WO2019230017A1 - Comprimé et son procédé de production - Google Patents

Comprimé et son procédé de production Download PDF

Info

Publication number
WO2019230017A1
WO2019230017A1 PCT/JP2018/040873 JP2018040873W WO2019230017A1 WO 2019230017 A1 WO2019230017 A1 WO 2019230017A1 JP 2018040873 W JP2018040873 W JP 2018040873W WO 2019230017 A1 WO2019230017 A1 WO 2019230017A1
Authority
WO
WIPO (PCT)
Prior art keywords
tablet
weight
pregabalin
present
mannitol
Prior art date
Application number
PCT/JP2018/040873
Other languages
English (en)
Japanese (ja)
Inventor
陽彦 洞口
保典 足立
泰徳 松田
功 船橋
耕太 影山
Original Assignee
武田テバファーマ株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 武田テバファーマ株式会社 filed Critical 武田テバファーマ株式会社
Publication of WO2019230017A1 publication Critical patent/WO2019230017A1/fr

Links

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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a tablet containing pregabalin that is stable over time and a method for producing the same.
  • Pregabalin is (S) -3-aminomethyl-5-methylhexanoic acid and has the following structure.
  • Pregabalin is a pharmaceutical active ingredient and is used for the treatment of pain associated with neuropathic pain and fibromyalgia, for example.
  • tablets containing pregabalin are commercially available under trade names such as Lyrica (registered trademark) OD tablets 25 mg.
  • pregabalin is a powder with poor compression moldability and fluidity
  • a pharmaceutically acceptable auxiliary is required for the production of tablets containing pregabalin.
  • JP 2000-34227 A describes that a water retention agent selected from ethylene glycol, propylene glycol, butylene glycol, sorbitol, glycerin and fatty acid esters thereof is blended in a solid preparation containing pregabalin.
  • JP-T-2010-524991 (Examples 4 and 7) describes that mannitol is added to a solid preparation containing pregabalin.
  • the present invention has been made to solve the above problems, and is a tablet containing pregabalin, which can suppress not only the lactam body of pregabalin but also other analogs over time, and particularly
  • An object of the present invention is to provide a tablet and a method for producing the same, which can suppress the formation of the analog over time regardless of whether the water content in the tablet is low or high.
  • the present invention provides a tablet having excellent hardness and disintegration in addition to the stable tablet over time, and a method for producing the tablet With the goal.
  • the present inventors have unexpectedly been able to suppress the production of not only the lactam body of pregabalin but also other analogs over time by using isomalt in addition to mannitol. I found out. Moreover, by using isomalt in addition to mannitol, it is possible to suppress the production of pregabalin analogs over time, regardless of whether the water content in the tablets is low or high, and the total amount of analogs can be reduced. It was also found that the increase can be suppressed. The present invention is based on these findings that exceed the expectations of those skilled in the art.
  • the first aspect of the present invention is: Pregabalin or a pharmaceutically acceptable salt thereof, Mannitol and It is a tablet containing isomalt.
  • the tablet of the present invention contains 0.85% or less or 1.80% by weight or more of water based on the weight of the tablet, and the total affinity of pregabalin contained in the tablet after sealed storage at 70 ° C. for 4 days.
  • the body weight is preferably 2.00% or less.
  • the amount of pregabalin or a pharmaceutically acceptable salt thereof in the tablet of the present invention is preferably 20 to 30% by weight based on the total weight of the tablet.
  • the amount of mannitol in the tablet of the present invention is preferably 5.00 to 65.00% by weight based on the weight of the tablet.
  • the amount of the isomalt in the tablet of the present invention is preferably 1.00 to 3.00% by weight based on the weight of the tablet.
  • the tablet of the present invention does not contain cellulose or a derivative thereof.
  • the tablet of the present invention preferably does not contain a binder.
  • the tablet of the present invention preferably has a hardness of 3.0 kgf or more.
  • the tablet of the present invention is preferably an orally disintegrating tablet.
  • a method for improving the performance This is a method of blending isomalt in the tablet.
  • a fourth aspect of the present invention includes blending isomalt with a tablet containing pregabalin or a pharmaceutically acceptable salt thereof and mannitol, and is 0.80% by weight or less or 1.80% by weight based on the weight of the tablet. Even if it contains the above water
  • a method for producing a tablet which is stable over time even if it contains water of 0.80% by weight or less or 1.80% by weight or more based on the weight of the tablet, including a tableting step for tableting the granulated product. is there.
  • the granulation step is performed by a fluidized bed granulation method. Moreover, it is preferable that the granulation liquid further contains mannitol.
  • the present invention it is possible to suppress not only the lactam form of pregabalin but also other analogues over time, and in particular, the analogues in any state where the water content in the tablet is low or high. Can be suppressed over time.
  • the present invention it is possible to suppress the increase in the total amount of pregabalin over time, and in particular, even if the amount of water in the tablet is low or high, the total pregabalin analog. Increase over time can be suppressed.
  • the present invention it is possible to improve the temporal stability of pregabalin in a tablet, and in particular, the temporal stability of pregabalin in a tablet with relatively little or high water content.
  • the tablet of the present invention can be stably stored or used over a long period of time, particularly in an environment where the humidity is low or high, and also in an environment where the humidity largely fluctuates up and down.
  • pregabalin-containing tablets having such high stability can be easily produced.
  • the tablet when the tablet is an orally disintegrating tablet, a pregabalin-containing tablet having both excellent hardness and disintegration can be easily produced.
  • Pregabalin The tablet of the present invention contains pregabalin or a pharmaceutically acceptable salt thereof. Pregabalin is relatively stable when stored alone.
  • pregabalin generally produces analogs when stored in contact with pharmaceutically acceptable excipients.
  • the formation of analogs is not preferred because it consumes pregabalin, which is a pharmaceutical active ingredient.
  • a typical analog is 4-isobutyl-pyrrolidin-2-one (lactam form), which is considered to be produced by a dehydration reaction between an amino group and a carboxy group present in the molecule of pregabalin. This dehydration reaction is promoted by contact with additives such as excipients, moisture environment in tablets, and the like.
  • the amount of lactam can be measured, for example, using high performance liquid chromatography according to the Japanese Pharmacopoeia, and can be calculated as the ratio of the peak area of the lactam to the peak area of pregabalin.
  • the total analog amount means the total amount of all detectable pregabalin analogs including lactam in the above measurement.
  • the pharmaceutically acceptable salt of pregabalin is not particularly limited, and examples thereof include acid addition salts and base addition salts.
  • Acids that can be used to form the acid addition salts are not particularly limited, but include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and organic acids.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid
  • organic acids for example, p-toluenesulfonic acid, salicylic acid, tartaric acid, ditartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, Examples include lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid.
  • Bases that can be used to form base addition salts include, but are not limited to, alkali metal hydroxides including sodium, potassium and lithium; hydroxides of alkaline earth metals such as calcium and magnesium Products; hydroxides of other metals such as aluminum and zinc; ammonia; organic amines such as mono-, di-, or tri-alkylamines, dicyclohexylamines, unsubstituted or substituted with hydroxyl groups; tributylamine; pyridine N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis- or tris-, such as N, N-dimethyl-N- (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine; (2-OH- (C 1 -C 6 ) -alkylamine); N-methyl-D-glucamine; mole Forin; thiomorpholine; piperidine; pyrrolidine; and amino acids such as argin
  • the amount of pregabalin or a pharmaceutically acceptable salt thereof contained in the tablet of the present invention is not particularly limited, but is preferably 20 to 30% by weight, more preferably 22 to 29% by weight in the tablet. 24 to 28% by weight is particularly preferable.
  • the tablet of the present invention contains mannitol.
  • mannitol D-mannitol is preferred. Further, mannitol has many crystal forms, but there is no particular problem as long as it is a commonly used crystal form. ⁇ -type, ⁇ -type, and ⁇ -type are preferable, and ⁇ -type mannitol is more preferable.
  • mannitol is stable per se, has no odor, has an appropriate sweetness and a refreshing feeling, is excellent in palatability, and is suitable as an excipient for the tablet of the present invention.
  • the form of mannitol is not particularly limited, but is preferably in the form of particles, more preferably the average particle diameter of primary particles (non-granulated product) is in the range of 10 to 200 ⁇ m, 20 to Even more preferably within the range of 160 ⁇ m.
  • the average particle diameter means a median diameter in a volume reference distribution measured using a laser diffraction particle size distribution measuring apparatus.
  • the amount of mannitol contained in the tablet of the present invention is not particularly limited, but it is preferably 5.00 to 65.00% by weight based on the total weight of the tablet, and is 6.00 to 60.00% by weight. It is more preferable.
  • the tablet of the present invention contains isomalt.
  • Isomalt is an equimolar mixture of two disaccharides, each of glucose and mannitol ( ⁇ -D-glucopyranoside-1,6-mannitol) and glucose and sorbitol ( ⁇ -D-glucopyranoside-1,6-mannitol) and glucose And sorbitol ( ⁇ -D-glucopyranose-1,6-sorbitol). That is, isomalt is equimolar of 6-O- ⁇ -D-Glucopyranosyl-D-sorbitol (1,6-GPS) and 1-O- ⁇ -D-Glucopyranosyl-D-mannitol dehydrate (1,1-GPM). It is a mixed composition. When isomalt is completely hydrolyzed, it becomes glucose (50%), sorbitol (25%), and mannitol (25%).
  • Isomalt is an odorless white crystal and can contain water of crystallization.
  • the amount of water of crystallization is typically 5% by weight or less.
  • pregabalin analogs By combining isomalt with mannitol and pregabalin or a pharmaceutically acceptable salt thereof, the time-dependent formation of pregabalin analogs can be suppressed. In particular, it is possible to suppress the production of pregabalin analogs over time, regardless of whether the water content in the tablet is low or high.
  • the present invention it is possible to suppress the increase in the total amount of pregabalin over time, and in particular, even if the amount of water in the tablet is low or high, the total pregabalin analog. Can be suppressed over time.
  • the tablet of the present invention high tablet hardness can be obtained by combining isomalt with mannitol and pregabalin or a pharmaceutically acceptable salt thereof.
  • the tablet hardness can be measured using a tablet breaking strength measuring device (for example, TH-303MP: manufactured by Toyama Sangyo Co., Ltd.).
  • the tablet hardness is not particularly limited as long as it has a hardness that does not cause breakage during production, transportation, administration, and the like.
  • the tablet hardness is preferably 3.0 kgf or more, more preferably 3.5 kgf or more, and even more preferably 4.0 kgf or more.
  • the tablet of the present invention preferably has a hardness of 10.0 kgf or less, more preferably 9.0 kgf or less, and even more preferably 8.0 kgf or less.
  • mannitol contained in the tablet of the present invention has a low bonding property between particles and tends to adhere to wrinkles, mortars, etc. during compression molding.
  • the compression molding is performed. Can be improved.
  • the tablet of the present invention good disintegration can be obtained by combining isomalt with mannitol and pregabalin or a pharmaceutically acceptable salt thereof.
  • the disintegration property can be evaluated by measuring the disintegration time of the tablet.
  • the disintegration time can be measured by performing a disintegration test according to the Japanese Pharmacopoeia.
  • the tablet of the present invention it is possible to measure the disintegration time using, for example, an orally disintegrating tablet tester in addition to the disintegration test method described above. That is, the tablet of the present invention can be an orally disintegrating tablet.
  • the tablet of the present invention is, for example, an orally disintegrating tablet, the tablet preferably disintegrates within 120 seconds, more preferably disintegrates within 60 seconds, and disintegrates within 40 seconds. Even more preferred.
  • Hardness and disintegration are usually a trade-off, and when one is increased, the other tends to decrease, but the tablet of the present invention can achieve both excellent hardness and disintegration.
  • isomalt for example, galen® IQ (manufactured by BENEO-Palatinit) can be used.
  • the form of isomalt is not particularly limited, and either powdered form or granulated product can be used.
  • the amount of isomalt contained in the tablet of the present invention is not particularly limited, but is preferably 1.00 to 3.00% by weight, and 1.10 to 2.50% by weight based on the total weight of the tablet. More preferably, the content is 1.20 to 2.00% by weight.
  • the increase in the total amount of pregabalin over time is suppressed, and in particular, whether the total amount of pregabalin in the tablet is low or high, Generation is suppressed.
  • the water content in the tablet is 0.80% by weight or less or 1.80% by weight or more based on the weight of the tablet, the generation of the total analog over time is suppressed.
  • the stability with time of pregabalin is improved, especially in any state where the water content in the tablet is low or high.
  • the stability of pregabalin with a tablet of the present invention is improved even when the water content in the tablet is 0.80% by weight or less or 1.80% by weight or more based on the weight of the tablet.
  • the tablet of the present invention can be stably stored or used over a long period of time, particularly even in an environment where the humidity is low or high, and also in an environment where the humidity greatly fluctuates up and down.
  • the moisture in the tablet of the present invention is not particularly limited, and may be, for example, 0.80% by weight or less, or 0.70% by weight or less based on the total weight of the tablet. 0.60% by weight or less. Further, the water content in the tablet of the present invention may be 1.20% by weight or more, 1.40% by weight or more, and 1.60% by weight based on the total weight of the tablet. The above may be sufficient and may be 1.80 weight% or more. On the other hand, the upper limit of moisture in the tablet of the present invention is preferably 5.0% by weight or less, more preferably 4.00% by weight or less, still more preferably 3.00% by weight or less, based on the total weight of the tablet. Most preferably, it is 2.00 weight% or less. In the present invention, the moisture value in the tablet can be measured using an infrared moisture meter (for example, FD-230: manufactured by Ketto Scientific Laboratory Co., Ltd.).
  • the tablet of the present invention is a general-purpose component in the field of solid pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, in addition to the essential components mannitol and isomalt. Can be included.
  • the excipient is not particularly limited, and examples thereof include carbohydrates, starches, and celluloses.
  • carbohydrates include monosaccharides, disaccharides, and sugar alcohols used in the field of solid pharmaceutical preparations. Specifically, lactose hydrate, anhydrous lactose, sucrose, purified sucrose, fructose, Examples thereof include glucose, glucose hydrate, sorbitol, xylitol, erythritol, maltitol and the like.
  • starches examples include corn starch, wheat starch, rice starch, and potato starch.
  • celluloses examples include crystalline cellulose and powdered cellulose.
  • the excipient one or more of these can be used, but two or more may be used.
  • the blending amount of the excipient is preferably 5% by weight or more, more preferably 10% by weight or more, still more preferably 15% by weight or more based on the total weight of the tablet.
  • the blending amount of the excipient is preferably 30% by weight or less, more preferably 25% by weight or less, and still more preferably 20% by weight or less based on the total weight of the tablet.
  • the binder is not particularly limited, and examples thereof include magnesium aluminate metasilicate, synthetic aluminum silicate, light anhydrous silicic acid, polyvinyl alcohol, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, povidone and the like. It is done.
  • the binder one or more of these can be used, but two or more may be used.
  • the blending amount of the binder may be 0.1% by weight or more, 0.5% by weight or more, or 1.0% by weight or more based on the total weight of the tablet.
  • the blending amount of the binder is preferably 10.0% by weight or less, more preferably 5.0% by weight or less, and still more preferably 3.0% by weight or less based on the total weight of the tablet. It is particularly preferred that the tablet of the present invention does not contain a binder.
  • the disintegrant is not particularly limited, but cellulosic disintegrants (croscarmellose sodium, carmellose calcium, carmellose sodium, low-substituted hydroxypropylcellulose, etc.), crospovidone, starch-based disintegrants (partial) Such as alpha starch, hydroxypropyl starch, etc.).
  • the disintegrant one or more of these can be used, but two or more may be used.
  • the amount of the disintegrant may be 0.1% by weight or more, 0.5% by weight or more, or 1.0% by weight or more based on the total weight of the tablet.
  • the blending amount of the disintegrant is preferably 10.0% by weight or less, more preferably 5.0% by weight or less, and still more preferably 3.0% by weight or less based on the total weight of the tablet. It is particularly preferable that the tablet of the present invention does not contain a disintegrant other than isomalt.
  • the lubricant is not particularly limited, and examples thereof include magnesium stearate, calcium stearate, stearyl alcohol, stearic acid, talc, hydrogenated oil, sucrose fatty acid ester, glycerin fatty acid ester and the like.
  • the lubricant one or more of these can be used, but two or more may be used.
  • the blending amount of the lubricant is preferably 0.1% by weight or more, more preferably 0.5% by weight or more, and still more preferably 1.0% by weight or more based on the total weight of the tablet.
  • the tablet of the present invention may not contain talc.
  • the tablet of the present invention can contain general-purpose ingredients in the field of solid pharmaceutical preparations such as a foaming agent, a fragrance, a colorant, and an artificial sweetener.
  • the tablet of the present invention does not contain cellulose or a derivative thereof.
  • cellulose derivatives include crystalline cellulose, powdered cellulose, hydroxypropylcellulose, hypromellose, carmellose sodium, methylcellulose and the like.
  • the shape and weight of the tablet of the present invention are not particularly limited.
  • the tablet of the present invention can have a substantially cylindrical shape with convex upper and lower surfaces.
  • the weight of the tablet of the present invention can be in the range of 90 to 540 mg.
  • the tablet of the present invention preferably does not have a surface coating layer such as an enteric coating.
  • the present invention is for improving the temporal stability of a tablet containing pregabalin or a pharmaceutically acceptable salt thereof, mannitol, and water of 0.80 wt% or less or 1.80 wt% or more based on the weight of the tablet. Also related to the use of isomalt.
  • the tablet containing pregabalin or a pharmaceutically acceptable salt thereof and mannitol contains 0.80% by weight or less or 1.80% by weight or more of water based on the weight of the tablet.
  • the stability over time of the tablet is improved by the action of isomalt.
  • the moisture in the tablet is not particularly limited, and may be, for example, 0.80% by weight or less, 0.70% by weight or less, based on the total weight of the tablet, It may be 60% by weight or less. Further, the water content in the tablet of the present invention may be 1.20% by weight or more, 1.40% by weight or more, and 1.60% by weight based on the total weight of the tablet. The above may be sufficient and may be 1.80 weight% or more. On the other hand, the upper limit of the water content in the tablet is preferably 5.00% by weight or less, more preferably 4.00% by weight or less, still more preferably 3.00% by weight or less, most preferably based on the total weight of the tablet. Is 2.00% by weight or less. In the present invention, the moisture value in the tablet can be measured using an infrared moisture meter (for example, FD-230: manufactured by Ketto Scientific Laboratory Co., Ltd.).
  • the increase in the total amount of pregabalin in the tablet over time is suppressed, and in particular, the total analog of pregabalin, regardless of whether the amount of water in the tablet is low or high. Is suppressed over time.
  • the stability with time of pregabalin in the tablet is improved and the stability with time of the tablet is improved, in particular, regardless of whether the water content in the tablet is low or high.
  • the tablet to which the use of the present invention is applied can be stably stored or used for a long period of time, particularly even in an environment where the humidity is low or high, or in an environment where the humidity varies greatly in the vertical direction.
  • the present invention is a method for improving the stability over time of a tablet comprising pregabalin or a pharmaceutically acceptable salt thereof, mannitol, and water of 0.80 wt% or less or 1.80 wt% or more based on the weight of the tablet.
  • the present invention also relates to a method of blending isomalt in the tablet.
  • the above explanation regarding the tablet of the present invention applies to pregabalin or a pharmaceutically acceptable salt thereof, mannitol, isomalt, and tablet in the above-described stability improving method.
  • the tablet containing pregabalin or a pharmaceutically acceptable salt thereof and mannitol contains 0.80% by weight or less or 1.80% by weight or more of water based on the weight of the tablet. Even in this case, the stability over time of the tablet is improved by the action of isomalt.
  • the moisture in the tablet is not particularly limited, and may be, for example, 0.80% by weight or less, 0.70% by weight or less, based on the total weight of the tablet, It may be 60% by weight or less. Further, the water content in the tablet of the present invention may be 1.20% by weight or more, 1.40% by weight or more, and 1.60% by weight based on the total weight of the tablet. The above may be sufficient and may be 1.80 weight% or more. On the other hand, the upper limit of the water content in the tablet is preferably 5.00% by weight or less, more preferably 4.00% by weight or less, still more preferably 3.00% by weight or less, most preferably based on the total weight of the tablet. Is 2.00% by weight or less. In the present invention, the moisture value in the tablet can be measured using an infrared moisture meter (for example, FD-230: manufactured by Ketto Scientific Laboratory Co., Ltd.).
  • the stability improving method of the present invention not only the lactam body of pregabalin in the tablet but also other analogs over time are suppressed.
  • the generation of not only the lactam body of pregabalin but also other analogs over time is suppressed regardless of whether the water content in the tablet is low or high.
  • the stability with time of pregabalin in the tablet is improved even when the amount of water in the tablet is low or high, and as a result, the stability with time of the tablet is improved.
  • the tablet to which the stability improving method of the present invention is applied can be stored and used stably over a long period of time, particularly even in an environment where the humidity is low or high, or in an environment where the humidity greatly fluctuates up and down. it can.
  • the present invention comprises blending isomalt with a tablet containing pregabalin or a pharmaceutically acceptable salt thereof and mannitol, containing 0.80% by weight or less or 1.80% by weight or more of water based on the weight of the tablet
  • the present invention also relates to a method for producing tablets that are stable over time.
  • tablet of the present invention applies to pregabalin or a pharmaceutically acceptable salt thereof, mannitol, isomalt and tablet in the above production method.
  • the production method of the present invention can be carried out by a conventional method.
  • the granulation method is not particularly limited, and for example, a wet granulation method, a dry granulation method, or the like can be employed.
  • a known granulation apparatus such as a fluidized bed granulation apparatus, a rolling type granulation apparatus, a Wurster type granulation apparatus, or a stirring granulation apparatus may be appropriately selected and used.
  • granulation means an operation of processing a powder raw material composed of a single component or a plurality of components into particles larger than the raw material by agglomerating using a binder or the like. include.
  • the tablet obtained by the production method of the present invention even when it contains 0.80% by weight or less or 1.80% by weight or more of water based on the weight of the tablet, Stability is improved.
  • the moisture in the tablet is not particularly limited, and may be, for example, 0.80% by weight or less, 0.70% by weight or less, based on the total weight of the tablet, It may be 60% by weight or less. Further, the water content in the tablet of the present invention may be 1.20% by weight or more, 1.40% by weight or more, and 1.60% by weight based on the total weight of the tablet. The above may be sufficient and may be 1.80 weight% or more. On the other hand, the upper limit of the water content in the tablet is preferably 5.00% by weight or less, more preferably 4.00% by weight or less, still more preferably 3.00% by weight or less, most preferably based on the total weight of the tablet. Is 2.00% by weight or less. In the present invention, the moisture value in the tablet can be measured using an infrared moisture meter (for example, FD-230: manufactured by Ketto Scientific Laboratory Co., Ltd.).
  • the tablet obtained by the above production method of the present invention not only the lactam body of pregabalin in the tablet but also other analogs over time are suppressed.
  • the generation of not only the lactam body of pregabalin but also other analogs over time is suppressed regardless of whether the water content in the tablet is low or high.
  • the increase in the total amount of pregabalin analog in the tablet over time is suppressed, and in particular, either in a state where the water content in the tablet is low or high.
  • the production of pregabalin analogs over time is suppressed.
  • the above-described production method of the present invention provides a tablet in which pregabalin in the tablet has improved stability over time, and thus has improved tablet stability over time, regardless of whether the moisture content is low or high. can do.
  • the tablet obtained by the above production method of the present invention can be stably stored or used over a long period of time, particularly even in an environment where the humidity is low or high, or in an environment where the humidity fluctuates up and down. .
  • the present invention also provides: A mixing step of mixing pregabalin or a pharmaceutically acceptable salt thereof with mannitol to obtain a mixture; A granulating step for obtaining a granulated product by spraying and drying a granulating liquid containing isomalt in the mixture; and A method for producing a tablet which is stable over time even if it contains water of 0.80% by weight or less or 1.80% by weight or more based on the weight of the tablet, including a tableting step for tableting the granulated product. Also related.
  • the production method of the present invention can be carried out by a conventional method.
  • the mixer that can be used for the above mixing is not particularly limited, and a known mixer can be used.
  • the granulation step can be preferably performed, for example, by a fluidized bed granulation method using a fluidized bed granulator.
  • the granulating liquid preferably contains a volatile aqueous medium at normal temperature and normal pressure.
  • aqueous medium water or a lower alcohol such as ethanol is more preferred, and water is even more preferred.
  • the granulation liquid preferably contains mannitol. That is, it is preferable not to use all of mannitol in the mixing step, but to add a part of it to the granulation liquid.
  • mannitol it is preferable not to use all of mannitol in the mixing step, but to add a part of it to the granulation liquid.
  • the tableting machine used for tableting is not particularly limited, and for example, a known tableting machine such as a rotary tableting machine or a single tableting machine may be appropriately selected and used.
  • the pressure applied when preparing the tablet is not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately set.
  • the pressure applied when preparing the tablet is preferably 300 kgf or more, more preferably 500 kgf or more, and still more preferably 800 kgf or more.
  • the pressure applied when preparing the tablet is preferably 2400 kgf or less, more preferably 2200 kgf or less, and still more preferably 2000 kgf or less.
  • the above explanation regarding the tablet of the present invention applies to pregabalin or a pharmaceutically acceptable salt thereof, mannitol, isomalt, and tablet.
  • the stability over time of the tablet is improved even when it contains 0.80% by weight or less or 1.80% by weight or more of moisture based on the weight of the tablet. .
  • the moisture in the tablet is not particularly limited, and may be, for example, 0.80% by weight or less, 0.70% by weight or less, based on the total weight of the tablet, It may be 60% by weight or less. Further, the water content in the tablet of the present invention may be 1.20% by weight or more, 1.40% by weight or more, and 1.60% by weight based on the total weight of the tablet. The above may be sufficient and may be 1.80 weight% or more. On the other hand, the upper limit of the water content in the tablet is preferably 5.00% by weight or less, more preferably 4.00% by weight or less, still more preferably 3.00% by weight or less, most preferably based on the total weight of the tablet. Is 2.00% by weight or less. In the present invention, the moisture value in the tablet can be measured using an infrared moisture meter (for example, FD-230: manufactured by Ketto Scientific Laboratory Co., Ltd.).
  • the tablet obtained by the above production method of the present invention not only the lactam body of pregabalin in the tablet but also other analogs over time are suppressed.
  • the generation of not only the lactam body of pregabalin but also other analogs over time is suppressed regardless of whether the water content in the tablet is low or high.
  • the increase in the total amount of pregabalin analog in the tablet over time is suppressed, and in particular, either in a state where the water content in the tablet is low or high.
  • the production of pregabalin analogs over time is suppressed.
  • the above-described production method of the present invention provides a tablet in which pregabalin in the tablet has improved stability over time, and thus has improved tablet stability over time, regardless of whether the moisture content is low or high. can do.
  • the tablet obtained by the above production method of the present invention can be stably stored or used over a long period of time, particularly even in an environment where the humidity is low or high, or in an environment where the humidity fluctuates up and down. .
  • pregabalin-containing tablets having such high stability can be easily produced.
  • the tablet obtained by any one of the above production methods of the present invention has increased dispersibility of pregabalin or a pharmaceutically acceptable salt thereof in the tablet, so that pregabalin or a pharmaceutically acceptable salt thereof is uniformly contained in the tablet. Can be dispersed.
  • the tablet of the present invention can be used for the treatment of pain associated with neuropathic pain and fibromyalgia.
  • neuropathic pain include postherpetic neuralgia, pain associated with diabetic peripheral neuropathy, and pain after spinal cord injury.
  • Example 1 pregabalin is mixed with D-mannitol, and an aqueous solution containing D-mannitol, isomalt and acesulfame potassium is sprayed and dried into the resulting mixture as a granulated liquid, and the granulated product is obtained by fluidized bed granulation. Obtained. Then, a premixed product (D-mannitol, corn starch), sucralose and a fragrance are added and mixed to the granulated product, and magnesium stearate is further added and mixed to the obtained mixture, and the resulting mixture is beaten. Tablets were prepared by tableting using a tablet machine.
  • Example 1 The tablets of Example 1, Comparative Example 1 and Comparative Example 2 were stored under the following conditions a to d, and four test preparations having different moisture contents in the tablets were prepared for each condition.
  • the water content of each test preparation is shown in Table 2 below.
  • Condition a The tablet is dried at 40 ° C. for 3 days.
  • Condition b The tablet is absorbed for 3 days at 25 ° C. and a relative humidity of 60%.
  • Condition c The tablet is absorbed for 3 days at 25 ° C. and 75% relative humidity.
  • Condition d Without adjusting the humidity as in the conditions a to c, the tablets are sealed in an airtight container in a room at 25 ° C. and stored for 3 days.
  • test preparations prepared under the above four conditions were each stored hermetically at 70 ° C. for 4 days. With respect to these specimens after storage, the amounts of lactam and total analogs were measured. The measurement was performed using high performance liquid chromatography (Alliance HPLC: manufactured by Nihon Waters Co., Ltd.) based on the test method described in EUROPEAN PHARMACOPEIA (European Pharmacopoeia). In addition, the quantity of the lactam body and the total analog was calculated
  • Non-Patent Document 1 the additives used in Lyrica OD tablets 75 mg are as shown in Table 4 below.
  • the tablet of Comparative Example 3 was unstable in a relatively high water content region, and in particular, the total analog content increased.
  • the tablet of Example 1 was stable even in a relatively high moisture region, and the generation of the total analog amount could be suppressed.
  • the tablet of Example 1 is stable in both a relatively low moisture region and a relatively high moisture region, and can suppress the production of lactam and total analog amounts, and in particular, the total analog amount. Was able to be suppressed.
  • Example 1 The tablets of Example 1, Comparative Example 1 and Comparative Example 2 were subjected to hardness and oral disintegration tests. As a result, the tablet of Example 1 had an excellent hardness of 8.0 kgf, and the oral disintegration property was extremely good. On the other hand, the tablet of Comparative Example 1 had tableting troubles during the compression production. The tablet of Comparative Example 2 was inferior in oral disintegration.
  • the present invention improves the stability of pregabalin in tablets containing pregabalin that can be used for the treatment of neuropathic pain and the like, and can be used over a long period of time (particularly in low or high humidity environments). This is useful.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un comprimé qui comprend de la prégabaline ou un sel pharmaceutiquement acceptable de celle-ci, du mannitol et de l'isomalt. Le comprimé selon la présente invention est capable d'inhiber la génération temporelle non seulement d'un lactame de prégabaline mais également d'autres analogues de ce composé, en particulier capable d'inhiber la génération temporelle desdits analogues indépendamment du fait que la teneur en eau du comprimé est faible ou élevée.
PCT/JP2018/040873 2018-05-31 2018-11-02 Comprimé et son procédé de production WO2019230017A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2018105154A JP6504638B1 (ja) 2018-05-31 2018-05-31 錠剤及びその製造方法
JP2018-105154 2018-05-31

Publications (1)

Publication Number Publication Date
WO2019230017A1 true WO2019230017A1 (fr) 2019-12-05

Family

ID=66324277

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2018/040873 WO2019230017A1 (fr) 2018-05-31 2018-11-02 Comprimé et son procédé de production

Country Status (2)

Country Link
JP (1) JP6504638B1 (fr)
WO (1) WO2019230017A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010524991A (ja) * 2007-04-23 2010-07-22 ラシオファルム ゲーエムベーハー プレガバリンを含有する安定化された医薬組成物
WO2011107812A2 (fr) * 2010-03-01 2011-09-09 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Composition pharmaceutique stabilisée
WO2017061426A1 (fr) * 2015-10-05 2017-04-13 大同化成工業株式会社 Produit composite granulé comprenant du sucre ou un alcool de sucre, un liant gonflant, un agent délitant et un excipient hautement absorbant, et procédé de fabrication dudit produit composite granulé
JP2018118966A (ja) * 2017-01-23 2018-08-02 日新製薬株式会社 ３位が置換されたγ−アミノ酪酸誘導体を含有する圧縮固形医薬組成物。
JP2018150287A (ja) * 2017-03-15 2018-09-27 武田テバファーマ株式会社 不快な味がマスキングされた経口医薬組成物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190328674A1 (en) * 2016-06-16 2019-10-31 Towa Pharmaceutical Co., Ltd. Orally disintegrating tablet

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010524991A (ja) * 2007-04-23 2010-07-22 ラシオファルム ゲーエムベーハー プレガバリンを含有する安定化された医薬組成物
WO2011107812A2 (fr) * 2010-03-01 2011-09-09 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Composition pharmaceutique stabilisée
WO2017061426A1 (fr) * 2015-10-05 2017-04-13 大同化成工業株式会社 Produit composite granulé comprenant du sucre ou un alcool de sucre, un liant gonflant, un agent délitant et un excipient hautement absorbant, et procédé de fabrication dudit produit composite granulé
JP2018118966A (ja) * 2017-01-23 2018-08-02 日新製薬株式会社 ３位が置換されたγ−アミノ酪酸誘導体を含有する圧縮固形医薬組成物。
JP2018150287A (ja) * 2017-03-15 2018-09-27 武田テバファーマ株式会社 不快な味がマスキングされた経口医薬組成物

Also Published As

Publication number Publication date
JP6504638B1 (ja) 2019-04-24
JP2019210218A (ja) 2019-12-12

Similar Documents

Publication Publication Date Title
EP2815752B1 (fr) Composition pharmaceutique orale
RU2600831C2 (ru) Перорально вводимая фармацевтическая композиция
JPWO2009084678A1 (ja) 口腔内崩壊錠およびその製造方法
TWI756177B (zh) 安定的經口投予用醫藥組成物
JP2022088683A (ja) 医薬組成物
KR100676617B1 (ko) 아목시실린 및/또는 클라불란산 또는 이의 염을 함유하는경구용 현탁정제 조성물
JP2019210276A (ja) 錠剤及びその製造方法
JP4329947B1 (ja) 内服用錠剤
JP5823592B2 (ja) 安定性が改善された製剤
JP2010111630A (ja) アズレンスルホン酸塩含有粒子及びその製造方法、ならびにこれを含む医薬製剤
US9271951B2 (en) Levothyroxine formulation with acacia
WO2019230017A1 (fr) Comprimé et son procédé de production
JP5113476B2 (ja) 保存安定性に優れた塩酸テモカプリルの錠剤
WO2020045607A1 (fr) Composition pharmaceutique pour administration par voie orale
KR20180085686A (ko) 엘로티닙염산염 함유 의약 조성물의 제조 방법
JP6283314B2 (ja) アナグリプチン含有固形製剤
US20230050931A1 (en) Solid pharmaceutical preparation
WO2014051024A1 (fr) Composition de médicament contenant de l'anagliptine
JP2013103924A (ja) 結晶性アトルバスタチンカルシウム含有錠剤の製造方法
JP2010168343A (ja) 内服用錠剤
JP2019202981A (ja) レボセチリジン固形製剤
JP2018012649A (ja) 錠剤及びその製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18920810

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18920810

Country of ref document: EP

Kind code of ref document: A1