WO2014051023A1 - Préparation contenant de l'anagliptine - Google Patents

Préparation contenant de l'anagliptine Download PDF

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Publication number
WO2014051023A1
WO2014051023A1 PCT/JP2013/076202 JP2013076202W WO2014051023A1 WO 2014051023 A1 WO2014051023 A1 WO 2014051023A1 JP 2013076202 W JP2013076202 W JP 2013076202W WO 2014051023 A1 WO2014051023 A1 WO 2014051023A1
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WIPO (PCT)
Prior art keywords
anagliptin
solid preparation
mass
salt
preparation according
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PCT/JP2013/076202
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English (en)
Japanese (ja)
Inventor
恒之 日比野
直也 落合
真弘 近藤
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株式会社 三和化学研究所
興和株式会社
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Application filed by 株式会社 三和化学研究所, 興和株式会社 filed Critical 株式会社 三和化学研究所
Priority to KR1020147032600A priority Critical patent/KR20150059720A/ko
Priority to JP2014538613A priority patent/JP6309895B2/ja
Publication of WO2014051023A1 publication Critical patent/WO2014051023A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention belongs to the pharmaceutical field, and specifically relates to a preparation containing anagliptin, which is an inhibitor of dipeptidyl peptidase IV, or a salt thereof.
  • a compound useful as an active ingredient of a pharmaceutical agent in general, it is difficult to administer a compound useful as an active ingredient of a pharmaceutical agent as it is from the viewpoint of ingestion and ensuring the accuracy of the dosage, and it is usually formulated and administered in some dosage form.
  • solid preparations such as powders, granules, tablets and the like have a merit that they are easier to handle and easier to manage the dose than liquids and the like, and are widely used dosage forms.
  • a solid preparation is required to have efficacy and safety as a pharmaceutical product, but chemical stability and physical stability of the preparation at the time of market distribution are also important. However, elution is generally delayed when the handleability and physical stability of a solid preparation are improved.
  • anagliptin there is no specific formulation or formulation technology that can be marketed as a pharmaceutical product as well as a solid product.
  • vildagliptin which is a structurally similar dipeptidyl peptidase IV (DPP-IV) inhibitor
  • DPP-IV dipeptidyl peptidase IV
  • a tablet containing microcrystalline cellulose, lactose, sodium starch glycolate, and magnesium stearate has been reported (Patent Document 1).
  • DPP-IV dipeptidyl peptidase IV
  • linagliptin which is also a DPP-IV inhibitor
  • Tableting obstacles are sticking (a phenomenon in which powder adheres to the heel), binding (a phenomenon in which friction between the die and the tablet increases), capping (a phenomenon in which the tablet peels into a cap shape), and laminating (a tablet peels in a layer) Phenomenon).
  • This document discloses a technique of further adding an excipient such as crystalline cellulose to granules containing a pharmaceutically active ingredient, mannitol, crystalline cellulose and the like, and compressing and molding into tablets.
  • Anagliptin is the most suitable tablet in view of its effective dose. However, in order to obtain a tablet with a size that is easy to handle, it becomes a high-content preparation containing anagliptin in a high content. In this case, the coexistence of the elution characteristics of the active ingredient, the physical stability of the tablet (tablet hardness and friability), and the chemical stability of the active ingredient (decomposition characteristics of the active ingredient) are all good. It was difficult. Therefore, an object of the present invention is to provide a technique for producing an anagliptin preparation having both high chemical stability and fast dissolution characteristics of an active ingredient anagliptin and excellent physical stability of a tablet.
  • anagliptin is unstable to water in the preparation
  • a preparation without problems with the chemical stability of anagliptin could be produced.
  • the inventors have found that a preparation having both high physical stability and fast dissolution can be obtained by blending crystalline cellulose and crospovidone, and completed the present invention.
  • this invention mentions also about the combination of an anagliptin and each additive.
  • the main configuration of the present invention is as follows.
  • Anagliptin or a salt thereof as an active ingredient, crospovidone as a disintegrating agent, crystalline cellulose as an excipient, and a binder, without a fluidizing agent, and part or all of the active ingredient and the containing ingredient A solid preparation produced by compression molding after wet granulation with a binder.
  • Hardness of solid preparation is 30N or more, 20 tablets of solid preparation were tested for 15 minutes at drum rotation speed of 25rpm using drum described in Japanese Pharmacopoeia tablet friability test method.
  • the solid preparation according to (1) having a dissolution rate of 1% or less and a dissolution rate of 15 minutes according to the Japanese Pharmacopoeia dissolution test method of 85% or more.
  • the solid preparation according to (2), wherein the degradation product amount in the stability test for 21 days is 3% or less under conditions of a temperature of 60 ° C. and a relative humidity of 75%.
  • the solid preparation according to (1), wherein the binder is one or more binders selected from the group consisting of hydroxypropylcellulose, povidone, hypromellose, pullulan, and starch paste.
  • the solid preparation according to (4), wherein the binder is hydroxypropylcellulose.
  • the solid preparation according to (1), wherein the content of the anagliptin or a salt thereof is 47% by mass to 83% by mass of the entire preparation.
  • the solid preparation according to (1), wherein the content of the anagliptin or a salt thereof is 55% to 75% by weight of the whole preparation.
  • the solid preparation according to (1), wherein the content of crospovidone is 7% to 35% by weight of the whole preparation.
  • the solid preparation according to (1), wherein the content of crospovidone is 8% to 25% by weight of the whole preparation.
  • a method for producing a solid preparation by granulating a powder mixture containing anagliptin or a salt thereof with a binder and then compression-molding the mixture, and wet-making at least anagliptin or a salt thereof in a solution containing the binder. At least the crystalline cellulose and crospovidone are added and mixed to the granules obtained by granulation, and the step of compression molding the obtained mixture, or at least anagliptin or a salt thereof, crystalline cellulose and crospovidone are mixed.
  • the manufacturing method of the solid formulation containing an anagliptin or its salt including the process of compression-molding the granule obtained by carrying out wet granulation of the obtained mixture in the solution containing a binder.
  • the binder is one or more binders selected from the group consisting of hydroxypropylcellulose, povidone, hypromellose, pullulan, and starch paste.
  • a solid preparation containing anagliptin or a salt thereof and crystalline cellulose (19) The solid preparation according to (18), further comprising crospovidone. (20) A solid preparation containing anagliptin or a salt thereof and crospovidone. (21) A solid preparation containing anagliptin or a salt thereof and ferric oxides. (22) The solid preparation according to any one of (18) to (21), wherein the solid preparation is a tablet, capsule, granule, fine granule, or powder.
  • anagliptin or a salt thereof in a preparation containing anagliptin or a salt thereof as an active ingredient, excellent chemical stability of the active ingredient, good dissolution characteristics of the active ingredient, and / or excellent physical stability of the preparation are obtained.
  • those effects can be sufficiently obtained, so that high quality as a pharmaceutical product of a preparation containing anagliptin or a salt thereof can be ensured.
  • Anagliptin is the compound of Example 2 of WO2004 / 067509 and can be synthesized with reference to the production method of Example 1 of WO2004 / 067509.
  • “anagliptin or a salt thereof” includes not only anagliptin itself, but also a pharmaceutically acceptable salt of anagliptin, or a solvate of anagliptin or a pharmaceutically acceptable salt thereof, water, alcohol or the like. Is also included.
  • Examples of the pharmaceutically acceptable salt include a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Suitable examples of salts with organic acids include acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzoic acid, and toluenesulfonic acid. And the like.
  • Preferable examples of the salt with basic amino acid include a salt with arginine and the like.
  • Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • anagliptin or a salt thereof is preferably free.
  • the content of anagliptin in this preparation is not particularly limited, but from the viewpoint of ensuring that the preparation is easy to take, and ensuring the expected dissolution characteristics and physical stability (hardness and friability) of the preparation.
  • it is 47% by mass to 83% by mass of the whole preparation, and more preferably 55% by mass to 75% by mass.
  • crospovidone is usually used as a disintegrant.
  • the content of crospovidone is not particularly limited, it is preferably 7% by mass to 35% by mass, more preferably from the viewpoint of ensuring the expected elution characteristics and making the formulation easy to take. Is 8% by mass to 25% by mass.
  • crospovidone is a crosslinked polymer of 1-vinyl-2-pyrrolidone, and in the present invention, any crospovidone having a different molecular weight or the like may be used, and these may be used alone or in combination of two or more. It may be used.
  • crospovidone a commercially available product may be used.
  • Kollidon CL for example, Kollidon CL, Kollidon CL-F, Kollidon CL-M, Kollidon CL-SF (above, manufactured by BASF), polyplastidone XL, Polyplaston XL-10, Polyplaston INF-10 (manufactured by IPS Japan Co., Ltd.) and the like.
  • other disintegrants and the like can be used in combination. Examples of such other disintegrants include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, and partially pregelatinized starch.
  • a binder is usually used for wet granulation.
  • the binder include hydroxypropyl cellulose, povidone, hypromellose, pullulan, and starch paste. These may be used alone or in combination of two or more. Among these binders, hydroxypropylcellulose, povidone, and hypromellose are preferable.
  • the content of the binder is not particularly limited, but it is preferably 0.1% to 5% by weight, more preferably 0.3%, more preferably 0.3% by weight of the whole preparation from the viewpoint of avoiding tableting troubles and ensuring expected dissolution characteristics. % By mass to 3% by mass, more preferably 0.5% by mass to 2% by mass.
  • crystalline cellulose is usually used as an excipient.
  • the content is not particularly limited, but from the viewpoint of ensuring the expected physical stability (hardness and friability) and ensuring the expected dissolution characteristics, it is preferably 7% to 37% by weight of the entire preparation. More preferably, it is 10% by mass to 35% by mass, and further preferably 15% by mass to 30% by mass.
  • the properties of the crystalline cellulose to be used are not particularly limited, and it may be powdery, finely divided (crystalline cellulose (fine particles)), or granulated (crystalline cellulose (grains)), and these may be used alone. , Or a combination of two or more. Further, as the crystalline cellulose, commercially available ones can be used.
  • additives that can be generally used as pharmaceutical additives may be blended.
  • the excipient include lactose hydrate, D-mannitol, corn starch, and anhydrous calcium hydrogen phosphate
  • examples of the lubricant include magnesium stearate, talc, stearic acid, calcium stearate, and Examples include sodium stearyl fumarate. These excipients may be used alone or in admixture of two or more.
  • this preparation may contain ferric oxide as a coloring agent.
  • the iron sesquioxides may be any component containing iron sesquioxide, and examples thereof include yellow iron sesquioxide, brown iron oxide, and iron sesquioxide, among which yellow iron sesquioxide and iron sesquioxide are preferable. . These are known compounds, which can be produced by known methods, and commercially available products can be used.
  • the content of ferric sesquioxide in the preparation is not particularly limited, but is preferably 0.005 to 0.5 mass%, more preferably 0.01 to 0.1 mass% of the entire preparation.
  • the iron sesquioxides may be present not in the compression molded product but in the film coating layer or sugar coating layer described later.
  • a film coating layer or a sugar coating layer can be provided.
  • a film coating layer consists of the combination of the additive used as a pharmaceutical additive, for example, is comprised from a hypromellose, a macrogol, a titanium oxide, etc.
  • the film coating layer or sugar coating layer may be colored by adding a colorant as described above. Further, a brightener may be added to increase the commercial value.
  • the physical stability is good if the hardness of the tablet measured with a load cell type hardness tester is at least 30 N or more.
  • the tablet hardness is preferably 40 N or more.
  • the friability of the tablet is preferably less than 1%. When the friability is less than 1%, it can be said that the physical stability is good.
  • the friability means the mass of 20 tablets measured using a friability tester (drum) described in the Japanese Pharmacopoeia tablet friability test method, put in a drum, and rotated at 25 rpm for 15 minutes. After rotation, the tablet is taken out and the mass is measured. Separately, 20 tablets were used as controls, and the friability after correcting moisture absorption from the mass before and after the test.
  • the dissolution property evaluation is performed in the “paddle method” of the “dissolution test method” category of the “formulation test method” category of the “general test method” category in the 16th revised Japanese pharmacopoeia.
  • the dissolution rate of the active ingredient in the tablet is measured at a paddle rotation speed of 50 rpm.
  • the dissolution rate of the active ingredient for 15 minutes according to the test method is preferably 85% or more. If the dissolution rate is less than that, the dissolution of anagliptin from the tablet is poor, which may cause efficacy problems.
  • the chemical stability evaluation of anagliptin that is, the stability test is performed as follows.
  • the formulation is subjected to an open 21-day severe test in an environment of a temperature of 60 ° C. and a relative humidity of 75%.
  • the ratio of the total peak area value (corresponding to the amount of degradation products of anagliptin) to the total peak area value is calculated.
  • the ratio is the ratio (%) of the degradation product amount of anagliptin, and in this preparation, the value is preferably 3% or less.
  • solid preparation may mean a solid preparation such as a capsule, granule, fine granule, powder, etc., except where there is a description limited to tablets produced by compression molding.
  • Each form of solid preparation can be produced by various methods according to common general technical knowledge. Among them, tablets produced by compression molding, which constitutes the main part of the present invention, are combined with a powder mixture containing at least anagliptin. The remaining components can be added to the granules formed by wet granulation with an agent, if necessary, and compression-molded.
  • anagliptin can be produced by adding and mixing at least crystalline cellulose and crospovidone to granules obtained by wet granulation with a solution containing a binder, and compression-molding the resulting mixture. it can. It can also be produced by compression molding granules obtained by wet granulating a mixture obtained by mixing at least anagliptin, crystalline cellulose and crospovidone with a solution containing a binder. Here, a lubricant or the like is added as necessary. Moreover, it is preferable that the whole anagliptin is wet-granulated.
  • Example and the comparative example in the following experiment examples is for the invention of (1) described in the means for solving the present problem, it is a comparative example for other inventions. May be an example or vice versa.
  • the basic measurement method in the experimental example is based on the following four methods. In all experiments, the active ingredient anagliptin was manufactured by Sekisui Medical Co., Ltd.
  • crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: Theolas PH-302) is dried at various temperatures (70 to 105 ° C) to prepare crystalline cellulose samples with different moisture contents.
  • the anagliptin was mixed in a plastic bag so that the blending ratio of anagliptin was 5%, and then quickly filled into a glass bottle (about 13 g in a 30 mL bottle) and sealed.
  • Such test specimens were subjected to stability tests at 60, 70, and 80 ° C. for 7, 14, and 21 days, and the amount of degradation products (%) before and after the stability test was measured.
  • the moisture content% of each test specimen before the stability test is shown in Table 1.
  • Table 2 shows the amount of decomposition products (%) before and after the stability test.
  • the obtained mixed powder was tableted using a ⁇ 8mm standard R ⁇ with a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: VIRG) at a tableting pressure of 10 kN / ⁇ to give a tablet weight of 160 mg to produce tablets. did.
  • the obtained mixed powder was tableted with a tableting pressure of 10 kN / ⁇ using a rotary tableting machine using a ⁇ 8 mm standard R ⁇ . These tablets contain 100 mg (66-68% by mass) of anagliptin in the tablet.
  • Example 1 Using 100 parts by mass of anagliptin in an aqueous solution of 1.5 parts by mass of hydroxypropylcellulose (Nippon Soda Co., Ltd .: HPC-L) using a fluidized bed granulator (Freund Sangyo Co., Ltd .: Flow coater FLO-5) Fluidized bed granulated, dried, and then sized with a sizing machine (Dalton Co., Ltd .: Power Mill P-04S).
  • a fluidized bed granulator Frund Sangyo Co., Ltd .: Flow coater FLO-5
  • the granules were mixed with 15 parts by mass of crospovidone (BASF: Kollidon CL) and crystalline cellulose ( Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802) 30 parts by mass was added and mixed in a plastic bag, then magnesium stearate (Tahei Chemical Industry Co., Ltd .: magnesium stearate vegetable) 1.5 parts by mass was added. Furthermore, the plastic bag was mixed.
  • BASF Kollidon CL
  • crystalline cellulose Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802
  • the obtained granules were tableted with a tableting pressure of 10 kN / kg and a tablet weight of 148 mg using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: VIRG) using a ⁇ 8 mm standard R ⁇ .
  • the tablet contains 100 mg (almost 68%) of anagliptin in 148 mg of the tablet.
  • Example 2 In Example 1, 1.5 parts by mass of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd .: HPC-L) was replaced with 1.5 parts by mass of povidone (manufactured by BASF: Kollidon K30), and fluidized bed granulator / dryer (Freund Sangyo Co., Ltd.) ): Flow coater FLO-5) was replaced with a fluidized bed granulator (Freund Sangyo Co., Ltd .: Flow coater FLO-2).
  • Example 3 In Example 2, 1.5 parts by mass of povidone was replaced with 1.5 parts by mass of hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd .: TC-5R).
  • Example 4 100 parts by mass of anagliptin, 15 parts by mass of crospovidone (manufactured by BASF: Kollidon CL), and 30 parts by mass of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation: Theolas KG-802) are produced by hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.): HPC-L) After mixing with 1.5 parts by mass of aqueous solution using a fluidized bed granulator (Freund Sangyo Co., Ltd .: Flow coater FLO-2), fluidized bed granulated, dried and granulated The size was adjusted with a Dalton Co., Ltd.
  • a fluidized bed granulator Frund Sangyo Co., Ltd .: Flow coater FLO-2
  • the test results are shown in Table 5 below.
  • the tablets of Examples 1 to 4 produced by wet granulation have a degradation product amount (%) of 3% or less even after 21 days of stability test, but they are directly compressed using a fluidizing agent.
  • the decomposition product amount (%) exceeded 3%. From this result, it was found that the fluidizing agent had an adverse effect on the chemical stability of anagliptin.
  • Binders that can be used in this preparation were examined. That is, the physical stability and dissolution characteristics of the tablets of Examples 1 to 4 and the tablets of Examples 5 and 6 below were evaluated.
  • Example 5 The same production as in Example 2 was carried out by replacing 1.5 parts by mass of povidone (BASF: Kollidon K30) with 1.5 parts by mass of pullulan (Hayashibara Co., Ltd .: pullulan).
  • BASF Kollidon K30
  • pullulan Hayashibara Co., Ltd .: pullulan
  • Example 6 A starch paste obtained by suspending 1.5 parts by weight of an aqueous solution of povidone (BASF: Kollidon K30) in 1.5 parts by weight of starch (Nihon Shokuhin Kako Co., Ltd .: corn starch) and watering it at 80 ° C or higher for 30 minutes or more. It replaced and manufactured similarly to Example 2.
  • BASF Kollidon K30
  • starch Nahon Shokuhin Kako Co., Ltd .: corn starch
  • Example 5 The amount of crospovidone, a disintegrant, was examined. That is, the physical stability and dissolution characteristics of the tablets of Examples 7 to 12 shown below were evaluated.
  • Example 7 to 12 The addition amount of crospovidone (manufactured by BASF: Kollidon CL) and the mass of one tablet were set to the ratios shown in Table 7, and tablets were produced in the same manner as in Example 1.
  • the test results are shown in Table 8. As the amount of crospovidone added increased, the hardness decreased and consistent results were not obtained with respect to the friability, but all showed good physical stability with a hardness of 40 N or more and a friability of 1% or less. On the other hand, the elution characteristics increased as the amount of crospovidone added increased, but only when the amount of crospovidone added was 5% by mass, the expected elution characteristics (15 minutes value of 85% or more) were not obtained. From the above results, it was found that the content of crospovidone is preferably 7% by mass or more, and most preferably about 15% by mass. Use of crospovidone in an amount exceeding 30% by mass is not preferable because the tablet becomes large and difficult to swallow.
  • Example 6 The disintegrant that can be used in this preparation was examined. That is, in the tablet of Example 1, the disintegrant crospovidone was replaced with another disintegrant, and the tablets of the following Comparative Examples 5 to 11 (both containing 10% by mass of the disintegrant as in Example 1), The physical stability and elution characteristics were evaluated.
  • Example 7 As in Experiment 6, the disintegrant that can be used in this preparation was examined. That is, in the tablet of Example 13, the tablet of the following Comparative Examples 12 to 16 in which the disintegrant crospovidone was replaced with another disintegrant (both containing 10% by mass of the disintegrant as in Example 13), The physical stability (hardness) and elution characteristics were evaluated.
  • Example 13 100 parts by mass of anagliptin was granulated using an aqueous hydroxypropylcellulose solution (1.6 parts by mass as hydroxypropylcellulose). The obtained granular material was dried, 16 parts by mass of crospovidone (manufactured by BASF: Kollidon CL), 24 parts by mass of D-mannitol and 16 parts by mass of crystalline cellulose were added and mixed. Next, 2.4 parts by mass of magnesium stearate was added and mixed to obtain tableting granules. The obtained granules for tableting were tableted to 160 mg per tablet. The obtained tablet contains 100 mg of anagliptin and 16 mg of crospovidone per tablet, and the content per tablet is 62.5% by mass of anagliptin and 10% by mass of crospovidone, respectively.
  • Example 13 In Example 13, it replaced with 16 mass parts of crospovidone, and replaced with 16 mass parts of disintegrating agents shown in Table 10, and it manufactured similarly to Example 13.
  • the following five disintegrants are carboxymethyl cellulose (manufactured by Gotoku Pharmaceutical Co., Ltd .: NS-300), sodium carboxymethyl starch (manufactured by ROQUTTE: Glicolis), croscarmellose sodium (manufactured by FMC Biopolymer: Ac- Di-Sol), low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd .: L-HPC LH-21), and carmellose calcium (Gotoku Pharmaceutical Co., Ltd .: ECG-505) were used.
  • Example 14 to 17 The amount of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802) added and the mass of one tablet were set to the ratio shown in Table 11, and tablets were produced in the same manner as in Example 1.
  • Example 14 where the addition amount of crystalline cellulose was 5% by mass, the expected physical stability was not shown, and when the addition amount of crystalline cellulose was 40% by mass, the expected dissolution characteristics (15 minutes value 85% or more) were shown. There wasn't. From the above results, it was found that an appropriate content of crystalline cellulose was 7 to 37% by mass.
  • Example 9 In this tablet, an excipient that can be replaced with crystalline cellulose was examined. That is, the physical stability of the tablets of Comparative Examples 17 to 19 (containing 20% by mass of the crystalline cellulose substitute as in Example 1) in which the crystalline cellulose was replaced with the substitute in the tablet of Example 1. Evaluation and elution characteristics were evaluated.
  • Example 1 30 parts by mass of crystalline cellulose, as shown in Table 13, 30 parts by mass of lactose hydrate (DMV: lactose 200M), D-mannitol (Mitsubishi Corporation Foodtech Co., Ltd .: Man Knit-P) 30 parts by mass and anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry Co., Ltd .: anhydrous calcium hydrogen phosphate) were replaced with 30 parts by mass.
  • DMV lactose 200M
  • D-mannitol Mitsubishi Corporation Foodtech Co., Ltd .: Man Knit-P
  • anhydrous calcium hydrogen phosphate manufactured by Kyowa Chemical Industry Co., Ltd .: anhydrous calcium hydrogen phosphate
  • Example 18 In Example 1, the addition amount of crospovidone (BASF Corporation: Kollidon CL), crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802), magnesium stearate (Taihei Chemical Industry Co., Ltd.): The amount of magnesium stearate vegetable) and the mass of 1 tablet were set to the ratios shown in Table 14 and were produced in the same manner as in Example 1.
  • crospovidone BASF Corporation: Kollidon CL
  • crystalline cellulose Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802
  • magnesium stearate Teaihei Chemical Industry Co., Ltd.
  • Example 20 In Example 1, the addition amount of crospovidone (BASF Corporation: Kollidon CL), crystalline cellulose (Asahi Kasei Chemicals Corporation: Theolas KG-802), magnesium stearate (Taihei Chemical Industry Co., Ltd.): The amount of magnesium stearate vegetable) and the mass of 1 tablet were set to the ratios shown in Table 14 and were produced in the same manner as in Example 1.
  • crospovidone BASF Corporation: Kollidon CL
  • crystalline cellulose Asahi Kasei Chemicals Corporation: Theolas KG-802
  • magnesium stearate Teaihei Chemical Industry Co., Ltd.
  • Example 20 and 21 Tablets were produced in the same manner as in Example 1 at the blending ratios in Table 16.
  • Example 20 is an uncoated tablet part, and a film-coated tablet on which film coating is further performed is Example 21.
  • Examples 22 to 26 Using the uncoated tablet of Example 20 of Experiment 11, a film coating having the composition shown in Table 18 below was applied to each tablet.
  • Table 19 shows the test results. As can be seen from Table 19, the tablets of Examples 25 and 26 containing ferric oxides had very little color difference before and after storage under any conditions. On the other hand, Example 22 containing no colorant, Example 23 containing edible yellow No. 5 aluminum lake, and Example 24 containing edible yellow No. 5 had large color differences before and after storage. Moreover, in Examples 23 and 24 containing Food Yellow No. 5, etc., the color difference was larger than when no colorant was contained. From these results, it is considered that iron sesquioxides exhibited an effect of specifically preventing discoloration of tablets in tablets containing anagliptin. Therefore, a solid preparation containing anagliptin or a salt thereof and ferric sesquioxide is excellent in long-term storage stability.
  • Examples 27 to 29 Using the uncoated tablet of Example 20 of Experiment 11, film coating having the composition shown in Table 20 below was applied to each tablet to prepare film-coated tablets.
  • the results are shown in Table 21. As is clear from Table 21, it was found that any tablet containing iron sesquioxide is excellent in storage stability. From the results of the above experiments 12 and 13, we have achieved the invention described in (21) of the means for solving the problem of a solid preparation containing anagliptin or a salt thereof and iron sesquioxide. More specifically, the invention is a solid preparation having a film coating containing anagliptin or a salt thereof and further containing iron sesquioxide.

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Abstract

Les objectifs de la présente invention sont d'obtenir une préparation d'anagliptine dotée d'une stabilité chimique élevée de l'anagliptine, de caractéristiques d'élution rapide et/ou d'une stabilité physique supérieure de la préparation dans une préparation contenant de l'anagliptine, qui est un inhibiteur de dipeptidyl-peptidase IV, et une technique pour la produire. La préparation de la présente invention contient de l'anagliptine comme ingrédient actif, de la crospovidone comme désintégrant, de la cellulose cristalline comme véhicule, et un liant, et ne contient pas de plastifiant. Des comprimés sont produits au moyen d'une granulation en conditions humides dans le liant d'une partie ou de la totalité des composants contenus et de l'ingrédient actif, suivie d'un moulage par compression.
PCT/JP2013/076202 2012-09-27 2013-09-27 Préparation contenant de l'anagliptine WO2014051023A1 (fr)

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WO2019004452A1 (fr) * 2017-06-30 2019-01-03 興和株式会社 Composition pharmaceutique
WO2019004453A1 (fr) * 2017-06-30 2019-01-03 興和株式会社 Préparation pharmaceutique
US11319566B2 (en) 2017-04-14 2022-05-03 Capsugel Belgium Nv Process for making pullulan
US11576870B2 (en) 2017-04-14 2023-02-14 Capsugel Belgium Nv Pullulan capsules

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Publication number Priority date Publication date Assignee Title
US11319566B2 (en) 2017-04-14 2022-05-03 Capsugel Belgium Nv Process for making pullulan
US11576870B2 (en) 2017-04-14 2023-02-14 Capsugel Belgium Nv Pullulan capsules
US11878079B2 (en) 2017-04-14 2024-01-23 Capsugel Belgium Nv Pullulan capsules
WO2019004452A1 (fr) * 2017-06-30 2019-01-03 興和株式会社 Composition pharmaceutique
WO2019004453A1 (fr) * 2017-06-30 2019-01-03 興和株式会社 Préparation pharmaceutique
US11298340B2 (en) 2017-06-30 2022-04-12 Kowa Company, Ltd. Pharmaceutical composition
US11419855B2 (en) 2017-06-30 2022-08-23 Kowa Company, Ltd. Pharmaceutical preparation
US11730719B2 (en) 2017-06-30 2023-08-22 Kowa Company, Ltd. Pharmaceutical composition

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