A medicine containing sitagliptin

Abstract

The present invention provides a pharmaceutical product containing sitagliptin or a salt thereof, wherein the generation of nitroso compounds derived from sitagliptin or a salt thereof is reduced. [Solution] A pharmaceutical according to one aspect of the present invention is a pharmaceutical containing sitagliptin or a salt thereof. This pharmaceutical has a water content of 2.8% by weight or less as measured by the Karl Fischer method, and a content of nitroso compounds derived from sitagliptin or a salt thereof of 1.0 ppm or less.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical product containing sitagliptin or a salt thereof. [Background technology]

[0002] Sitagliptin is a compound whose general formula is (3R)-3-amino-1-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-1-one. This compound is a selective DPP-4 inhibitor and is approved in Japan as a treatment for type 2 diabetes.

[0003] N-nitroso compounds are a general term for compounds in which a nitroso group is bonded to the nitrogen atom that makes up an amine. Their general structure is N(R 1 )(R 2 It is represented as )-N=O. Some N-nitroso compounds are suspected of being carcinogenic, and there have been cases where pharmaceuticals in which N-nitroso compounds were detected have been voluntarily recalled (see, for example, Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Ministry of Health, Labour and Welfare Notification (Yakusei Yakushinhatsu 1008 No. 1, Yakusei Anhatsu 1008 No. 1, Yakusei Kanmahatsu 1008 No. 1) "Regarding Voluntary Inspections on the Risk of Nitrosamine Contamination in Pharmaceuticals" October 8, 2021 [Overview of the project] [Problems that the invention aims to solve]

[0005] It is known that sitagliptin's hydrolysates are nitrosated to produce nitroso compounds. There has been a need to develop methods to reduce the formation of these nitroso compounds through this mechanism.

[0006] One aspect of the present invention aims to provide a pharmaceutical product containing sitagliptin or a salt thereof, wherein the generation of nitroso compounds derived from sitagliptin or a salt thereof is reduced. [Means for solving the problem]

[0007] The present invention includes the following embodiments. <1> A pharmaceutical product containing sitagliptin or a salt thereof, said pharmaceutical product The moisture content measured by the Karl Fischer method is 2.8% by weight or less. The content of sitagliptin or nitroso compounds derived from its salts is 1.0 ppm or less. Pharmaceuticals. <2> The above-mentioned pharmaceutical product contains granules containing sitagliptin or a salt thereof, and other ingredients. The moisture content of the other components, as measured by loss on drying, is 3.0% by weight or less. <1> The pharmaceuticals described above. <3> The content of the above sitagliptin or nitroso compounds derived from its salts is 0.5 ppm or less. <1> or <2> The pharmaceuticals described above. <4> <1> ~ <3> A pharmaceutical product described in any of the above, and a desiccant, Packaged pharmaceuticals. <5> A packaged pharmaceutical product containing a pharmaceutical product and a desiccant, wherein the pharmaceutical product is A pharmaceutical product containing sitagliptin or a salt thereof, The content of sitagliptin or nitroso compounds derived from its salts is 1.0 ppm or less. Packaged pharmaceuticals. <6> A packaged pharmaceutical product containing a pharmaceutical product and a desiccant, wherein the pharmaceutical product is A pharmaceutical product containing sitagliptin or a salt thereof, The moisture content, as measured by the Karl Fischer method, is 2.8% by weight or less. Packaged medicine <7> A packaged medicine containing a medicine and a desiccant, wherein the medicine is a medicine containing sitagliptin or a salt thereof, Packaged medicine <8> The desiccant is one or more selected from the group consisting of zeolite, allophane, silica gel, calcium oxide, calcium chloride, magnesium oxide, magnesium chloride, activated carbon, and an oxygen scavenger with a drying function, The packaged medicine according to any one of <4> to <7>. <9> A method for producing a medicine containing sitagliptin or a salt thereof, comprising a step of adjusting the water content of the medicine to 2.8% by weight or less, wherein the content of the nitroso compound derived from sitagliptin or a salt thereof in the medicine is 1.0 ppm or less, Production method <10> A method for reducing the generation of a nitroso compound derived from sitagliptin or a salt thereof in a medicine containing sitagliptin or a salt thereof, comprising a step of adjusting the water content of the medicine to 2.8% by weight or less, wherein the content of the nitroso compound in the medicine is 1.0 ppm or less, Method

Advantages of the Invention

[0008] According to one aspect of the present invention, there is provided a medicine containing sitagliptin or a salt thereof, in which the generation of a nitroso compound derived from sitagliptin or a salt thereof is reduced.

Brief Description of the Drawings

[0009] [Figure 1] XRD spectra of various crystals of sitagliptin phosphate [Figure 2]This graph shows the particle size distribution of hydroxypropyl cellulose (HPC-L fine powder, manufactured by Nippon Soda Co., Ltd.). [Figure 3] This graph shows the particle size distribution of low-substituted hydroxypropyl cellulose (LH-31, Shin-Etsu Chemical Co., Ltd.). [Modes for carrying out the invention]

[0010] One embodiment of the present invention is described below, but the present invention is not limited thereto. The present invention is not limited to the configurations described below, and various modifications are possible within the scope of the claims, and embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention.

[0011] Unless otherwise specified in this specification, "A to B" representing a numerical range means "greater than or equal to A, and less than or equal to B."

[0012] [1. Pharmaceuticals containing sitagliptin or its salts] [1.1. Sitagliptin or its salts, water, and nitroso compounds] A pharmaceutical product according to one aspect of the present invention contains sitagliptin or a salt thereof. Examples of sitagliptin salts include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, maleate, fumarate, citrate, benzoate, and methanesulfonate. In one embodiment, the pharmaceutical product contains sitagliptin phosphate.

[0013] Sitagliptin or its salts may be crystalline or amorphous. If sitagliptin or its salts are crystalline, their crystalline form is not particularly limited. In one embodiment, sitagliptin phosphate is anhydrous type I crystal.

[0014] Sitagliptin or its salts may be anhydrous or hydrated. When sitagliptin or its salts are hydrated, the number of waters of hydration is not particularly limited.

[0015] In one embodiment, sitagliptin or a salt thereof is sitagliptin anhydrous, sitagliptin hydrate, sitagliptin anhydrous, sitagliptin salt hydrate, or any combination thereof.

[0016] Pharmaceuticals may contain adhering water. In pharmaceuticals, the presence or absence of adhering water, or the amount it contains, is not particularly limited.

[0017] The lower limit of the sitagliptin and its salt content in a pharmaceutical product may be 1 mg or more, 5 mg or more, or 10 mg or more, when converted to sitagliptin equivalent. The upper limit of the sitagliptin and its salt content in a pharmaceutical product may be 500 mg or less, 400 mg or less, 300 mg or less, or 200 mg or less, when converted to sitagliptin equivalent.

[0018] The lower limit of the sitagliptin and salt content in a pharmaceutical product may be 3% or more by weight, 5% or more by weight, or 7% or more by weight, when converted to sitagliptin equivalent and using the weight of the pharmaceutical product as 100% by weight. The upper limit of the sitagliptin and salt content in a pharmaceutical product may be 50% or less by weight, 40% or less by weight, 30% or less by weight, or 25% or less by weight, when converted to sitagliptin equivalent and using the weight of the pharmaceutical product as 100% by weight.

[0019] In one embodiment, the amount of sitagliptin and its salt contained in the pharmaceutical is 100 mg, 50 mg, 25 mg, or 12.5 mg in terms of sitagliptin. In one embodiment, the amount of sitagliptin phosphate contained in the pharmaceutical is 100 mg, 50 mg, 25 mg, or 12.5 mg in terms of sitagliptin.

[0020] In one embodiment, the water content of the pharmaceutical is reduced. In this specification, the water content of the pharmaceutical is measured by the Karl Fischer method. The upper limit of the water content may be 2.8% by weight or less, 2.7% by weight or less, or 2.6% by weight or less. The lower limit of the water content may be 0.1% by weight or more, 0.5% by weight or more, or 1.0% by weight or more. In a pharmaceutical with reduced water content, the formation of nitroso compounds derived from sitagliptin or its salts is reduced.

[0021] One example of a means to reduce the moisture content is to use materials with a low moisture content. The moisture content of sitagliptin or its salt active pharmaceutical ingredient may be reduced, or the moisture content of pharmaceutical excipients may be reduced.

[0022] In one embodiment, the pharmaceutical product comprises granules containing sitagliptin or a salt thereof and other components. In this case, the water content of the granules containing sitagliptin or a salt thereof may be reduced, or the water content of the other components may be reduced. In one embodiment, the water content of the other components is reduced. Surprisingly, the inventors have found that in a pharmaceutical product comprising granules containing sitagliptin or a salt thereof and other components, the amount of nitroso compounds derived from sitagliptin or a salt thereof can also be reduced by reducing the water content of the other components.

[0023] Examples of "other ingredients" as used herein include granules that do not contain sitagliptin or a salt thereof, and post-production powders. These ingredients are formed into tablets, for example, together with granules containing sitagliptin or a salt thereof. In this specification, "granules" refers to particles formed primarily from powder material, and the particle size of the granules is larger than the particle size of the primary particles of the powder material. In this specification, "post-production powder" refers to powder material that has not been formed into granules, and is compressed into tablets together with granules containing sitagliptin or a salt thereof. The pharmaceutical product may contain only granules that do not contain sitagliptin or a salt thereof as other ingredients, or only post-production powders, or both of these.

[0024] The upper limit of the moisture content of other components may be 3.0% by weight or less, 2.5% by weight or less, or 2.0% by weight or less, based on the weight of the other component as 100% by weight. The lower limit of the moisture content of other components may be 0.1% by weight or more, or 0.3% by weight or more, based on the weight of the other component as 100% by weight. In this specification, the moisture content of other components refers to the loss on drying when the sample is left standing at 80°C and the weight loss over 30 seconds becomes 0.05% by weight or less, based on the weight at the start of the measurement.

[0025] In one embodiment, the moisture content of the other components mentioned above is the moisture content of the granules that do not contain sitagliptin or a salt thereof. In one embodiment, the moisture content of the other components mentioned above is the moisture content of the final powder. In one embodiment, the moisture content of the other components mentioned above is the moisture content of the combined portion of the granules that do not contain sitagliptin or a salt thereof and the final powder.

[0026] In one embodiment, the pharmaceutical product has a reduced content of nitroso compounds derived from sitagliptin or a salt thereof. In this specification, nitroso compounds refer to N(R) 1 )(R 2 It is a compound having a structure represented by the general formula )-N=O. 1 and R 2 The structures of each are independent, and for example, they are hydrocarbon groups that may have heteroatom-containing groups. Alternatively, R 1 and R 2 These may be bonded together to form a ring. Examples of hydrocarbon groups include alkyl groups, cycloalkyl groups, and aryl groups. Heteroatom-containing groups may consist of only one or more heteroatom atoms, or they may contain both one or more heteroatom atoms and carbon and / or hydrogen atoms.

[0027] In one embodiment, the nitroso compound derived from sitagliptin or a salt thereof is 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine. Hereinafter, this compound is abbreviated as "NTTP". NTTP is produced by the nitrosation of DP-II, a hydrolysate of sitagliptin. Alternatively, NTTP is produced by the nitrosation of DP-II present as an impurity in the active pharmaceutical ingredient. [ka]

[0028] The content of nitroso compounds derived from sitagliptin or its salts in pharmaceuticals may be 1.0 ppm or less, 0.7 ppm or less, 0.5 ppm or less, 0.4 ppm or less, or 0.37 ppm or less, based on the weight of sitagliptin or its salt originally contained in the pharmaceutical, converted to sitagliptin equivalent. The content of nitroso compounds derived from sitagliptin or its salts is measured by LC-MS / MS analysis.

[0029] Pharmaceuticals are usually distributed with a specified sitagliptin content. In this case, the specified content is considered the amount of sitagliptin originally contained in the pharmaceutical. For example, if the sitagliptin content is stated in the package insert, that stated content is considered the amount of sitagliptin originally contained in the pharmaceutical. In pharmaceuticals where the sitagliptin content is not specified, the amount of sitagliptin originally contained in the pharmaceutical is estimated from the amount of sitagliptin and the amount of nitroso compounds derived from sitagliptin or its salts contained in the pharmaceutical at the time of measurement.

[0030] [1.2. Ingredients other than sitagliptin or its salts] A pharmaceutical product may contain ingredients other than sitagliptin or its salts. Examples of such ingredients include active ingredients other than sitagliptin and pharmaceutical additives. Examples of pharmaceutical additives include excipients, disintegrants, binders, lubricants or fluidizers (anti-adhesion agents), colorants, fragrances, sweeteners, preservatives or antiseptics, and coatings. Each of these ingredients may be present individually or in combination of two or more types.

[0031] Examples of excipients include sugars (lactose monohydrate, sucrose, maltose, fructose, glucose, trehalose, etc.), sugar alcohols (mannitol (especially D-mannitol), maltitol, sorbitol, xylitol, erythritol, lactitol, etc.), starches (starch, pregelatinized starch, partially pregelatinized starch, etc.), celluloses (crystalline cellulose, etc.), dextrin, dextran, glycerol fatty acid esters, and inorganic powders (magnesium aluminometasilicate, synthetic hydrotalcite, etc.).

[0032] Examples of binders include povidone, celluloses (methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (hypromellose), croscarmellose sodium, etc.), starch, gelatin, agar, thickening polysaccharides (alginic acid, sodium alginate, tragacanth, xanthan gum, acacia gum, pullulan, dextrin, etc.), polyvinyl alcohol-polyethylene glycol graft copolymer, carboxyvinyl polymer, polyethylene oxide, copolividone, polyoxyethylene hydrogenated castor oil, polymers including N-isopropylacrylamide and / or derivatives of acrylamide with a hydrophobic group introduced at the N position, polyoxyethylene-polyoxypropylene glycol, polyvinyl alcohol (including partially saponified polyvinyl alcohol), basic (meth)acrylate copolymer, and polyethylene glycol.

[0033] Examples of disintegrants include crospovidone, celluloses (carboxymethylcellulose (carmellose), carmellose sodium, carmellose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, crystalline cellulose, etc.), starches (starch, pregelatinized starch, partially pregelatinized starch, carboxymethyl starch sodium, carboxystarch sodium, hydroxypropyl starch, etc.), dextrin, calcium silicate, calcium citrate, and light anhydrous silicic acid.

[0034] Examples of lubricants or fluidizing agents (anti-adhesion agents) include stearic acid, stearates (magnesium stearate, calcium stearate, aluminum stearate, zinc stearate, etc.), sodium stearyl fumarate, glyceryl monostearate, glyceryl palmitostearate, sodium lauryl sulfate, polyethylene glycol, talc, glycerin fatty acid esters, sucrose fatty acid esters, potassium sodium tartrate, carnauba wax, L-leucine, polyethylene glycol, hydrogenated oils, silicic acid compounds (light anhydrous silicic acid, magnesium aluminometasilicate, hydrated silicon dioxide, synthetic aluminum silicate, etc.), and titanium dioxide.

[0035] Examples of colorants include yellow ferric oxide, ferric oxide, titanium dioxide, black iron oxide, food tar dyes, and natural pigments (such as beta-carotene and riboflavin).

[0036] Examples of sweeteners include sucralose, mannitol, sucrose, aspartame, stevia, and acesulfame potassium.

[0037] Examples of flavorings include peppermint, l-menthol, lemon micron, strawberry micron, peppermint micron, peach micron, lychee micron, and pineapple micron.

[0038] Examples of preservatives or antiseptics include ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, benzoic acid, and sodium benzoate.

[0039] Examples of coating agents include water-insoluble polymers. As used herein, the category of "water-insoluble polymers" includes polymers that are poorly soluble in water in addition to polymers that are completely insoluble in water. Examples of water-insoluble polymers include cellulose-based coating agents (such as ethyl cellulose, carboxymethyl ethyl cellulose, hypromellose phthalate, hypromellose acetate succinate, cellulose acetate, cellulose acetate phthalate, etc.), vinyl-based polymers (such as polyvinyl acetal diethylaminoacetate, polyvinyl acetate phthalate, etc.), methacrylate polymers or polymethacrylic acid polymers, and polysiloxane-based coating agents (such as dimethyl polysiloxane, dimethyl polysiloxane - silicon dioxide mixture, etc.).

[0040] One or more additives may be used in combination with the coating agent. Examples of such additives include plasticizers, binders, fluidizing agents or lubricants (anti-adhesion agents), colorants, and sweeteners.

[0041] [1.3. Dosage Forms of Pharmaceuticals] The dosage form of the pharmaceutical is not particularly limited. In one embodiment, the pharmaceutical is a solid preparation. Examples of solid preparations include tablets, powders, granules, and capsules. Examples of tablets include plain tablets, film-coated tablets, and orally disintegrating tablets. In one embodiment, the pharmaceutical is an orally disintegrating tablet.

[0042] In one embodiment, the pharmaceutical contains granules. For example, the pharmaceutical is a tablet formed by tableting a material containing granules. The granules may or may not contain sitagliptin or a salt thereof.

[0043] The shape of the granules varies depending on the granulation method and is not particularly limited. As an example, spherical, cylindrical, and oblong (elongated ellipsoidal) shapes can be mentioned. The D of the granules 50The lower limit may be 50 μm or more, or 100 μm or more. 50 The upper limit may be 1000 μm or less or 800 μm or less. In this specification, D 50 This is calculated from the particle size distribution obtained according to the particle size measurement method by laser diffraction in the particle size measurement method of the 17th edition of the Japanese Pharmacopoeia.

[0044] In one embodiment, sitagliptin or a salt thereof is contained within the granules but not in the outermost layer. Surprisingly, the inventors have found that even when sitagliptin or a salt thereof is contained within the granules and does not come into direct contact with the other components mentioned above, the formation of nitroso compounds derived from sitagliptin or a salt thereof can be reduced by adjusting the moisture content of the pharmaceutical (and consequently, the moisture content of the other components).

[0045] [2. Packaged Pharmaceuticals] One aspect of the present invention is a packaged pharmaceutical comprising the above-described pharmaceutical and desiccant. In this aspect, the moisture content of the pharmaceutical can be reduced by using the desiccant. In one embodiment, the moisture content of the pharmaceutical is within the preferred range described above. In one embodiment, the content of nitroso compounds derived from sitagliptin or its salt in the pharmaceutical is within the preferred range described above.

[0046] Examples of desiccants include zeolite, allophane, silica gel, calcium oxide, calcium chloride, magnesium oxide, magnesium chloride, and activated carbon. In one embodiment, the desiccant is zeolite. Examples of zeolites include natural zeolite, synthetic zeolite, and artificial zeolite. Preferably, the zeolite is synthetic zeolite. Examples of synthetic zeolites include synthetic zeolite 3A and synthetic zeolite 4A. Only one type of desiccant may be used, or multiple types may be used in combination. In addition, a desiccant and an oxygen absorber may be used in combination. An example of such an oxygen absorber with drying function is PharmaKeep® (registered trademark) (Mitsubishi Gas Chemical Company, Inc.).

[0047] The pharmaceutical and the desiccant may be contained in the same packaging container, or one or both may be further contained in other packaging containers. Therefore, the desiccant may be contained in the same container as the primary packaging of the pharmaceutical, or in the same container as the secondary packaging of the pharmaceutical.

[0048] Examples of primary packaging for pharmaceuticals include PTP packaging, strip packaging, bottle packaging, and aluminum packaging.

[0049] Examples of materials for PTP packaging include resins (polyvinyl chloride, polypropylene (such as unoriented polypropylene), polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, polycarbonate, etc.) and metals (such as aluminum). These materials may be used individually or in combination. Examples of material combinations include laminates of polyvinyl chloride and polyvinylidene chloride, and laminates of polyvinyl chloride and polychlorotrifluoroethylene. Tablets can be PTP packaged by forming a resin sheet with pockets using a known method, placing tablets in the pockets, and then covering them with aluminum foil.

[0050] The resin used in PTP packaging is preferably polyvinyl chloride, unoriented polypropylene, or polyvinyl chloride / polychlorotrifluoroethylene laminate. Of these, unoriented polypropylene or polyvinyl chloride / polychlorotrifluoroethylene laminate is more preferred, and polyvinyl chloride / polychlorotrifluoroethylene laminate is even more preferred.

[0051] Examples of bottles used in bottle packaging include glass or plastic bottles. Examples of plastic bottle materials include those exemplified above as resins for PTP packaging. A desiccant may be contained within the bottle packaging.

[0052] An example of secondary packaging for pharmaceuticals is aluminum pillow packaging. The aluminum pillow packaging may contain pharmaceuticals that have been primarily packaged in PTP packaging, strip packaging, bottle packaging, or aluminum packaging. A desiccant may also be included in the aluminum pillow packaging.

[0053] The packaged pharmaceuticals may also contain an oxygen absorber. Examples of oxygen absorbers include iron-based oxygen absorbers (such as iron powder) and organic oxygen absorbers (such as ascorbic acid, isoascorbic acid, hydroquinone, and catechol). Only one type of oxygen absorber may be used, or multiple types may be used in combination. As mentioned above, a combination of desiccant and oxygen absorber may also be used.

[0054] [3. Method of manufacturing pharmaceuticals] One aspect of the present invention is a method for producing a pharmaceutical product containing sitagliptin or a salt thereof. In one embodiment, this method may include a step of adjusting the moisture content of the pharmaceutical product to 2.8% by weight or less. In one embodiment, the resulting pharmaceutical product may contain 1.0 ppm or less of a nitroso compound derived from sitagliptin or a salt thereof. In one embodiment, the pharmaceutical product produced comprises granules containing sitagliptin or a salt thereof and other components. In this embodiment, the moisture content of the other components may be 3.0% by weight or less.

[0055] Examples of specific methods for adjusting the moisture content to 2.8% by weight or less include the following: • Select pharmaceutical raw materials and reduce the amount of moisture introduced from those raw materials. • Reduce the amount of water used in the pharmaceutical manufacturing process. • Adjust the pharmaceutical manufacturing process to reduce the amount of moisture remaining after manufacturing (after drying). • Improve the manufacturing environment for pharmaceuticals and reduce the amount of moisture absorbed from the environment.

[0056] According to the manufacturing method described above, the water content of the pharmaceutical product obtained can be reduced. This reduces the generation of nitroso compounds derived from sitagliptin or its salts.

[0057] One aspect of the present invention is a method for manufacturing packaged pharmaceuticals. This manufacturing method includes the step of placing the pharmaceutical and a desiccant into a container. In one embodiment, the desiccant is one or more selected from the group consisting of zeolite, allophane, silica gel, calcium oxide, calcium chloride, magnesium oxide, magnesium chloride, and activated carbon.

[0058] According to the manufacturing method described above, the water content of stored pharmaceuticals can be reduced. This reduces the formation of nitroso compounds derived from sitagliptin or its salts.

[0059] Other matters concerning pharmaceuticals or packaged pharmaceuticals are as described in sections [1] and [2], so they will not be described again.

[0060] [4. Methods for reducing the formation of nitroso compounds derived from sitagliptin or its salts] One aspect of the present invention is a method for reducing the generation of nitroso compounds derived from sitagliptin or a salt thereof in a pharmaceutical product containing sitagliptin or a salt thereof. In one embodiment, the method may include a step of adjusting the moisture content of the pharmaceutical product to 2.8% by weight or less. In one embodiment, the pharmaceutical product to which the method is applied or the pharmaceutical product to which the method is applied may contain nitroso compounds derived from sitagliptin or a salt thereof in a quantity of 1.0 ppm or less. In one embodiment, the pharmaceutical product to be produced contains granules containing sitagliptin or a salt thereof and other components. In this embodiment, the moisture content of the other components may be 3.0% by weight or less.

[0061] In addition to those mentioned above in Section [3], specific methods for adjusting the moisture content to 2.8% by weight or less include the following: • Improve the storage environment for pharmaceuticals and reduce moisture absorption from the environment. For example, store pharmaceuticals together with a desiccant.

[0062] According to the method described above, the moisture content of pharmaceuticals obtained through manufacturing and stored pharmaceuticals can be reduced. In other words, this method can be used for both the manufacture and storage of pharmaceuticals. This reduces the formation of nitroso compounds derived from sitagliptin or its salts.

[0063] Other matters concerning pharmaceuticals or packaged pharmaceuticals are as described in sections [1] and [2], so they will not be described again. [Examples]

[0064] 〔material〕 Details of the materials used in manufacturing examples 1 and 2 are as follows. ◆Granule A (Granules containing sitagliptin or a salt thereof) (granulated powder) • Sitagliptin phosphate (anhydrous type I crystals) • Hydroxypropylcellulose (HPC-L fine powder, manufactured by Nippon Soda Co., Ltd.) • Low-substituted hydroxypropyl cellulose (LH-31, Shin-Etsu Chemical Co., Ltd.) (shielding layer) • Hydroxypropylcellulose (HPC-SL, Nippon Soda Co., Ltd.) • Talc (MICRO ACE P-3, Nippon Talc Co., Ltd.) (Carbonate layer) • Sodium bicarbonate (sodium hydrogen carbonate, AGC Inc.) • Hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) • Talc (MICRO ACE P-3, Nippon Talc Co., Ltd.) (Masking layer) • Aminoalkyl methacrylate copolymer E (Eudragit E100, Evonik) • Talc (MICRO ACE P-3, Nippon Talc Co., Ltd.) • Light anhydrous silicic acid ◆B Granules (Granules that do not contain sitagliptin or its salts) Corn starch • Crosspovidone D-mannitol • Crystalline cellulose Ethylcellulose • Light anhydrous silicic acid ◆The end • Light anhydrous silicic acid • Aspartame (Ajinomoto Co., Inc.) Ethylcellulose Magnesium stearate (Taihei Chemical Industry Co., Ltd.)

[0065] The various physical properties of each component used in the material were measured. The results are as follows.

[0066] ◆Sitagliptin phosphate The XRD spectra of the crystals are shown in Figure 1. For reference, in addition to the anhydrous type I crystals used in the manufacturing example, the XRD spectra of the anhydrous type III crystals and monohydrate are also shown. Furthermore, the physical properties of the anhydrous type I crystals used in the manufacturing example are as shown in Table 1 below. The particle size distribution was measured using a wet method with a Mastersizer 3000 (Malvern Panalytical). For reference, the physical properties of the monohydrate were also measured. The physical properties were measured in the state of distribution and after grinding (passing once through a grinder at 18,000 rpm). [Table 1]

[0067] ◆Hydroxypropylcellulose (HPC-L fine powder, Nippon Soda Co., Ltd.) ·Viscosity (20℃): 7.7Pa·s pH: 5.8 ·Drying loss: 0.9% ·Ignition residue: 0.2% • Particle size distribution (see also Figure 2): D 10 =23.2μm, D 50 =74.0μm, D 90=140.8μm, Percentage of particles with a diameter of 150μm or less =99.9%, Kurtosis =2.54 (HPC-SL, Nippon Soda Co., Ltd.) ·Viscosity (2%, 20℃): 5.1mPa·s pH: 5.8 ·Drying loss: 1.4% ·Ignition residue: 0.2% ·Particle size distribution: D 10 =17.47μm, D 50 = 57.73 μm, D 90 = 145.92 μm

[0068] ◆Low-substituted hydroxypropyl cellulose (LH-31, Shin-Etsu Chemical Co., Ltd.) pH: 6.3 ·Drying loss: 2.2% ·Ignition residue: 0.15% ·Particle size distribution: D 50 =19.8μm, D 90 = 73.6 μm • Particle size distribution (measured by Mastersizer 3000, see also Figure 3): D 10 =6.2μm, D 50 =20.3μm, D 90 =84.1μm, kurtosis: 3.71

[0069] ◆Talc (MICRO ACE P-3, Nippon Talc Co., Ltd.) • Particle size distribution (laser diffraction method): D 50 = 5.0 ± 0.5 μm

[0070] ◆ Aminoalkyl methacrylate copolymer E (Eudragit E100, Evonik) ·Drying loss: 0.2% ·Viscosity: 3.4mm 2 / s

[0071] ◆Aspartame (Ajinomoto Co., Inc.) pH: 5.4 ·Drying loss: 3.1% ·Ignition residue: 0.20% or less

[0072] ◆Magnesium stearate (Taihei Chemical Industry Co., Ltd.) ·Drying loss: 3.7%

[0073] [Manufacturing Example 1] Orally disintegrating tablets containing sitagliptin phosphate were manufactured according to the following procedure. See Table 2 for the amounts of each component (unit: mg). These orally disintegrating tablets were used in Example 1.

[0074] [1. Manufacturing of granules (Granule A) containing sitagliptin phosphate] (Formation of granulated powder) 1. Hydroxypropyl cellulose was sieved using 140-mesh and 200-mesh sieves. This separated the hydroxypropyl cellulose that passed through the 140-mesh sieve and remained on the 200-mesh sieve. 2. Sitagliptin phosphate, hydroxypropyl cellulose sieved in step 1, and low-substituted hydroxypropyl cellulose were placed in a high-speed stirring granulator and mixed. 3. Purified water and 99.5% ethanol were mixed to prepare a granulation solution. The mixture obtained in step 2 was sprayed with the granulation solution to granulate it, and then dried. 4. The granulated material was sieved using a 30-mesh sieve and a 200-mesh sieve. The material that passed through the 30-mesh sieve and remained on the 200-mesh sieve was considered the granulated powder. (Formation of a shielding layer) 5. Hydroxypropyl cellulose was dissolved in 99.5% ethanol. Talc was dispersed in this solution. In this way, the coating solution was prepared. 6. The granulated powder was placed in a rolling fluidized bed granulator and dryer. The entire amount of the coating solution prepared in step 5 was sprayed onto the granulated powder to coat it. This was then dried to form a shielding layer. 7. The coated granulated powder was sieved using a 30-mesh sieve and a 200-mesh sieve. The material that passed through the 30-mesh sieve and remained on the 200-mesh sieve was used as the shielding layer granules. (Formation of carbonate layer) 8. Sodium bicarbonate was crushed using an impact pulverizer. 9. Hydroxypropyl cellulose was dissolved in 99.5% ethanol. Grinding sodium bicarbonate and talc were dispersed in this solution. The coating solution was thus prepared. 10. The shielding layer granules were placed in a rolling fluidized bed granulator and dryer. The entire amount of the coating solution prepared in step 9 was sprayed onto the shielding layer granules to coat them. This was then dried to form a carbonate layer. 11. The coated shielding layer granules were sieved using a 30-mesh sieve and a 200-mesh sieve. The granules that passed through the 30-mesh sieve and remained on the 200-mesh sieve were identified as the carbonate layer granules. (Formation of a masking layer) 12. Purified water and 99.5% ethanol were mixed. Aminoalkyl methacrylate copolymer E was dissolved in the mixture, and then talc was dispersed. In this way, the coating solution was prepared. 13. The carbonate layer granules were placed in a rolling fluidized bed granulator and dryer. The entire amount of the coating solution prepared in step 12 was sprayed onto the carbonate layer granules to coat them. This was then dried to form a masking layer. 14. Light anhydrous silicic acid was added to the coated carbonate layer granules and sieved using a 30-mesh sieve. The granules that passed through the 30-mesh sieve were designated as granules containing sitagliptin phosphate (granule A).

[0075] [2. Manufacturing of granules (Granule B) that do not contain sitagliptin phosphate] 1. Corn starch and crospovidone were dispersed in purified water. The coating solution was prepared in this manner. 2. D-mannitol, crystalline cellulose, ethylcellulose, and light anhydrous silicic acid were placed in a fluidized bed granulator and mixed. The entire amount of the coating solution prepared in step 1 was sprayed onto the mixture to coat it, and then dried. 3. The coated mixture was sieved through a 30-mesh sieve. The granules that passed through the 30-mesh sieve were designated as granules (Granule B) that did not contain sitagliptin phosphate.

[0076] In the production of granules without sitagliptin phosphate, in step 2, the intake air temperature to the fluidized bed granulator was maintained at 60°C, while the exhaust temperature at the end of drying was varied. In this way, granules with varying moisture content were obtained. The moisture content of the granules, expressed as loss on drying, varied from approximately 0.6% by weight to approximately 8.5% by weight. Generally, the lower the exhaust temperature, the higher the moisture content tended to be.

[0077] [3. Manufacturing of orally disintegrating tablets] 1. Granules containing sitagliptin phosphate, granules not containing sitagliptin phosphate, light anhydrous silicic acid, aspartame, and ethylcellulose were mixed using a diffusion mixer. 2. Magnesium stearate was added to the resulting mixture and mixed further. In this way, tablet powder was obtained. 3. The tablet powder was compressed using a rotary tablet press. In this way, orally disintegrating tablets were manufactured.

[0078] [Manufacturing Example 2] Orally disintegrating tablets containing sitagliptin phosphate were manufactured by modifying Manufacturing Example 1 as described below. These orally disintegrating tablets were used in Example 2. In the manufacturing process 14 of the granules containing sitagliptin phosphate, light anhydrous silicic acid was not added. • In manufacturing step 1 of the orally disintegrating tablets, ethylcellulose was not added.

[0079] Furthermore, in manufacturing step 14 of the granules containing sitagliptin phosphate, light anhydrous silicic acid is added to prevent the granules from sticking together due to static electricity. Also, in manufacturing step 1 of the orally disintegrating tablets, ethylcellulose is added to improve the strength of the tablets. Therefore, the differences between manufacturing example 1 and manufacturing example 2 do not substantially affect the moisture content of the resulting orally disintegrating tablets.

[0080] [Table 2]

[0081] [Example 1: Investigation of the effect of water content in pharmaceuticals] The effect of the water content of pharmaceuticals on the formation of nitroso compounds (NTTPs) was investigated. The specific procedure is as follows. 1. As shown in Table 3, a sample of the orally disintegrating tablet obtained in Manufacturing Example 1 was prepared in packaging. Details of the materials used are as follows. • PTP sheets: Unoriented polypropylene film and aluminum foil • Aluminum pillow: Aluminum-polyethylene laminated pillow • Bottle: Polyethylene bottle • Desiccant (for aluminum pillows): Zeolite-based desiccant (MS-Ceram-W, synthetic zeolite, Tokai Chemical Industry Co., Ltd.) • Desiccant (for bottles): Zeolite-based desiccant (MS-Tablet-W, synthetic zeolite, Tokai Chemical Industry Co., Ltd.) 2. Samples were stored at 40°C for 3 months or 6 months. 3. The water content and NTTP content of the orally disintegrating tablets were quantified. The water content was measured by the Karl Fischer method. The NTTP content was measured by LC-MS / MS analysis.

[0082] [result] The results are shown in Table 3. [Table 3]

[0083] As can be seen from Table 3, orally disintegrating tablets with a moisture content exceeding 2.8% by weight at the start of administration tended to have a higher NTTP content after 6 months of storage. This value is unsuitable for achieving the current NTTP intake standard in Japan, which is "37 ng or less per day." This result suggests that pharmaceuticals with a moisture content of 2.8% by weight or less can reduce the amount of nitroso compounds derived from sitagliptin phosphate even after storage.

[0084] In this embodiment, the moisture content of the orally disintegrating tablets was adjusted by adjusting the moisture content of the granules that did not contain sitagliptin phosphate, and the same granules containing sitagliptin phosphate were used in all experiments. Thus, the fact that the formation of nitroso compounds derived from sitagliptin phosphate could be reduced by controlling the moisture content of components other than the granules containing sitagliptin phosphate was an unexpected result for those skilled in the art. In particular, this result was unexpected for those skilled in the art, even though the granules that did not contain sitagliptin phosphate did not come into direct contact with sitagliptin phosphate (they were separated by a shielding layer, a carbonate layer, and a masking layer).

[0085] The moisture content of components other than the granules containing sitagliptin phosphate (such as granules that do not contain sitagliptin phosphate) is preferably 3.0% by weight or less.

[0086] [Measurement results of various physical properties] In addition, in this example, the physical properties of the manufactured orally disintegrating tablets and intermediate materials were measured. The results are shown in Table 4 below. [Table 4]

[0087] [Example 2: Examination of the effects of packaging materials] The effect of packaging material use on the formation of nitroso compounds (NTTP) was investigated. The specific procedure is as follows. 1. As shown in Table 5, a sample of the orally disintegrating tablet obtained in Manufacturing Example 2 was prepared in packaging. Details of the materials used are as follows. • PTP Sheet 1: Unoriented polypropylene film and aluminum foil • PTP Sheet 2: Polyvinyl chloride film and aluminum foil • Aluminum pillow: Aluminum-polyethylene laminated pillow • Bottle: Polyethylene bottle • Desiccant 1: Zeolite-based desiccant (MS-Ceram-W, synthetic zeolite, Tokai Chemical Industry Co., Ltd.) • Desiccant 2: Calcium chloride-based desiccant (Dry Mat, Central Co., Ltd.) 2. The samples were stored under specified conditions. 3. The water content and NTTP content of the orally disintegrating tablets were quantified. The water content was measured by the Karl Fischer method. The NTTP content was measured by LC-MS / MS analysis.

[0088] [result] The results are shown in Tables 5A and 5B. [Table 5]

[0089] As can be seen from Tables 5A and 5B, regardless of the packaging material used, the NTTP content after storage was kept below a certain level (e.g., 0.37 ppm or less). Comparing the packaging materials, PTP packaging is preferred as the packaging form, polypropylene is preferred as the PTP material, and zeolite is preferred as the desiccant.

[0090] [Prescription Example 1] Orally disintegrating tablets may be manufactured according to the compositions shown in Table 6 below. The manufacturing method can follow, for example, Manufacturing Example 1 described above. [Table 6]

[0091] [Prescription Example 2] A pharmaceutical product according to one aspect of the present invention may be implemented as a tablet other than an orally disintegrating tablet. As an example, a formulation example of a film-coated tablet is shown in Table 7 below. [Table 7]

[0092] [Manufacturing Example 3] Film-coated tablets containing sitagliptin phosphate were manufactured using the following procedure. (Manufacturing of whole grain powder) 1. The active ingredient, excipient, and disintegrant from the granulated material were placed in a stirring (mixing) granulator and mixed. Then, a portion of the purified water was sprayed onto the mixture. In this way, wet powder was obtained. 2. Hydroxypropyl cellulose was dissolved in the remaining purified water to prepare a solution. 3. Anhydrous alcohol was mixed with the dissolving solution to prepare the granulation solution. 4. The wet powder obtained in step 1 was placed in a fluidized bed granulator. The granulation solution obtained in step 3 was sprayed onto the powder to granulate it, and then it was dried. In this way, a dried powder was obtained. 5. The dried powder was sized using a sizing machine to obtain sized powder. (Manufacturing of uncoated tablets) 6. Of the materials for the tablet powder, the whole granules, excipients, and fluidizers were mixed in a diffusion mixer. Then, a lubricant was added, and the tablets were compressed in a rotary tablet press. Plain tablets were obtained in this way. (Manufacturing of film-coated tablets) 7. A polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer was dissolved in a portion of purified water. Then, talc was added and dispersed. Dispersion I was obtained in this way. 8. Titanium dioxide was added to the remaining purified water and dispersed. For tablets other than the 12.5 mg tablets, yellow ferric oxide and ferric oxide were also dispersed together. Dispersion II was thus obtained. 9. Dispersion I and Dispersion II were mixed to prepare a film coating solution. 10. The uncoated tablets were placed in a film coating machine, coated with a film coating solution, and dried. Film-coated tablets were obtained in this way.

[0093] [Example 3: Examination of the effects of packaging materials (2)] The effect of packaging material use on the formation of nitroso compounds (NTTP) was investigated. The specific procedure is as follows. 1. Film-coated tablets of 12.5 mg, 50 mg, and 100 mg were manufactured according to Manufacturing Example 3, based on the composition described in Formulation Example 2 (Table 7). 2. Samples of the obtained film-coated tablets were prepared by packaging them. Details of the materials used are as follows. • PTP sheets: Laminated film of polychlorotrifluoroethylene and polyvinyl chloride and aluminum foil • Aluminum pillow: Aluminum-polyethylene laminated pillow • Bottle: Polyethylene bottle • Desiccant 1: Zeolite • Desiccant 2: Dryer 2. The samples were stored under specified conditions. 3. The amount of NTTP contained in the film-coated tablets was measured by LC-MS / MS analysis.

[0094] [result] Table 8 shows the NTTP content (ppm). [Table 8]

[0095] As can be seen from Table 8, regardless of the packaging material used, the NTTP content after storage was kept below a certain level (for example, 1.0 ppm or less). Comparing the packaging materials, it is preferable to package with a desiccant when storing for a long period of time, and a zeolite-based desiccant is preferred.

[0096] [Viscosity of polymers] The viscosity of polymer-type additives that can be used as raw materials for pharmaceuticals was measured. The results are shown in Table 9. [Table 9] [Industrial applicability]

[0097] This invention can be used in the manufacture of pharmaceuticals containing sitagliptin or a salt thereof.

Claims

1. A pharmaceutical product containing sitagliptin or a salt thereof, said pharmaceutical product The moisture content measured by the Karl Fischer method is 2.8% by weight or less. The content of sitagliptin or nitroso compounds derived from its salts is 1.0 ppm or less. Pharmaceuticals.

2. The above-mentioned pharmaceutical product contains granules containing sitagliptin or a salt thereof, and other ingredients. The moisture content of the other components, as measured by loss on drying, is 3.0% by weight or less. The pharmaceutical product according to claim 1.

3. The content of the nitroso compound derived from sitagliptin or its salt is 0.5 ppm or less. The pharmaceutical product according to claim 1.

4. A pharmaceutical product according to any one of claims 1 to 3, and a desiccant, Packaged pharmaceuticals.

5. A packaged pharmaceutical product containing a pharmaceutical product and a desiccant, wherein the pharmaceutical product is A pharmaceutical product containing sitagliptin or a salt thereof, The content of sitagliptin or nitroso compounds derived from its salts is 1.0 ppm or less. Packaged pharmaceuticals.

6. A packaged pharmaceutical product containing a pharmaceutical product and a desiccant, wherein the pharmaceutical product is A pharmaceutical product containing sitagliptin or a salt thereof, The moisture content measured by the Karl Fischer method is 2.8% by weight or less. Packaged pharmaceuticals.

7. A packaged pharmaceutical product containing a pharmaceutical product and a desiccant, wherein the pharmaceutical product is A pharmaceutical product containing sitagliptin or a salt thereof. Packaged pharmaceuticals.

8. The above-mentioned desiccant is one or more selected from the group consisting of zeolite, allophane, silica gel, calcium oxide, calcium chloride, magnesium oxide, magnesium chloride, activated carbon, and oxygen absorbers with drying function. The packaged pharmaceutical product according to any one of claims 5 to 7.

9. A method for producing a pharmaceutical product containing sitagliptin or a salt thereof, The process includes adjusting the moisture content of the above-mentioned pharmaceutical to 2.8% by weight or less. The content of sitagliptin or nitroso compounds derived from its salts in the above-mentioned pharmaceutical product is 1.0 ppm or less. Manufacturing method.

10. A method for reducing the generation of nitroso compounds derived from sitagliptin or a salt thereof in a pharmaceutical product containing sitagliptin or a salt thereof, The process includes adjusting the moisture content of the above-mentioned pharmaceutical to 2.8% by weight or less. The content of the above-mentioned nitroso compound in the above-mentioned pharmaceutical is 1.0 ppm or less. method.

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