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
  • A61K31/33—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
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • 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

Definitions

• One embodiment of the present invention relates to a teneligliptin-containing formulation.
• one embodiment of the present invention relates to a formulation comprising teneligliptin-containing particles.
• Teneligliptin ([(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl] (1,3-thiazolidin-3-yl)methanone) is a selective inhibitor of dipeptidyl peptidase IV (DPP-4) and is used clinically as a treatment for type 2 diabetes.
• a solid formulation containing teneligliptin hydrobromide hydrate is described, for example, in Patent Document 1.
• an orally disintegrating tablet containing teneligliptin hydrobromide hydrate is described, for example, in Patent Document 2. Both of these are formulations that contain the active ingredient in a crystalline form.
• amorphous formulations that contain active ingredients in an amorphous form are expected to improve the dissolution of the active ingredient and its absorption rate in the body compared to formulations that contain the active ingredient in a crystalline form.
• the amorphous form is physically and chemically unstable, it is known that it is prone to transition to a more energetically stable crystalline form and that related substances are easily generated.
• amorphous formulations may require special measures to ensure the quality of the formulation, such as measures to maintain the amorphous form during the manufacturing process of the formulation, measures to maintain the amorphous form even if it is exposed to extreme conditions such as high temperature and high humidity during distribution and storage until administration, and measures to suppress the generation of related substances during manufacturing and the above-mentioned storage.
• Patent Document 3 describes a teneligliptin-containing pharmaceutical composition that contains amorphous teneligliptin hydrobromide and an amorphous maintaining polymer.
• Patent Document 3 describes a formulation in which the active ingredient in the formulation is maintained in an amorphous form after storage under sealed conditions, or a formulation in which the amount of related substances that increases when stored under open conditions is reduced, but does not describe a teneligliptin-containing formulation in which the active ingredient in the formulation is maintained in an amorphous form even after storage under open conditions and in which the production of related substances is suppressed.
• Patent No. 5775463 International Publication No. 2020/209350 JP 2020-070260 A
• One of the objectives of one embodiment of the present invention is to provide a teneligliptin-containing formulation that maintains the amorphous form of teneligliptin and inhibits the increase of related substances even after storage under open conditions that are more susceptible to the effects of humidity.
• a teneligliptin-containing formulation which comprises porous silica, amorphous teneligliptin supported on the porous silica, an organic acid, and propyl gallate.
• the teneligliptin-containing formulation may include particles that include porous silica, amorphous teneligliptin supported on the porous silica, and an organic acid.
• the porous silica may be one or more porous silicic acids selected from the group consisting of silicon dioxide, hydrous silicon dioxide, and light anhydrous silicic acid, or one or more porous silicates selected from the group consisting of magnesium aluminometasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate, and aluminum silicate.
• the porous silica may be selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid, and magnesium aluminometasilicate.
• the porous silica may be hydrous silicon dioxide.
• the organic acid may be one or more organic acids selected from the group consisting of lactic acid, ascorbic acid, citric acid, tartaric acid, fumaric acid, and malic acid.
• the organic acid may be selected from the group consisting of lactic acid, citric acid, tartaric acid, and malic acid.
• the organic acid may be selected from the group consisting of citric acid, tartaric acid, and malic acid.
• the organic acid may be lactic acid.
• the organic acid may be citric acid.
• the porous silica may be hydrous silicon dioxide, and the organic acid may be lactic acid.
• the teneligliptin-containing formulation may include particles that include porous silica, amorphous teneligliptin supported on the porous silica, and an organic acid.
• a formulation containing teneligliptin that maintains the amorphous form of teneligliptin and inhibits the increase of related substances even after storage under open conditions that are more susceptible to the effects of humidity.
• teneligliptin-containing formulation of the present invention will be described below.
• teneligliptin may include its free form and pharmacologically acceptable salts or solvates, and teneligliptin hydrobromide may also include its solvates.
• the teneligliptin-containing formulation of the present invention should not be interpreted as being limited to the description of the embodiments and examples shown below.
• teneligliptin-containing formulations include, but are not limited to, tablets, powders, granules, and capsules.
• the teneligliptin-containing formulation comprises porous silica, amorphous teneligliptin supported by the porous silica, an organic acid, and propyl gallate.
• the teneligliptin-containing formulation comprises teneligliptin-containing particles and propyl gallate as an antioxidant disposed on the exterior of the teneligliptin-containing particles.
• the teneligliptin-containing particles comprise porous silica, amorphous teneligliptin supported by the porous silica, and an organic acid.
• each tablet contains, for example, 20 mg or 40 mg of teneligliptin (free form), but the content of teneligliptin (free form) can be changed as appropriate within a range in which a therapeutic effect is obtained.
• the teneligliptin-containing formulation may further contain one or more pharma- ceutically acceptable additives.
• the teneligliptin-containing formulation may be provided as a tablet obtained by mixing and compressing teneligliptin-containing particles, an antioxidant, and one or more pharma- ceutically acceptable additives.
• the teneligliptin-containing formulation may be provided as a plain tablet obtained by mixing and compressing teneligliptin-containing particles, an antioxidant, and one or more pharma-ceutically acceptable additives, and a film-coated tablet having a film covering the plain tablet.
• the teneligliptin-containing particles contain porous silica, amorphous teneligliptin supported on the porous silica, and an organic acid.
• Porous silica has pores.
• the pores are spaces that connect the surface of the porous silica to its interior, and can support teneligliptin, or teneligliptin and an organic acid.
• Porous silica can support teneligliptin, or teneligliptin and an organic acid on its surface and/or within the pores.
• porous silica supports teneligliptin, or teneligliptin and an organic acid
• teneligliptin, or teneligliptin and an organic acid are retained on the surface and/or within the pores of the porous silica, and/or teneligliptin, or teneligliptin and an organic acid are adsorbed on the surface and/or within the pores of the porous silica, and/or teneligliptin, or teneligliptin and an organic acid are disposed on the surface and/or within the pores of the porous silica.
• porous silica refers to one or more porous silicic acids selected from the group consisting of silicon dioxide, hydrous silicon dioxide, and light anhydrous silicic acid, or one or more porous silicates selected from the group consisting of magnesium aluminometasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate, and aluminum silicate.
• the porous silica contained in the teneligliptin-containing particles according to this embodiment is a carrier for supporting amorphous teneligliptin or amorphous teneligliptin and an organic acid.
• a carrier for supporting amorphous teneligliptin or amorphous teneligliptin and an organic acid By supporting teneligliptin or teneligliptin and an organic acid on the porous silica carrier, the teneligliptin supported by the porous silica can be maintained in an amorphous form.
• the porous silica contained in the teneligliptin-containing particles supporting amorphous teneligliptin or amorphous teneligliptin and an organic acid means that the teneligliptin after being supported by the porous silica is in an amorphous form.
• the porous silica contained in the teneligliptin-containing particles is preferably hydrated silicon dioxide.
• the teneligliptin-containing particles according to this embodiment may be coated. In one embodiment, when the teneligliptin-containing particles are coated, the porous silica is preferably spherical.
• the porous silica contained in the teneligliptin-containing particles may be selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid, and magnesium aluminometasilicate. In one embodiment, the porous silica contained in the teneligliptin-containing particles is preferably hydrous silicon dioxide.
• the organic acid is a stabilizer that is involved in maintaining the amorphous form of teneligliptin and suppresses the production of related substances during production.
• the organic acid may be supported on the porous silica together with teneligliptin, or may be added separately from the porous silica.
• the powder X-ray diffraction measurement method can be performed in accordance with the 18th revised Japanese Pharmacopoeia.
• the organic acid contained in the teneligliptin-containing particles according to this embodiment may be, for example, one or more organic acids selected from the group consisting of lactic acid, ascorbic acid, citric acid, tartaric acid, fumaric acid, and malic acid, but is not limited thereto.
• the organic acid contained in the teneligliptin-containing particles may be selected from the group consisting of lactic acid, citric acid, tartaric acid, and malic acid. Also, in one embodiment, the organic acid contained in the teneligliptin-containing particles may be selected from the group consisting of citric acid, tartaric acid, and malic acid. In one embodiment, the organic acid contained in the teneligliptin-containing particles is preferably lactic acid. Also, in one embodiment, the organic acid contained in the teneligliptin-containing particles is preferably citric acid.
• the teneligliptin-containing particles according to this embodiment can stably maintain the amorphous form of teneligliptin by supporting teneligliptin on porous silica. As shown in the Reference Examples and Examples described later, even when stored for one month under open conditions at 25°C and a relative humidity of 75%, the teneligliptin-containing particles according to this embodiment can maintain the amorphous form of teneligliptin. Furthermore, the teneligliptin-containing particles according to this embodiment can suppress the production of related substances during production in addition to maintaining the amorphous form of teneligliptin by supporting teneligliptin together with an organic acid on porous silica. In one embodiment, the teneligliptin-containing formulation preferably includes particles containing porous silica, and amorphous teneligliptin and an organic acid supported on the porous silica.
• propyl gallate is an antioxidant that suppresses the increase of related substances of teneligliptin.
• propyl gallate By disposing propyl gallate on the outside of the teneligliptin-containing particles, the increase of related substances of teneligliptin can be suppressed even during storage under open conditions.
• a teneligliptin-containing formulation containing teneligliptin-containing particles containing amorphous teneligliptin and an organic acid supported on porous silica and propyl gallate can significantly suppress the increase of related substances of teneligliptin not only during storage under sealed conditions but also during storage under open conditions.
• the content of propyl gallate in the teneligliptin-containing formulation according to this embodiment is 0.01% by weight or more and 10% by weight or less, preferably 0.1% by weight or more and 10% by weight or less, more preferably 0.5% by weight or more and 10% by weight or less, based on the weight of the formulation.
• propyl gallate in the teneligliptin-containing formulation it is possible to reduce an increase in related substances of teneligliptin.
• the measurement of related substances can be determined by calculating the ratio of the peak area of related substances derived from teneligliptin to the total of all peak areas detected by measurement using liquid chromatography.
• Examples of one or more pharma- ceutically acceptable additives contained in the teneligliptin-containing formulation of this embodiment include, but are not limited to, excipients, binders, disintegrants, flow agents, and lubricants.
• excipients include, but are not limited to, D-mannitol, sorbitol, xylitol, corn starch, potato starch, lactose, crystalline cellulose, calcium hydrogen phosphate, etc.
• Binders include, but are not limited to, hydroxypropyl cellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose, etc.
• Disintegrants include, but are not limited to, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose calcium, crospovidone, etc.
• Flow agents include, but are not limited to, light anhydrous silicic acid, hydrated silicon dioxide, talc, etc.
• Lubricants include, but are not limited to, magnesium stearate, calcium stearate, talc, stearic acid, sucrose fatty acid esters, etc.
• the teneligliptin-containing particles according to the present invention can be produced, for example, by supporting teneligliptin or teneligliptin and an organic acid on porous silica using a known silica adsorption method.
• teneligliptin hydrobromide or its hydrate or other solvate, is dissolved in a solvent (purified water) or a stabilizer-containing solvent in which an organic acid is dissolved in a solvent (purified water), and the obtained teneligliptin solution is mixed with porous silica, and the solvent is removed to obtain amorphous teneligliptin or particles in which amorphous teneligliptin and an organic acid are supported on porous silica.
• the drug substance dissolved in the solvent or the like may be an amorphous or crystalline form of teneligliptin hydrobromide, or may be a hydrate or other solvate thereof.
• particles in which amorphous teneligliptin is supported on porous silica can be obtained by going through the above-mentioned production method.
• the obtained teneligliptin-containing particles may also be coated to give coated particles.
• teneligliptin-containing formulation for example, powders, granules, tablets, or capsules can be produced by the following methods A to C.
• A) Teneligliptin-containing powder or teneligliptin-containing granules can be produced by mixing teneligliptin-containing particles with propyl gallate and, if necessary, various additives such as excipients, disintegrants, flow agents, lubricants, etc., and optionally granulating the mixture.
• a teneligliptin-containing tablet can be produced by compressing the above-mentioned powder or granules.
• the teneligliptin-containing tablet produced by the above-mentioned process may be coated to produce a coated tablet.
• C) The powder or granules described above can be filled into a capsule to produce a capsule containing teneligliptin.
• the amounts of teneligliptin and each additive used are basically the amounts per teneligliptin-containing tablet. Even when teneligliptin-containing particles are manufactured, they may be subsequently tableted, so the amounts are listed as the amounts per tablet.
• a polyvinyl alcohol solution was prepared by dissolving 10 mg of polyvinyl alcohol (partially saponified) (PVA: EG-05PW, Mitsubishi Chemical Corporation) in 90 mg of solvent (purified water). The polyvinyl alcohol solution was sprayed onto the teneligliptin-containing particles of Reference Example 1-1 using a fluidized bed granulation dryer (MP-01, Powrex Corporation) to obtain the teneligliptin-containing granules of Reference Example 1-2.
• PVA polyvinyl alcohol (partially saponified)
• solvent purified water
• the teneligliptin-containing particles of Reference Example 1-1, the teneligliptin-containing granules of Reference Example 1-2, and the teneligliptin-containing tablets of Reference Example 1-3 were stored for one month under open conditions at 25°C and a relative humidity of 75%.
• Table 1 show that the teneligliptin-containing particles of Reference Example 1-1, the teneligliptin-containing granules of Reference Example 1-2, and the teneligliptin-containing tablets of Reference Example 1-3 were able to maintain their amorphous form not only immediately after production, but also when stored under open conditions. On the other hand, an increase in the amount of related substances was observed immediately after production (initial) and after storage under open conditions.
• the teneligliptin-containing formulation manufactured by the silica adsorption method maintained the amorphous form of teneligliptin immediately after manufacturing and after storage under open conditions, but the amount of related substances increased immediately after manufacturing and after storage under open conditions.
• the obtained teneligliptin solution was added to 45 mg of hydrated silicon dioxide (Fujisil (registered trademark), Fuji Chemical Industry Co., Ltd.) as porous silica while mixing.
• the obtained particles were dried in a fluidized bed granulation dryer (Powrex Corporation, MP-01 type) to produce teneligliptin-containing particles of Reference Example 2-1.
• a polyvinyl alcohol solution was prepared by dissolving 5 mg of polyvinyl alcohol (partially saponified) (PVA: Mitsubishi Chemical Corporation, EG-05PW) in 95 mg of solvent (purified water). The polyvinyl alcohol solution was sprayed onto the teneligliptin-containing particles of Example 2-1 using a fluidized bed granulation dryer (Powrex Corporation, MP-01 type) to obtain teneligliptin-containing granules. The teneligliptin-containing granules were sieved through a No. 22 sieve and sized.
• the resulting granulated product was mixed in a vinyl bag with 6 mg of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11), 31.02 mg of D-mannitol (Freund Corporation, Granutol F), 0.5 mg of light anhydrous silicic acid (Freund Corporation, Adsolider (registered trademark) 101), and 1.0 mg of magnesium stearate (Taihei Chemical Industry Co., Ltd., magnesium stearate (vegetable)) and compressed with a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain a teneligliptin-containing tablet of Reference Example 2-2 weighing 120 mg.
• Reference Example 3-1 Teneligliptin-containing particles of Reference Example 3-1 were produced by the same production method as in Reference Example 2-1, except that lactic acid was changed to 0.52 mg of hydrochloric acid (Fujifilm Wako Pure Chemical Industries, Ltd., special grade hydrochloric acid).
• a polyvinyl alcohol solution was prepared by dissolving 5 mg of polyvinyl alcohol (partially saponified) (PVA: Mitsubishi Chemical Corporation, EG-05PW) in 95 mg of solvent (purified water). The polyvinyl alcohol solution was sprayed onto the teneligliptin-containing particles of Reference Example 3-1 using a fluidized bed granulation dryer (Powrex Corporation, MP-01 type) to obtain teneligliptin-containing granules. The teneligliptin-containing granules were sieved through a No. 22 sieve and sized.
• the resulting sized product was mixed in a vinyl bag with 6 mg of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11), 32.50 mg of D-mannitol (Freund Corporation, Granutol F), 0.5 mg of light anhydrous silicic acid (Freund Corporation, Adsolider (registered trademark) 101), and 1.0 mg of magnesium stearate (Taihei Chemical Industry Co., Ltd., magnesium stearate (vegetable)) and compressed with a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain a teneligliptin-containing tablet of Reference Example 3-2 weighing 120 mg.
• Reference Example 4 The teneligliptin-containing particles of Reference Example 4 were produced by the same production method as in Reference Example 2-1, except that lactic acid was changed to 2 mg of ascorbic acid (Kyowa Pharma Chemical Co., Ltd., ascorbic acid 100M).
• Reference Example 5 An attempt was made to produce teneligliptin-containing particles of Reference Example 5 by the same production method as in Reference Example 2-1, except that lactic acid was changed to 2 mg of sodium pyrosulfite (Fujifilm Wako Pure Chemical Industries, Ltd., sodium pyrosulfite). However, when a teneligliptin solution was prepared, teneligliptin precipitated, and a solution could not be prepared.
• Lactic acid was changed to 2 mg of sodium sulfite (Fujifilm Wako Pure Chemical Industries, Ltd., sodium sulfite).
• sodium sulfite When sodium sulfite was used, when an attempt was made to prepare a teneligliptin solution by adding teneligliptin to a stabilizer-containing solvent, teneligliptin precipitated and a solution could not be prepared, so sodium sulfite was added as a powder.
• 29.48 mg of teneligliptin hydrobromide was dissolved in 100 mg of solvent (purified water) to prepare a teneligliptin solution.
• the obtained teneligliptin solution was added to a mixture of 45 mg of hydrated silicon dioxide (Fuji Chemical Industry Co., Ltd., Fujisil (registered trademark)) as porous silica and 2 mg of sodium sulfite, while being mixed.
• the obtained particles were dried in a fluidized bed granulation dryer (Powrex Corporation, MP-01 type) to produce teneligliptin-containing particles of Reference Example 6-1.
• a polyvinyl alcohol solution was prepared by dissolving 10 mg of polyvinyl alcohol (partially saponified) (PVA: Mitsubishi Chemical Corporation, EG-05PW) in 90 mg of solvent (purified water). The polyvinyl alcohol solution was sprayed onto the teneligliptin-containing particles of Reference Example 6-1 using a fluidized bed granulation dryer (Powrex Corporation, MP-01 type) to obtain a teneligliptin-containing granule. The teneligliptin-containing granule was sieved through a No. 22 sieve and sized.
• the sized product was mixed with 42.52 mg of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11) and 1.0 mg of magnesium stearate (Taihei Chemical Industry Co., Ltd., magnesium stearate (vegetable)) in a vinyl bag and tableted using a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) to obtain a teneligliptin-containing tablet of Reference Example 6-2 weighing 130 mg.
• L-HPC Shin-Etsu Chemical Co., Ltd., LH-11
• magnesium stearate Tegetable
• the teneligliptin-containing particles of Reference Examples 2-1, 3-1, 4, and 6-1, and the teneligliptin-containing tablets of Reference Examples 2-2, 3-2, and 6-2 were stored for one month under open conditions at 25°C and 75% relative humidity.
• the crystal form, individual maximum related substance amount, and total related substance amount were evaluated for the teneligliptin-containing particles of Reference Examples 2-1, 3-1, 4, and 6-1 immediately after production (initial) and for the teneligliptin-containing tablets of Reference Examples 2-2, 3-2, and 6-2, using the measurement methods described above.
• the evaluation results are shown in Table 2.
• the evaluation results for the teneligliptin-containing particles of Reference Example 1-1 and the teneligliptin-containing tablets of Reference Example 1-3 are shown again in Table 2.
• the teneligliptin-containing particles of Reference Examples 2-1 and 3-1 and the teneligliptin-containing tablets of Reference Examples 2-2 and 3-2 which maintained an amorphous state, showed a significant increase in related substances, while the increase in related substances was suppressed in the crystallized teneligliptin-containing particles of Reference Example 6-1 and the teneligliptin-containing tablets of Reference Example 6-2.
• the teneligliptin-containing particles of Reference Examples 2-1, 3-1, 4, and 6-1 and the teneligliptin-containing tablets of Reference Examples 2-2, 3-2, and 6-2 were all unable to suppress the increase in related substances while maintaining an amorphous state after storage under open conditions.
• Reference Example 7 The teneligliptin-containing particles of Reference Example 7 were produced by the same production method as in Reference Example 1-1.
• Reference Example 8 The teneligliptin-containing particles of Reference Example 8 were produced by the same production method as in Reference Example 4.
• Reference Example 9 The teneligliptin-containing particles of Reference Example 9 were produced by the same manufacturing method as that of Reference Example 8, except that 0.5 mg of citric acid (Fujifilm Wako Pure Chemical Industries, Ltd., citric acid monohydrate) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.
• citric acid Flujifilm Wako Pure Chemical Industries, Ltd., citric acid monohydrate
• Reference Example 10 The teneligliptin-containing particles of Reference Example 10 were produced by the same manufacturing method as that of Reference Example 8, except that 0.5 mg of tartaric acid (DL-tartaric acid, Yamazen Pharmaceutical Co., Ltd.) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.
• tartaric acid DL-tartaric acid, Yamazen Pharmaceutical Co., Ltd.
• Reference Example 11 The teneligliptin-containing particles of Reference Example 11 were produced by the same manufacturing method as that of Reference Example 8, except that 0.33 mg of fumaric acid (Fujifilm Wako Pure Chemical Industries, Ltd., fumaric acid) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.
• fumaric acid Flujifilm Wako Pure Chemical Industries, Ltd., fumaric acid
• Reference Example 12 The teneligliptin-containing particles of Reference Example 12 were produced by the same manufacturing method as that of Reference Example 8, except that 0.5 mg of malic acid (DL-malic acid, manufactured by Fuso Chemical Co., Ltd.) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.
• malic acid DL-malic acid, manufactured by Fuso Chemical Co., Ltd.
• Reference Example 13 The teneligliptin-containing particles of Reference Example 13 were produced by the same production method as that of Reference Example 8, except that 0.5 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.
• L-lactic acid Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid
• Reference Example 14 The teneligliptin-containing particles of Reference Example 14 were produced by the same production method as that of Reference Example 8, except that 1 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.
• L-lactic acid Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid
• Reference Example 15 The teneligliptin-containing particles of Reference Example 15 were produced by the same production method as in Reference Example 2-1.
• Reference Example 16 The teneligliptin-containing particles of Reference Example 16 were produced by the same production method as that of Reference Example 8, except that 3 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.
• L-lactic acid Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid
• Reference Example 17 The teneligliptin-containing particles of Reference Example 17 were produced by the same production method as that of Reference Example 8, except that 4 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.
• L-lactic acid Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid
• Reference Example 18 The teneligliptin-containing particles of Reference Example 18 were produced by the same production method as in Reference Example 3-1.
• the teneligliptin-containing particles of Reference Examples 7 to 18 were stored for 2 weeks or 1 month at 25°C and 75% relative humidity under open conditions. Using the measurement method described above, the crystal form of teneligliptin after 1 month of storage under open conditions and the amount of related substances immediately after production (initial) and after 2 weeks of storage under open conditions were evaluated. The evaluation results are shown in Table 3.
• Reference Examples 2-1, 2-2, 3-1, 3-2, and Reference Examples 4 to 18 reveal that by including an organic acid as a stabilizer in the teneligliptin-containing particles produced by the silica adsorption method, the amorphous form of teneligliptin is maintained even after storage under open conditions, while the amount of related substances immediately after production (initial) is significantly reduced. On the other hand, no formulation was obtained that suppressed the increase in related substances when stored under open conditions.
• Reference Example 20 The teneligliptin-containing particles of Reference Example 20 were produced by the same production method as in Reference Example 2-1.
• Example 1 When an antioxidant was mixed with teneligliptin-containing particles containing amorphous teneligliptin supported on porous silica and a stabilizer, it was examined whether the teneligliptin-containing particles could maintain the amorphous form and whether the increase in related substances could be suppressed. Specifically, 76.48 mg of the teneligliptin-containing particles obtained in Reference Example 20, 2 mg of propyl gallate (FUJIFILM Wako Pure Chemical Industries, Ltd., propyl gallate), and 2 mg of light anhydrous silicic acid (Freund Corporation, Adsolider (registered trademark) 101) were mixed in a mortar to obtain the teneligliptin-containing formulation of Example 1.
• Comparative Examples 1 to 9 Teneligliptin-containing formulations of Comparative Examples 1 to 9 were produced by the same production method as in Example 1, except that 2 mg of propyl gallate was changed to 2 mg of each of the antioxidants in Table 4 below.
• Example 2 It was examined whether the increase of related substances could be suppressed under open conditions even when a preparation containing an antioxidant was tableted. Specifically, 76.48 mg of the teneligliptin-containing particles of Reference Example 2-1, 2 mg of propyl gallate (FUJIFILM Wako Pure Chemical Industries, Ltd., propyl gallate), 6 mg of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11), 34.02 mg of D-mannitol (Freund Corporation, Granutol (registered trademark) F), 0.5 mg of light anhydrous silicic acid (Freund Corporation, Adsolider (registered trademark) 101), and 1 mg of magnesium stearate (Taihei Chemical Industry Co., Ltd., magnesium stearate (plant)) were mixed in a mortar. The mixture obtained was compressed and molded using a rotary tablet press to obtain the teneligliptin-containing tablets of Example 2.
• Example 2 and Comparative Example 20 were stored at 25°C and 75% relative humidity under open conditions for 2 weeks, 4 weeks, and 12 weeks. Using the measurement methods described above, the crystal form and amount of related substances were evaluated initially (immediately after production) and after storage under open conditions. The evaluation results are shown in Table 7.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Diabetes (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Endocrinology (AREA)
• Emergency Medicine (AREA)
• Inorganic Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (2)

Applications Claiming Priority (2)

Publications (1)

Family

ID=93430149

Family Applications (1)

Country Status (3)

Citations (4)

• 2024
  • 2024-04-11 JP JP2025519350A patent/JPWO2024232216A1/ja active Pending
  • 2024-04-11 CN CN202480002678.5A patent/CN119300831A/zh active Pending
  • 2024-04-11 WO PCT/JP2024/014708 patent/WO2024232216A1/ja active Application Filing

Patent Citations (4)

Also Published As

Similar Documents

Legal Events