JP2023083990A - Stabilization method and use of oral formulation of anhydrous sitagliptin phosphate - Google Patents

Abstract

To provide an oral formulation of anhydrous sitagliptin phosphate, which can suppress conversion of anhydrous sitagliptin phosphate to a hydrate and generation of analogous substances due to hydrolysis, etc., even if anhydrous sitagliptin phosphate is used as an active ingredient.SOLUTION: Stability of anhydrous sitagliptin phosphate can be improved by packaging an oral solid preparation comprising anhydrous sitagliptin phosphate in an aluminum pillow. Further, in a tablet production method comprising: a granulation step of obtaining granules by granulating a raw material for granulation containing sitagliptin phosphate; and a tableting step of obtaining uncoated tablets by tableting a composition for tableting containing the granules, tableting troubles can be suppressed by adjusting the volume-based cumulative 50% particle diameter (D50) of the granules supplied to the tableting step to 80 μm or more, and stability of the anhydrous sitagliptin phosphate can be improved by adjusting a water content of the granule precursor in the granulation step not to exceed 25% by mass.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to a method for stabilizing an oral formulation containing sitagliptin phosphate anhydride, which is used as a therapeutic agent for type 2 diabetes, as an active ingredient, and uses thereof.

Type 2 diabetes is a metabolic disease characterized primarily by chronic hyperglycemia due to insufficient insulin secretion and action, and accounts for over 90% of all diabetic patients. In Japan, the number of patients with type 2 diabetes is also on the rise, and with the increase in the number of patients, there is a need for new therapeutic agents such as suppression of side effects. As part of this, dipeptidyl peptidase (DPP)-4 inhibitors have been developed as therapeutic agents with a reduced risk of developing hypoglycemia. DPP-4 inhibitors are therapeutic agents that reduce excessively high blood sugar levels to the normal range by selectively inhibiting DPP-4, which inactivates incretins (gastrointestinal hormones) secreted with meals. . Incretins have insulin secretion-promoting effects and glucagon secretion-suppressing effects, but by inhibiting DPP-4, when the blood sugar level reaches the normal range, the effects of incretins on insulin and glucagon are diminished. Excessive effects (hypoglycemia) are said to be rare.

As a DPP-4 inhibitor, tablets containing sitagliptin phosphate hydrate (a monohydrate of the dihydrogen phosphate of sitagliptin) are commercially available, and sitagliptin has the chemical name: (3R)-3-amino -1-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5 -trifluorophenyl)butan-1-one, or (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]-triazolo[4,3- a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine represented by the following formula.

On the other hand, with regard to sitagliptin phosphate anhydride, Japanese Patent Application Laid-Open No. 2019-172672 (Patent Document 1) discloses that sitagliptin phosphate anhydride and mannitol, etc., are used to improve the chemical stability of sitagliptin phosphate. Tablets obtained by compressing a composition containing excipients are described. In addition, Japanese Patent Application Laid-Open No. 2021-66718 (Patent Document 2) describes 1 selected from the group consisting of sitagliptin phosphate anhydride, stearic acid, sodium stearyl fumarate, sucrose fatty acid ester, hydrogenated oil and talc. A tablet containing more than one seed and a lubricant is described.

JP 2019-172672 A Japanese Patent Application Laid-Open No. 2021-66718

However, the sitagliptin phosphate anhydrate described in Patent Documents 1 and 2 can be expected to have improved absorbability in vivo compared to the hydrate, but the anhydride readily absorbs water. It is difficult to manufacture and manage because it is likely to transfer to a hydrate or hydrolyze to generate analogues. Therefore, even the tablets of Patent Documents 1 and 2 do not have sufficient chemical stability, and transition to hydrates or generate analogous substances. Furthermore, when the inventors of the present invention examined tableting using sitagliptin phosphate anhydride as an active ingredient, they found that in addition to the chemical stability being likely to decrease, binding (the vertical It was also found that tableting troubles called "scratches" tend to occur.

Therefore, the object of the present disclosure is to provide an oral formulation of sitagliptin phosphate anhydride that can suppress the transition to a hydrate or the generation of related substances due to hydrolysis or the like even when sitagliptin phosphate anhydride is used as an active ingredient. An object is to provide a stabilization method and use.

Another object of the present disclosure is to provide a method for producing an oral dosage form of sitagliptin phosphate anhydride that can suppress tableting trouble even when tablets are produced using sitagliptin phosphate anhydride as an active ingredient. .

As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that by packaging an oral solid preparation containing sitagliptin phosphate anhydride in an aluminum pillow, even sitagliptin phosphate anhydride as an active ingredient can be hydrated. The inventors have found that it is possible to suppress the generation of analogues by hydrolysis or the like, and have completed the present invention.

That is, the method of the present disclosure is a method for improving the stability of sitagliptin phosphate anhydride by packaging an oral solid preparation containing sitagliptin phosphate anhydride with aluminum pillows. In this method, the oral solid preparation is a film-coated tablet, and the oral solid preparation may be PTP (press through pack) packaged and then aluminum pillow packaged. The film-coated tablet may be coated with a film-coating agent containing a vinyl alcohol polymer.

The present disclosure includes a granulation step of obtaining granules by granulating a raw material for granulation containing sitagliptin phosphate, and a tableting step of obtaining uncoated tablets by compressing a tableting composition containing the granules. In the method for producing tablets, a method of controlling tableting trouble by adjusting the volume-based cumulative 50% particle diameter (D ₅₀ ) of the granules subjected to the tableting step to 80 μm or more is also included. In the present disclosure, in the method of inhibiting tableting disturbances, sitagliptin phosphate is not limited to anhydrous and may be hydrated, but anhydrous is preferred.

The present disclosure includes a granulation step for obtaining granules by wet granulating a raw material for granulation containing sitagliptin phosphate anhydride by a fluid bed granulation method, and tableting a tableting composition containing the granules. In the tablet manufacturing method including a tableting step to obtain an uncoated tablet, the moisture content of the granule precursor is adjusted so as not to exceed 25% by mass during the wet granulation process, and the stability of the sitagliptin phosphate anhydrate is improved. Also included are methods of improving

The present disclosure includes a granulation step for obtaining granules by wet granulating a raw material for granulation containing sitagliptin phosphate anhydride by a fluid bed granulation method, and tableting a tableting composition containing the granules. In the tablet manufacturing method including a tableting step to obtain an uncoated tablet, a mixed solvent of water and an aqueous solvent is used as a granulation solvent for the wet granulation to improve the stability of the sitagliptin phosphate anhydrate. be

The present disclosure includes a granulation step of granulating a granulation raw material containing sitagliptin phosphate anhydride to obtain granules, and a tableting step of tableting a tableting composition containing the granules to obtain uncoated tablets. , wherein the volume-based cumulative 50% particle diameter (D ₅₀ ) of the granules subjected to the tableting step is 80 μm or more. The volume-based cumulative 50% particle diameter (D ₅₀ ) of the granules subjected to the tableting step may be 115 μm or more, and the proportion of granules having a particle diameter of 75 μm or less may be 30% by mass or less in all granules. In the granulation step, wet granulation may be performed by adjusting the water content of the granule precursor not to exceed 25% by mass. In the granulation step, the raw material powder containing sitagliptin phosphate anhydride, an excipient and a disintegrant is wet granulated by a fluidized bed granulation method in which a granulation liquid containing a binder and a granulation solvent is sprayed. may The granulation solvent may be a mixed solvent of water and an aqueous solvent, and the mass ratio of the water and the aqueous solvent may be the former/the latter=90/10 to 10/90. The production method may further include a film-coating step of coating the uncoated tablet with a film-coating agent to obtain a film-coated tablet.

The present disclosure also includes a method of manufacturing a package for packaging the tablets obtained by the manufacturing method with aluminum pillows. In the manufacturing method, the tablets may be PTP-packaged and then aluminum pillow-packaged.

The present disclosure also includes a package in which a PTP-packaged film-coated tablet is packaged in an aluminum pillow, wherein the film-coated tablet comprises sitagliptin phosphate anhydrous.

The present disclosure also includes compositions comprising granules comprising sitagliptin phosphate and having a volume-based cumulative 50% particle size ( _D50 ) of 80 μm or greater. Further, in the present disclosure, a raw material for granulation containing sitagliptin phosphate anhydride is obtained by wet granulation by adjusting the water content of the granule precursor not to exceed 25% by mass during the granulation process. Also included are compositions comprising granules containing Additionally, the present disclosure includes oral formulations comprising the compositions.

In the present disclosure, by packaging an oral solid preparation containing sitagliptin phosphate anhydride in aluminum pillows, even if sitagliptin phosphate anhydride is used as an active ingredient, it can be converted to hydrates or hydrolyzed to generate related substances. For example, the stability of sitagliptin phosphate anhydride can be improved even after long-term storage. Moreover, when the oral formulation is a tablet, the stability of sitagliptin phosphate anhydrate in the obtained tablet can be improved by adjusting the water content in the granulation process. Further, by adjusting the average particle size of the granules obtained by the granulation to 80 μm or more, tableting problems such as binding can be suppressed. Therefore, by packaging the tablet in an aluminum pillow, the stability of the active ingredient sitagliptin phosphate anhydrate can be improved in both the manufacturing process and the storage process.

FIG. 1 is a graph showing changes in moisture content and related substance content of film-coated tablets when the package obtained in Example 2 was stored. FIG. 2 is a graph showing changes in moisture content and related substance content of film-coated tablets when the package obtained in Example 3 was stored. FIG. 3 is a graph showing changes in moisture content and related substance content of film-coated tablets when the package obtained in Example 4 was stored. FIG. 4 is a graph showing changes in moisture content and related substance content of film-coated tablets when the package obtained in Example 5 was stored. FIG. 5 is a graph showing changes in loss on drying of granule precursors in the granulation process of Examples 6-12. FIG. 6 is a graph showing changes in water content of granule precursors in the granulation steps of Examples 6-12. FIG. 7 is a graph showing the relationship between the process progress rate of the granule precursor and the loss on drying in the granulation process of Examples 6-10.

[sitagliptin phosphate anhydrate]
In the present disclosure, the stability of sitagliptin phosphate anhydrate, which is an active ingredient contained in oral solid formulations, can be improved.

The crystal form of sitagliptin phosphate anhydrate is not particularly limited, and may be amorphous or crystalline. Among these, crystalline forms are preferable from the viewpoint of stability and the like.

The shape of sitagliptin phosphate anhydride is not particularly limited, and may be amorphous, fibrous, ellipsoidal, spherical, tabular, powdery or granular, and usually amorphous or powdery or granular. be.

The volume-based cumulative 50% particle size (D ₅₀ ) of sitagliptin phosphate anhydrate may be 3 μm or more, for example, 3 to 50 μm, preferably 5 to 30 μm, more preferably 8 to 20 μm, more preferably 10 μm. ˜15 μm. If the particle size of sitagliptin phosphate anhydride is too small, the dissolution properties may decrease.

The volume-based cumulative 10% particle size (D ₁₀ ) of sitagliptin phosphate anhydrate may be 1 μm or more, for example 1-10 μm, preferably 2-8 μm, more preferably 3-5 μm.

The volume-based cumulative 90% particle size (D ₉₀ ) of sitagliptin phosphate anhydrate may be 10 μm or more, for example 10-100 μm, preferably 15-50 μm, more preferably 20-30 μm.

In the present specification and claims, the volume-based cumulative 50% particle size ( _D50 ), cumulative 10% particle size ( _D10 ) and cumulative 90% particle size ( _D90) of sitagliptin phosphate anhydrate ) can be measured using a laser diffraction particle size distribution meter, and in detail, can be measured by the method described in Examples below.

The BET specific surface area of sitagliptin phosphate anhydride is, for example, 5 to 300 m ² /g, preferably 10 to 100 m ² /g, more preferably 20 to 80 m ² /g, more preferably 30 to 50 m ² /g. .

In the present specification and claims, the BET specific surface area of sitagliptin phosphate anhydride can be measured by a conventional method, for example, a nitrogen adsorption method.

[Oral solid formulation]
The oral solid preparation of the present disclosure contains, in addition to sitagliptin phosphate anhydrate as an active ingredient, conventional ingredients that are blended in oral solid preparations, such as excipients, disintegrants, binders, glidants, and lubricants. Lubricants, coating agents, colorants, and the like may also be included. The proportion of sitagliptin phosphate anhydrate may be 5-80% by weight, preferably 10-70% by weight, more preferably 20-60% by weight in the oral solid preparation.

Oral solid preparations containing sitagliptin phosphate anhydrate are not particularly limited, and examples thereof include tablets, powders, fine granules, granules, pills, capsules, dry syrups and the like. Among these, tablets are preferable because the stabilizing effect of the present disclosure is large.

Examples of tablets include sugar-coated tablets, gelatin-coated tablets, film-coated tablets, enteric-coated tablets, dry-coated tablets (compression-coated tablets), multilayer tablets (double-layered or triple-layered tablets), and the like. Among these, film-coated tablets are particularly preferable because the stabilizing effect of the present disclosure is likely to be exhibited.

The tablet diameter (average diameter) of the film-coated tablet is, for example, 3 to 20 mm, preferably 5 to 15 mm, more preferably 5.5 to 12 mm. In addition, let the tablet diameter be the average value of a long axis and a short axis, when it is an anisotropic shape.

The thickness of the film-coated tablet is, for example, 1-10 mm, preferably 1.5-8 mm, more preferably 2-5 mm.

The hardness of film-coated tablets may be, for example, 55N or higher, preferably 60-200N, more preferably 70-150N.

In the present specification and claims, the hardness of film-coated tablets can be measured by the method described in Examples below.

[Package]
In the present disclosure, the stability of sitagliptin phosphate anhydrate can be improved by packaging the oral solid preparation in aluminum pillow packaging (aluminum pillow packaging) to prepare an aluminum pillow packaging. A conventional aluminum pillow package can be used as the aluminum pillow package.

The aluminum pillow package may be a pillow package formed of a film having an aluminum layer, and a pillow package formed of a laminated film (laminate film) of an aluminum foil and a plastic film, or an aluminum vapor deposition film. A pillow package formed of a plastic film (aluminum-deposited film) may also be used. Examples of plastic films include films made of polyolefins such as polyethylene and polypropylene; films made of polyesters such as polyethylene terephthalate; and polyamide films made of polyamides such as polyamide 6.

The moisture permeability of the aluminum pillow package may be 0.1 g/m ² /24 hr or less, preferably 0.01 g/m ² /24 hr or less, more preferably 0.001 g/m ² /24 hr or less. .

In addition, in this specification and claims, moisture permeability can be measured by a conventional method, for example, a method based on JIS K7129 or JIS Z0208.

A desiccant and/or an oxygen scavenger may be contained in the aluminum pillow package in addition to the oral solid preparation. As the desiccant, a commonly used desiccant can be used, and examples thereof include silica gel, calcium chloride, zeolite and the like. As the oxygen scavenger, a commonly used oxygen scavenger can be used, and examples thereof include iron-based oxygen scavengers and organic-based oxygen scavengers.

The oral solid preparation housed in the aluminum pillow package may be in an unpackaged form such as a bulk tablet, or may be in a conventional package. Examples of conventional packages housed in aluminum pillow packages include film packages (film packages sealed by heat sealing, etc.), stick packages, SP (strip packages) packages, PTP (press through packs) ) packaging and the like. Among these, the PTP package is preferable because the stability of sitagliptin phosphate anhydride can be improved by combining with the aluminum pillow package.

The PTP package is usually formed of a base sheet made of resin and having a plurality of pockets for containing solid oral preparations, and a film having an aluminum layer, and containing solids contained in the pockets. It is formed with a lid material (or cover material) for sealing the formulation. In the PTP package, at least the pocket portion should be made of a resin sheet, and from the viewpoint of productivity, the base sheet is preferably made of a resin sheet.

The film having an aluminum layer may be an aluminum foil, a laminate of an aluminum foil and a resin layer, or an aluminum deposited film. The average thickness of the film having the aluminum layer is, for example, 0.03-1 mm, preferably 0.05-0.5 mm, more preferably 0.1-0.3 mm.

Examples of the resin constituting the resin sheet include polyethylene, polypropylene, cyclic polyolefin (COC), ethylene-vinyl acetate copolymer (EVA), ethylene-vinyl alcohol copolymer, ionomer resin (IO), ethylene-methacrylic acid. Olefin resins such as copolymers (EMAA); chlorine-containing resins such as polyvinyl chloride (PVC) and polyvinylidene chloride (PVDC); polychlorotrifluoroethylene (PCTFE), tetrafluoroethylene/perfluoroalkyl vinyl ether copolymers coalescence (PFA), tetrafluoroethylene/hexafluoropropylene copolymer (FEP), tetrafluoroethylene/hexafluoropropylene/perfluoroalkyl vinyl ether (EPA), tetrafluoroethylene/ethylene copolymer (ETFE), polyvinylidene fluoride (PVDF), fluororesins such as chlorotrifluoroethylene-ethylene copolymer (ECTFE), and the like. These resins can be used alone or in combination of two or more.

Different resin sheets may be laminated to adjust the moisture permeability. Moreover, the thickness of the resin sheet, which will be described later, may be adjusted in order to adjust the moisture permeability.

Examples of resin sheets include olefin resin sheets such as unstretched polypropylene (CPP) sheets and COC sheets, chlorine-containing resin sheets such as PVC sheets and PVDC sheets, and fluororesin layers such as laminated sheets of a PCTFE layer and a PVC layer. A laminated sheet with a containing resin layer is preferable, and a laminated sheet with a fluororesin layer and a chlorine-containing resin layer is particularly preferable because it has high moisture resistance and can improve the stability of sitagliptin phosphate anhydride.

In a laminated sheet of a fluororesin layer (particularly a PCTFE layer) and a chlorine-containing resin layer (particularly a PVC layer), the thickness of the chlorine-containing resin layer is preferably, for example, 2 to 30 times the thickness of the fluororesin layer. is 3 to 20 times, more preferably 5 to 15 times, more preferably 6 to 10 times. If the thickness ratio of the fluororesin layer is too small, the moisture resistance may deteriorate, and if it is too large, the moldability may deteriorate.

The moisture permeability of the resin sheet may be 10 g/m ² /24 hr or less, for example 0.01 to 10 g/m ² /24 hr, preferably 0.03 to 6 g/m ² /24 hr, more preferably 0.03 to 6 g/m 2 /24 hr. 05 to 1 g/m ² /24 hr, more preferably 0.08 to 0.5 g/m ² /24 hr, most preferably 0.1 to 0.3 g/m ² /24 hr. If the moisture permeability is too high, the stability of the active ingredient may deteriorate.

The average thickness of the resin sheet is, for example, 0.05 to 3 mm, preferably 0.1 to 1 mm, more preferably 0.15 to 0.5 mm.

[Tablet manufacturing method]
In the present disclosure, a granulation step of granulating a granulation raw material containing sitagliptin phosphate anhydride to obtain granules, and a tableting step of obtaining uncoated tablets by compressing a tableting composition containing the granules. In the method for producing a tablet containing, by adjusting the particle size of the granules subjected to the tableting step, tableting failure can be suppressed, or the moisture content of the granule precursor is adjusted in the granulation process to perform wet granulation Thereby, the stability of sitagliptin phosphate anhydride can be improved.

(Granulation process)
In the granulation step, a raw material for granulation containing sitagliptin phosphate anhydride as an active ingredient (or medicinal ingredient) is granulated to obtain granules.

(A) Sitagliptin phosphate anhydride In the raw material for granulation, the proportion of sitagliptin phosphate anhydride may be 10% by mass or more relative to the total amount of the raw material for granulation, for example 10 to 95% by mass, It is preferably 30 to 90% by mass, more preferably 60 to 85% by mass, more preferably 70 to 80% by mass. If the proportion of sitagliptin phosphate anhydrate is too small, the stability of the active ingredient in the solid formulation may decrease.

(B) Excipient The raw material for granulation may further contain an excipient (first excipient) in addition to the active ingredient. Excipients include, for example, sugars such as lactose, glucose, fructose, maltose, sucrose, sucrose, powdered reduced maltose starch syrup; Sugar alcohols such as palatinose and 4-carbon sugar obtained by fermenting glucose (e.g., erythritol); Celluloses such as microcrystalline cellulose, crystalline cellulose, and powdered cellulose; Silicic anhydride such as talc, light silicic anhydride, and hydrated silicon dioxide , calcium silicate, magnesium silicate, synthetic aluminum silicate, magnesium aluminometasilicate, and other silicates; metal oxides, such as magnesium oxide and titanium oxide; carbonates, such as precipitated calcium carbonate and magnesium carbonate; calcium lactate, etc. phosphates such as anhydrous calcium hydrogen phosphate and calcium monohydrogen phosphate; and minerals such as bentonite, synthetic hydrotalcite, and kaolin. These excipients can be used alone or in combination of two or more.

Among these excipients, sugar alcohols such as mannitol, silicic acids such as talc and light anhydrous silicic acid, and phosphates such as anhydrous calcium hydrogen phosphate are preferred. Salt alone is more preferred, and phosphate alone is more preferred.

When sugar alcohol and phosphate are combined, the mass ratio of the former/latter = 90/10 to 10/90, preferably 80/20 to 20/80, more preferably 70/30 to 30/70, More preferably 60/40 to 40/60.

The proportion of phosphate (particularly anhydrous calcium hydrogen phosphate) may be 50% by mass or more, preferably 80% by mass or more, more preferably 90% by mass or more, more preferably 90% by mass or more in the first excipient. is 100% by mass.

The ratio of the first excipient is, for example, 1 to 100 parts by mass, preferably 3 to 50 parts by mass, more preferably 5 to 30 parts by mass, more preferably 100 parts by mass of sitagliptin phosphate anhydride. 8 to 20 parts by weight, most preferably 10 to 15 parts by weight. The ratio of the first excipient is 1 to 50% by mass, preferably 3 to 30% by mass, more preferably 5 to 20% by mass, most preferably 7 to 10% by mass, relative to the total amount of the raw material for granulation. is. A proportion of these first excipients may be a proportion of phosphate (particularly anhydrous calcium hydrogen phosphate). If the proportion of the excipient is too small, the mechanical properties may deteriorate, and if it is too large, the dissolution of the active ingredient may deteriorate.

(C) Disintegrant The raw material for granulation may further contain a disintegrant (first disintegrant) in addition to the active ingredient. Disintegrants include, for example, crospovidone (crosslinked polyvinylpyrrolidone), crosslinked polyvinylpyrrolidones such as crospovidone copolymer; carmellose sodium, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose (L-HPC), etc. cellulose ethers; agar, carrageenan, alginic acid, sodium alginate, propylene glycol alginate, guar gum, locust bing gum, gum arabic, tragacanth gum, pullulan, xanthan gum, hyaluronic acid, pectin, polysaccharides such as sodium chondroitin sulfate; gelatin, casein, proteins such as soybean protein; minerals such as bentonite, synthetic hydrotalcite, and kaolin; These disintegrants can be used alone or in combination of two or more.

Among these disintegrants, cellulose ethers are preferred, croscarmellose salts are more preferred, and croscarmellose sodium is most preferred.

The ratio of the first disintegrant is, for example, 1 to 100 parts by mass, preferably 2 to 50 parts by mass, more preferably 3 to 20 parts by mass, more preferably 5 parts by mass, relative to 100 parts by mass of sitagliptin phosphate anhydride. ~15 parts by weight, most preferably 8-12 parts by weight. The proportion of the disintegrant is 1-50% by mass, preferably 3-30% by mass, more preferably 3-20% by mass, most preferably 5-10% by mass, relative to the total amount of the raw material for granulation. If the proportion of the disintegrant is too small, the dissolution of the active ingredient may be lowered, and if it is too large, the stability of the solid preparation may be lowered.

(D) Binder The raw material for granulation may further contain a binder in addition to the active ingredient. Examples of binders include polyvinylpyrrolidones (povidone, vinyl acetate-vinylpyrrolidone copolymer, etc.), polyvinyl alcohol, carboxyvinyl polymer, polyacrylic acid-based polymer (sodium polyacrylate, acrylic acid copolymer, etc.), Synthetic polymers such as polylactic acid, polyethylene glycol, and polyvinyl acetate; Carboxymethylcellulose (carmellose or CMC), carboxyalkyl cellulose such as carboxymethylethylcellulose (CMEC); Hydroxyethylcellulose, Hydroxypropylcellulose (HPC), Hydroxypropylmethylcellulose (Hypromellose or HPMC); and cellulose esters such as cellulose acetate. These binders can be used alone or in combination of two or more.

Among these binders, cellulose ethers having hydroxy C _2-4 alkyl groups such as HPC and HPMC are preferred, and hydroxy C _2-4 alkyl celluloses such as HPC are more preferred.

The ratio of the binder is, for example, 1 to 100 parts by weight, preferably 2 to 50 parts by weight, more preferably 3 to 20 parts by weight, more preferably 5 to 15 parts by weight, per 100 parts by weight of sitagliptin phosphate anhydride. parts, most preferably 7 to 12 parts by weight. The proportion of the binder is 1-50% by mass, preferably 2-30% by mass, more preferably 3-20% by mass, most preferably 5-10% by mass, relative to the total amount of the raw material for granulation. If the ratio of the binder is too low, the stability of the solid preparation may be lowered, and if it is too high, the dissolution of the active ingredient may be lowered.

(E) Other Ingredients In addition to the active ingredient, the raw material for granulation may further contain conventional additives blended in oral preparations as other ingredients. Usual additives include, for example, fluidizing agents (first fluidizing agents), lubricants (first lubricant), plasticizers, surfactants, pH adjusters, colorants, sweeteners or Flavoring agents, flavoring or cooling agents, antioxidants, preservatives or preservatives, humectants, antistatic agents, disintegration aids and the like. These additives can be used alone or in combination of two or more. The total proportion of these additives may be 5 parts by mass or less (for example, 0.01 to 5 parts by mass) relative to 100 parts by mass of sitagliptin phosphate anhydride, preferably 3 parts by mass or less, more preferably is 2 parts by mass or less. The total proportion of these additives may be 5% by mass or less (for example, 0.01 to 5% by mass), preferably 3% by mass or less, and more preferably It is 2% by mass or less.

(F) Granulation Means The method for granulating the raw material for granulation is not particularly limited, and a conventional granulation method can be used. Conventional granulation methods may be dry granulation, but wet granulation is preferred. The wet granulation method may be any method as long as it uses a granulation solvent to granulate the raw material for granulation. method, spray drying granulation method, vibration granulation method, and the like. These wet granulation methods may be used in combination.

Among these wet granulation methods, the mixing/stirring granulation method and the fluidized bed granulation method are widely used from the viewpoint of productivity. A method combined with a granulation method is particularly preferred.

The fluidized bed granulation method is not particularly limited as long as it is a method of obtaining granules by spraying a granulating liquid onto raw material powder fluidized by an air flow, and a conventional method can be used. The method of preparing the raw material powder is not particularly limited, and it may be prepared in a fluid bed granulator or by other granulation methods. As another granulation method, a mixing/stirring granulation method is preferable from the viewpoint of convenience.

In the fluid bed granulation method, the granulation liquid may contain a binder and a granulation solvent, and is usually an aqueous dispersion or aqueous solution comprising a binder and a granulation solvent.

The granulation solvent is not particularly limited, but from the viewpoint of safety, water, an aqueous solvent, and the like can be used. Aqueous solvents include, for example, lower alcohols (eg, C _2-4 alkanols such as ethanol and isopropanol), aliphatic ketones (eg, acetone, etc.), and the like. These solvents can be used alone or in combination of two or more.

Among these granulation solvents, water alone and a mixed solvent of water and an aqueous solvent are preferable, and from the viewpoint of stability of the active ingredient, a mixed solvent of water and an aqueous solvent is more preferable, and a mixture of water and a C _2-4 alkanol A solvent is more preferred, and a mixed solvent of water and ethanol is most preferred. When a mixed solvent of water and an aqueous solvent is used as the granulation solvent, it is possible to suppress the transition of sitagliptin phosphate anhydride to a hydrate or to change to a related substance due to hydrolysis or the like.

When the granulation solvent is a mixed solvent of water and an aqueous solvent, the mass ratio of water and aqueous solvent (especially ethanol) can be selected from the range of about 90/10 to 10/90. /20 to 20/80, preferably 70/30 to 30/70, more preferably 60/40 to 40/60. If the proportion of the aqueous solvent is too small, it may be difficult to stabilize the active ingredient easily, and if it is too large, the handleability may deteriorate.

The proportion of the granulation solvent is, for example, 50 to 200 parts by weight, preferably 80 to 150 parts by weight, more preferably 100 to 130 parts by weight, per 100 parts by weight of sitagliptin phosphate anhydride.

The raw material powder may contain sitagliptin phosphate anhydride, an excipient and a disintegrant, and may further contain other ingredients than the binder. The raw material powder may be produced by a method such as the mixing/stirring granulation method, as described above, and may further contain, for example, the granulation solvent used in the mixing/stirring granulation method. As the granulation solvent for the mixing/stirring granulation method, the solvent exemplified as the granulation solvent for the fluid bed granulation method can be used. Among the solvents, water and/or ethanol are preferred.

In the present disclosure, when granulating granules by a fluidized bed granulation method using a granulation liquid, by adjusting the water content of the granule precursor generated in the process of fluidized bed granulation (wet granulation), effective Ingredient stability can be improved. That is, by adjusting the water content of the granule precursor so as not to be excessive, it is possible to suppress the transition of sitagliptin phosphate anhydride to a hydrate due to water or to change to a related substance due to hydrolysis or the like.

The water content of the granule precursor is preferably adjusted so as not to exceed 25% by mass in the granule precursor (so that the maximum water content is 25% by mass or less), more preferably 20% by mass or less. Preferably, it is more preferably adjusted to 15% by mass or less.

In the present specification and claims, the moisture content of the granule precursor is determined by the loss-on-drying method (LOD) using an infrared moisture meter for the granule precursor taken out over time until the drying of the granule is completed. Specifically, it can be measured by the method described in Examples below. Moreover, when water and an aqueous solvent are combined as a granulation solvent, the water content is a numerical value converted into the proportion of water in the granulation liquid. That is, when a mixed solvent of water and ethanol is used as the granulation solvent, the calculation is performed on the assumption that water and ethanol evaporate at a constant rate.

Examples of the method for adjusting the water content of the granule precursor within the above range include a method using a mixed solvent of water and an aqueous solvent as the granulation solvent, and a method adjusting the spray rate of the granulation liquid. Specifically, by mixing water and an aqueous solvent (particularly, ethanol) as the granulation solvent at the above mass ratio, the water content can be easily suppressed within the above range. Also, in the method of adjusting the spray rate of the granulation liquid, the amount of water can be suppressed by reducing the spray rate, which is particularly effective when water is used alone as the granulation solvent or when water is used as the main solvent. When the granulation solvent is water alone, the spray rate of the granulation liquid may be 50 g/min or less, preferably 30 g/min or less, more preferably 20 g/min or less, and more preferably 15 g/min or less. , most preferably less than or equal to 10 g/min.

The shape of the obtained granules is not particularly limited, and may be amorphous, fibrous, ellipsoidal, spherical, tabular, powdery or granular, and usually amorphous or powdery. Further, the shape of the granules may be a hollow shape, but a solid shape is preferable from the viewpoint of the feeling of taking the medicine.

(Sizing process)
The granules obtained in the granulation process are subjected to the tableting process, and in the present disclosure, by adjusting the particle size of the granules subjected to the tableting process, tableting problems such as binding can be suppressed. That is, in the present disclosure, tableting trouble can be suppressed by adjusting the particle size of the granules subjected to the tableting step to be relatively large.

Specifically, the volume-based cumulative 50% particle diameter (D ₅₀ ) of the granules may be adjusted to 115 μm or more (eg, 115 to 200 μm), preferably 120 μm or more (eg, 120 to 180 μm), more preferably It is 130 μm or more (for example, 130 to 150 μm). If the _D50 of the granules is too small, tableting problems may occur.

The volume-based cumulative 10% particle diameter (D ₁₀ ) of the granules may be 50 μm or more (for example, 50 to 100 μm), preferably 55 μm or more (for example, 55 to 90 μm), more preferably 60 μm or more (for example, 60 to 80 μm).

The volume-based cumulative 90% particle diameter (D ₉₀ ) of the granules may be 200 μm or more (eg, 200 to 300 μm), preferably 210 μm or more (eg, 210 to 260 μm), more preferably 220 μm or more (eg, 220 to 240 μm).

In the present specification and claims, the volume-based cumulative 50% particle size (D ₅₀ ), cumulative 10% particle size (D ₁₀ ) and cumulative 90% particle size (D ₉₀ ) of granules are referred to as sonic vibration. It can be measured using a sieving distribution measuring apparatus, and more specifically, it can be measured by the method described in Examples below.

The proportion of granules having a particle diameter of 75 μm or less may be 30% by mass or less, preferably 25% by mass or less, more preferably 20% by mass or less, and more preferably 10% by mass or less.

In addition, in the present specification and claims, the proportion of granules having a particle size of 75 μm or less can be measured by a sieving method.

If the _D50 of the granules obtained in the granulation step is 115 μm or more, the tableting step may be performed _without providing a sizing step. As a pre-process, it is preferable to provide a sieving process for adjusting the particle diameter of the granules obtained in the granulation process by sieving or the like. Furthermore, even if the _D50 of the granules is 115 μm or more, it is preferable to adjust the particle size of the granules by providing a sizing step, and to suppress tableting troubles to a high degree.

(Tabletting process)
The granules obtained in the granulation step (particularly, the sizing powder prepared in the sizing step) are mixed with the rear powder component to form a composition for tableting (tablet powder or mixed powder for tableting). may be prepared and subjected to the tableting process.

The proportion of granules can be appropriately selected according to the type of tablet, content of active ingredient, etc., and is 10 to 90% by mass, preferably 20 to 80% by mass, more preferably 25 to 65% by mass in the composition for tableting. be.

The final component may contain an excipient (second excipient). Examples of the second excipient include the excipients exemplified as the first excipient of the raw material for granulation. The above excipients can be used alone or in combination of two or more. As the second excipient, among the above excipients, phosphates such as anhydrous calcium hydrogen phosphate are preferred. The proportion of the second excipient is, for example, 10 to 500 parts by weight, preferably 30 to 300 parts by weight, more preferably 50 to 250 parts by weight, per 100 parts by weight of the granules. The proportion of the second excipient is 10-90% by weight, preferably 20-80% by weight, more preferably 30-70% by weight in the tablet composition.

The final component may contain a disintegrant (second disintegrant). Examples of the second disintegrant include the disintegrants exemplified as the first disintegrant of the raw material for granulation. The disintegrants can be used alone or in combination of two or more. Among the disintegrants described above, the second disintegrant is preferably a cellulose ether, more preferably a croscarmellose salt, and most preferably croscarmellose sodium. The proportion of the second disintegrant is, for example, 1 to 20 parts by mass, preferably 2 to 15 parts by mass, and more preferably 3 to 12 parts by mass with respect to 100 parts by mass of the granules. The proportion of the second disintegrant is 0.5 to 10% by weight, preferably 1 to 5% by weight, more preferably 2 to 4% by weight in the tablet composition.

The post-powder component may contain a fluidizing agent (second fluidizing agent). Fluidizing agents include minerals such as talc, bentonite, synthetic hydrotalcite, and kaolin; light anhydrous silicic acid, calcium silicate, magnesium silicate, synthetic aluminum silicate, magnesium aluminometasilicate, and hydrous silicon dioxide. and silicic acids such as These fluidizing agents can be used alone or in combination of two or more. Among these fluidizing agents, silicic acids such as light anhydrous silicic acid are preferred. The proportion of the second fluidizing agent is, for example, 1 to 15 parts by mass, preferably 2 to 10 parts by mass, and more preferably 3 to 8 parts by mass with respect to 100 parts by mass of the granules. The proportion of the second glidant is 0.1 to 10% by weight, preferably 0.5 to 5% by weight, more preferably 1 to 3% by weight in the tablet composition.

The final component may further contain a lubricant (second lubricant). Examples of lubricants include fatty acids such as stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, and sodium coconut oil fatty acid or metal salts thereof; silicon oxides such as hydrous silicon dioxide and silicon dioxide; dimethylpolysiloxane; oils such as hydrogenated oils and cacao butter; waxes such as beeswax, bleached beeswax, carnauba wax, lanolin, paraffin, petrolatum, and the like. These lubricants can be used alone or in combination of two or more. Among these lubricants, fatty acid metal salts such as magnesium stearate are preferred. The proportion of the second lubricant is, for example, 0.1 to 10 parts by weight, preferably 0.5 to 5 parts by weight, and more preferably 1 to 3 parts by weight with respect to 100 parts by weight of the granules. The proportion of the second lubricant is 0.05 to 5% by weight, 0.1 to 3% by weight, more preferably 0.3 to 1% by weight in the tableting composition.

The final powder component may further contain conventional additives that are blended in oral preparations. Commonly used additives include the additives exemplified as common additives for the raw material for granulation (additives other than fluidizers and lubricants), the above binders, and the like. The above additives can be used alone or in combination of two or more. The total proportion of the additives may be 5 parts by mass or less (for example, 0.01 to 5 parts by mass) with respect to 100 parts by mass of the granules, preferably 3 parts by mass or less, more preferably 2 parts by mass or less. be. Further, the total proportion of these additives may be 5% by mass or less (eg, 0.01 to 5% by mass) in the tablet composition, preferably 3% by mass or less, more preferably 2% by mass or less. is.

The method of mixing the granules and the latter component is not particularly limited, and conventional stirring means and kneading means can be used, and a conventional mixer (homomixer, homogenizer, homodisper, Henschel mixer, Banbury mixer, ribbon mixer, V type A method using a mixer, etc.) may also be used.

In the tableting step, the composition for tableting is tableted to obtain uncoated tablets. As a tableting method, a conventional method can be used. The tableting pressure is, for example, 4-20 kN, preferably 5-16 kN, more preferably 6-12 kN.

(Film coating process)
When the tablet of the present disclosure is a film-coated tablet, it may further include a film-coating step of coating the uncoated tablet obtained in the tableting step with a film-coating agent to obtain a coated tablet.

In the film coating step, as a film coating method, a conventional method can be used, and pan coating is preferred.

The film coating agent may contain a vinyl alcohol polymer as a coating agent or binder. Examples of the vinyl alcohol polymer include polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like. These vinyl alcohol-based resins can be used alone or in combination of two or more. Among these, preferred are copolymers of vinyl alcohol units and (meth)acrylic acid units, such as polyvinyl alcohol-acrylic acid-methyl methacrylate copolymers in which acrylic acid and methyl methacrylate are copolymerized with polyvinyl alcohol.

The film coating agent may further contain a metal oxide in addition to the vinyl alcohol polymer. Examples of metal oxides include magnesium oxide and titanium oxide. These metal oxides can be used alone or in combination of two or more. Among these, titanium oxide is preferred. The ratio of the metal oxide is, for example, 1 to 50 parts by mass, preferably 5 to 30 parts by mass, and more preferably 10 to 20 parts by mass with respect to 100 parts by mass of the vinyl alcohol polymer.

The film coating agent may further contain silicic acid in addition to the vinyl alcohol polymer. Silicic acids include, for example, silicic anhydrides such as talc and light anhydrous silicic acid, hydrous silicon dioxide, calcium silicate, magnesium silicate, synthetic aluminum silicate, and magnesium aluminometasilicate. These silicic acids can be used alone or in combination of two or more. Of these, talc is preferred. The proportion of silicic acid is, for example, 10 to 100 parts by weight, preferably 30 to 70 parts by weight, more preferably 40 to 60 parts by weight, per 100 parts by weight of the vinyl alcohol polymer.

The film coating agent may further contain a colorant in addition to the vinyl alcohol polymer. Examples of coloring agents include yellow iron sesquioxide, iron sesquioxide, food blue No. 1, food blue No. 2, food yellow No. 4, food yellow No. 5, food green No. 3, food red No. 2, and food red No. 3. , Food Red No. 102, Food Red No. 104, Food Red No. 105, Food Red No. 106, food lake pigment, red iron oxide, turmeric extract, riboflavin, sodium riboflavin phosphate, carotene liquid, tar pigment, caramel, etc. . These colorants can be used alone or in combination of two or more. Of these, iron oxides such as yellow iron sesquioxide and iron sesquioxide are preferred. The proportion of the coloring agent is, for example, 0.1 to 30 parts by weight, preferably 0.3 to 10 parts by weight, more preferably 0.5 to 5 parts by weight, per 100 parts by weight of the vinyl alcohol polymer.

The ratio of the film coating agent is, for example, 0.5 to 30 parts by weight, preferably 1 to 10 parts by weight, more preferably 2 to 5 parts by weight, per 100 parts by weight of the uncoated tablet.

The film coating agent is preferably used as a film coating liquid by further blending a solvent. As the solvent, the solvent exemplified as the granulation solvent can be used. The solvents can be used alone or in combination of two or more. Among the solvents, water and/or ethanol are preferred, water being particularly preferred.

The proportion of the solvent is, for example, 100 to 5000 parts by weight, preferably 300 to 3000 parts by weight, and more preferably 500 to 1500 parts by weight with respect to 100 parts by weight of the film coating agent.

EXAMPLES The present invention will be described in more detail below based on examples, but the present invention is not limited by these examples. In the following examples, details of the drug substance and packaging materials used and the methods evaluated are provided below.

[Manufacturing raw materials]
Sitagliptin phosphate anhydrate: Cumulative 10% particle size based on volume ( _D10 ) 4.7 μm, Cumulative 50% particle size based on volume ( _D50 ) 12.0 μm, Cumulative 90% particle size based on volume ( _D90) ) 22.1 μm, BET specific surface area 43.2 m ² /g
Anhydrous calcium hydrogen phosphate: "DI-CAFOS A 150" manufactured by Chemische Fabrik Budenheim KG
D- mannitol: "PERLITOL 50C" manufactured by ROQUETTE
Croscarmellose sodium: DuPont Nutrition USA Inc.; Made by "Akujisol"
Hydroxypropyl cellulose: "HPC-L" manufactured by Nippon Soda Co., Ltd.
Light anhydrous silicic acid: manufactured by Fuji Silysia Chemical Co., Ltd. Magnesium stearate: manufactured by Taihei Chemical Industry Co., Ltd., grade “Vegetable (Taihei)”
Polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer: "POVACOAT" manufactured by Daido Chemical Co., Ltd.
Titanium oxide: "Titanium oxide FG" manufactured by Freund Corporation
Talc: "Talcan Hayashi" manufactured by Hayashi Kasei Co., Ltd.
Yellow sesquioxide: manufactured by Kishi Kasei Co., Ltd. Iron sesquioxide: manufactured by Kishi Kasei Co., Ltd.

[Packaging materials]
PVC sheet: manufactured by Mitsubishi Chemical Corporation, model number Vinifoil C-0436, polyvinyl chloride sheet for PTP, thickness 0.2 mm, moisture permeability 4.7 g/m ² /24 hr
PVC/PCTFE sheet: manufactured by Mitsubishi Chemical Corporation, model number Vinyl Foil L-2223, polyvinyl chloride/polychlorotrifluoroethylene composite sheet for PTP, thickness 0.223 mm (PVC layer 0.2 mm, PCTFE layer 0.023 mm), moisture permeability 0.26g/ ^m2 /24hr
Aluminum foil for PVC: Made by UACJ Foil Co., Ltd., model number: Matt OP VC (Daiwa Kasei) For PVC with aluminum pillow chuck: Made by Seisan Nihon Co., Ltd., model number AL-14.

[Evaluation method]
(Particle size distribution of sitagliptin phosphate anhydrous)
Particle size distributions (D ₁₀ , D ₅₀ , D ₉₀ ) were measured on a volume basis using a laser diffraction particle size distribution analyzer (manufactured by Malvern, trade name "Mastersizer 3000").

(Particle size distribution of sized powder)
Particle size distributions (D ₁₀ , D ₅₀ , D ₉₀ ) were measured on a volume basis using a sonic vibration sieving particle size distribution analyzer (trade name “Robot Shifter RPS-205” manufactured by Seishin Enterprise Co., Ltd.).

(tablet hardness)
The tablet hardness was measured using an ERWEKA-type tablet hardness tester (manufactured by ERWEKA, trade name "tablet hardness tester TBH425TD") by applying a load to the tablet with an indenter using an electric weight load.

(Disintegration time (Japanese Pharmacopoeia 17th Edition))
A disintegration tester (compliant with the Japanese Pharmacopoeia) was used. 900 mL of water at 37° C. was placed in a glass container, a basket (with a net-like bottom) containing the tablets was moved up and down in the water in the container, and the time until the tablets crumbled was measured.

(Powder X-ray diffraction)
Powder X-ray diffraction (XRD) was measured using a powder X-ray diffractometer (“D8 ADVANCE” manufactured by Bruker). As for tablets, pulverized material was used as a sample.

(Amount of related substance in coated tablet)
After adding 80 mL of the extraction solvent (20 mL for the 12.5 mg tablet and 25 mg tablet) to the sample and shaking well, the sample was treated with ultrasonic waves, and the extraction solvent was added to make 100 mL. This liquid is filtered through a membrane filter with a pore size of 0.45 μm. Remove the first 5 mL of the filtrate and add the extraction solvent to the next 1 mL of the filtrate to make 100 mL of the sample solution. 20 μL of the sample solution is tested by liquid chromatography under the following conditions. The peak area of each sample solution is measured by the automatic integration method, and their amounts are determined by the area percentage method. As an extraction solvent, a 1000-fold diluted phosphoric acid aqueous solution/acetonitrile mixed solution (volume ratio 19/1) was used. The peak areas with relative retention times of about 0.34 (H-SGTRC03), about 0.42 (H-SGTRC04) and about 2.73 (H-SGTRC01) relative to sitagliptin are sensitive to the area determined by the automatic integration method. The values are multiplied by coefficients 1.8, 2.0 and 2.2. The method measures the total amount of analogues of sitagliptin.

<Test conditions>
Detector: UV absorption photometer (measurement wavelength: 205 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm is packed with 5 μm cyanopropylsilylated silica gel for liquid chromatography.

Column temperature: constant temperature around 40° C. Mobile phase A: 1.36 g of potassium dihydrogen phosphate is dissolved in 100 mL of water, and phosphoric acid is added to adjust the pH to 2.0.

Mobile phase B: Acetonitrile Feeding of mobile phase: The mixing ratio of mobile phase A and mobile phase B is changed as shown in Table 1 to control the concentration gradient.

Flow rate: 1.0 mL per minute (retention time of sitagliptin approximately 9 minutes)
Sample cooler temperature: 4°C
Analysis time: 70 minutes Area measurement range: 50 minutes after sample solution injection.

(Moisture content of coated tablet)
Put the solvent in a titration bottle and titrate it with Karl Fischer reagent to make it dry. Add the lightly crushed sample to the titration bottle. The water content was measured using a Karl Fischer reagent whose titer had been standardized in advance with purified water.

<Test conditions>
Measuring instrument: "MKV-710" manufactured by Kyoto Electronics Industry Co., Ltd.
Solvent: "Hayashi Solvent FM-II Dehydrated Solvent (for Sugars)" manufactured by Hayashi Pure Chemical Industries, Ltd.
Karl Fischer reagent: "Aquamicron (registered trademark) Titrant SS-Z 3 mg" manufactured by Mitsubishi Chemical Corporation.

(Loss on drying and water content of granule precursor)
The loss on drying (LOD) of the granule precursor was measured by an infrared moisture meter (manufactured by Shimadzu Corporation "Model: MOC- 12H", 80° C., end condition: variation 0.05%). In addition, when a mixed solvent of water and ethanol was used as the granulation solvent, the water content was a numerical value converted to the ratio of water in the granulation liquid. That is, it was calculated on the assumption that water and ethanol were evaporated at the same rate (equal volume).

(Presence or absence of tableting failure)
The uncoated tablets after tableting were visually observed for the presence or absence of binding.

Example 1
(Kneading process)
Sitagliptin phosphate anhydrate, anhydrous calcium hydrogen phosphate, D-mannitol and croscarmellose sodium were placed in a stirring granulator at the ratios shown in Table 2 and mixed, and then purified water was sprayed to form raw material powder. A wet flour was prepared.

(Granulation process)
Separately, hydroxypropylcellulose was added to and dissolved in purified water at the ratio shown in Table 2 to prepare a granulation liquid.

The wet powder was placed in a fluidized bed granulator dryer, and the granulating liquid was sprayed at a liquid speed of 15 g/min to granulate the powder, followed by drying to prepare dry powder in the form of granules.

(Sizing process)
The obtained dried powder was sized with a sizing machine to prepare a sized powder. The sieved powder had a cumulative 10% particle size (D ₁₀ ) of 97 µm, a cumulative 50% particle size (D ₅₀ ) of 176 µm, and a cumulative 90% particle size (D ₉₀ ) of 281 µm.

(Tabletting powder preparation step)
Sized powder, anhydrous calcium hydrogen phosphate, croscarmellose sodium and light anhydrous silicic acid were mixed in a diffusion mixer in the proportions shown in Table 2, and magnesium stearate was added and mixed. A tablet composition) was prepared.

(Tabletting process)
The tableting powder was tableted using a rotary tableting machine to prepare uncoated tablets. The uncoated tablet had a tablet diameter of 8.5 mm, a tablet thickness of 3.5 mm, a hardness of 63 N, and a disintegration time of 120 seconds.

(Film coating FC process)
Polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer was added to and dissolved in purified water at the ratio shown in Table 2, and then talc was added and dispersed to prepare dispersion liquid I.

Separately, titanium oxide, yellow iron sesquioxide and iron sesquioxide were added to purified water in the proportions shown in Table 2 and dispersed to prepare dispersion liquid II.

Dispersion I and Dispersion II were mixed to prepare a film coating liquid.

The uncoated tablets were placed in a film coating machine, coated with a film coating liquid, and dried to prepare film-coated tablets (active ingredient 100 mg tablets). The coated tablet had a tablet diameter of 8.6 mm, a tablet thickness of 3.6 mm, a hardness of 95 N, and a disintegration time of 180 seconds.

(packaging process)
Using a PVC sheet and PVC aluminum foil, the resulting coated tablet was PTP-packaged with a PTP molding machine to obtain a PTP package. The obtained PTP package was packaged with an aluminum pillow using an aluminum pillow chuck to obtain an aluminum pillow package.

After storing the PTP package and the aluminum pillow package obtained in Example 1 under the conditions of 40°C and 75% RH for 6 months, the tablets were pulverized and subjected to XRD analysis to determine the presence of sitagliptin phosphate anhydrate. The presence or absence of transition to hydrate was evaluated. Specifically, based on the comparison between the XRD analysis results of sitagliptin phosphate anhydrate and the XRD analysis results of sitagliptin phosphate monohydrate, the film-coated tablets obtained in Example 1 (before starting the storage test When comparing the XRD analysis results of the PTP package and the XRD analysis results of the aluminum pillow package, the transition to hydrate was observed in the PTP package, similar to the film-coated tablet. In contrast, no transition to hydrate was observed in the aluminum pillow package. Therefore, it was confirmed that the transfer to hydrate can be suppressed by PTP-packaging film-coated tablets and aluminum pillow packaging. In addition, regarding the evaluation of the XRD pattern of syntagliptin phosphate anhydrate, evaluation may be performed with reference to the known pattern described in Japanese Patent Application Laid-Open No. 2007-504230, etc. Sitagliptin phosphate monohydrate Regarding the evaluation of the XRD pattern of, the known pattern described in Japanese Patent No. 4463768 or the like may be referred to for evaluation.

Examples 2-5
(Kneading process)
Sitagliptin phosphate anhydrate, anhydrous calcium hydrogen phosphate, D-mannitol and croscarmellose sodium were placed in a stirring granulator at the ratios shown in Table 3 and mixed. A wet flour was prepared.

(Granulation process)
Separately, purified water and ethanol (99.5) were mixed at the ratio shown in Table 3, and hydroxypropylcellulose was added and dissolved to prepare a granulation liquid.

The wet powder was placed in a fluidized bed granulator and granulated by spraying the granulating liquid at a liquid speed of 90 g/min, followed by drying to prepare dry powder in the form of granules.

(Sizing process)
The obtained dried powder was sized with a sizing machine to prepare a sized powder. The particle diameters of the sized powder were _D10 : 37.8 µm, _D50 : 72.3 µm, and _D90 : 145.6 µm.

(Tabletting powder preparation step)
Sized powder, anhydrous calcium hydrogen phosphate, croscarmellose sodium and light anhydrous silicic acid were mixed in a diffusion mixer at the ratio shown in Table 3, and magnesium stearate was added and mixed to prepare tableting powder. bottom.

(Tabletting process)
The tableting powder was tableted using a rotary tableting machine to prepare uncoated tablets. The characteristics of the obtained uncoated tablet were as follows.

Example 2: Tablet diameter 5.5 mm, tablet thickness 2.3 mm, hardness 64 N, disintegration time 20 seconds Example 3: tablet diameter 9.0 × 3.7 mm, tablet thickness 2.7 mm, hardness 66 N, disintegration time 30 seconds Example 4: Tablet diameter 11.4 × 4.7 mm, tablet thickness 3.4 mm, hardness 91 N, disintegration time 30 seconds Example 5: tablet diameter 8.5 mm, tablet thickness 3.5 mm, hardness 73 N, disintegration time 90 seconds .

(Film coating process)
Polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer was added to and dissolved in purified water at the ratio shown in Table 3, and then talc was added and dispersed to prepare Dispersion I.

Separately, titanium oxide, yellow iron sesquioxide and iron sesquioxide were added to purified water in the proportions shown in Table 3 and dispersed (in Example 2, only titanium oxide was used) to prepare dispersion liquid II.

Dispersion I and Dispersion II were mixed to prepare a film coating liquid.

The uncoated tablets were placed in a film coating machine, coated with a film coating liquid, and dried to prepare film-coated tablets. The properties of the obtained film-coated tablets were as follows.

Example 2: Tablet diameter 5.6 mm, tablet thickness 2.4 mm, hardness 75 N, disintegration time 60 seconds Example 3: tablet diameter 9.1 × 3.8 mm, tablet thickness 2.8 mm, hardness 85 N, disintegration time 65 seconds Example 4: Tablet diameter 11.5 × 4.8 mm, tablet thickness 3.5 mm, hardness 126 N, disintegration time 80 seconds Example 5: tablet diameter 8.6 mm, tablet thickness 3.6 mm, hardness 101 N, disintegration time 140 seconds .

(packaging process)
Using a PVC/PCTFE roll and an aluminum roll for PVC, the resulting film-coated tablet was PTP-packaged with a PTP molding machine to obtain a PTP package. Using an aluminum pillow chuck, the obtained PTP package was subjected to aluminum pillow packaging with an aluminum pillow packaging machine to obtain an aluminum pillow package.

The PTP package and the aluminum pillow package obtained in Examples 2 to 5 were stored under conditions of 40° C. and 75% RH for 6 months, respectively, and then the amounts of related substances and water content of the coated tablets were measured over time. .

FIG. 1 is a graph showing changes in moisture content and related substance content of film-coated tablets when the package obtained in Example 2 was stored. As is clear from FIG. 1, in the PTP package, the water content increased significantly in about two months after storage, and the amount of related substances increased over time, compared to the aluminum pillow package.

FIG. 2 is a graph showing changes in moisture content and related substance content of film-coated tablets when the package obtained in Example 3 was stored. As is clear from FIG. 2, in the PTP package, the water content began to increase from 1 month after storage 2, and the amount of related substances increased over time, compared to the aluminum pillow package.

FIG. 3 is a graph showing changes in moisture content and related substance content of film-coated tablets when the package obtained in Example 4 was stored. As is clear from FIG. 3, in the PTP package, both the moisture content and the amount of related substances increased over time as compared to the aluminum pillow package.

FIG. 4 is a graph showing changes in moisture content and related substance content of film-coated tablets when the package obtained in Example 5 was stored. As is clear from FIG. 4, in the PTP package, the water content increased over time compared to the aluminum pillow package, and the amount of related substances began to increase after 3 months of storage.

Example 6
(Kneading process)
Sitagliptin phosphate anhydrate, anhydrous calcium hydrogen phosphate, D-mannitol and croscarmellose sodium were placed in a stirring granulator at the ratios shown in Table 4 and mixed, and then purified water was sprayed to form raw material powder. A wet flour was prepared.

(Granulation process)
Separately, hydroxypropylcellulose was added to and dissolved in purified water at the ratio shown in Table 4 to prepare a granulation liquid.

The wet powder was placed in a fluidized bed granulator and granulated by spraying the granulating liquid at a liquid speed of 10 g/min, followed by drying to prepare dry powder as granules.

Example 7
A dry powder was prepared in the same manner as in Example 6, except that in the granulation step, the liquid velocity of the granulation liquid was changed to 15 g/min.

Example 8
A dry powder was prepared in the same manner as in Example 6, except that in the granulation step, the liquid velocity of the granulation liquid was changed to 65 g/min.

Example 9
(Kneading process)
Sitagliptin phosphate anhydrate, anhydrous calcium hydrogen phosphate, D-mannitol and croscarmellose sodium were placed in a stirring granulator at the ratios shown in Table 4 and mixed, and then purified water was sprayed to form raw material powder. A wet flour was prepared.

(Granulation process)
Separately, purified water and ethanol (99.5) were mixed at the ratio shown in Table 4, and hydroxypropylcellulose was added and dissolved to prepare a granulation liquid.

The wet powder was placed in a fluidized bed granulator and granulated by spraying the granulation liquid at a liquid speed of 40 to 55 g/min, followed by drying to prepare dry powder in the form of granules.

Example 10
A dry powder was prepared in the same manner as in Example 9, except that in the granulation step, the liquid velocity of the granulation liquid was changed to 175 g/min.

Example 11
(Kneading process)
Sitagliptin phosphate anhydrate, anhydrous calcium hydrogen phosphate, D-mannitol and croscarmellose sodium were placed in a stirring granulator at the ratios shown in Table 4 and mixed, and then purified water was sprayed to form raw material powder. A wet flour was prepared.

(Granulation process)
Separately, purified water and ethanol (99.5) were mixed at the ratio shown in Table 4, and hydroxypropylcellulose was added and dissolved to prepare a granulation liquid.

The wet powder was placed in a fluidized bed granulator and granulated by spraying the granulating liquid at a liquid speed of 60 g/min, followed by drying to prepare dry powder in the form of granules.

Example 12
A dry powder was prepared in the same manner as in Example 11, except that the proportions of purified water and ethanol were changed to those shown in Table 4.

In the granulation step of Example 6, FIG. 5 shows the measurement results of the drying weight loss of the wet powder, which is the granule precursor, and FIG. 6 shows the results converted into water content. As is clear from FIG. 6, in Example 6, the moisture content of the granule precursor was less than 25% by mass, but there was a period of time when the moisture content slightly exceeded 15% by mass. As a result of XRD analysis of the obtained granules, it was confirmed that sitagliptin phosphate anhydrate did not transition to a hydrate.

In the granulation step of Example 7, the results of measuring the weight loss on drying of the wet powder, which is the granule precursor, are shown in FIG. 5, and the results converted into water content are shown in FIG. As is clear from FIG. 6, in Example 7, the moisture content of the granule precursor was less than 25% by mass, but exceeded 15% by mass, and there was a period of time close to 25% by mass. As a result of XRD analysis of the obtained granules, it was confirmed that sitagliptin phosphate anhydrate did not transition to a hydrate.

In the granulation step of Example 8, the results of measuring the drying weight loss of the wet powder, which is the granule precursor, are shown in FIG. 5, and the results converted into water content are shown in FIG. As is clear from FIG. 6, in Example 8, there was a time zone in which the water content of the granule precursor exceeded 25% by mass. As a result of XRD analysis of the obtained granules, transition to hydrate of sitagliptin phosphate anhydride was confirmed.

In the granulation process of Examples 9 to 12, the results of measuring the weight loss on drying of the wet powder, which is the granule precursor, are shown in FIG. 5, and the results converted into water content are shown in FIG. As is clear from FIG. 6, in Examples 9 to 12, the water content of the granule precursor was 15% by mass or less. As a result of XRD analysis of the obtained granules, it was confirmed that sitagliptin phosphate anhydride did not transition to a hydrate in any of the examples.

FIG. 7 shows the relationship between the process progress rate of the granule precursor in the granulation process of Examples 6 to 10 and the loss on drying. As is clear from FIG. 7, it can be observed that the increase in loss on drying is suppressed in Examples 6 and 8 as compared to Examples 9 and 10 even as the process progresses.

Examples 13-15
(Kneading process)
After mixing sitagliptin phosphate anhydrate, anhydrous calcium hydrogen phosphate, D-mannitol and croscarmellose sodium in a stirring granulator in the proportions shown in Table 5 (Example 15 did not add D-mannitol). ), and purified water was sprayed to prepare a wet powder as a raw material powder.

(Granulation process)
Separately, purified water and ethanol (99.5) were mixed at the ratio shown in Table 5, and hydroxypropylcellulose was added and dissolved to prepare a granulation liquid.

The wet powder was placed in a fluidized bed granulator and granulated by spraying the granulation liquid at a liquid speed of 65 to 70 g/min, followed by drying to prepare dry powder in the form of granules.

(Sizing process)
The obtained dried powder was sized with a sizing machine to prepare a sized powder. The particle size of the sieved powder was as shown in Table 5.

(Tabletting powder preparation step)
Sized powder, anhydrous calcium hydrogen phosphate, croscarmellose sodium and light anhydrous silicic acid were mixed in a diffusion mixer at the ratio shown in Table 5, and magnesium stearate was added and mixed to prepare tableting powder. bottom.

(Tabletting process)
The tableting powder was tableted using a rotary tableting machine to prepare uncoated tablets. The characteristics of the obtained uncoated tablet were as follows.

Example 13: Tablet diameter 8.5 mm, tablet thickness 3.5 mm, hardness 71 N, disintegration time 120 seconds Example 14: tablet diameter 8.5 mm, tablet thickness 3.5 mm, hardness 87 N, disintegration time 240 seconds Example 15: Tablet diameter 8.5 mm, tablet thickness 3.6 mm, hardness 104 N, disintegration time 110 seconds

As a result of evaluating the presence or absence of tableting failure in the uncoated tablets obtained in Examples 13 to 15, in Example 13 in which the particle size of the sizing powder was small, thin scratches extending in the thickness direction of the uncoated tablet were formed on the sides of the uncoated tablet. (binding) was observed, whereas no binding was observed in Examples 14 and 15 in which the sized powder had a large particle size.

Examples 16-18
(Kneading process)
Sitagliptin phosphate anhydride, anhydrous calcium hydrogen phosphate, and croscarmellose sodium were mixed in a stirring granulator at the ratios shown in Table 6, and then purified water was sprayed to obtain wet powder, which is raw material powder. was prepared.

(Granulation process)
Separately, purified water and ethanol (99.5) were mixed at the ratio shown in Table 6, and hydroxypropylcellulose was added and dissolved to prepare a granulation liquid.

The wet powder was placed in a fluidized bed granulator and granulated by spraying the granulation liquid at a liquid speed of 40 to 55 g/min, followed by drying to prepare dry powder in the form of granules.

(Sizing process)
The obtained dried powder was sized with a sizing machine to prepare a sized powder.

(Tabletting powder preparation step)
Sized powder, anhydrous calcium hydrogen phosphate, croscarmellose sodium, and light anhydrous silicic acid were mixed in a diffusion mixer in the proportions shown in Table 6, and magnesium stearate was added and mixed to prepare tableting powder. bottom.

(Tabletting process)
The tableting powder was tableted using a rotary tableting machine to prepare uncoated tablets. The characteristics of the obtained uncoated tablet were as follows.

Example 16: Tablet diameter 5.5 mm, tablet thickness 2.3 mm, hardness 60 N, disintegration time 20 seconds Example 17: tablet diameter 9.0 × 3.7 mm, tablet thickness 2.6 mm, hardness 65 N, disintegration time 30 seconds Example 18: Tablet diameter 11.4 × 4.7 mm, tablet thickness 3.4 mm, hardness 80 N, disintegration time 30 seconds

(Film coating process)
Polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer was added to and dissolved in purified water at the ratio shown in Table 6, and then talc was added and dispersed to prepare dispersion liquid I.

Separately, titanium oxide, yellow iron sesquioxide and iron sesquioxide were added to and dispersed in purified water in the proportions shown in Table 6 (in Example 16, only titanium oxide was used) to prepare dispersion liquid II.

Dispersion I and Dispersion II were mixed to prepare a film coating liquid.

The uncoated tablets were placed in a film coating machine, coated with a film coating liquid, and dried to prepare film-coated tablets. The properties of the obtained film-coated tablets were as follows.

Example 16: Tablet diameter 5.6 mm, tablet thickness 2.4 mm, hardness 75 N, disintegration time 60 seconds Example 17: tablet diameter 9.1 × 3.8 mm, tablet thickness 2.7 mm, hardness 80 N, disintegration time 60 seconds Example 18: Tablet diameter 11.5 × 4.8 mm, tablet thickness 3.5 mm, hardness 120 N, disintegration time 80 seconds

(packaging process)
Using a PVC/PCTFE roll and an aluminum roll for PVC, the resulting film-coated tablet was PTP-packaged with a PTP molding machine to obtain a PTP package. Using an aluminum pillow chuck, the obtained PTP package was subjected to aluminum pillow packaging with an aluminum pillow packaging machine to obtain an aluminum pillow package.

Since the oral formulation contained in the package of the present disclosure contains sitagliptin phosphate anhydride as an active ingredient, it can be effectively used as a therapeutic drug for type 2 diabetes.

Claims (17)

A method for improving the stability of sitagliptin phosphate anhydrate by packaging an oral solid preparation containing sitagliptin phosphate anhydrate with an aluminum pillow. The method according to claim 1, wherein the solid oral preparation is a film-coated tablet, and the solid oral preparation is PTP-packaged and then aluminum pillow-packaged. The method according to claim 1 or 2, wherein the film-coated tablet is coated with a film-coating agent containing a vinyl alcohol polymer. In a tablet manufacturing method comprising a granulation step of obtaining granules by granulating a raw material for granulation containing sitagliptin phosphate, and a tableting step of obtaining uncoated tablets by compressing a tableting composition containing the granules and a method for suppressing tableting trouble by adjusting the volume-based cumulative 50% particle diameter (D ₅₀ ) of the granules subjected to the tableting step to 80 μm or more. A granulation step of obtaining granules by wet granulating a raw material for granulation containing sitagliptin phosphate anhydride by a fluidized bed granulation method, and compressing a tableting composition containing the granules to obtain uncoated tablets. A method for producing a tablet comprising a tableting process, wherein the moisture content of the granule precursor is adjusted not to exceed 25% by mass during the wet granulation process to improve the stability of the sitagliptin phosphate anhydrate. A granulation step of obtaining granules by wet granulating a raw material for granulation containing sitagliptin phosphate anhydride by a fluidized bed granulation method, and compressing a tableting composition containing the granules to obtain uncoated tablets. A method for improving the stability of sitagliptin phosphate anhydrate by using a mixed solvent of water and an aqueous solvent as a granulation solvent for the wet granulation in a method for producing a tablet comprising a tableting step. Manufacture of tablets including a granulation step of obtaining granules by granulating a raw material for granulation containing sitagliptin phosphate anhydride, and a tableting step of obtaining uncoated tablets by compressing a tableting composition containing the granules. A manufacturing method, wherein the volume-based cumulative 50% particle diameter ( _D50 ) of the granules subjected to the tableting step is 80 µm or more. 8. The granules subjected to the tableting step have a volume-based cumulative 50% particle diameter ( _D50 ) of 115 μm or more, and a proportion of granules having a particle diameter of 75 μm or less is 30% by mass or less in all granules. manufacturing method. 9. The production method according to claim 7 or 8, wherein in the granulation step, wet granulation is performed by adjusting the water content of the granule precursor not to exceed 25% by mass. In the granulation step,
wet granulation by a fluidized bed granulation method in which a raw material powder containing sitagliptin phosphate anhydride, an excipient and a disintegrant is sprayed with a granulation liquid containing a binder and a granulation solvent;
10. The production method according to claim 9, wherein the granulation solvent is a mixed solvent of water and an aqueous solvent, and the mass ratio of the water and the aqueous solvent is 90/10 to 10/90. The production method according to any one of claims 7 to 10, further comprising a film coating step of coating the uncoated tablet with a film coating agent to obtain a film-coated tablet. A method for producing a package in which the tablet obtained by the production method according to any one of claims 7 to 11 is packaged with an aluminum pillow. 13. The method for producing a package according to claim 12, wherein the tablets are PTP-packaged and then aluminum pillow-packaged. A packaging body in which a PTP-packaged film-coated tablet is packaged in an aluminum pillow, wherein the film-coated tablet contains sitagliptin phosphate anhydrate. A composition comprising granules containing sitagliptin phosphate and having a volume-based cumulative 50% particle diameter ( _D50 ) of 80 μm or more. A composition comprising granules obtained by wet granulating a raw material for granulation containing sitagliptin phosphate anhydride, adjusting the moisture content of the granule precursor during the granulation process so that the water content of the granule precursor does not exceed 25% by mass. 17. An oral formulation comprising the composition of claim 15 or 16.

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