the above [1] to [13], which contains canagliflozin or a pharmaceutically acceptable salt thereof in an amount of 50 to 200 mg per day as canagliflozin.
[15] The solid preparation of the above-mentioned [13], which comprises 20 mg of tenegligliptin or a pharmaceutically acceptable salt thereof in a daily amount in terms of tenegliptin.
[16] The solid preparation according to the above-mentioned [14], comprising 100 mg of canagliflozin or a pharmaceutically acceptable salt thereof in a daily amount in terms of canagliflozin.
[17] The solid preparation according to any one of the above [1] to [16], wherein the teneregliptin or a pharmaceutically acceptable salt thereof is tenerigliptin hydrobromide.
[18] The solid preparation according to any of the above [1] to [17], wherein the canagliflozin or a pharmaceutically acceptable salt thereof is canagliflozin hydrate.
[19] With respect to 100% by weight of the solid preparation,
(A) a solid composition comprising from 0.1 to 50% by weight of teneregliptin or a pharmaceutically acceptable salt thereof, from 0 to 50% by weight of an excipient and from 0 to 5% by weight of a binder;
(B) a solid composition comprising 0.1 to 95% by weight of canagliflozin or a pharmaceutically acceptable salt thereof, 0 to 50% by weight of an excipient and 0 to 5% by weight of a binder. A solid preparation which is independently contained and in which tenegligliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof are arranged so as not to be in contact with each other.
[20] With respect to 100% by weight of the solid preparation,
The solid preparation of the above-mentioned [19], comprising 0.1 to 99% by weight of tenegligliptin or a pharmaceutically acceptable salt thereof and a portion substantially free of canagliflozin or a pharmaceutically acceptable salt thereof.
[21] With respect to 100% by weight of the solid preparation,
(A) a solid composition comprising 12.5% by weight of teneregliptin hydrobromide hydrate, 18.8% by weight of mannitol and 1.0% by weight of hydroxypropylcellulose;
(B) Tenerigliptin bromide, independently containing a solid composition containing 41.3% by weight of canagliflozin hydrate, 7.3% by weight of mannitol and 1.6% by weight of hydroxypropylcellulose A solid preparation in which hydrochloride hydrate and canagliflozin hydrate are arranged so as not to be in contact with each other.
[22] 9.7% by weight of low-substituted hydroxypropylcellulose and 9.7% by weight of teneregliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof as a portion substantially free of The solid preparation according to the above [21], comprising 8% by weight of sodium stearyl fumarate.
[23] The solid preparation according to any one of the above [1] to [22], for treating and / or preventing diabetes or diabetes-related symptoms.

  The solid preparation of the present invention contains tenegligliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof, and has excellent storage stability. In terms of the dissolution properties of tenerigliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof, the solid preparation of the present invention is characterized in that the only active ingredient is tenerigliptin or a pharmaceutically acceptable salt thereof. And a solid preparation containing only canagliflozin or a pharmaceutically acceptable salt thereof as an active ingredient. From this, the solid preparation of the present invention suppresses the adverse effects (reduced storage stability and reduced dissolution stability) due to the interaction between these two active ingredients, and contains the single component. Compared with the combination of the two preparations described above, it is more convenient in taking medicine, and is useful as a therapeutic agent for type 2 diabetes.

FIG. 1 shows the results of dissolution tests of the tablet of Example 1 before storage and the tablet of Example 1 stored at 60 ° C. for one month. No dissolution delay was observed in the tablet of Example 1 after storage. FIG. 2 shows the results of a dissolution test of the tablet of Example 2 before storage and the tablet of Example 2 stored at 60 ° C. for one month. No dissolution delay was observed in the tablet of Example 2 after storage. FIG. 3 shows the results of dissolution tests of the tablet of Comparative Example 1 and the tablet of Comparative Example 1 stored at 60 ° C. for one month. In the tablet of Comparative Example 1 stored at 60 ° C. for one month, a dissolution delay was confirmed. FIG. 4 shows the results of a dissolution test of the tablet of Comparative Example 2 and the tablet of Comparative Example 2 stored at 60 ° C. for one month. In the tablet of Comparative Example 2 stored at 60 ° C. for one month, a dissolution delay was confirmed. FIG. 5 shows the results of a dissolution test of the tablet of Example 1 and the tablet of Example 1 stored at 60 ° C. for one month. In the tablet of Example 1 stored at 60 ° C for one month, no dissolution delay was observed. FIG. 6 shows the results of a dissolution test of the tablet of Example 2 and the tablet of Example 2 stored at 60 ° C. for one month. No dissolution delay was observed in the tablet of Example 2 stored at 60 ° C. for one month. FIG. 7 shows the results of a dissolution test of the tablet of Comparative Example 1 and the tablet of Comparative Example 1 stored at 60 ° C. for one month. In the tablet of Comparative Example 1 stored at 60 ° C. for one month, no dissolution delay was observed. FIG. 8 shows the results of a dissolution test of the tablet of Comparative Example 2 and the tablet of Comparative Example 2 stored at 60 ° C. for one month. In the tablet of Comparative Example 2, it was confirmed that the dissolution of both tablets before storage and after storage at 60 ° C. for one month was delayed.

  The solid preparation of the present invention comprises tenegligliptin or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as “salts of tenegliptin etc.”) and canagliflozin or a pharmaceutically acceptable salt thereof (hereinafter, “canagliflozin”). And the like, which are also referred to as “salts, etc.”) so as not to substantially contact each other. Hereinafter, the solid preparation of the present invention will be described in detail.

  The salt and the like of teneregliptin mixed in the solid preparation of the present invention include not only teneregliptin but also pharmaceutically acceptable salts of teneregliptin and hydrates thereof. These are known compounds, which can be produced by a known method, and commercially available ones can be used.

  Similarly, the salts of canagliflozin used in the solid preparation of the present invention include not only canagliflozin, but also pharmaceutically acceptable salts of canagliflozin, and hydrates thereof. These are known compounds, which can be produced by a known method, and commercially available ones can be used.

  Pharmaceutically acceptable salts of teneligliptin or canagliflozin include salts with inorganic acids, salts with organic acids, and the like. Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of salts with organic acids include benzoic acid, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid , P-toluenesulfonic acid and the like.

  Preferred examples of the pharmaceutically acceptable salt of tenegliptin include hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid, and salts with p-toluenesulfonic acid, and more preferably hydrobromic acid. Salts.

  In the present invention, as the salt of tenegliptin, the hydrate of 2.5 hydrobromide of tenegliptin is most preferred.

  In the present invention, as a salt of canagliflozin, a hydrate of canagliflozin is most preferred.

The solid preparation of the present invention is a solid preparation prepared by mixing a part containing a salt of tenerigliptin and the like and a part containing a salt and the like of canagliflozin, and a salt of tenerigliptin and the like and a salt of canagliflozin And the like are present independently in the preparation so as not to substantially contact each other.
In the solid preparation of the present invention, the “portion containing a salt of teneregliptin or the like” does not substantially contain a salt or the like of canagliflozin.
The term "substantially free of canagliflozin salt or the like" means that the content of the canagliflozin salt or the like is, for example, 1 part by weight or less based on 100 parts by weight of the portion containing the teneregliptin salt or the like. , Preferably 0.1 parts by weight or less, more preferably 0 parts by weight.
In the solid preparation of the present invention, the “portion containing a salt or the like of canagliflozin” does not substantially contain a salt or the like of teneligliptin.
The term "substantially free of teneregliptin salt or the like" means that the content of the canagliflozin salt or the like is, for example, 1 part by weight or less based on 100 parts by weight of the portion containing the canagliflozin salt or the like. , Preferably 0.1 parts by weight or less, more preferably 0 parts by weight.
In the present invention, the `` solid preparation comprising a portion containing a salt of teneregliptin and the like and a portion containing a salt and the like of canagliflozin '' refers to a salt of canagliflozin and the like containing a salt of teneregliptin and the like. And a solid preparation having a component containing a salt of canagliflozin and the like and substantially not containing a salt of teneregliptin and the like. As will be described later, the solid preparation of the present invention may further have other constituent parts (for example, constituent parts substantially not containing a salt of teneregliptin, a salt of canagliflozin, and the like).

Here, in the present specification, “blending” and “blending” mean that two or more active ingredients are contained in one solid preparation, and “blending agent” is one solid preparation. A solid preparation containing two or more active ingredients in the preparation.
The “portion containing tenegligliptin or a pharmaceutically acceptable salt thereof” in the solid preparation of the present invention contains, if necessary, an additive (eg, an excipient) commonly used in the field of formulation, such as a salt of tenegliptin. Part (solid composition). The portion containing a salt of teneglipitin or the like can form a solid preparation together with a portion containing a salt or the like of canagliflozin described later, and can have any shape and size as long as it can be administered to a living body (preferably, orally). It may be.

It is preferable that the portion containing the salt of tenegliptin and the like contains an excipient.
As excipients in the portion containing the salt of tenegliptin, etc., lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch, denatured Carbohydrates such as corn starch, potato starch, wheat starch, rice starch, dextrin / dextrin, maltodextrin and saccharides for compression; calcium citrate, calcium phosphate and calcium aluminate metasilicate, calcium carbonate, dicalcium phosphate and calcium sulfate And inorganic cellulose derivatives such as crystalline cellulose and wood cellulose. Also, a mixture of two or more of the above excipients may be used. Preferably, mannitol, xylitol, and corn starch are used, and more preferably, mannitol.

The content of the salt and the like of tenegliptin is preferably 0.1 to 100 parts by weight, more preferably 1 to 70 parts by weight, and still more preferably 10 to 65 parts by weight based on 100 parts by weight of the portion containing the salt of tenegliptin. Parts, particularly preferably 30 to 55 parts by weight.
The content of the excipient in the portion containing the salt and the like of tenegliptin is preferably 0 to 99 parts by weight, more preferably 1 to 95 parts by weight, based on 100 parts by weight of the portion containing the salt and the like of tenegliptin. It is preferably from 10 to 90 parts by weight, particularly preferably from 40 to 67 parts by weight.
In one embodiment of the present invention, the content of the portion containing the salt of tenegliptin is 0.5 to 90 parts by weight, more preferably 5 to 80 parts by weight, particularly preferably 100 parts by weight of the solid preparation. 15 to 50 parts by weight.
The content of the salt of teneregliptin and the like in the solid preparation of the present invention may be determined by appropriately examining the dose, the number of administrations, and the administration route of the solid preparation. Preferably, the content of the salt of tenerigliptin or the like is 0.1 to 50 parts by weight, more preferably 1 to 35 parts by weight, further preferably 5 to 30 parts by weight, particularly preferably 10 to 100 parts by weight of the solid preparation. -20 parts by weight. In the case of a solid preparation for once-a-day administration, the amount is 5 to 80 mg, preferably 10 to 40 mg, more preferably 15 to 25 mg, per adult, in terms of tenegligliptin. The term “tenerigliptin conversion” means a state as tenerigliptin excluding inorganic acids, organic acids, water of hydration, and the like.
In the solid preparation of the present invention, the content of the excipient in the portion containing the salt of teneregliptin and the like is 0 to 50 parts by weight, more preferably 1 to 45 parts by weight, still more preferably 5 to 50 parts by weight, per 100 parts by weight of the solid preparation. -30 parts by weight, particularly preferably 15-25 parts by weight.

  The “portion containing a salt of canagliflozin or a pharmaceutically acceptable salt thereof” in the present invention may be a salt of canagliflozin or the like, and if necessary, an additive (eg, an excipient) commonly used in the pharmaceutical field. ) Is contained (solid composition). The portion containing canagliflozin salt or the like can form a solid preparation together with the above-mentioned portion containing teneregliptin salt or the like, and can have any shape and size as long as it can be administered to a living body (preferably orally). It may be.

The portion containing canagliflozin salt or the like preferably contains an excipient.
Examples of the excipient in the portion containing the salt or the like of canagliflozin include those exemplified as the excipient in the portion containing the salt or the like of teneregliptin. Preferably, it is lactose, sucrose, erythritol, mannitol, and more preferably, mannitol.

The content of the canagliflozin salt or the like is preferably 0.1 to 100 parts by weight, more preferably 20 to 95 parts by weight, and still more preferably 100 parts by weight of the portion containing the canagliflozin salt or the like. It is 30 to 90 parts by weight, particularly preferably 65 to 90 parts by weight.
The content of the excipient in the portion containing the canagliflozin salt and the like is preferably 0 to 99 parts by weight, more preferably 5 to 80 parts by weight, based on 100 parts by weight of the portion containing the canagliflozin salt and the like. Parts by weight, more preferably 9 to 69 parts by weight, particularly preferably 9 to 34 parts by weight.
In one embodiment of the present invention, the content of the portion containing the salt of canagliflozin is 0.5 to 95 parts by weight, more preferably 10 to 90 parts by weight, particularly preferably 100 parts by weight of the solid preparation. Is 30 to 80 parts by weight.
The content of the canagliflozin salt and the like in the solid preparation of the present invention may be determined by appropriately examining the dose, the number of administrations, and the administration route. Preferably, the content of the salt of canagliflozin or the like is 0.1 to 90 parts by weight, more preferably 10 to 80 parts by weight, particularly preferably 20 to 60 parts by weight based on 100 parts by weight of the solid preparation. In the case of a solid preparation for once-a-day administration, the dosage is 20 to 300 mg, preferably 50 to 200 mg, more preferably 50 to 150 mg, particularly preferably 80 to 120 mg, per adult, in terms of canagliflozin. In addition, "in terms of canagliflozin" means a state as canagliflozin excluding inorganic acids, organic acids, water of hydration and the like.
The content of the excipient in the portion containing the canagliflozin salt or the like in the solid preparation of the present invention is 0 to 50 parts by weight, more preferably 2 to 40 parts by weight, and still more preferably 100 parts by weight of the solid preparation. Is 5 to 35 parts by weight, particularly preferably 5 to 20 parts by weight.

  The “portion containing a salt of teneregliptin and the like” or the “portion containing a salt and the like of canagliflozin” may further contain additives commonly used in the field of pharmaceuticals. Examples of the additives include disintegrants, binders, lubricants, coloring agents, pH adjusters, surfactants, stabilizers, corrigents, fragrances, fluidizers, coating bases, coating additives, and the like. Can be These additives are used in conventional amounts in the pharmaceutical field unless otherwise specified.

  Preferred examples of the disintegrant include carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, croscarmellose sodium, croscarmellose calcium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylstarch and the like. Of these, low-substituted hydroxypropylcellulose is preferred.

  Preferable examples of the binder include crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic and the like. Of these, hydroxypropyl cellulose is preferred.

  Preferable examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate and the like. Of these, sodium stearyl fumarate is preferred.

  Suitable examples of coloring agents include carotenoids, iron oxide and chlorophyll. Examples of coloring agents also include food color red Nos. 2 and 3, food color yellows 4 and 5, food color green No. 3, food color blue Nos. 1 and 2, Food lakes include aluminum lake, iron sesquioxide and yellow iron sesquioxide.

  Preferred examples of the pH adjuster include citric acid, magnesium carbonate, magnesium aluminate metasilicate, magnesium oxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, aluminum silicate, phosphoric acid Examples include sodium dihydrogen, potassium dihydrogen phosphate, and sodium acetate. These may be used alone or in combination of two or more.

  Preferred examples of the surfactant include sodium lauryl sulfate, sodium stearate, polyoxyethylene sorbitan monooleate, and sucrose fatty acid ester.

  Preferable examples of the stabilizer include ascorbic acid, sodium edetate, erythorbic acid, tocopherol and the like.

  Preferable examples of the flavoring agent include acidifiers such as citric acid, malic acid, acetic acid, tartaric acid, fumaric acid, and ascorbic acid, and sweeteners such as saccharin and aspartame.

  Preferable examples of the flavor include menthol, peppermint oil, orange oil, lemon oil and the like.

  Preferable examples of the fluidizing agent include light anhydrous silicic acid, hydrated silicon dioxide, talc and the like.

  Preferable examples of the coating base include a sugar coating base, a water-soluble film coating base, an enteric film coating base, a sustained release film coating base and the like.

  As the sugar-coating base, for example, sugar alcohols such as sucrose, purified sucrose, erythritol and the like are used, and one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like are used in combination. May be.

  Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; Molecule: a polysaccharide such as pullulan and the like.

  Examples of the enteric film coating base include cellulose-based polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L, methacrylic acid copolymer LD, Acrylic acid-based polymers such as methacrylic acid copolymer S; natural products such as shellac;

  Examples of the sustained-release film coating base include cellulose-based polymers such as ethylcellulose; acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS and ethyl acrylate / methyl methacrylate copolymer suspension. No.

  Preferable examples of the coating additive include a light-shielding agent such as titanium oxide, a fluidizing agent such as talc, and / or a coloring agent such as iron sesquioxide and yellow iron sesquioxide; polyethylene glycol, propylene glycol, triethyl citrate, Plasticizers such as castor oil and polysorbates; and organic acids such as citric acid, tartaric acid, malic acid, and ascorbic acid.

  The above-mentioned additives may be used by mixing two or more kinds in an appropriate ratio.

In the present invention, the portion containing a salt of tenegliptin, etc., preferably contains an excipient (preferably, mannitol) and a binder (preferably, hydroxypropylcellulose), such as a salt of tenegliptin.
The content of the excipient in the portion containing the salt and the like of tenegliptin is preferably 0 to 99 parts by weight, more preferably 1 to 95 parts by weight, based on 100 parts by weight of the portion containing the salt and the like of tenegliptin. It is preferably 10 to 90 parts by weight, particularly preferably 40 to 67 parts by weight, and the content of the binder in the portion containing the salt and the like of teneregliptin is 100 parts by weight based on 100 parts by weight of the portion containing the salt and the like of teneregliptin. Preferably it is 0 to 10 parts by weight, more preferably 0 to 5 parts by weight, further preferably 1 to 5 parts by weight.
In the solid preparation of the present invention, the content of the excipient in the portion containing the salt of teneregliptin and the like is 0 to 50 parts by weight, more preferably 1 to 45 parts by weight, still more preferably 5 to 50 parts by weight, per 100 parts by weight of the solid preparation. To 30 parts by weight, particularly preferably 15 to 25 parts by weight, and the content of the binder in the portion containing the salt of teneregliptin is 0 to 5 parts by weight, more preferably 0 to 5 parts by weight, per 100 parts by weight of the solid preparation. To 3 parts by weight, more preferably 0.5 to 3 parts by weight.

The portion containing a salt of canagliflozin in the present invention preferably contains an excipient (preferably mannitol) and a binder (preferably hydroxypropylcellulose) such as a salt of canagliflozin.
The content of the excipient in the portion containing the canagliflozin salt and the like is preferably 0 to 99 parts by weight, more preferably 5 to 80 parts by weight, based on 100 parts by weight of the portion containing the canagliflozin salt and the like. Parts by weight, more preferably 9 to 69 parts by weight, particularly preferably 9 to 34 parts by weight, and the content of the binder in the portion containing the salt of canagliflozin contains the salt of canagliflozin and the like. The amount is preferably 0 to 10 parts by weight, more preferably 0 to 5 parts by weight, and still more preferably 1 to 5 parts by weight with respect to 100 parts by weight of the portion.
The content of the excipient in the portion containing the canagliflozin salt or the like in the solid preparation of the present invention is 0 to 50 parts by weight, more preferably 2 to 40 parts by weight, and still more preferably 100 parts by weight of the solid preparation. Is 5 to 35 parts by weight, particularly preferably 5 to 20 parts by weight, the content of the binder in the portion containing the salt of canagliflozin is 0 to 5 parts by weight, based on 100 parts by weight of the solid preparation, The amount is more preferably 0 to 3 parts by weight, and still more preferably 0.5 to 3 parts by weight.

  In the solid preparation of the present invention, the portion containing the salt of tenerigliptin and the like and the portion containing the salt and the like of canagliflozin are usually solid. In addition, the shape is particularly limited as long as it is possible that the salt of teneregliptin etc. and the salt of canagliflozin etc. independently exist in the solid preparation of the present invention so as not to substantially contact each other as described later. However, it may be granular or lump-shaped, and is preferably granular. In the present specification, “granular” is a concept including fine granular and granular.

When the portion is granular, the particle size is not particularly limited. Preferably, the weight average particle diameter (hereinafter, referred to as “D50”) is 30 μm or more and 350 μm or less, and more preferably, D50 is 50 μm or more and 250 μm or less. In the case of a portion containing a salt of tenegliptin, etc., the particle size is more preferably about 80 to 250 μm, and particularly preferably about 100 to 150 μm. In the case of a portion containing a salt of canagliflozin or the like, the particle size is more preferably about 50 to 100 μm.
The term "weight average particle diameter" used in the present specification is, by a sieving method, using a plurality of sieves having different openings, stacking such that a sieve having a larger opening is located on the upper stage, and measuring the uppermost stage. The powder is charged, vibrated manually or mechanically, and the amount of powder remaining on each sieve is measured. The particle size at the time when 50% by weight of the particles are separated is meant.

In the present invention, `` existing so as not to substantially contact each other '' means that in a solid preparation, a salt of teneregliptin and a salt of canagliflozin do not come into contact to such an extent that no interaction occurs. It means that it is contained, but it is preferable that it is contained so that the salt of teneregliptin or the like and the salt or the like of canagliflozin do not come into direct contact. That is, it is preferable that the solid preparation of the present invention has a portion substantially not containing a salt of tenerigliptin and the like and a salt of canagliflozin.
In the solid preparation of the present invention, between the portion containing the salt and the like of teneregliptin and the portion containing the salt and the like of canagliflozin, a portion substantially free of the salt and the like of teneregliptin and the like and the salt of canagliflozin are present. Preferably it is present. The term "substantially free" means that the salt of tenegligliptin, the salt of canagliflozin, and the like are each based on 100 parts by weight of the portion substantially free of the salt of teneregliptin and the like and the salt of canagliflozin. For example, 1 part by weight or less, preferably 0.1 part by weight or less, more preferably 0 part by weight.
Specifically, a portion substantially free of a salt of tenegliptin and the like and a salt of canagliflozin constitutes a continuous phase (solid phase), and a portion containing a salt of tenegligliptin and the like in the continuous phase (for example, , A granule containing a salt of tenerigliptin, etc.) and a portion containing a salt, etc. of canagliflozin (eg, a granule containing a salt, etc. of canagliflozin) are respectively dispersed in a solid preparation (eg, a tablet) Is one embodiment of the solid preparation of the present invention.
Further, in a continuous phase (solid phase) substantially free of a salt or the like of tenegliptin and a salt or the like of canagliflozin, a portion containing a salt or the like of tenegliptin (eg, a granule containing a salt or the like of tenegliptin) is dispersed. And a portion containing a canagliflozin salt or the like (for example, a salt of canagliflozin) in a continuous phase (solid phase) substantially free of a salt of teneregliptin or a salt of canagliflozin or the like. A solid preparation (for example, a tablet) in which a layer in which granules containing the above are dispersed is exemplified as one embodiment of the solid preparation of the present invention.

The portion substantially free of the salt of tenerigliptin and the like and the salt of canagliflozin and the like is a portion containing additives commonly used in the field of pharmaceuticals. Such additives include excipients, disintegrants, binders, lubricants, coloring agents, pH adjusters, surfactants, stabilizers, corrigents, fragrances, fluidizers, coating bases, and coating additives. Agents and the like. These additives are used in conventional amounts in the pharmaceutical field unless otherwise specified. Examples of these additives include the same additives as those described in the description of the “portion containing a salt of teneregliptin or the like” or the “portion containing a salt of canagliflozin”.
In the present invention, the portion substantially free of the salt of tenerigliptin and the like and the salt of canagliflozin and the like are preferably a disintegrant (preferably low-substituted hydroxypropylcellulose) and a lubricant (preferably sodium stearyl fumarate). ).
The content of the portion substantially free of salts and the like of teneregliptin and salts of canagliflozin is preferably 0.1 to 99 parts by weight, more preferably 1 to 50 parts by weight, based on 100 parts by weight of the solid preparation, Particularly preferably, it is 5 to 25 parts by weight.

  The solid preparation of the present invention is not particularly limited as long as it is a preparation in which a part containing a salt of teneregliptin and the like and a part containing a salt of canagliflozin are integrally molded. Can be mixed with the above-mentioned additives according to a method known per se and compression-molded, or can be produced by coating one part with the other part. Preferred additives include a lubricant (preferably sodium stearyl fumarate) and a disintegrant (preferably low substituted hydroxypropylcellulose).

  Specific examples of the solid preparation of the present invention include a portion containing a salt of teneregliptin and the like (preferably a portion containing teneregliptin hydrobromide or a hydrate thereof) and a portion containing a salt of canagliflozin and the like ( It preferably contains a portion containing canagliflozin hydrate), a disintegrant (preferably low-substituted hydroxypropylcellulose), and a lubricant (preferably sodium stearyl fumarate).

Further, the solid preparation of the present invention comprises an inert intermediate layer (such as a salt of tenerigliptin or a salt of canagliflozin) between a portion containing a salt or the like of teneregliptin and a portion containing a salt or the like of canagliflozin. Etc.).
For example, when the portion containing the salt of teneregliptin and / or the portion containing the salt of canagliflozin is in the form of granules (fine granules, granules) or lump, the particles or lump are coated to be inert. May be formed.

Examples of the material for the intermediate layer include those exemplified above as the coating base and the coating additive. The content of the intermediate layer in the solid preparation is usually about 0.1 to 50 parts by weight, preferably about 0.5 to 45 parts by weight, more preferably about 1 to 20 parts by weight, based on 100 parts by weight of the preparation. It is. The formation of the intermediate layer can be performed by a conventional method.
Further, the intermediate layer may be formed of not only one layer but also a plurality of layers (preferably, two or three layers).

  When the solid preparation of the present invention has such an intermediate layer, the adverse effects of the active ingredients acting on each other (reduction of storage stability such as decomposition of active ingredients over time and reduction of activity, elution of active ingredients over time) A decrease in elution stability such as a change in pattern, etc.) can be suppressed more effectively.

  Although the dosage form of the solid preparation of the present invention is not particularly limited, oral administration preparations such as capsules, pills, granules, fine granules, powders, tablets and the like can be mentioned from the viewpoint of easy taking. The solid preparation of the present invention may be coated with a sugar coating, a film coating or the like by a known method.

One embodiment of the solid preparation of the present invention includes the following.
(A) a solid composition containing a salt and the like of tenegliptin and an excipient, and (B) a solid composition containing a salt and the like of canagliflozin and an excipient, and a salt and the like of tenegligliptin and canagliph A solid preparation in which rosin salt and the like are arranged so as not to be in contact with each other.
The forms of the solid compositions (A) and (B) are, for example, powder, granules (fine granules, granules), and tablets.

  Specific forms of the solid preparation of the present invention include the following (a) to (f) and the like. These can be produced and formulated by known methods using appropriate additives as described above. can do.

(A) Powders or granules obtained by granulating any one of a salt of tenerigliptin, etc., and a salt of canagliflozin, etc. by an appropriate method into granules, and mixing the other salt, etc. without granulation. And the like, and a preparation obtained by further coating the granules with a suitable method.
(B) Tenerigliptin salt and the like, and canagliflozin salt and the like are separately granulated by an appropriate method to obtain granules, and powders or granules manufactured by blending these, and the granules are prepared. Formulations further coated by a suitable method.
(C) Capsules prepared by filling capsules with the powder or granules prepared in (a) or (b) above.
(D) A tablet obtained by tableting the granules or the like produced in (a) or (b) above by an appropriate method such as compression molding.
(E) Multilayer tablets produced by, for example, compression molding or the like so that the salt of tenerigliptin and the like and the salt of canagliflozin do not substantially come into contact with each other, and a preparation obtained by further coating the multilayer tablet by an appropriate method. As the multi-layered tablet, a tablet in which a salt of teneregliptin and the like and a salt of canagliflozin and the like are formed in different layers is preferable. In addition, as the salt of tenerigliptin and the like and the salt of canagliflozin and the like, the granules produced in the above (a) and (b) can be used.
(F) One of the salt of tenerigliptin, etc., and the salt of canagliflozin, etc. are arranged as a core tablet (also referred to as a core tablet or a central tablet), and the salt of tenegligliptin, etc., and the salt of canagliflozin, etc. are substantially And dry coated tablets prepared so that they do not come into contact with each other, and preparations coated with the dry coated tablets by an appropriate method.

In the present invention, granulation (for example, the granules in (a) and (b) above) includes, for example, extrusion granulation (eg, using a screw extrusion granulator, a roll extrusion granulator, etc.), tumbling granulation. (Eg, by a rotary drum type granulator, a centrifugal rolling type granulator, etc.), stirring granulation (eg, by a stirring granulator, high speed stirring granulator, etc.), fluidized bed granulation (eg, fluidized bed Granulation device, tumbling fluidized bed granulation device, etc.), spray drying granulation (eg, by spray drying granulation device, etc.), crushing granulation (eg, screen type crushing granulator, screenless type crushing granulation) And a known granulation method such as melt granulation (eg, by a method such as a flaker type, an injection type, and a dropping type on a plate).
In the present invention, it is preferable that the granules containing the salt of teneregliptin and the like are produced by fluidized bed granulation, and the granules containing the salt of canagliflozin and the like are produced by high speed stirring granulation.

In the present invention, mixing (for example, blending (mixing) in each of the above steps) includes, for example, a mixer such as a V-type mixer and a tumbler mixer; and a high-speed stirring granulator, a fluidized-bed granulator / dryer, and an extrusion machine. It can be performed using a granulator such as a granulator and a roller compactor.
In the present invention, compression molding (for example, compression molding in each of the above steps) can be performed using, for example, a single-shot tablet machine, a rotary tableting machine, or the like. In addition, when using a single-shot tablet machine, a rotary tableting machine, or the like, it is preferable to adopt a tableting pressure of usually 1 to 35 kN / cm ² (preferably 5-35 kN / cm ² ), and further, to prevent capping. For this purpose, it is preferable to use a tapered die.
In the present invention, coating (for example, coating in each of the above steps) can be performed using, for example, a film coating apparatus or the like.

The solid preparation of the present invention can also be provided in the form of a laminated tablet. The laminated tablet can be preferably produced according to the following production steps.
1) Granulation of a salt of tenegliptin and an excipient using a solvent dispersion of a binder.
2) The obtained granules are dried and sized, and then the obtained sized powder is mixed with a disintegrant, a lubricant, and, if necessary, an excipient to obtain granules. obtain.
1 ′) Granulation of canagliflozin salt and the like and an excipient using a solvent dispersion of a binder.
2 ′) The obtained granules are dried and sized, and the obtained sized powder is mixed with a disintegrant, a lubricant, and, if necessary, an excipient to obtain granules. Get.
3) The granules obtained in 2) and the granules obtained in 2 ′) are stacked in layers and compression-molded (preferably tableted).

The solid preparation of the present invention can also be provided in the form of a dry-coated tablet. The dry-coated tablet can be preferably produced according to the following production steps.
1) Granulate a salt of tenegliptin or the like (or a salt of canagliflozin) and an excipient using a solvent dispersion of a binder.
2) The obtained granules are dried and sized, and then the obtained sized powder is mixed with a disintegrant, a lubricant, and, if necessary, an excipient, and compression-molded ( (Preferably tableting) to obtain an uncoated tablet. Preferably, the uncoated tablet is coated to avoid drug contact.
1 ') Granulate a salt of canagliflozin (or a salt of teneregliptin) and an excipient using a solvent dispersion of a binder.
2 ′) The obtained granules are dried and sized, and the obtained sized powder is mixed with a disintegrant, a lubricant, and, if necessary, an excipient to obtain granules. Get.
3) The tablet containing the salt of teneregliptin obtained in 2) above is used as an inner core tablet, and the granules containing the salt of canagliflozin obtained in 2 ′) are subjected to compression molding (preferably tableting) as an outer layer portion. Alternatively, the tablet containing the salt of canagliflozin obtained in 2) above is used as an inner core tablet, and the granules containing the salt of tenerigliptin obtained in 2 ′) are subjected to compression molding (preferably tableting) as an outer layer portion. .

Capsules prepared by filling the above-mentioned laminated tablets or dry-coated tablets into capsules (eg, gelatin capsules) are also included in the solid preparation of the present invention.
Further, a film-coated preparation produced by film-coating the above-mentioned laminated tablet or nucleated tablet with a coating agent and a coating additive is also included in the solid preparation of the present invention.

  The solid preparation of the present invention is useful as a medicament. Specifically, various diseases caused by SGLT2 by the SGLT2 inhibitory action of canagliflozin, such as various diseases caused by DPP-4 by the DPP-4 inhibitory action of teneregliptin, and the like. Oral to humans and non-human mammals (eg, mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.) for the treatment or prevention of diseases, etc. Can be safely administered. Therefore, the solid preparation of the present invention can be used for treating, preventing or delaying diabetes or diabetes-related symptoms. Diabetes-related condition means various pathological signs associated with, caused by, or resulting from diabetes. The invention can preferably be used for the treatment and / or prevention of type 2 diabetes or diabetes-related symptoms.

  As a route for taking the solid preparation of the present invention, oral administration is preferred. When the solid preparation of the present invention is orally administered, it is administered once a day, preferably once a day before breakfast.

  As a particularly preferred specific example of the solid preparation of the present invention, "canaliflozine hydrate (100 mg in terms of canagliflozin) and tenegligliptin 2.5 hydrobromide hydrate (20 mg in terms of tenegligliptin) per tablet are preferably used. Containing coated tablets, laminated tablets or dry-coated tablets ".

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples, but the present invention is not limited thereto.
Note that, in the examples, as Tenerigliptin hydrobromide hydrate, Tenerigliptin 2.5 hydrobromide X hydrate or Tenerigliptin 2.5 hydrobromide 1.0-2.0 hydrate is used. Using. Canagliflozin hemihydrate was used as canagliflozin hydrate. Opadry (Colorcon) was used as a coating agent.

Example 1 Combination of Teneregliptin and Canagliflozin (1)
According to the formulation shown in Table 1, a portion containing tenerigliptin or a pharmaceutically acceptable salt thereof (such as a salt of teneregliptin) and canagliflozin or a pharmaceutically acceptable salt thereof (canagliflozin) are prepared according to the following method. ) Were prepared independently of each other in such a manner that the portions containing the same did not substantially contact each other.
In Table 1, <the intragranular component of the granules containing tenerigliptin hydrobromide hydrate> is the component of the "portion containing the salt of teneregliptin and the like" in the present invention, and <contains canagliflozin hydrate. The intragranular component of the granule> is the component of the “portion containing a salt of canagliflozin” in the present invention, and the <extragranular component> and Opadry are substantially the same as “the salt of teneregliptin and the salt of canagliflozin”. Components that are not included ".
(1) Tenerigliptin hydrobromide hydrate (12.5% by weight) and mannitol (18.8% by weight) were homogenized in a fluidized bed granulating dryer (NFLO-30SJ, Freund Corporation, Japan). Then, the mixture was granulated while spraying an aqueous solution containing hydroxypropylcellulose (1.0% by weight), and then dried to obtain a granulated powder. The obtained granulated powder is crushed using a Comil (QC-194S, Powrex Co., Japan) equipped with a 1 mmφ round hole screen, and the granules containing teneregliptin hydrobromide hydrate are washed with teneregliptin salt or the like. It was obtained as a part to contain.

(2) Canagliflozin hydrate (41.1% by weight), mannitol (7.3% by weight) and hydroxypropylcellulose (1) were placed in a high-speed stirring granulator (FM-VG-100, Powrex, Japan). (0.6% by weight), and purified water was charged to granulate. The obtained granulated powder is pulverized using a new speed mill (ND-10S, Okada Seiko Co., Ltd., Japan) equipped with a 5 mm circular hole screen, and then a fluidized bed dryer (NFLO-30SJ, Freund Industrial Co., Ltd.) Company, Japan) and dried. Further, the granules after drying were sized with a 22-mesh sieve, and granules containing canagliflozin hydrate were produced as portions containing salts of canagliflozin and the like.

(3) One part (32.3% by weight) of the granules containing teneregliptin hydrobromide hydrate obtained in (1) and one of the granules containing canagliflozin hydrate obtained in (2) Parts (50.0% by weight), low-substituted hydroxypropylcellulose (9.7% by weight) and sodium stearyl fumarate (2.8% by weight) were added, and a W-type mixer (W-60, Tokuju Corporation) The granules for tableting were obtained by mixing at Kobosakusho, Japan).

(4) The granules for tableting obtained in (3) were molded using an 8.5 mmφ punch with a rotary tableting machine (VIRGO518SS2AZ, Kikusui Seisakusho, Japan) to obtain plain tablets.

(5) Using a coating machine (HC-LABO, Freund Corporation, Japan), spray the coating liquid obtained by dispersing and dissolving Opadry (5.2% by weight) in purified water onto the uncoated tablet obtained in (4). As a result, 248 mg of a coated tablet was obtained per tablet.

Example 2 Combination agent of tenegliptin and canagliflozin (2)
According to the formulation shown in Table 2, a preparation was prepared in which the portion containing the salt and the like of teneregliptin and the portion containing the salt and the like of canagliflozin were present independently so as not to substantially contact each other.
In Table 2, <the intragranular component of the granules containing the teneregliptin hydrobromide hydrate> is the component of the "portion containing the salt of teneregliptin or the like" in the present invention, and <including the canagliflozin hydrate. The intragranular component of the granule> is the component of the “portion containing canagliflozin salt or the like” in the present invention, and the <extragranular component of the granule containing teneregliptin hydrobromide hydrate>, <canagliflozin Extragranular component of granules containing hydrate> and Opadry are components of “parts substantially free of salts of teneregliptin and salts of canagliflozin”.
(1) Low-substituted hydroxypropylcellulose (3.7% by weight) was added to a part (32.3% by weight) of the granules containing teneligliptin hydrobromide hydrate obtained in (1) of Example 1 And sodium stearyl fumarate (1.1% by weight) were added and mixed in a plastic bag to obtain granules (I) for tableting.
(2) Low-substituted hydroxypropylcellulose (5.7% by weight) and fumar were added to a part (50.2% by weight) of the granules containing canagliflozin hydrate obtained in (2) of Example 1 By adding sodium stearyl acid (1.7% by weight) and mixing in a plastic bag, granules (II) for tableting were obtained.

(3) Granules for tableting (I) (37.1% by weight) and granules for tableting (II) (57.6% by weight) were converted into a rotary tableting machine (AQUARIUS LDA, Kikusui Seisakusho, Japan). Was molded into a layer using an 8.5 mmφ punch to obtain an uncoated tablet.

(4) Using a coating machine (HC-LABO, Freund Corporation, Japan), apply the coating liquid obtained by dispersing and dissolving Opadry (5.3% by weight) in purified water to the uncoated tablet obtained in (3). By spraying, 247 mg per tablet was obtained as a coated tablet.

Comparative Example 1 Combination of Teneregliptin and Canagliflozin (3)
The formulation was manufactured according to the formulation shown in Table 3.

(1) Tenerigliptin hydrobromide hydrate (12.7% by weight), canagliflozin hydrate (41.8% by weight) in a high-speed stirring granulator (FS-GS-2J, Fukae Powtech Co., Ltd., Japan). %), Mannitol (26.5% by weight) and hydroxypropylcellulose (2.6% by weight), and purified water was charged to granulate. The obtained granulated powder was dried using a fluid bed drier (MP-01, Powrex, Japan). The dried powder was sized with a 22-mesh sieve to produce granules containing teneligliptin hydrobromide hydrate and canagliflozin hydrate.

(2) Low-substituted hydroxypropylcellulose (9.8% by weight) was added to a part (83.6% by weight) of the obtained granules containing teneregliptin hydrobromide hydrate and canagliflozin hydrate. Granules for tableting were obtained by adding sodium stearyl fumarate (2.9% by weight) and mixing in a plastic bag.

(3) The granules for tableting were molded with a rotary tableting machine (VELA2, Kikusui Seisakusho, Japan) using an 8.5 mmφ punch to obtain plain tablets.

(4) Using a coating machine (HC-LABO, Freund Corporation, Japan), apply a coating liquid obtained by dispersing and dissolving Opadry (3.7% by weight) in purified water to the uncoated tablet obtained in (3). By spraying, 244 mg per tablet was obtained as a coated tablet.

Comparative Example 2 Combination of Teneregliptin and Canagliflozin (4)
The formulation was manufactured according to the formulation shown in Table 3. At that time, canagliflozin hydrate and tenerigliptin hydrobromide hydrate of production lots different from those used in Comparative Example 1 were used.

Test Example 1 Interaction study-1
Teneligliptin hydrobromide hydrate and canagliflozin hydrate were weighed into a beaker and mixed using a stirrer. % And kneaded. The obtained kneaded product was dried at 60 ° C. for 1 hour, placed in a collection vial (20 mL), and stored for one month under various storage conditions. Immediately after the start of storage, the state in the collection vial after one month was evaluated under various storage conditions, and the results are shown in Table 4.

  As shown in Table 4, when a kneaded / dried product of teneregliptin hydrobromide hydrate and canagliflozin hydrate was prepared and stored, discoloration and generation of acetic acid odor or sulfuric acid odor were observed.

Test Example 2 Chemical Stability Test Tablets of Example 1, Example 2, Comparative Example 1 and Comparative Example 2 were stored at 60 ° C. or 40 ° C. and 75% RH under sealed glass bottle conditions, and were treated with tenerigliptin and canaglyph. Chemical stability was evaluated by measuring the amount of total related substances derived from rosin. Table 5 shows the results.

As shown in Table 5, the tablets of the present invention were found to be tablets with improved chemical stability.

Test Example 3 Dissolution test 1
The tablets of Example 1, Example 2, Comparative Example 1 and Comparative Example 2 were stored at 60 ° C. under sealed glass bottle conditions, and the elution of tenegliptin was evaluated by the paddle method (50 rpm) using purified water. . The results are shown in FIGS. Each value shows the average value of the dissolution rate of 3 to 6 tablets.

  In Examples 1 and 2 (FIGS. 1 and 2), no elution delay was observed after storage. On the other hand, in Comparative Examples 1 and 2 (FIGS. 3 and 4), the elution was delayed by storage. From this, it was shown that the solid preparation of the present invention had improved elution properties of tenegliptin before and after storage, and was excellent as an immediate release preparation.

Test Example 4 Dissolution test 2
The tablets of Example 1, Example 2, Comparative Example 1 and Comparative Example 2 were stored at 60 ° C. under sealed glass bottle conditions, and contained a phosphate buffer containing 0.1% (w / w) polysorbate 80. The dissolution of canagliflozin was evaluated by the paddle method (75 rpm) using pH 6.8 (second liquid of JP16). The results are shown in FIGS. Each value shows the average value of the dissolution rate of 3 to 6 tablets.

  In Examples 1 and 2 and Comparative Example 1 (FIGS. 5 to 7), no elution delay was observed after storage. On the other hand, in Comparative Example 2 (FIG. 8), the elution was delayed. This indicated that the solid preparation of the present invention had improved dissolution of canagliflozin before and after storage, and was excellent as an immediate release preparation.

  The solid preparation of the present invention is useful as a therapeutic agent for diabetes and the like, and has both excellent storage stability and dissolution stability.

  This application is based on a patent application No. 2014-262702 filed in Japan, the contents of which are incorporated in full herein.

Claims (25)

A solid preparation comprising a part containing tenegliptin or a pharmaceutically acceptable salt thereof, and a part containing canagliflozin or a pharmaceutically acceptable salt thereof,
Lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch in the part containing the teneregliptin or a pharmaceutically acceptable salt thereof. , Modified corn starch, potato starch, wheat starch, rice starch, dextrin, dextrate, maltodextrin, sugars for compression, calcium citrate, calcium phosphate, calcium aluminate metasilicate, calcium carbonate, dicalcium phosphate, calcium sulfate, crystals Cellulose, containing one or more selected from wood cellulose,
In the portion containing the canagliflozin or a pharmaceutically acceptable salt thereof, lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, Corn starch, modified corn starch, potato starch, wheat starch, rice starch, dextrin, dextrate, maltodextrin, sugars for compression, calcium citrate, calcium phosphate, calcium aluminate metasilicate, calcium carbonate, dicalcium phosphate, calcium sulfate Containing one or more selected from crystalline cellulose and wood cellulose,
A solid preparation characterized in that tenegligliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof are independently present in the preparation so as not to substantially contact each other. . A part containing tenegligliptin or a pharmaceutically acceptable salt thereof, and a part containing canagliflozin or a pharmaceutically acceptable salt thereof, and further, tenerigliptin or a pharmaceutically acceptable salt thereof. A solid preparation containing a salt and a portion substantially free of canagliflozin or a pharmaceutically acceptable salt thereof,
Carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, croscarmellose sodium, croscarmellose sodium, in the portion substantially free of the tenegligliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof. One or more selected from carmellose calcium, crospovidone, low-substituted hydroxypropylcellulose, and hydroxypropyl starch, and stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, and fumaric acid Contains one or more selected from stearyl sodium,
A solid preparation characterized in that tenegligliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof are independently present in the preparation so as not to substantially contact each other. . In the part containing tenegliptin or a pharmaceutically acceptable salt thereof, lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch, Modified corn starch, potato starch, wheat starch, rice starch, dextrin, dextrate, maltodextrin, sugar for compression, calcium citrate, calcium phosphate, calcium aluminate metasilicate, calcium carbonate, dicalcium phosphate, calcium sulfate, crystalline cellulose , And one or more selected from wood cellulose,
In the portion containing canagliflozin or a pharmaceutically acceptable salt thereof, lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn Starch, modified corn starch, potato starch, wheat starch, rice starch, dextrin, dextrate, maltodextrin, compression sugars, calcium citrate, calcium phosphate, calcium metasilicate aluminate, calcium carbonate, dicalcium phosphate, calcium sulfate, The solid preparation according to claim 2, comprising one or more kinds selected from crystalline cellulose and wood cellulose. In the part containing tenegligliptin or a pharmaceutically acceptable salt thereof, the content of tenerigliptin or a pharmaceutically acceptable salt thereof is 1 to 70 parts by weight relative to 100 parts by weight of the part, and lactose; Mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch, modified corn starch, potato starch, wheat starch, rice starch, dextrin, dextrin, From maltodextrin, sugars for compression, calcium citrate, calcium phosphate, calcium aluminate metasilicate, calcium carbonate, dicalcium phosphate, calcium sulfate, crystalline cellulose, and wood cellulose One or more content barrel is 1-95 parts by weight,
In the portion containing canagliflozin or a pharmaceutically acceptable salt thereof, canagliflozin or a pharmaceutically acceptable salt thereof is 20 to 95 parts by weight relative to 100 parts by weight of the portion, and Lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch, modified corn starch, potato starch, wheat starch, rice starch, dextrin Select from straight, maltodextrin, compression saccharides, calcium citrate, calcium phosphate, calcium aluminate metasilicate, calcium carbonate, dicalcium phosphate, calcium sulfate, crystalline cellulose, and wood cellulose One or more content of 5 to 80 parts by weight, according to claim 1 or 3 solid preparation according that. Lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch, denatured in the part containing tenegliptin or a pharmaceutically acceptable salt thereof Corn starch, potato starch, wheat starch, rice starch, dextrin, dextrin, maltodextrin, compression sugars, calcium citrate, calcium phosphate, calcium aluminate metasilicate, calcium carbonate, dicalcium phosphate, calcium sulfate, crystalline cellulose, And one or more selected from wood cellulose, and crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Polyvinyl pyrrolidone, and contain one or more selected from gum arabic,
Lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch in the portion containing canagliflozin or a pharmaceutically acceptable salt thereof , Modified corn starch, potato starch, wheat starch, rice starch, dextrin, dextrate, maltodextrin, sugars for compression, calcium citrate, calcium phosphate, calcium aluminate metasilicate, calcium carbonate, dicalcium phosphate, calcium sulfate, crystals One or more selected from cellulose and wood cellulose, and crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Polyvinyl pyrrolidone, and containing one or more selected from gum arabic, solid preparation according to claim 1 or 3. In the part containing tenegligliptin or a pharmaceutically acceptable salt thereof, the content of tenerigliptin or a pharmaceutically acceptable salt thereof is 1 to 70 parts by weight relative to 100 parts by weight of the part, and lactose, mannitol, Xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch, modified corn starch, potato starch, wheat starch, rice starch, dextrin, dextrin, maltitol , Selected from compression sugars, calcium citrate, calcium phosphate, calcium aluminate metasilicate, calcium carbonate, dicalcium phosphate, calcium sulfate, crystalline cellulose, and wood cellulose The content of one or more species is 1 to 95 parts by weight, and the content of one or more selected from crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and gum arabic is 1 to 5 parts by weight. In parts by weight that contain canagliflozin or a pharmaceutically acceptable salt thereof, canagliflozin or a pharmaceutically acceptable salt thereof is contained in an amount of 30 to 90 parts by weight based on 100 parts by weight of the part. Yes, lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch, modified corn starch, potato starch, wheat starch, rice starch, de One or more selected from string, dextrate, maltodextrin, sugar for compression, calcium citrate, calcium phosphate, calcium metasilicate aluminate, calcium carbonate, dicalcium phosphate, calcium sulfate, crystalline cellulose, and wood cellulose Is 9 to 69 parts by weight, and the content of one or more selected from crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and gum arabic is 1 to 5 parts by weight, The solid preparation according to claim 5. The solid preparation according to any one of claims 1 to 6, wherein the part containing tenegliptin or a pharmaceutically acceptable salt thereof is a granule which is a fluidized-bed granulated substance . The solid preparation according to any one of claims 1 to 7, wherein the portion containing canagliflozin or a pharmaceutically acceptable salt thereof is a granule that is a high-speed agitation granule.   The portion containing tenegligliptin or a pharmaceutically acceptable salt thereof is granular, and the portion containing canagliflozin or a pharmaceutically acceptable salt thereof is granular, according to any one of claims 1 to 6, wherein The solid preparation as described in the above.   The particle size of the portion containing tenegligliptin or a pharmaceutically acceptable salt thereof is a particle having a weight average particle size of 30 μm or more and 350 μm or less, and the particles of a portion containing canagliflozin or a pharmaceutically acceptable salt thereof The solid preparation according to claim 9, wherein the solid preparation has a weight average particle diameter of 30 µm or more and 350 µm or less. A solid preparation comprising a part containing tenegliptin or a pharmaceutically acceptable salt thereof, and a part containing canagliflozin or a pharmaceutically acceptable salt thereof,
An excipient, a disintegrant, a binder, a lubricant, a colorant, a pH adjuster, a surfactant, a stabilizer, and a flavoring agent are added to the portion containing the tenegliptin or a pharmaceutically acceptable salt thereof. Containing one or more selected from fragrances, fluidizers, coating bases, and coating additives,
In the portion containing the canagliflozin or a pharmaceutically acceptable salt thereof, an excipient, and a disintegrant, a binder, a lubricant, a coloring agent, a pH adjuster, a surfactant, a stabilizer, Contains one or more selected from flavoring agents, flavors, fluidizers, coating bases, and coating additives,
A solid preparation characterized in that tenegligliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof are independently present in the preparation so as not to substantially contact each other. . A part containing tenegligliptin or a pharmaceutically acceptable salt thereof, and a part containing canagliflozin or a pharmaceutically acceptable salt thereof, and further, tenerigliptin or a pharmaceutically acceptable salt thereof. A solid preparation containing a salt and a portion substantially free of canagliflozin or a pharmaceutically acceptable salt thereof,
Excipients, disintegrants, binders, lubricants, coloring agents, in the part that does not substantially contain the tenegligliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof, It contains one or more selected from pH adjusters, surfactants, stabilizers, flavoring agents, flavors, fluidizers, coating bases, and coating additives,
A solid preparation characterized in that tenegligliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof are independently present in the preparation so as not to substantially contact each other. . A solid preparation in which (A) a portion containing tenerigliptin or a pharmaceutically acceptable salt thereof, and a portion containing canagliflozin or a pharmaceutically acceptable salt thereof are dispersed respectively;
(B) a solid preparation in which a portion containing tenegligliptin or a pharmaceutically acceptable salt thereof, and a portion containing canagliflozin or a pharmaceutically acceptable salt thereof are laminated, or (C) tenerigliptin or a pharmaceutically acceptable salt thereof A portion containing a chemically acceptable salt, and a solid preparation in which either one of canagliflozin or a portion containing a pharmaceutically acceptable salt thereof is arranged as a core tablet, the solid preparation according to claim 1. The solid preparation according to any one of the preceding claims. (A) Tenerigliptin or a pharmaceutically acceptable salt thereof, and lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch, Modified corn starch, potato starch, wheat starch, rice starch, dextrin, dextrate, maltodextrin, sugar for compression, calcium citrate, calcium phosphate, calcium aluminate metasilicate, calcium carbonate, dicalcium phosphate, calcium sulfate, crystalline cellulose And a solid composition containing one or more selected from wood cellulose;
(B) canagliflozin or a pharmaceutically acceptable salt thereof, and lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn Starch, modified corn starch, potato starch, wheat starch, rice starch, dextrin, dextrate, maltodextrin, sugar for compression, calcium citrate, calcium phosphate, calcium aluminate metasilicate, calcium carbonate, dicalcium phosphate, calcium sulfate, A crystalline cellulose, and a solid composition containing one or more selected from wood cellulose,
A solid preparation in which tenegligliptin or a pharmaceutically acceptable salt thereof and canagliflozin or a pharmaceutically acceptable salt thereof are arranged so as not to be in contact with each other. Tenerigliptin or a pharmaceutically acceptable salt thereof, and lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch, modified corn starch , Potato starch, wheat starch, rice starch, dextrin, dextrate, maltodextrin, sugars for compression, calcium citrate, calcium phosphate, calcium aluminate metasilicate, calcium carbonate, dicalcium phosphate, calcium sulfate, crystalline cellulose, and wood The solid preparation according to claim 14, wherein the solid composition containing one or more kinds selected from cellulose is a granule that is a fluidized-bed granulated product. Canagliflozin or a pharmaceutically acceptable salt thereof, and lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch, denatured Corn starch, potato starch, wheat starch, rice starch, dextrin, dextrate, maltodextrin, sugar for compression, calcium citrate, calcium phosphate, calcium aluminate metasilicate, calcium carbonate, dicalcium phosphate, calcium sulfate, crystalline cellulose, 16. The solid preparation according to claim 14 or 15, wherein the solid composition containing one or more selected from wood cellulose is a granule that is a high-speed stirring granulated product.   The solid preparation according to any one of claims 1 to 16, wherein the dosage form is a capsule, a pill, a granule, a fine granule, a powder, or a tablet.   The solid preparation according to any one of claims 1 to 17, wherein the solid preparation contains 10 to 40 mg of tenegliptin or a pharmaceutically acceptable salt thereof in a daily amount in terms of tenegliptin.   The solid preparation according to any one of claims 1 to 18, comprising 50 to 200 mg of canagliflozin or a pharmaceutically acceptable salt thereof as a daily dose in terms of canagliflozin.   20. The solid preparation according to any one of claims 1 to 19, wherein the tenegliptin or a pharmaceutically acceptable salt thereof is tenegliptin hydrobromide.   21. The solid preparation according to any one of claims 1 to 20, wherein the canagliflozin or a pharmaceutically acceptable salt thereof is canagliflozin hydrate. For 100% by weight of solid preparation,
(A) 0.1 to 50% by weight of tenerigliptin or a pharmaceutically acceptable salt thereof, 0 to 50% by weight of lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, sucrose, Starch, pregelatinized starch, dextrose, corn starch, modified corn starch, potato starch, wheat starch, rice starch, dextrin, dextrate, maltodextrin, compression sugars, calcium citrate, calcium phosphate, calcium aluminate calcium metasilicate, carbonated One or more selected from calcium, dicalcium phosphate, calcium sulfate, crystalline cellulose, and wood cellulose, and 0 to 5% by weight of crystalline cellulose, hydroxypropyl cellulose , Hydroxypropyl methyl cellulose, polyvinylpyrrolidone, and solid compositions containing one or more selected from gum arabic and,
(B) 0.1-95% by weight of canagliflozin or a pharmaceutically acceptable salt thereof, 0-50% by weight of lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, sucrose, Sucrose, starch, pregelatinized starch, dextrose, corn starch, modified corn starch, potato starch, wheat starch, rice starch, dextrin, dextrate, maltodextrin, sugars for compression, calcium citrate, calcium phosphate, calcium aluminate metasilicate , Calcium carbonate, dicalcium phosphate, calcium sulfate, crystalline cellulose, and wood cellulose, and 0 to 5% by weight of crystalline cellulose, hydroxypropyl cellulose , Hydroxypropyl methylcellulose, polyvinylpyrrolidone, and a solid composition containing one or more selected from gum arabic, independently containing tenerigliptin or a pharmaceutically acceptable salt thereof and canagliflozin or A solid preparation wherein the pharmaceutically acceptable salts are arranged so as not to contact each other. For 100% by weight of solid preparation,
23. The solid preparation according to claim 22, comprising 0.1 to 99% by weight of tenegligliptin or a pharmaceutically acceptable salt thereof and a portion substantially free of canagliflozin or a pharmaceutically acceptable salt thereof.   The solid preparation according to any one of claims 1 to 23, wherein the solid preparation is a laminated tablet or a dry coated tablet.   25. The solid preparation according to any one of claims 1 to 24, for treating and / or preventing diabetes or diabetes-related symptoms.