WO2015012365A1 - Pharmaceutical preparation - Google Patents

Pharmaceutical preparation Download PDF

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Publication number
WO2015012365A1
WO2015012365A1 PCT/JP2014/069599 JP2014069599W WO2015012365A1 WO 2015012365 A1 WO2015012365 A1 WO 2015012365A1 JP 2014069599 W JP2014069599 W JP 2014069599W WO 2015012365 A1 WO2015012365 A1 WO 2015012365A1
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WIPO (PCT)
Prior art keywords
metformin
salt
inhibitor
dpp
pharmaceutical preparation
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PCT/JP2014/069599
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French (fr)
Japanese (ja)
Inventor
直也 落合
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株式会社 三和化学研究所
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Application filed by 株式会社 三和化学研究所 filed Critical 株式会社 三和化学研究所
Priority to JP2015528341A priority Critical patent/JP5922310B2/en
Publication of WO2015012365A1 publication Critical patent/WO2015012365A1/en

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Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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 relates to a pharmaceutical preparation containing a DPP-IV inhibitor and metformin, wherein the DPP-IV inhibitor in the preparation is chemically stabilized, and a preparation method thereof.
  • DPP-IV inhibitor and metformin are effective compounds for the treatment of diabetes, especially type 2 diabetes, and both are currently used in clinical practice and are often administered in combination.
  • a combination preparation containing a DPP-IV inhibitor and metformin as active ingredients has been developed, and an oral solid preparation has been adopted as the dosage form from the viewpoint of ingestion.
  • a method of producing a DPP-IV inhibitor-containing granule granulated with a solvent such as ethanol or isopropanol and a metformin-containing granule as a multilayer tablet is disclosed.
  • Patent Document 2 discloses a method of adding BHT or BHA as an antioxidant in order to ensure chemical stability when a DPP-IV inhibitor, which is an active ingredient, and metformin are blended. Has been. Further, in Patent Document 3, in order to ensure chemical stability when a DPP-IV inhibitor as an active ingredient and metformin are blended, a granule containing only each active ingredient is produced and then physically mixed. A method for reducing physical contact between both active ingredients by compression molding is disclosed. Furthermore, Patent Document 4 discloses a nucleophilic and / or basic drug as a stabilizer in order to ensure chemical stability when a DPP-IV inhibitor which is an active ingredient and metformin are blended. A method of adding L-arginine is disclosed.
  • cyclodextrin is often used as a stabilizer, but usually exhibits an effect by inclusion of a drug to be stabilized, and the molar ratio with the drug to be stabilized is 1: 1. In order to make it to the extent, there is a problem that the usage amount increases.
  • An example of the use of such cyclodextrin as a stabilizer is not for a DPP-IV inhibitor, but is disclosed in Patent Document 5, for example.
  • an object of the present invention is to provide a new chemical stabilization method for a DPP-IV inhibitor in a pharmaceutical preparation containing the DPP-IV inhibitor and metformin.
  • the main configuration of the present invention is as follows.
  • a DPP-IV inhibitor and metformin or a salt thereof as active ingredients, further containing a cyclic oligosaccharide, and the metformin or a salt thereof is granulated are A pharmaceutical preparation characterized in that it is mixed and granulated separately from the cyclic oligosaccharide).
  • the chemical stability of the pharmaceutical preparation is indicated by a maximum yield of a DPP-IV inhibitor degradation product of 0.2% or less after storage for 21 days at a temperature of 60 ° C. (1 ) To (13). (15) The pharmaceutical preparation according to any one of (1) to (14), wherein the DPP-IV inhibitor is anagliptin or a salt thereof.
  • a pharmaceutical preparation comprising a DPP-IV inhibitor and metformin or a salt thereof, in which the chemical stability of the DPP-IV inhibitor is ensured, can be provided.
  • the chemical stability of the DPP-IV inhibitor can be secured without using an organic solvent or an antioxidant harmful to the human body, which is advantageous from the viewpoint of safety.
  • the product of the present invention does not require a complicated manufacturing process, it is advantageous in manufacturing.
  • the DPP-IV inhibitor used in the present invention is not particularly limited, but anagliptin or a salt thereof, linagliptin or a salt thereof, vildagliptin or a salt thereof, sitagliptin or a salt thereof, teneligliptin or a salt thereof, alogliptin or a salt thereof And saxagliptin or a salt thereof.
  • anagliptin or a salt thereof, sitagliptin or a salt thereof, teneligliptin or a salt thereof, alogliptin or a salt thereof are preferable, and anagliptin or a salt thereof is particularly preferable.
  • anagliptin is expressed as “N- [2-( ⁇ 2-[(2S) -2-cyanopyrrolidin-1-yl] -2-oxoethyl ⁇ amino) -2-methylpropyl] -2-methylpyrazolo [1,5 -a] pyrimidine-6-carboxamide ", which can be produced with reference to Examples 1 and 2 of WO2004 / 067509.
  • linagliptin or a salt thereof in WO2004 / 018468 vildagliptin or a salt thereof in WO00 / 34241, sitagliptin or a salt thereof in WO2003 / 004498, teneligliptin or a salt thereof in WO02 / 14271, alogliptin or a salt thereof in JP2005263780, Saxagliptin or a salt thereof is described in WO01 / 068603, respectively.
  • metformin or a salt thereof is an antidiabetic drug that has been often used as a biguanide, and is preferably in the form of a pharmaceutically acceptable salt.
  • the compounding amount of the DPP-IV inhibitor in the pharmaceutical preparation of the present invention is usually 2 to 30% by mass, preferably 5 to 30% by mass, and more preferably 5 to 15% by mass with respect to the whole preparation. This is 12.5 mg to 200 mg, preferably 25 mg to 200 mg, more preferably 50 mg to 100 mg, when expressed in terms of the content in a single pharmaceutical preparation.
  • the amount of metformin or a salt thereof in a pharmaceutical preparation is usually 30 to 90% by mass, preferably 40 to 90% by mass, and more preferably 50 to 80% by mass of the entire preparation. This is 125 mg to 1,000 mg, preferably 250 mg to 500 mg, when expressed in the content of a single pharmaceutical preparation.
  • the blending ratio of the DPP-IV inhibitor and metformin or a salt thereof in a pharmaceutical preparation is usually 1:11 to 1: 1, preferably 1: 6 to 1: 2.
  • the compounding ratio of anagliptin or a salt thereof and metformin or a salt thereof in a pharmaceutical preparation is usually 1:10, 1: 5, or 2: 5. Become.
  • the cyclic oligosaccharide used in the present invention is a cyclic oligosaccharide having a cyclic structure in which D-glucose is bonded by an ⁇ 1-4 glucoside bond, that is, a cyclodextrin having 6 to 8 glucose bonded. It is.
  • a cyclic oligosaccharide ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin are preferable.
  • the cyclic oligosaccharide includes a cyclic oligosaccharide derivative.
  • Cyclic oligosaccharide derivatives include hydroxypropyl ⁇ -cyclodextrin, acetylated ⁇ -cyclodextrin, methylated ⁇ -cyclodextrin, monochlorotriazinylated ⁇ -cyclodextrin, dimethyl ⁇ -cyclodextrin, 2-hydroxyethyl ⁇ -cyclodextrin Examples include dextrin, 3-hydroxypropyl ⁇ -cyclodextrin, and trimethyl ⁇ -cyclodextrin.
  • the content rate of the cyclic oligosaccharide is low, and is usually 0.1% by mass or more and 25% by mass or less, preferably 0.2% by mass or more and 20% by mass or less, based on the total amount of active ingredients. Preferably they are 1 mass% or more and 15 mass% or less. If it is less than 0.1% by mass, the chemical stability of the DPP-IV inhibitor in the pharmaceutical preparation may be impaired. If it exceeds 25% by mass, the mass of the preparation increases and the size of the preparation increases. Inconvenience such as the above occurs, which is not preferable for commercialization.
  • metformin or a salt thereof it is usually 0.1% by mass to 35% by mass and preferably 0.2% by mass to 25% by mass.
  • metformin or a salt thereof it is usually 0.1% by mass to 35% by mass and preferably 0.2% by mass to 25% by mass.
  • the pharmaceutical preparation of the present invention is a preparation in which part or all of the ingredients are granulated by a dry processing method or a wet processing method. That is, at least metformin or a salt thereof is granulated. In this granulation, it is preferable to granulate metformin or a salt thereof separately from the DPP-IV inhibitor. That is, it is preferable that the DPP-IV inhibitor is not granulated or that metformin or a salt thereof and the DPP-IV inhibitor are granulated separately. Further, in the granulation of metformin or a salt thereof, it is preferable to granulate with the cyclic oligosaccharide.
  • Embodiments of granulating active ingredients are (1) mixing and granulating two active ingredients, (2) granulating metformin or a salt thereof and not granulating a DPP-IV inhibitor, (3 ) It is divided into three embodiments of granulating the DPP-IV inhibitor and metformin or a salt thereof separately. These can be further divided according to whether or not granulation is performed together with the cyclic oligosaccharide in each granulation. In the embodiment in which the two active ingredients of (1) are mixed and granulated, the cyclic oligosaccharide must be granulated together with the cyclic oligosaccharide in a situation where mixing and granulation tend to be unstable.
  • the subject of the present invention is to improve the chemical stability of the active ingredient DPP-IV inhibitor, but instead of adding a cyclic oligosaccharide as a stabilizer to the DPP-IV inhibitor.
  • cyclic oligosaccharide is added to and mixed with metformin or a salt thereof and granulated, it is also a surprising effect that cannot be predicted.
  • the pharmaceutical preparation of the present invention can be in various dosage forms, for example, provided as granules, fine granules, powders, capsules, or tablets.
  • the pharmaceutical preparation of the present invention is provided as a tablet, it is provided as a multilayer tablet such as a monolayer tablet, a bilayer tablet or a trilayer tablet, a dry tablet, or a film-coated tablet thereof.
  • a tablet is generally produced by granulating a part or all of the ingredients and then compression molding.
  • the granulation method is preferably a granulation by a wet processing method, that is, a wet granulation method.
  • the chemical stability of the DPP-IV inhibitor is the amount of the maximum degradation product of the DPP-IV inhibitor after storage for 21 days at a temperature of 60 ° C. Judge by (%).
  • the value of 0.20% or less is used as the standard for good chemical stability.
  • the numerical value is preferably 0.15% or less, more preferably 0.1% or less.
  • anagliptin was used as an active ingredient DPP-IV inhibitor.
  • the stability test of the preparations obtained in the examples and comparative examples was conducted by confirming the amount of each decomposition product produced after storing each test specimen for 21 days at a temperature of 60 ° C. This was done by evaluating the chemical stability of DPP-IV inhibitors by physical quantity. By this stability test, the effectiveness of the added stabilizer was determined.
  • the maximum degradation product amount is determined by measuring the DPP-IV inhibitor (anagliptin) and all degradation products derived from the DPP-IV inhibitor with a well-known analytical method (HPLC), and all the peak area values obtained. Was calculated by calculating the amount (%) of each decomposed product as an area percentage of the peak area value of each confirmed decomposed product.
  • Test Example 1 Necessity of granulation of metformin and standard setting of chemical stability of DPP-IV inhibitor
  • all ingredients other than lubricants that were not granulated were weighed.
  • a lubricant was mixed so that the blending ratio shown in Table 1 was obtained to obtain a tableting powder.
  • the blending ratio is the same as that in Example 25 described later.
  • the tableting powder was attempted to be tableted using a tableting machine VIRG (manufactured by Kikusui Seisakusho Co., Ltd.), but due to the lack of fluidity of the tableting powder, the tableting powder was pressed from the hopper.
  • the tablet was not supplied and could not be tableted. As can be seen from the test, it is understood that granulation of metformin or a salt thereof with a high content is essential in order to produce a compounding agent of anagliptin and metformin or a salt thereof.
  • the degradation product amount (%) of anagliptin was measured and found to be 0.22%. Therefore, an anagliptin degradation product amount of 0.2% or less was set as a criterion that the chemical stability of the DPP-IV inhibitor as a preparation was particularly good.
  • Test Example 2 Identification of Stabilizer Having Anagliptin Decomposition Suppressing Effect
  • the stabilizer shown in Table 2 was used to examine the effect of DPP-IV inhibitors on chemical stability.
  • the preparations of Example 1 and Comparative Examples 1 to 6 were filled in glass bottles (about 2 g in a 20 mL bottle) immediately after preparation and sealed as follows. Such a test specimen was subjected to a stability test, and the degradation product amount (%) of anagliptin was measured. In the following tests, when the ingredients are granulated and used, the fact is clearly stated, and those without such description are used without granulation.
  • Example 1 Each component was mixed according to the blending ratio of Example 1 in Table 2, purified water was added, wet granulation was performed, and drying was performed to prepare a granular preparation.
  • Comparative Example 1 Production was carried out in the same manner as in Example 1 except for the stabilizer of Example 1.
  • Comparative Examples 2 to 6 The same procedure as in Example 1 was performed using the stabilizers described in Table 2 instead of the stabilizer in Example 1.
  • Example 3 shows the results of stability tests of Example 1 and Comparative Examples 1 to 6.
  • Example 1 using ⁇ -cyclodextrin which is a cyclic oligosaccharide as a stabilizer
  • the maximum degradation product derived from anagliptin is 0.26% or less at 0.16%
  • Comparative Example 1 containing no stabilizer the maximum degradation product derived from anagliptin was 0.42%.
  • Test Example 3 Verification of anagliptin degradation inhibitory effect when stabilizer is granulated with all active ingredients DPP-IV inhibition when granulated together with all active ingredients for cyclic oligosaccharide as a stabilizer used in the present invention The effect of suppressing the degradation of the drug was examined together with the compounding ratio of the cyclic oligosaccharide.
  • Examples 1 to 4 were prepared as follows, and immediately filled into a glass bottle (about 1 g in a 20 mL bottle) and sealed. Such a test specimen was subjected to a stability test, and the degradation product amount (%) of anagliptin was measured.
  • Example 1 Already described in Test Example 2 (Examples 2 to 4) Each component was mixed according to the blending ratio in Table 4 and manufactured in the same manner as in Example 1.
  • Test Example 4 Verification of the anagliptin degradation inhibitory effect when the stabilizer was granulated with metformin hydrochloride
  • the cyclic oligosaccharide which is a stabilizer used in the present invention, was granulated with metformin hydrochloride which is one of the active ingredients.
  • the effect of inhibiting the degradation of anagliptin in some cases was examined together with the molecular weight and blending ratio of the cyclic oligosaccharide.
  • Examples 5 to 19 were prepared as follows and immediately filled into a glass bottle (about 1 g in a 20 mL bottle) and sealed. Such a test specimen was subjected to a stability test, and the degradation product amount (%) of anagliptin was measured.
  • Example 5 Metformin hydrochloride and ⁇ -cyclodextrin, which is a cyclic oligosaccharide, were mixed according to the blending ratios shown in Table 6, purified water was added and wet granulation was performed, followed by drying to obtain a granulated product. Anagliptin was mixed with the obtained granulated product according to the blending ratio shown in Table 6 to prepare a preparation which is a granule / powder mixture. (Example 11) Purified water was added to metformin hydrochloride and wet granulation was performed, followed by drying to obtain a granulated product.
  • the resulting granulated product was mixed with cyclic oligosaccharides ⁇ -cyclodextrin and anagliptin in accordance with the blending ratios shown in Table 6 to prepare a formulation as a granule / powder mixture.
  • Metformin hydrochloride and ⁇ -cyclodextrin, which is a cyclic oligosaccharide were mixed according to the blending ratios shown in Table 7, purified water was added and wet granulation was performed, followed by drying to obtain a granulated product.
  • Anagliptin was mixed with the obtained granulated material according to the blending ratio shown in Table 7 to prepare a preparation which is a granule / powder mixture.
  • Example 16 to 19 Metformin hydrochloride and cyclic oligosaccharide ⁇ -cyclodextrin were mixed in accordance with the blending ratios shown in Table 8, purified water was added and wet granulation was performed, followed by drying to obtain a granulated product. Anagliptin was mixed with the obtained granulated material according to the blending ratio shown in Table 8 to prepare a preparation which is a granule / powder mixture.
  • Example 5 which is an extremely low dose of ⁇ -cyclodextrin of 0.17%, the amount of the maximum degradation product derived from anagliptin is less than 0.1%, and the effect of suppressing the degradation of anagliptin is at a level that can be said to be remarkable.
  • the cyclic oligosaccharide that is a stabilizer is effective even when added without granulation, but by granulating with metformin hydrochloride, a DPPIV inhibitor It was found that the effect of inhibiting the degradation of anagliptin, which is an extremely low dose of ⁇ -cyclodextrin of 0.17%, the amount of the maximum degradation product derived from anagliptin is less than 0.1%, and the effect of suppressing the degradation of anagliptin is at a level that can be said to be remarkable.
  • the cyclic oligosaccharide that is a stabilizer is effective even when added without granulation, but by granulating with metformin hydroch
  • Test Example 5 Influence of Anagliptin and Metformin Hydrochloride on the Effect of Stabilizer Effect of Anagliptin and Metformin Hydrochloride on the Effect of Inhibiting Degradation of Anagliptin by Stabilizer ⁇ -Cyclodextrin was examined.
  • Examples 7 and 8 and Examples 20 to 24 were filled in glass bottles (about 1 g in a 20 mL bottle) immediately after preparation and sealed as follows. Such a test specimen was subjected to a stability test, and the amount (%) of an anagliptin degradation product was measured.
  • Examples 7 and 8 Already described in Test Example 4 (Examples 20 to 24)
  • metformin hydrochloride and ⁇ -cyclodextrin were mixed according to the blending ratio in Table 10, purified water was added and wet granulation was performed, followed by drying to obtain a granulated product.
  • Anagliptin was mixed with the obtained granulated material according to the blending ratio shown in Table 10 to prepare a preparation as a granule / powder mixture.
  • Test Example 6 Verification of Anagliptin Decomposition Suppressing Effect of Stabilizer in Tablet The effect of the stabilizer in the present invention to suppress the degradation of anagliptin in the tablet was verified.
  • Examples 25 and 26 were filled in glass bottles (2 tablets in a 20 mL bottle) immediately after preparation and sealed as follows. Such a test specimen was subjected to a stability test, and the amount (%) of an anagliptin degradation product was measured. (Examples 25 and 26) Metformin hydrochloride and a stabilizer were mixed according to the blending ratio shown in Table 12, purified water was added and wet granulation was performed, followed by drying to obtain a granulated product.
  • the diameter is 11.5 mm and the pressure is about 10 kN with a (R15) circular ridge. Compressed to obtain tablets containing 100 mg anagliptin and 500 mg metformin hydrochloride per tablet.

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Abstract

Provided is a pharmaceutical preparation which comprises a DPP-IV inhibitor and metformin and in which the DPP-IV inhibitor therein is chemically stabilized. A pharmaceutical preparation which comprises a DPP-IV inhibitor and metformin or a salt thereof as active ingredients and, in addition, a cyclic oligosaccharide, characterized in that the aforesaid metformin or a salt thereof is granulated (excluding a case wherein the DPP-IV inhibitor and metformin or a salt thereof are mixed and granulated together separately from the cyclic oligosaccharide).

Description

医薬製剤Pharmaceutical formulation
　本発明は、DPP-IV阻害薬及びメトホルミンを含み、当該製剤中のDPP-IV阻害薬が化学的に安定化された医薬製剤、及びその調整方法に関する。 The present invention relates to a pharmaceutical preparation containing a DPP-IV inhibitor and metformin, wherein the DPP-IV inhibitor in the preparation is chemically stabilized, and a preparation method thereof.
　DPP-IV阻害薬及びメトホルミンは、糖尿病、とりわけ２型糖尿病の治療に有効な化合物であり、現在、共に臨床現場にて利用され、しばしば併用で投与されている。また、近年、DPP-IV阻害薬とメトホルミンとを活性成分として含む配合剤が開発されており、その剤形は、服用性の観点から経口固形製剤が採用されている。 DPP-IV inhibitor and metformin are effective compounds for the treatment of diabetes, especially type 2 diabetes, and both are currently used in clinical practice and are often administered in combination. In recent years, a combination preparation containing a DPP-IV inhibitor and metformin as active ingredients has been developed, and an oral solid preparation has been adopted as the dosage form from the viewpoint of ingestion.
　一方、DPP-IV阻害薬とメトホルミンの両化合物を一つの製剤中に配合した医薬製剤（配合剤）では、活性成分の一つであるDPP-IV阻害薬の化学的安定性が低下し、分解生成物を生じることが報告されている。例えば、特許文献１では、DPP-IV阻害薬の水分に対する感受性に起因する化学的な不安定化が問題視されており、活性成分であるDPP-IV阻害薬とメトホルミンとを配合した際の化学的安定性を確保するために、エタノール、イソプロパノール等の溶媒にて造粒したDPP-IV阻害薬含有顆粒と、メトホルミン含有顆粒を多層錠として製する方法が開示されている。 On the other hand, in a pharmaceutical preparation (combination drug) in which both a DPP-IV inhibitor and metformin are combined in one preparation, the chemical stability of the DPP-IV inhibitor, which is one of the active ingredients, is reduced and decomposed It is reported to produce a product. For example, in Patent Document 1, chemical destabilization due to the sensitivity of a DPP-IV inhibitor to moisture is regarded as a problem, and the chemistry when an active ingredient DPP-IV inhibitor and metformin are combined is considered as a problem. In order to ensure physical stability, a method of producing a DPP-IV inhibitor-containing granule granulated with a solvent such as ethanol or isopropanol and a metformin-containing granule as a multilayer tablet is disclosed.
　他にも、特許文献２には、活性成分であるDPP-IV阻害薬とメトホルミンとを配合した際の化学的安定性を確保するために、抗酸化剤としてBHT若しくはBHAを添加する方法が開示されている。また、特許文献３には、活性成分であるDPP-IV阻害薬とメトホルミンとを配合した際の化学的安定性を確保するために、各活性成分のみを含む顆粒を製した後に、物理混合し圧縮成型することで、両活性成分の物理的接触を軽減する方法が開示されている。更に、特許文献４には、活性成分であるDPP-IV阻害薬とメトホルミンとを配合した際の化学的安定性を確保するために、安定化剤として求核性及び／又は塩基性薬剤であるL-アルギニンを添加する方法が開示されている。 In addition, Patent Document 2 discloses a method of adding BHT or BHA as an antioxidant in order to ensure chemical stability when a DPP-IV inhibitor, which is an active ingredient, and metformin are blended. Has been. Further, in Patent Document 3, in order to ensure chemical stability when a DPP-IV inhibitor as an active ingredient and metformin are blended, a granule containing only each active ingredient is produced and then physically mixed. A method for reducing physical contact between both active ingredients by compression molding is disclosed. Furthermore, Patent Document 4 discloses a nucleophilic and / or basic drug as a stabilizer in order to ensure chemical stability when a DPP-IV inhibitor which is an active ingredient and metformin are blended. A method of adding L-arginine is disclosed.
　一方、シクロデキストリンは、安定化剤としてよく使用されるものであるが、通常、安定化したい薬物を包接することにより効果を発揮するものであり、安定化したい薬物とのモル比を１：１程度にするため、使用量が多くなるという問題を抱えている。このようなシクロデキストリンの安定化剤としての使用例は、DPP-IV阻害薬に対するものではないが、例えば、特許文献５である。 On the other hand, cyclodextrin is often used as a stabilizer, but usually exhibits an effect by inclusion of a drug to be stabilized, and the molar ratio with the drug to be stabilized is 1: 1. In order to make it to the extent, there is a problem that the usage amount increases. An example of the use of such cyclodextrin as a stabilizer is not for a DPP-IV inhibitor, but is disclosed in Patent Document 5, for example.
特表２００９－５１００６８Special table 2009-510068 特表２００９－５１９９３４Special table 2009-519934 特表２０１０－５３３６４３Special table 2010-533643 特表２０１１－５１６４５６Special table 2011-516456 特表２００３－５１７４３２Special table 2003-517432
　以上のように、従来技術においても、DPP-IV阻害薬とメトホルミンとを含む医薬製剤において、DPP-IV阻害薬の製剤中における化学的安定性を確保するために、種々の安定化手法を開示しているが、その安定化手法は必ずしも有用とは言い難い。従って、本発明は、DPP-IV阻害薬とメトホルミンとを含む医薬製剤中におけるDPP-IV阻害薬の新たな化学的安定化手法を提供することを目的とする。 As described above, even in the prior art, various stabilization methods are disclosed in pharmaceutical preparations containing DPP-IV inhibitors and metformin in order to ensure chemical stability in the preparations of DPP-IV inhibitors. However, the stabilization method is not necessarily useful. Accordingly, an object of the present invention is to provide a new chemical stabilization method for a DPP-IV inhibitor in a pharmaceutical preparation containing the DPP-IV inhibitor and metformin.
　上記問題に鑑み、本発明者らは、化学的に安定化されたDPP-IV阻害薬とメトホルミンとを含む医薬製剤について鋭意検討した。まず、含量の多いメトホルミンは、造粒しないと、製剤化することが難しいことが判明した。また、安定化剤としては、環状オリゴ糖に着目した。環状オリゴ糖、すなわちシクロデキストリンは、その包接能により薬物の安定性を改善することが知られているが、本発明者らは、包接が期待できないような少量の環状オリゴ糖を添加し、造粒と組み合わせて安定性を検討した。その結果、そのような少量の環状オリゴ糖により、DPP-IV阻害薬の化学的安定性が改善することを見出し、本発明を完成させた。本発明においては、更に驚くべきことに、安定化したいDPP-IV阻害薬ではなく、メトホルミンを環状オリゴ糖とともに造粒することで、特に優れた効果を得ることができた。 In view of the above problems, the present inventors have intensively studied a pharmaceutical preparation containing a chemically stabilized DPP-IV inhibitor and metformin. First, it was found that metformin with a high content is difficult to formulate unless it is granulated. As a stabilizer, attention was paid to cyclic oligosaccharides. Cyclic oligosaccharides, i.e. cyclodextrins, are known to improve drug stability due to their inclusion ability, but we have added a small amount of cyclic oligosaccharides that are not expected to be included. The stability was examined in combination with granulation. As a result, it was found that such a small amount of cyclic oligosaccharide improves the chemical stability of the DPP-IV inhibitor, and the present invention has been completed. Surprisingly, in the present invention, it was possible to obtain a particularly excellent effect by granulating metformin together with a cyclic oligosaccharide rather than a DPP-IV inhibitor to be stabilized.
　即ち、本発明の主な構成は次のとおりである。
（１）DPP-IV阻害薬及びメトホルミン又はその塩を有効成分として含み、更に環状オリゴ糖を含み、前記メトホルミン又はその塩が造粒されている（DPP-IV阻害薬とメトホルミン又はその塩とが環状オリゴ糖とは別に混合造粒されている場合を除く）ことを特徴とする、医薬製剤。
（２）前記メトホルミン又はその塩が前記環状オリゴ糖とともに造粒されている、（１）に記載の医薬製剤。
（３）前記メトホルミン又はその塩が前記DPP-IV阻害薬とは分離して造粒されている、（１）又は（２）に記載の医薬製剤。
（４）前記造粒が湿式造粒である、（１）～（３）のいずれかに記載の医薬製剤。
（５）前記環状オリゴ糖が、α-シクロデキストリン、β-シクロデキストリン、及びγ-シクロデキストリンからなる群から選択される１種以上である、（１）～（４）のいずれかに記載の医薬製剤。 That is, the main configuration of the present invention is as follows.
(1) A DPP-IV inhibitor and metformin or a salt thereof as active ingredients, further containing a cyclic oligosaccharide, and the metformin or a salt thereof is granulated (a DPP-IV inhibitor and metformin or a salt thereof are A pharmaceutical preparation characterized in that it is mixed and granulated separately from the cyclic oligosaccharide).
(2) The pharmaceutical preparation according to (1), wherein the metformin or a salt thereof is granulated together with the cyclic oligosaccharide.
(3) The pharmaceutical preparation according to (1) or (2), wherein the metformin or a salt thereof is granulated separately from the DPP-IV inhibitor.
(4) The pharmaceutical preparation according to any one of (1) to (3), wherein the granulation is wet granulation.
(5) The cyclic oligosaccharide according to any one of (1) to (4), wherein the cyclic oligosaccharide is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. Pharmaceutical formulation.
（６）前記DPP-IV阻害薬の配合割合が、製剤全体に対し５～３０質量％である、（１）～（５）のいずれかに記載の医薬製剤。
（７）前記メトホルミン又はその塩の配合割合が、製剤全体に対し４０～９０質量％である、（１）～（６）のいずれかに記載の医薬製剤。
（８）前記DPP-IV阻害薬と前記メトホルミン又はその塩の配合比率が、１：１１～１：１である、（１）～（７）のいずれかに記載の医薬製剤。
（９）前記DPP-IV阻害薬と前記メトホルミン又はその塩の配合比率が、１：６～１：２である、（８）に記載の医薬製剤。
（１０）前記環状オリゴ糖の配合割合が、有効成分総量に対し０．１～２５質量％である、（１）～（９）のいずれかに記載の医薬製剤。 (6) The pharmaceutical preparation according to any one of (1) to (5), wherein the blending ratio of the DPP-IV inhibitor is 5 to 30% by mass with respect to the whole preparation.
(7) The pharmaceutical preparation according to any one of (1) to (6), wherein the compounding ratio of metformin or a salt thereof is 40 to 90% by mass with respect to the whole preparation.
(8) The pharmaceutical preparation according to any one of (1) to (7), wherein the blending ratio of the DPP-IV inhibitor and metformin or a salt thereof is 1:11 to 1: 1.
(9) The pharmaceutical preparation according to (8), wherein the blending ratio of the DPP-IV inhibitor and metformin or a salt thereof is 1: 6 to 1: 2.
(10) The pharmaceutical preparation according to any one of (1) to (9), wherein the compounding ratio of the cyclic oligosaccharide is 0.1 to 25% by mass with respect to the total amount of active ingredients.
（１１）前記環状オリゴ糖の配合割合が、前記メトホルミン又はその塩に対し０．１～３５質量％である、（１）～（１０）のいずれかに記載の医薬製剤。
（１２）前記環状オリゴ糖の配合割合が、前記メトホルミン又はその塩に対し１～２５質量％である、（１１）に記載の医薬製剤。
（１３）前記医薬製剤の製剤形態が、顆粒剤、細粒剤、散剤、カプセル剤、及び錠剤からなる群から選択される、（１）～（１２）のいずれかに記載の医薬製剤。
（１４）前記医薬製剤の化学的安定性が、温度60℃の条件下で21日間保管した後の、DPP-IV阻害薬の最大分解生成物の生成量が0.2％以下で示される、（１）～（１３）のいずれかに記載の医薬製剤。
（１５）前記DPP-IV阻害薬がアナグリプチン又はその塩である、（１）～（１４）のいずれかに記載の医薬製剤。 (11) The pharmaceutical preparation according to any one of (1) to (10), wherein a blending ratio of the cyclic oligosaccharide is 0.1 to 35% by mass with respect to the metformin or a salt thereof.
(12) The pharmaceutical preparation according to (11), wherein a blending ratio of the cyclic oligosaccharide is 1 to 25% by mass with respect to the metformin or a salt thereof.
(13) The pharmaceutical preparation according to any one of (1) to (12), wherein the preparation form of the pharmaceutical preparation is selected from the group consisting of granules, fine granules, powders, capsules, and tablets.
(14) The chemical stability of the pharmaceutical preparation is indicated by a maximum yield of a DPP-IV inhibitor degradation product of 0.2% or less after storage for 21 days at a temperature of 60 ° C. (1 ) To (13).
(15) The pharmaceutical preparation according to any one of (1) to (14), wherein the DPP-IV inhibitor is anagliptin or a salt thereof.
　本発明によれば、DPP-IV阻害薬の化学的安定性が確保された、DPP-IV阻害薬とメトホルミン又はその塩とを含む医薬製剤を提供できる。また、本発明では、有機溶媒や人体に有害な抗酸化剤を使用しなくても、DPP-IV阻害薬の化学的安定性を確保でき、安全性の観点から有利である。更に、本発明品は、煩雑な製造工程を要さないため、製造の上でも有利である。 According to the present invention, a pharmaceutical preparation comprising a DPP-IV inhibitor and metformin or a salt thereof, in which the chemical stability of the DPP-IV inhibitor is ensured, can be provided. In the present invention, the chemical stability of the DPP-IV inhibitor can be secured without using an organic solvent or an antioxidant harmful to the human body, which is advantageous from the viewpoint of safety. Furthermore, since the product of the present invention does not require a complicated manufacturing process, it is advantageous in manufacturing.
　以下に、本発明を更に詳細に説明する。本発明で用いられるDPP-IV阻害薬は、特に限定されるものではないが、アナグリプチン又はその塩、リナグリプチン又はその塩、ビルダグリプチン又はその塩、シタグリプチン又はその塩、テネリグリプチン又はその塩、アログリプチン又はその塩、及びサクサグリプチン又はその塩が挙げられる。なかでも、アナグリプチン又はその塩、シタグリプチン又はその塩、テネリグリプチン又はその塩、アログリプチン又はその塩が好ましく、とりわけ、アナグリプチン又はその塩が好適である。尚、アナグリプチンは、「N-[2-({2-[(2S)-2-シアノピロリジン-1-イル]-2-オキソエチル}アミノ)-2-メチルプロピル]-2-メチルピラゾロ[1,5-a]ピリミジン-6-カルボキサミド」であり、WO2004/067509の実施例１及び２を参考に製造することができる。また、リナグリプチン又はその塩はWO2004/018468に、ビルダグリプチン又はその塩はWO00/34241に、シタグリプチン又はその塩はWO2003/004498に、テネリグリプチン又はその塩はWO02/14271に、アログリプチン又はその塩はJP2005263780に、サクサグリプチン又はその塩はWO01/068603に、それぞれ記載されている。一方、メトホルミン又はその塩は、ビグアナイド剤の一つとして、昔からよく使用されている糖尿病治療薬であり、好ましくは、薬学的に許容される塩の形態のものである。 Hereinafter, the present invention will be described in more detail. The DPP-IV inhibitor used in the present invention is not particularly limited, but anagliptin or a salt thereof, linagliptin or a salt thereof, vildagliptin or a salt thereof, sitagliptin or a salt thereof, teneligliptin or a salt thereof, alogliptin or a salt thereof And saxagliptin or a salt thereof. Among these, anagliptin or a salt thereof, sitagliptin or a salt thereof, teneligliptin or a salt thereof, alogliptin or a salt thereof are preferable, and anagliptin or a salt thereof is particularly preferable. In addition, anagliptin is expressed as “N- [2-({2-[(2S) -2-cyanopyrrolidin-1-yl] -2-oxoethyl} amino) -2-methylpropyl] -2-methylpyrazolo [1,5 -a] pyrimidine-6-carboxamide ", which can be produced with reference to Examples 1 and 2 of WO2004 / 067509. Also, linagliptin or a salt thereof in WO2004 / 018468, vildagliptin or a salt thereof in WO00 / 34241, sitagliptin or a salt thereof in WO2003 / 004498, teneligliptin or a salt thereof in WO02 / 14271, alogliptin or a salt thereof in JP2005263780, Saxagliptin or a salt thereof is described in WO01 / 068603, respectively. On the other hand, metformin or a salt thereof is an antidiabetic drug that has been often used as a biguanide, and is preferably in the form of a pharmaceutically acceptable salt.
　本発明の医薬製剤中の前記DPP-IV阻害薬の配合量は、通常、製剤全体の2～30質量％であり、好ましくは5～30質量％、更に好ましくは5～15質量％である。これは、1回分の医薬製剤中の含有量で表すと、12.5mg～200mgであり、好ましくは25mg～200mgであり、更に好ましくは50mg～100mgである。また、前記メトホルミン又はその塩の医薬製剤中の配合量は、通常、製剤全体の30～90質量％であり、好ましくは40～90質量％、更に好ましくは50～80質量％である。これは、1回分の医薬製剤中の含有量で表すと、125mg～1,000mgであり、好ましくは250mg～500mgである。また、前記DPP-IV阻害薬とメトホルミン又はその塩の医薬製剤中の配合比率は、通常1：11～1：1であり、好ましくは1：6～1：2である。DPP-IV阻害薬として、アナグリプチン又はその塩を使用する場合、アナグリプチン又はその塩とメトホルミン又はその塩との医薬製剤中の配合比率は、通常、1：10、1：5、又は2：5となる。 The compounding amount of the DPP-IV inhibitor in the pharmaceutical preparation of the present invention is usually 2 to 30% by mass, preferably 5 to 30% by mass, and more preferably 5 to 15% by mass with respect to the whole preparation. This is 12.5 mg to 200 mg, preferably 25 mg to 200 mg, more preferably 50 mg to 100 mg, when expressed in terms of the content in a single pharmaceutical preparation. In addition, the amount of metformin or a salt thereof in a pharmaceutical preparation is usually 30 to 90% by mass, preferably 40 to 90% by mass, and more preferably 50 to 80% by mass of the entire preparation. This is 125 mg to 1,000 mg, preferably 250 mg to 500 mg, when expressed in the content of a single pharmaceutical preparation. In addition, the blending ratio of the DPP-IV inhibitor and metformin or a salt thereof in a pharmaceutical preparation is usually 1:11 to 1: 1, preferably 1: 6 to 1: 2. When anagliptin or a salt thereof is used as a DPP-IV inhibitor, the compounding ratio of anagliptin or a salt thereof and metformin or a salt thereof in a pharmaceutical preparation is usually 1:10, 1: 5, or 2: 5. Become.
　本発明で用いられる環状オリゴ糖とは、D-グルコースがα１-4グルコシド結合によって結合し、環状構造をとった環状オリゴ糖、すなわち、シクロデキストリンであり、グルコースが６個から８個結合したものである。このような環状オリゴ糖としては、α-シクロデキストリン、β-シクロデキストリン、及びγ-シクロデキストリンが好ましい。当該環状オリゴ糖には、環状オリゴ糖誘導体を含む。環状オリゴ糖誘導体としては、ヒドロキシプロピルβ-シクロデキストリン、アセチル化β-シクロデキストリン、メチル化β-シクロデキストリン、モノクロロトリアジノ化β-シクロデキストリン、ジメチルβ-シクロデキストリン、2-ヒドロキシエチルβ-シクロデキストリン、3-ヒドロキシプロピルβ-シクロデキストリン、及びトリメチルβ-シクロデキストリン等が挙げられる。 The cyclic oligosaccharide used in the present invention is a cyclic oligosaccharide having a cyclic structure in which D-glucose is bonded by an α1-4 glucoside bond, that is, a cyclodextrin having 6 to 8 glucose bonded. It is. As such a cyclic oligosaccharide, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin are preferable. The cyclic oligosaccharide includes a cyclic oligosaccharide derivative. Cyclic oligosaccharide derivatives include hydroxypropyl β-cyclodextrin, acetylated β-cyclodextrin, methylated β-cyclodextrin, monochlorotriazinylated β-cyclodextrin, dimethyl β-cyclodextrin, 2-hydroxyethyl β-cyclodextrin Examples include dextrin, 3-hydroxypropyl β-cyclodextrin, and trimethyl β-cyclodextrin.
　本発明の特徴の一つは、前記環状オリゴ糖の含有率が低いことであり、有効成分総量に対し通常0.1質量％以上25質量％以下で、好ましくは0.2質量％以上20質量％以下、更に好ましくは1質量％以上15質量％以下である。0.1質量％を下回ると、医薬製剤中のDPP-IV阻害薬の化学的な安定性が損なわれる可能性があり、25質量％を超えると、製剤の質量が増加し、製剤のサイズが大きくなる等の不都合が発生し、製品化する上で好ましくない。また、メトホルミン又はその塩に対しては、通常0.1質量％以上35質量％以下で、0.2質量％以上25質量％以下が好ましい。このような少量の環状オリゴ糖では、通常、有効成分の包接は期待できないため、DPP-IV阻害薬の化学的安定性の改善は期待できないのであるが、驚くべきことに、本発明においては、このような少量の環状オリゴ糖により、DPP-IV阻害薬の化学的安定性の改善を達成している。 One of the characteristics of the present invention is that the content rate of the cyclic oligosaccharide is low, and is usually 0.1% by mass or more and 25% by mass or less, preferably 0.2% by mass or more and 20% by mass or less, based on the total amount of active ingredients. Preferably they are 1 mass% or more and 15 mass% or less. If it is less than 0.1% by mass, the chemical stability of the DPP-IV inhibitor in the pharmaceutical preparation may be impaired. If it exceeds 25% by mass, the mass of the preparation increases and the size of the preparation increases. Inconvenience such as the above occurs, which is not preferable for commercialization. Moreover, with respect to metformin or a salt thereof, it is usually 0.1% by mass to 35% by mass and preferably 0.2% by mass to 25% by mass. With such a small amount of cyclic oligosaccharide, inclusion of an active ingredient cannot normally be expected, so improvement in the chemical stability of a DPP-IV inhibitor cannot be expected. With such a small amount of cyclic oligosaccharide, the chemical stability of the DPP-IV inhibitor is improved.
　本発明の医薬製剤は、成分の一部又は全部が乾式処理法又は湿式処理法にて造粒された製剤である。すなわち、少なくともメトホルミン又はその塩が造粒されている。この造粒においては、メトホルミン又はその塩をDPP-IV阻害薬と分離して造粒するのが好ましい。すなわち、DPP-IV阻害薬を造粒しない形態とするか、メトホルミン又はその塩とDPP-IV阻害薬とを別々に造粒する形態とすることが好ましい。また、メトホルミン又はその塩の造粒においては、前記環状オリゴ糖とともに造粒するのが好ましい。有効成分の造粒についての実施形態は、(1)2種の有効成分を混合して造粒する、(2)メトホルミン又はその塩を造粒しDPP-IV阻害薬を造粒しない、(3)DPP-IV阻害薬とメトホルミン又はその塩とを別々に造粒する　の３つの実施形態に分けられる。これらは更に、それぞれの造粒において、環状オリゴ糖とともに造粒するかどうかで、分けることができる。尚、前記(1)の2種の有効成分を混合して造粒する実施形態においては、混合して造粒するという不安定になりやすい状況下で環状オリゴ糖とともに造粒しないと、環状オリゴ糖が2種の有効成分と分離して存在することになり、環状オリゴ糖の効果が十分に発揮できないため、2種の有効成分を混合して造粒する場合は、環状オリゴ糖とともに造粒する実施形態に限定される。すなわち、DPP-IV阻害薬とメトホルミン又はその塩とが環状オリゴ糖とは別に混合造粒されている場合を除く。これら実施形態の中で特に好ましいのは、メトホルミン又はその塩をDPP-IV阻害薬と分離した上で環状オリゴ糖とともに造粒する実施形態であり、前記(2)及び(3)の実施形態でメトホルミン又はその塩を環状オリゴ糖とともに造粒した実施形態に該当する。ただし、医薬製剤の製造工程の煩雑さを考慮すると、前記(2)の実施形態が最も好ましいと考えられる。 The pharmaceutical preparation of the present invention is a preparation in which part or all of the ingredients are granulated by a dry processing method or a wet processing method. That is, at least metformin or a salt thereof is granulated. In this granulation, it is preferable to granulate metformin or a salt thereof separately from the DPP-IV inhibitor. That is, it is preferable that the DPP-IV inhibitor is not granulated or that metformin or a salt thereof and the DPP-IV inhibitor are granulated separately. Further, in the granulation of metformin or a salt thereof, it is preferable to granulate with the cyclic oligosaccharide. Embodiments of granulating active ingredients are (1) mixing and granulating two active ingredients, (2) granulating metformin or a salt thereof and not granulating a DPP-IV inhibitor, (3 ) It is divided into three embodiments of granulating the DPP-IV inhibitor and metformin or a salt thereof separately. These can be further divided according to whether or not granulation is performed together with the cyclic oligosaccharide in each granulation. In the embodiment in which the two active ingredients of (1) are mixed and granulated, the cyclic oligosaccharide must be granulated together with the cyclic oligosaccharide in a situation where mixing and granulation tend to be unstable. Since the sugar exists separately from the two active ingredients and the effect of the cyclic oligosaccharide cannot be fully exerted, granulate together with the cyclic oligosaccharide when granulating the two active ingredients. It is limited to embodiment to do. That is, the case where the DPP-IV inhibitor and metformin or a salt thereof are mixed and granulated separately from the cyclic oligosaccharide is excluded. Particularly preferred among these embodiments is an embodiment in which metformin or a salt thereof is separated from a DPP-IV inhibitor and granulated with a cyclic oligosaccharide. In the embodiments (2) and (3) above, This corresponds to an embodiment in which metformin or a salt thereof is granulated with a cyclic oligosaccharide. However, considering the complexity of the manufacturing process of the pharmaceutical preparation, the embodiment (2) is considered to be most preferable.
　尚、ここでもまた、本願発明の予測できない効果が見出される。すなわち、本願発明の課題は、有効成分であるDPP-IV阻害薬の化学的安定性の改善であるが、当該DPP-IV阻害薬に安定化剤である環状オリゴ糖を添加するのではなく、メトホルミン又はその塩に環状オリゴ糖を添加混合し造粒する実施形態において、特に優れた効果を発揮することもまた、予測できない驚くべき効果である。 In this case, too, the unpredictable effects of the present invention are found. That is, the subject of the present invention is to improve the chemical stability of the active ingredient DPP-IV inhibitor, but instead of adding a cyclic oligosaccharide as a stabilizer to the DPP-IV inhibitor. In the embodiment in which cyclic oligosaccharide is added to and mixed with metformin or a salt thereof and granulated, it is also a surprising effect that cannot be predicted.
　本発明の医薬製剤は、様々な剤型とすることができ、例えば、顆粒剤、細粒剤、散剤、カプセル剤、又は錠剤として提供される。本発明の医薬製剤を錠剤として提供する場合、単層錠、二層錠若しくは三層錠のような多層錠、有核錠、又はこれらのフィルムコーティング錠として提供される。このような錠剤は、前述のように、一部又は全部の成分を造粒した後に圧縮成型して製造するのが一般的である。尚、造粒方法は、湿式処理法による造粒、すなわち、湿式造粒法が好ましい。 The pharmaceutical preparation of the present invention can be in various dosage forms, for example, provided as granules, fine granules, powders, capsules, or tablets. When the pharmaceutical preparation of the present invention is provided as a tablet, it is provided as a multilayer tablet such as a monolayer tablet, a bilayer tablet or a trilayer tablet, a dry tablet, or a film-coated tablet thereof. As described above, such a tablet is generally produced by granulating a part or all of the ingredients and then compression molding. In addition, the granulation method is preferably a granulation by a wet processing method, that is, a wet granulation method.
　本発明において、有効成分の１つであるDPP-IV阻害薬の化学的安定性は、温度60℃の条件下で21日間保管した後の、DPP-IV阻害薬の最大分解生成物の生成量（％）で判定する。当該数値が0.20％以下を化学的安定性が良好とする基準とする。当該数値は、好ましくは0.15％以下であり、更に好ましくは0.1％以下である。 In the present invention, the chemical stability of the DPP-IV inhibitor, which is one of the active ingredients, is the amount of the maximum degradation product of the DPP-IV inhibitor after storage for 21 days at a temperature of 60 ° C. Judge by (%). The value of 0.20% or less is used as the standard for good chemical stability. The numerical value is preferably 0.15% or less, more preferably 0.1% or less.
　以下、実施例及び比較例を挙げて本発明を詳細に説明するが、これらは本発明をなんら限定するものではない。尚、いずれの実験においても、有効成分であるDPP-IV阻害薬としてアナグリプチンを使用した。また、実施例及び比較例にて得られた製剤の安定性試験は、各試験検体を温度60℃の条件下で21日間保管した後の各分解生成物生成量の確認を行い、最大分解生成物量にてDPP-IV阻害薬の化学的安定性を評価することにより行った。この安定性試験により、添加した安定化剤の有効性を判定した。最大分解生成物量は、DPP-IV阻害薬（アナグリプチン）及び当該DPP-IV阻害薬に由来する全ての分解生成物を周知の分析方法（HPLC）にて測定し、得られた全てのピーク面積値の総和当たりの、確認された各分解生成物のピーク面積値の面積百分率にて各々の分解物の生成量（％）を算出することにより求めた。 Hereinafter, the present invention will be described in detail with reference to examples and comparative examples, but these do not limit the present invention. In all experiments, anagliptin was used as an active ingredient DPP-IV inhibitor. In addition, the stability test of the preparations obtained in the examples and comparative examples was conducted by confirming the amount of each decomposition product produced after storing each test specimen for 21 days at a temperature of 60 ° C. This was done by evaluating the chemical stability of DPP-IV inhibitors by physical quantity. By this stability test, the effectiveness of the added stabilizer was determined. The maximum degradation product amount is determined by measuring the DPP-IV inhibitor (anagliptin) and all degradation products derived from the DPP-IV inhibitor with a well-known analytical method (HPLC), and all the peak area values obtained. Was calculated by calculating the amount (%) of each decomposed product as an area percentage of the peak area value of each confirmed decomposed product.
試験例１　メトホルミンの造粒の必要性及びDPP-IV阻害薬の化学的安定性の基準設定
　表１の参考例１の配合比率に従って、いずれも造粒していない滑沢剤以外の成分を量りとり、目開き1mmの篩にて篩過後、表１の配合比率となるように滑沢剤を混合し、打錠用粉体を得た。尚、当該配合比率は、後述の実施例25のそれと同じものである。当該打錠用粉体について、打錠機VIRG（株式会社菊水製作所製）を使用して打錠を試みたが、打錠用粉体の流動性不足により、打錠用粉体がホッパーから打錠機へ供給されず、打錠することができなかった。当該試験からもわかるように、アナグリプチンとメトホルミン又はその塩との配合剤を製造するためには、含量の多いメトホルミン又はその塩の造粒が必須であることがわかる。 Test Example 1 Necessity of granulation of metformin and standard setting of chemical stability of DPP-IV inhibitor In accordance with the blending ratio of Reference Example 1 in Table 1, all ingredients other than lubricants that were not granulated were weighed. Then, after passing through a sieve having an opening of 1 mm, a lubricant was mixed so that the blending ratio shown in Table 1 was obtained to obtain a tableting powder. The blending ratio is the same as that in Example 25 described later. The tableting powder was attempted to be tableted using a tableting machine VIRG (manufactured by Kikusui Seisakusho Co., Ltd.), but due to the lack of fluidity of the tableting powder, the tableting powder was pressed from the hopper. The tablet was not supplied and could not be tableted. As can be seen from the test, it is understood that granulation of metformin or a salt thereof with a high content is essential in order to produce a compounding agent of anagliptin and metformin or a salt thereof.
　一方、メトホルミン塩酸塩に精製水を加え湿式造粒後乾燥し造粒物を得た。メトホルミン塩酸塩のみ当該造粒物を使用し、他の成分はいずれも未造粒物を使用して、表１の参考例２の配合比率に従って各成分を量り取り混合後、直径11.5mm、（R15）円形杵にて、圧力約10kNにて圧縮成形し、１錠あたりアナグリプチンを100mg、メトホルミン塩酸塩を500mg含む錠剤を得た。当該錠剤を調製後速やかにガラス瓶に充填（20mL瓶に2錠）し密閉し、所定の安定性試験を行ってアナグリプチンの分解生成物量（％）を測定したところ、0.22％であった。従って、アナグリプチンの分解生成物量が0.2％以下のものを、製剤としてDPP-IV阻害薬の化学的安定性が特に良好であるとする基準とした。 Meanwhile, purified water was added to metformin hydrochloride and wet granulation was performed, followed by drying to obtain a granulated product. Only the metformin hydrochloride is used for the granulated product, and all other components are used for the non-granulated product. Each component is weighed and mixed according to the mixing ratio of Reference Example 2 in Table 1, and then the diameter is 11.5 mm. R15) Compressed with a circular punch at a pressure of about 10 kN to obtain tablets containing 100 mg anagliptin and 500 mg metformin hydrochloride per tablet. Immediately after preparation, the tablets were filled into glass bottles (2 tablets in a 20 mL bottle), sealed, and subjected to a predetermined stability test. The degradation product amount (%) of anagliptin was measured and found to be 0.22%. Therefore, an anagliptin degradation product amount of 0.2% or less was set as a criterion that the chemical stability of the DPP-IV inhibitor as a preparation was particularly good.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
試験例２　アナグリプチン分解抑制効果を有する安定化剤の特定
　安定化剤として表２に示すものを使用して、DPP-IV阻害薬の化学的安定性に対する効果を調べた。実施例１及び比較例１～６の製剤は、以下のように調製後速やかにガラス瓶に充填（20mL瓶に約2g）し密閉した。このような試験検体について安定性試験を行い、アナグリプチンの分解生成物量（％）を測定した。尚、以降の試験において、成分を造粒して使用する場合にその旨明記してあり、特にそのような記載がないものは、未造粒で使用している。
（実施例１）
　各成分を表２の実施例１の配合比率に従い混合し、精製水を加え湿式造粒後乾燥し、顆粒状の製剤を製した。
（比較例１）
　実施例１の安定化剤を除いて、実施例１と同様に製造した。
（比較例２～６）
　実施例１の安定化剤の代わりに、表２に記載された安定化剤を用いて、実施例１と同様に製造した。 Test Example 2 Identification of Stabilizer Having Anagliptin Decomposition Suppressing Effect The stabilizer shown in Table 2 was used to examine the effect of DPP-IV inhibitors on chemical stability. The preparations of Example 1 and Comparative Examples 1 to 6 were filled in glass bottles (about 2 g in a 20 mL bottle) immediately after preparation and sealed as follows. Such a test specimen was subjected to a stability test, and the degradation product amount (%) of anagliptin was measured. In the following tests, when the ingredients are granulated and used, the fact is clearly stated, and those without such description are used without granulation.
Example 1
Each component was mixed according to the blending ratio of Example 1 in Table 2, purified water was added, wet granulation was performed, and drying was performed to prepare a granular preparation.
(Comparative Example 1)
Production was carried out in the same manner as in Example 1 except for the stabilizer of Example 1.
(Comparative Examples 2 to 6)
The same procedure as in Example 1 was performed using the stabilizers described in Table 2 instead of the stabilizer in Example 1.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　実施例１及び比較例１～６の安定性試験の結果を表３に示す。安定化剤として環状オリゴ糖であるα-シクロデキストリンを用いた実施例１において、アナグリプチン由来の最大分解生成物が0.16％で0.2％以下となり、また、比較例１との比較から見ても、アナグリプチンの分解を抑制する効果を示した。これに対し、安定化剤を含まない比較例１において、アナグリプチン由来の最大分解生成物は0.42％であった。一方、先行技術にて開示されている安定化剤等を用いた比較例２～６においては、安定化剤を含まない比較例１を上回る分解生成物の生成が認められ、アナグリプチンの分解を抑制する効果は得られなかった。当該結果より、環状オリゴ糖であるα-シクロデキストリンを用いることで、DPPIV阻害薬であるアナグリプチンの分解を抑制する効果が得られることが判明した。 Table 3 shows the results of stability tests of Example 1 and Comparative Examples 1 to 6. In Example 1 using α-cyclodextrin, which is a cyclic oligosaccharide as a stabilizer, the maximum degradation product derived from anagliptin is 0.26% or less at 0.16%, and also from a comparison with Comparative Example 1, It showed the effect of suppressing the degradation of anagliptin. On the other hand, in Comparative Example 1 containing no stabilizer, the maximum degradation product derived from anagliptin was 0.42%. On the other hand, in Comparative Examples 2 to 6 using the stabilizer disclosed in the prior art, the production of decomposition products exceeding Comparative Example 1 not containing the stabilizer was observed, and the degradation of anagliptin was suppressed. The effect to do was not obtained. From these results, it was found that the use of α-cyclodextrin, which is a cyclic oligosaccharide, has the effect of suppressing the degradation of anagliptin, which is a DPPIV inhibitor.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
試験例３　安定化剤を全有効成分と共に造粒した場合のアナグリプチン分解抑制効果の検証
　本発明に用いる安定化剤である環状オリゴ糖について、全有効成分と共に造粒した場合の、DPP-IV阻害薬の分解を抑制する効果を、環状オリゴ糖の配合比率と併せて検討した。実施例１～４は以下のように調製後、速やかにガラス瓶に充填（20mL瓶に約1g）し密閉した。このような試験検体について安定性試験を行い、アナグリプチンの分解生成物量（％）を測定した。
（実施例１）
　試験例２に記載済
（実施例２～４）
　各成分を表４の配合比率に従い混合し、実施例１と同様に製造した。 Test Example 3 Verification of anagliptin degradation inhibitory effect when stabilizer is granulated with all active ingredients DPP-IV inhibition when granulated together with all active ingredients for cyclic oligosaccharide as a stabilizer used in the present invention The effect of suppressing the degradation of the drug was examined together with the compounding ratio of the cyclic oligosaccharide. Examples 1 to 4 were prepared as follows, and immediately filled into a glass bottle (about 1 g in a 20 mL bottle) and sealed. Such a test specimen was subjected to a stability test, and the degradation product amount (%) of anagliptin was measured.
Example 1
Already described in Test Example 2 (Examples 2 to 4)
Each component was mixed according to the blending ratio in Table 4 and manufactured in the same manner as in Example 1.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　当該安定性試験の結果を表５に示す。安定化剤としてα-シクロデキストリンを用いた実施例１～４において、全有効成分と共に湿式造粒することで、α-シクロデキストリンの配合比率に依存して、DPPIV阻害薬であるアナグリプチンの分解を抑制する効果を示した。DPPIV阻害薬であるアナグリプチンとメトホルミン塩酸塩とを混合して造粒する試験系においては、試験例２の比較例１との比較で安定化剤の有効性は判定されるべきで、そのような意味では、α-シクロデキストリンの低用量においても、十分な効果を発揮している。 The results of the stability test are shown in Table 5. In Examples 1 to 4, where α-cyclodextrin was used as a stabilizer, wet granulation with all the active ingredients can cause degradation of anagliptin, a DPPIV inhibitor, depending on the blending ratio of α-cyclodextrin. The suppression effect was shown. In the test system in which the DPPIV inhibitor anagliptin and metformin hydrochloride are mixed and granulated, the effectiveness of the stabilizer should be determined by comparison with Comparative Example 1 of Test Example 2. In a sense, even at a low dose of α-cyclodextrin, a sufficient effect is exhibited.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
試験例４　安定化剤をメトホルミン塩酸塩と共に造粒した場合のアナグリプチン分解抑制効果の検証
　本発明に用いる安定化剤である環状オリゴ糖について、有効成分の１つであるメトホルミン塩酸塩と共に造粒した場合のアナグリプチンの分解を抑制する効果を、環状オリゴ糖の分子量及び配合比率と併せて検討した。実施例５～１９は以下のように調製後、速やかにガラス瓶に充填（20mL瓶に約1g）し密閉した。このような試験検体について安定性試験を行い、アナグリプチンの分解生成物量（％）を測定した。
（実施例５～１０）
　メトホルミン塩酸塩及び環状オリゴ糖であるα-シクロデキストリンを表６の配合比率に従い混合し、精製水を加え湿式造粒後乾燥し、造粒物を得た。得られた造粒物にアナグリプチンを表６の配合比率に従い混合し、顆粒・粉体混合物である製剤を製した。
（実施例１１）
　メトホルミン塩酸塩に精製水を加え湿式造粒後乾燥し、造粒物を得た。得られた造粒物に環状オリゴ糖であるα-シクロデキストリン及びアナグリプチンを表６の配合比率に従い混合し、顆粒・粉体混合物である製剤を製した。
（実施例１２～１５）
　メトホルミン塩酸塩及び環状オリゴ糖であるβ-シクロデキストリンを表７の配合比率に従い混合し、精製水を加え湿式造粒後乾燥し、造粒物を得た。得られた造粒物にアナグリプチンを表７の配合比率に従い混合し、顆粒・粉体混合物である製剤を製した。
（実施例１６～１９）
　メトホルミン塩酸塩及び環状オリゴ糖であるγ-シクロデキストリンを表８の配合比率に従い混合し、精製水を加え湿式造粒後乾燥し、造粒物を得た。得られた造粒物にアナグリプチンを表８の配合比率に従い混合し、顆粒・粉体混合物である製剤を製した。 Test Example 4 Verification of the anagliptin degradation inhibitory effect when the stabilizer was granulated with metformin hydrochloride The cyclic oligosaccharide, which is a stabilizer used in the present invention, was granulated with metformin hydrochloride which is one of the active ingredients. The effect of inhibiting the degradation of anagliptin in some cases was examined together with the molecular weight and blending ratio of the cyclic oligosaccharide. Examples 5 to 19 were prepared as follows and immediately filled into a glass bottle (about 1 g in a 20 mL bottle) and sealed. Such a test specimen was subjected to a stability test, and the degradation product amount (%) of anagliptin was measured.
(Examples 5 to 10)
Metformin hydrochloride and α-cyclodextrin, which is a cyclic oligosaccharide, were mixed according to the blending ratios shown in Table 6, purified water was added and wet granulation was performed, followed by drying to obtain a granulated product. Anagliptin was mixed with the obtained granulated product according to the blending ratio shown in Table 6 to prepare a preparation which is a granule / powder mixture.
(Example 11)
Purified water was added to metformin hydrochloride and wet granulation was performed, followed by drying to obtain a granulated product. The resulting granulated product was mixed with cyclic oligosaccharides α-cyclodextrin and anagliptin in accordance with the blending ratios shown in Table 6 to prepare a formulation as a granule / powder mixture.
(Examples 12 to 15)
Metformin hydrochloride and β-cyclodextrin, which is a cyclic oligosaccharide, were mixed according to the blending ratios shown in Table 7, purified water was added and wet granulation was performed, followed by drying to obtain a granulated product. Anagliptin was mixed with the obtained granulated material according to the blending ratio shown in Table 7 to prepare a preparation which is a granule / powder mixture.
(Examples 16 to 19)
Metformin hydrochloride and cyclic oligosaccharide γ-cyclodextrin were mixed in accordance with the blending ratios shown in Table 8, purified water was added and wet granulation was performed, followed by drying to obtain a granulated product. Anagliptin was mixed with the obtained granulated material according to the blending ratio shown in Table 8 to prepare a preparation which is a granule / powder mixture.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　当該安定性試験の結果を表９に示す。安定化剤として分子量の異なるシクロデキストリンを、配合比率を変えて用いた実施例５～１０及び１２～１９において、安定化剤であるシクロデキストリンを、DPPIV阻害薬のパートナー薬であるメトホルミン塩酸塩と共に湿式造粒し、得られた造粒物に対しアナグリプチンを配合することで、いずれの分子量のシクロデキストリンをいずれの配合比率で添加した場合でも、DPPIV阻害薬であるアナグリプチン由来の最大分解生成物の生成物量は0.2％を下回り、アナグリプチンの分解を抑制する効果を示した。しかも、α-シクロデキストリンが0.17％の極めて低用量の実施例５を除き、アナグリプチン由来の最大分解生成物の生成物量は0.1％を下回り、アナグリプチンの分解を抑制する効果は著効と言えるレベルであった。
　一方、実施例７及び実施例１１の結果より、安定化剤である環状オリゴ糖は、造粒せずに添加するだけでも効果があるが、メトホルミン塩酸塩と共に造粒することで、DPPIV阻害薬であるアナグリプチンの分解を抑制する効果がより顕著に得られることが判明した。 The results of the stability test are shown in Table 9. In Examples 5 to 10 and 12 to 19 in which cyclodextrins having different molecular weights were used as stabilizers in different blending ratios, the cyclodextrin as a stabilizer and metformin hydrochloride as a partner drug of a DPPIV inhibitor were used. When wet granulation is performed and anagliptin is added to the resulting granulated product, the maximum degradation product derived from anagliptin, which is a DPPIV inhibitor, can be added regardless of the cyclodextrin of any molecular weight. The amount of the product was less than 0.2%, which showed the effect of suppressing the degradation of anagliptin. Moreover, except for Example 5, which is an extremely low dose of α-cyclodextrin of 0.17%, the amount of the maximum degradation product derived from anagliptin is less than 0.1%, and the effect of suppressing the degradation of anagliptin is at a level that can be said to be remarkable. there were.
On the other hand, from the results of Example 7 and Example 11, the cyclic oligosaccharide that is a stabilizer is effective even when added without granulation, but by granulating with metformin hydrochloride, a DPPIV inhibitor It was found that the effect of inhibiting the degradation of anagliptin, which is
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
試験例５　アナグリプチンとメトホルミン塩酸塩の配合比率が安定化剤の効果に及ぼす影響
　アナグリプチンとメトホルミン塩酸塩の配合比率が、安定化剤であるα-シクロデキストリンによるアナグリプチンの分解を抑制する効果に及ぼす影響について検討した。実施例７，８及び実施例２０～２４は、以下のように調製後速やかにガラス瓶に充填（20mL瓶に約1g）し密閉した。このような試験検体について安定性試験を行い、アナグリプチン分解生成物量（％）を測定した。　
（実施例７，８）
　試験例４に記載済
（実施例２０～２４）　
　実施例７，８と同様に、メトホルミン塩酸塩及びα-シクロデキストリンを表１０の配合比率に従い混合し、精製水を加え湿式造粒後乾燥し、造粒物を得た。得られた造粒物にアナグリプチンを表１０の配合比率に従い混合し、顆粒・粉体混合物である製剤を製した。 Test Example 5 Influence of Anagliptin and Metformin Hydrochloride on the Effect of Stabilizer Effect of Anagliptin and Metformin Hydrochloride on the Effect of Inhibiting Degradation of Anagliptin by Stabilizer α-Cyclodextrin Was examined. Examples 7 and 8 and Examples 20 to 24 were filled in glass bottles (about 1 g in a 20 mL bottle) immediately after preparation and sealed as follows. Such a test specimen was subjected to a stability test, and the amount (%) of an anagliptin degradation product was measured.
(Examples 7 and 8)
Already described in Test Example 4 (Examples 20 to 24)
In the same manner as in Examples 7 and 8, metformin hydrochloride and α-cyclodextrin were mixed according to the blending ratio in Table 10, purified water was added and wet granulation was performed, followed by drying to obtain a granulated product. Anagliptin was mixed with the obtained granulated material according to the blending ratio shown in Table 10 to prepare a preparation as a granule / powder mixture.
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
　当該安定性試験の結果を表１１に示す。α-シクロデキストリンをメトホルミン塩酸塩とともに造粒した場合、試験を行ったアナグリプチンとメトホルミン塩酸塩の配合比１：１０～２：５の範囲でいずれも、アナグリプチン由来の最大分解生成物が0.2％以下となり、安定化剤であるα-シクロデキストリンによるアナグリプチンの分解を抑制する効果が確認された。また、アナグリプチンとメトホルミン塩酸塩の配合比１：５～２：５の範囲では、アナグリプチン由来の最大分解生成物が0.1％以下となり、α-シクロデキストリンによるアナグリプチンの分解を抑制する効果は著効と言えるレベルであった。以上の結果より、安定化剤として環状オリゴ糖を用いることで、有効成分としてのDPPIV阻害薬とパートナー薬であるメトホルミン塩酸塩の配合比率が少なくとも１：１０～２：５の範囲で、DPPIV阻害薬の分解を抑制する効果が得られるとともに、アナグリプチン含量比率が高い方が、アナグリプチンの安定性は良好であることが判明した。 The results of the stability test are shown in Table 11. When α-cyclodextrin is granulated with metformin hydrochloride, the maximum degradation product derived from anagliptin is 0.2% or less in any of the ratios of anagliptin and metformin hydrochloride tested in the range of 1:10 to 2: 5. Thus, the effect of suppressing the degradation of anagliptin by α-cyclodextrin as a stabilizer was confirmed. In addition, when the ratio of anagliptin to metformin hydrochloride is in the range of 1: 5 to 2: 5, the maximum degradation product derived from anagliptin is 0.1% or less, and the effect of inhibiting the degradation of anagliptin by α-cyclodextrin is remarkable. It was a level to say. From the above results, by using cyclic oligosaccharide as a stabilizer, DPPIV inhibition is achieved when the blending ratio of DPPIV inhibitor as an active ingredient and metformin hydrochloride as a partner drug is at least 1:10 to 2: 5. It has been found that the effect of suppressing the degradation of the drug is obtained and the stability of anagliptin is better when the anagliptin content ratio is higher.
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
試験例６　錠剤中における安定化剤のアナグリプチン分解抑制効果の検証
　本発明における安定化剤が、錠剤中において、アナグリプチンの分解を抑制する効果を検証した。実施例２５，２６は、以下のように調製後速やかにガラス瓶に充填（20 mL瓶に2錠）し密閉した。このような試験検体について安定性試験を行い、アナグリプチン分解生成物量（％）を測定した。
（実施例２５，２６）
　メトホルミン塩酸塩及び安定化剤を表１２の配合比率に従い混合し、精製水を加え湿式造粒後乾燥し、造粒物を得た。得られた造粒物に、アナグリプチン、結晶セルロース、クロスポビドン、ヒドロキシプロピルセルロース、及びステアリン酸マグネシウムを表１２の配合比率に従い混合後、直径11.5mm、（R15）円形杵にて、圧力約10kNにて圧縮成形し、１錠あたりアナグリプチンを100mg、メトホルミン塩酸塩を500mg含む錠剤を得た。 Test Example 6 Verification of Anagliptin Decomposition Suppressing Effect of Stabilizer in Tablet The effect of the stabilizer in the present invention to suppress the degradation of anagliptin in the tablet was verified. Examples 25 and 26 were filled in glass bottles (2 tablets in a 20 mL bottle) immediately after preparation and sealed as follows. Such a test specimen was subjected to a stability test, and the amount (%) of an anagliptin degradation product was measured.
(Examples 25 and 26)
Metformin hydrochloride and a stabilizer were mixed according to the blending ratio shown in Table 12, purified water was added and wet granulation was performed, followed by drying to obtain a granulated product. After mixing the resulting granulated product with anagliptin, crystalline cellulose, crospovidone, hydroxypropyl cellulose, and magnesium stearate according to the blending ratios in Table 12, the diameter is 11.5 mm and the pressure is about 10 kN with a (R15) circular ridge. Compressed to obtain tablets containing 100 mg anagliptin and 500 mg metformin hydrochloride per tablet.
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
　当該安定性試験の結果を表１３に示す。安定化剤としてα-シクロデキストリン及びβ-シクロデキストリンを用いた実施例２５，２６において、DPPIV阻害薬であるアナグリプチン由来の最大分解生成物が0.1％以下となり、アナグリプチンの分解を抑制する効果は著効と言えるレベルであった。当該結果より、製剤を錠剤形状に加工した場合であっても、環状オリゴ糖の安定化剤としての効果は維持されることが判明した。 The results of the stability test are shown in Table 13. In Examples 25 and 26 using α-cyclodextrin and β-cyclodextrin as stabilizers, the maximum degradation product derived from anagliptin which is a DPPIV inhibitor is 0.1% or less, and the effect of suppressing the degradation of anagliptin is remarkable. It was a level that could be said to be effective. From the results, it was found that even when the preparation was processed into a tablet shape, the effect of the cyclic oligosaccharide as a stabilizer was maintained.
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013

Claims (15)

  1. 　DPP-IV阻害薬及びメトホルミン又はその塩を有効成分として含み、更に環状オリゴ糖を含み、前記メトホルミン又はその塩が造粒されている（DPP-IV阻害薬とメトホルミン又はその塩とが環状オリゴ糖とは別に混合造粒されている場合を除く）ことを特徴とする、医薬製剤。 It contains a DPP-IV inhibitor and metformin or a salt thereof as active ingredients, further contains a cyclic oligosaccharide, and the metformin or a salt thereof is granulated (the DPP-IV inhibitor and metformin or a salt thereof are cyclic oligosaccharides) A pharmaceutical preparation characterized in that it is mixed and granulated separately).
  2. 　前記メトホルミン又はその塩が前記環状オリゴ糖とともに造粒されている、請求項１に記載の医薬製剤。 The pharmaceutical preparation according to claim 1, wherein the metformin or a salt thereof is granulated together with the cyclic oligosaccharide.
  3. 　前記メトホルミン又はその塩が前記DPP-IV阻害薬とは分離して造粒されている、請求項１又は２に記載の医薬製剤。 The pharmaceutical preparation according to claim 1 or 2, wherein the metformin or a salt thereof is granulated separately from the DPP-IV inhibitor.
  4. 　前記造粒が湿式造粒である、請求項１～３のいずれかに記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 3, wherein the granulation is wet granulation.
  5. 　前記環状オリゴ糖が、α-シクロデキストリン、β-シクロデキストリン、及びγ-シクロデキストリンからなる群から選択される１種以上である、請求項１～４のいずれかに記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 4, wherein the cyclic oligosaccharide is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.
  6. 　前記DPP-IV阻害薬の配合割合が、製剤全体に対し５～３０質量％である、請求項１～５のいずれかに記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 5, wherein the blending ratio of the DPP-IV inhibitor is 5 to 30% by mass with respect to the whole preparation.
  7. 　前記メトホルミン又はその塩の配合割合が、製剤全体に対し４０～９０質量％である、請求項１～６のいずれかに記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 6, wherein the compounding ratio of metformin or a salt thereof is 40 to 90 mass% with respect to the whole preparation.
  8. 　前記DPP-IV阻害薬と前記メトホルミン又はその塩の配合比率が、１：１１～１：１である、請求項１～７のいずれかに記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 7, wherein a mixing ratio of the DPP-IV inhibitor and the metformin or a salt thereof is from 1:11 to 1: 1.
  9. 　前記DPP-IV阻害薬と前記メトホルミン又はその塩の配合比率が、１：６～１：２である、請求項８に記載の医薬製剤。 The pharmaceutical preparation according to claim 8, wherein the blending ratio of the DPP-IV inhibitor and metformin or a salt thereof is 1: 6 to 1: 2.
  10. 　前記環状オリゴ糖の配合割合が、有効成分総量に対し０．１～２５質量％である、請求項１～９のいずれかに記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 9, wherein the blending ratio of the cyclic oligosaccharide is 0.1 to 25% by mass with respect to the total amount of active ingredients.
  11. 　前記環状オリゴ糖の配合割合が、前記メトホルミン又はその塩に対し０．１～３５質量％である、請求項１～１０のいずれかに記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 10, wherein a blending ratio of the cyclic oligosaccharide is 0.1 to 35 mass% with respect to the metformin or a salt thereof.
  12. 　前記環状オリゴ糖の配合割合が、前記メトホルミン又はその塩に対し１～２５質量％である、請求項１１に記載の医薬製剤。 The pharmaceutical preparation according to claim 11, wherein the compounding ratio of the cyclic oligosaccharide is 1 to 25% by mass with respect to the metformin or a salt thereof.
  13. 　前記医薬製剤の製剤形態が、顆粒剤、細粒剤、散剤、カプセル剤、及び錠剤からなる群から選択される、請求項１～１２のいずれかに記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 12, wherein the preparation form of the pharmaceutical preparation is selected from the group consisting of granules, fine granules, powders, capsules, and tablets.
  14. 　前記医薬製剤の化学的安定性が、温度60℃の条件下で21日間保管した後の、DPP-IV阻害薬の最大分解生成物の生成量が0.2％以下で示される、請求項１～１３のいずれかに記載の医薬製剤。 The chemical stability of the pharmaceutical preparation is indicated by a maximum degradation product of DPP-IV inhibitor of 0.2% or less after storage for 21 days at a temperature of 60 ° C. The pharmaceutical formulation in any one of.
  15. 　前記DPP-IV阻害薬がアナグリプチン又はその塩である、請求項１～１４のいずれかに記載の医薬製剤。
          The pharmaceutical preparation according to any one of claims 1 to 14, wherein the DPP-IV inhibitor is anagliptin or a salt thereof.
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RU2742418C1 (en) * 2017-02-03 2021-02-05 Гленмарк Фармасьютикалс Лимитед Dosage forms containing teneligliptin oxalate salts and solvates thereof
WO2020208201A1 (en) * 2019-04-11 2020-10-15 Add Advanced Drug Delivery Technologies Ltd. Process for continuous production of an active ingredient granulate
CN114126591A (en) * 2019-04-11 2022-03-01 埃德先进药物输送技术有限责任公司 Method for continuously producing active ingredient particles
CN114302711A (en) * 2019-04-11 2022-04-08 埃德先进药物输送技术有限责任公司 Method for continuously producing active ingredient particles

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