WO2019230017A1 - Tablet and production method therefor - Google Patents

Tablet and production method therefor Download PDF

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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
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WO
WIPO (PCT)
Prior art keywords
tablet
weight
pregabalin
present
mannitol
Prior art date
Application number
PCT/JP2018/040873
Other languages
French (fr)
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/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
    • A61K31/185—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.

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Abstract

The present invention pertains to a tablet that comprises pregabalin or a pharmaceutically acceptable salt thereof, mannitol, and isomalt. The tablet according to the present invention is capable of inhibiting temporal generation of not only a lactam of pregabalin but also other analogs thereof, in particular able to inhibit temporal generation of said analogs regardless of whether the water content in the tablet is low or high.

Description

錠剤及びその製造方法Tablet and production method thereof
　本発明は、経時的に安定なプレガバリンを含む錠剤及びその製造方法に関する。 The present invention relates to a tablet containing pregabalin that is stable over time and a method for producing the same.
　プレガバリンは、（Ｓ）－３－アミノメチル－５－メチルヘキサン酸であり、以下の構造を有する。 Pregabalin is (S) -3-aminomethyl-5-methylhexanoic acid and has the following structure.
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　プレガバリンは医薬有効成分であり、例えば、神経障害性疼痛及び線維筋痛症に伴う疼痛の治療に使用されている。現在、プレガバリンを含む錠剤は、リリカ（登録商標）OD錠２５ｍｇ等の商品名で市販されている。 Pregabalin is a pharmaceutical active ingredient and is used for the treatment of pain associated with neuropathic pain and fibromyalgia, for example. At present, tablets containing pregabalin are commercially available under trade names such as Lyrica (registered trademark) OD tablets 25 mg.
　プレガバリンは、圧縮成形性及び流動性が乏しい粉末であるため、プレガバリンを配合する錠剤の製造には薬学的に許容可能な助剤を必要とする。 Since pregabalin is a powder with poor compression moldability and fluidity, a pharmaceutically acceptable auxiliary is required for the production of tablets containing pregabalin.
　しかしながら、そのような助剤の多くはプレガバリンと経時的に反応し、プレガバリンの分子内に存在するアミノ基とカルボキシ基との脱水反応を促進して以下の構造を有する４－イソブチル－ピロリジン－２－オン（ラクタム体）を生成すると考えられている。
Figure JPOXMLDOC01-appb-C000002
 However, many of such auxiliaries react with pregabalin over time, and promote the dehydration reaction between the amino group and carboxy group present in the molecule of pregabalin to give 4-isobutyl-pyrrolidine-2 having the following structure: -It is thought to produce on (lactam form).
Figure JPOXMLDOC01-appb-C000002
　そこで、ラクタム体の経時的な生成を抑制するために種々の工夫が提案されている。例えば、特開２０００－３４２２７号公報には、エチレングリコール、プロピレングリコール、ブチレングリコール、ソルビトール並びにグリセリン及びその脂肪酸エステルから選ばれる保水剤をプレガバリンを含む固形製剤に配合することが記載されている。また、特表２０１０－５２４９９１号公報（実施例４及び実施例７）には、マンニトールをプレガバリンを含む固形製剤に配合することが記載されている。 Therefore, various devices have been proposed in order to suppress the formation of lactam bodies over time. For example, 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.
特開２０００－３４２２７号公報JP 2000-34227 A 特表２０１０－５２４９９１号公報JP 2010-524991 Gazette
　しかし、プレガバリンと共にマンニトールを含む錠剤では、確かに、ラクタム体の経時的な生成が比較的抑制されるものの、当該ラクタム体以外の類縁体の経時的な生成を抑制することは困難であり、総類縁体量が経時的に増大する。特に、錠剤中の水分が少ない場合及び多い場合のいずれの場合においても、類縁体の経時的な生成がより増大し、総類縁体量がより増大することがある。 However, in the tablet containing mannitol together with pregabalin, although the production of lactams over time is relatively suppressed, it is difficult to suppress the production of analogs other than the lactam over time. The amount of analog increases over time. In particular, in both cases where the water content in the tablet is low and high, the production of analogs over time may increase, and the total analog amount may increase.
　本発明は、上記の課題を解決すべくなされたものであり、プレガバリンを含む錠剤であって、プレガバリンのラクタム体のみならずその他の類縁体の経時的な生成をも抑制することができ、特に、錠剤中の水分が少ない状態及び多い状態のいずれであっても当該類縁体の経時的な生成を抑制可能である、錠剤及びその製造方法を提供することを目的とする。また、本発明は、錠剤が口腔内崩壊錠である場合、当該経時的に安定な錠剤であることに加えて、優れた硬度と崩壊性も兼ね備えている、錠剤及びその製造方法を提供することを目的とする。 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. In addition, when the tablet is an orally disintegrating tablet, 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.
　本発明者らは上記課題について鋭意検討した結果、予期しないことに、マンニトールに加えてイソマルトを使用することによって、プレガバリンのラクタム体のみならずその他の類縁体の経時的な生成を抑制可能であることを見出した。また、マンニトールに加えてイソマルトを使用することによって、錠剤中の水分が少ない状態及び多い状態のいずれであっても、プレガバリンの類縁体の経時的な生成を抑制可能であり、総類縁体量の増加を抑制できることも判明した。本発明は当業者の予測を超えるこれらの知見に基づくものである。 As a result of intensive studies on the above problems, 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.
本発明の第１の態様は、
プレガバリン又はその薬学上許容可能な塩、
マンニトール、及び、
イソマルト
を含む錠剤である。 The first aspect of the present invention is:
Pregabalin or a pharmaceutically acceptable salt thereof,
Mannitol and
It is a tablet containing isomalt.
　本発明の錠剤は、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含む場合に７０℃の条件下で４日間密封貯蔵後に錠剤に含まれるプレガバリンの総類縁体量が２．００％以下であることが好ましい。 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.
本発明の錠剤中の前記プレガバリン又はその薬学的に許容可能な塩の量は錠剤の全重量を基準として２０～３０重量％であることが好ましい。 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.
本発明の錠剤中の前記マンニトールの量は錠剤の重量を基準として５．００～６５．００重量％であることが好ましい。 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.
本発明の錠剤中の前記イソマルトの量が錠剤の重量を基準として１．００～３．００重量％であることが好ましい。 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.
本発明の錠剤はセルロース又はその誘導体を含まないことが好ましい。 It is preferable that the tablet of the present invention does not contain cellulose or a derivative thereof.
本発明の錠剤は結合剤を含まないことが好ましい。 The tablet of the present invention preferably does not contain a binder.
　本発明の錠剤は３．０ｋｇｆ以上の硬度を有することが好ましい。 The tablet of the present invention preferably has a hardness of 3.0 kgf or more.
本発明の錠剤は口腔内崩壊錠であることが好ましい。 The tablet of the present invention is preferably an orally disintegrating tablet.
本発明の第２の態様は、プレガバリン又はその薬学上許容可能な塩、マンニトール、及び、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含む錠剤の経時安定性向上のためのイソマルトの使用である。 According to a second aspect of the present invention, there is provided the stability over time 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. Isomalt to improve the performance.
本発明の第３の態様は、プレガバリン又はその薬学上許容可能な塩、マンニトール、及び、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含む錠剤の経時安定性向上方法であって、
前記錠剤にイソマルトを配合する方法である。 According to a third aspect of the present invention, there is provided the stability over time 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. A method for improving the performance,
This is a method of blending isomalt in the tablet.
本発明の第４の態様は、プレガバリン又はその薬学上許容可能な塩及びマンニトールを含む錠剤にイソマルトを配合することを含む、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含有しても経時的に安定な錠剤の製造方法である。 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 | moisture content, it is a manufacturing method of a tablet stable over time.
本発明の第５の態様は、
プレガバリン又はその薬学上許容可能な塩をマンニトールと混合して混合物を得る混合工程、
前記混合物にイソマルトを含む造粒液を噴霧及び乾燥して造粒物を得る造粒工程、及び、
前記造粒物を錠剤化する錠剤化工程
を含む、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含有しても経時的に安定な錠剤の製造方法である。 According to a fifth aspect of the present invention,
A mixing step of mixing pregabalin or a pharmaceutically acceptable salt thereof with mannitol to obtain a mixture;
A granulation step of spraying and drying a granulation liquid containing isomalt to the mixture to obtain a granulated product; 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. is there.
　前記造粒工程が流動層造粒法によって行われることが好ましい。また、前記造粒液が更にマンニトールを含むことが好ましい。 It is preferable that the granulation step is performed by a fluidized bed granulation method. Moreover, it is preferable that the granulation liquid further contains mannitol.
　本発明によれば、プレガバリンのラクタム体のみならずその他の類縁体の経時的な生成を抑制可能であり、特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、当該類縁体の経時的な生成を抑制可能である。 According to 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.
したがって、本発明によれば、プレガバリンの総類縁体量の経時的な増大を抑制することができ、特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンの総類縁体の経時的な増大を抑制可能である。 Therefore, according to 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.
　すなわち、本発明により、錠剤中のプレガバリンの経時安定性を、特に、水分が比較的少ない又は多い錠剤中のプレガバリンの経時安定性を改善することができる。 That is, according to 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.
斯くして、本発明の錠剤は長期に亘って、特に、湿度の低い又は高い環境下でも、また、湿度が上下に大きく変動する環境下でも、安定に保存乃至使用することができる。 Thus, 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.
　また、本発明によれば、そのような高い安定性を備えたプレガバリン含有錠剤を容易に製造することができる。 Further, according to the present invention, pregabalin-containing tablets having such high stability can be easily produced.
　また、本発明によれば、錠剤が口腔内崩壊錠である場合、優れた硬度と崩壊性を兼ね備えたプレガバリン含有錠剤を容易に製造することができる。 Moreover, according to the present invention, when the tablet is an orally disintegrating tablet, a pregabalin-containing tablet having both excellent hardness and disintegration can be easily produced.
［プレガバリン］
　本発明の錠剤はプレガバリン又はその薬学上許容可能な塩を含む。プレガバリンは単独で保存された場合には比較的安定である。 [Pregabalin]
The tablet of the present invention contains pregabalin or a pharmaceutically acceptable salt thereof. Pregabalin is relatively stable when stored alone.
　一方、プレガバリンは、薬学的に許容可能な賦形剤と接触した状態で保存すると、一般に、類縁体を生成する。類縁体の生成は医薬有効成分であるプレガバリンを消費するので好ましくない。代表的な類縁体はプレガバリンの分子内に存在するアミノ基とカルボキシ基との脱水反応により生成すると考えられている４－イソブチル－ピロリジン－２－オン（ラクタム体）である。この脱水反応は、賦形剤等の添加剤との接触、錠剤中の水分環境等によって促進される。 On the other hand, 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.
また、その他の類縁体の生成も、賦形剤等の添加剤との接触、錠剤中の水分環境等によって促進される。 The production of other analogs is also promoted by contact with additives such as excipients, moisture environment in tablets, and the like.
本発明において、ラクタム体量は、例えば、日本薬局方に準じて、高速液体クロマトグラフィを用いて測定可能であり、プレガバリンのピーク面積に対するラクタム体のピーク面積の比率として算出することができる。また総類縁体量は、上記測定において、ラクタム体を含む、検出可能な全てのプレガバリン類縁体の総量を意味する。 In the present invention, 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.
　プレガバリンの薬学上許容可能な塩は、特に限定されるものではないが、酸付加塩又は塩基付加塩が挙げられる。 The pharmaceutically acceptable salt of pregabalin is not particularly limited, and examples thereof include acid addition salts and base addition salts.
　酸付加塩を形成するために使用可能な酸としては、特に限定されるものではないが、無機酸、例えば、塩酸、臭化水素酸、ヨウ化水素酸、硫酸及びリン酸、並びに、有機酸、例えば、p-トルエンスルホン酸、サリチル酸、酒石酸、二酒石酸、アスコルビン酸、マレイン酸、ベシル酸、フマル酸、グルコン酸、グルクロン酸、ギ酸、グルタミン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、乳酸、シュウ酸、p-ブロモフェニルスルホン酸、炭酸、コハク酸、クエン酸、安息香酸及び酢酸が挙げられる。 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. 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.
塩基付加塩を形成するために使用可能な塩基としては、特に限定されるものではないが、ナトリウム、カリウム及びリチウムを含むアルカリ金属の水酸化物；カルシウム及びマグネシウム等のアルカリ土類金属の水酸化物；アルミニウム及び亜鉛等の他の金属の水酸化物；アンモニア；無置換又はヒドロキシル基で置換されたモノ－、ジ－、又は、トリ－アルキルアミン、ジシクロヘキシルアミン等の有機アミン；トリブチルアミン；ピリジン；Ｎ－メチル、Ｎ－エチルアミン；ジエチルアミン；トリエチルアミン；Ｎ，Ｎ－ジメチル－Ｎ－（２－ヒドロキシエチル）アミン又はトリ－（２－ヒドロキシエチル)アミン等のモノ－、ビス－、又は、トリス－(２－ＯＨ－（Ｃ１－Ｃ６）－アルキルアミン)；Ｎ－メチル－Ｄ－グルカミン；モルフォリン；チオモルフォリン；ピペリジン；ピロリジン；及び、アルギニン、リジン等のアミノ酸が挙げられる。 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 arginine and lysine.
　本発明の錠剤に含まれるプレガバリン又はその薬学上許容可能な塩の配合量は特に限定されないが、錠剤中に２０～３０重量％であることが好ましく、２２～２９重量％であることがより好ましく、２４～２８重量％であることが特に好ましい。 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.
［マンニトール］
　本発明の錠剤はマンニトールを含む。 [Mannitol]
The tablet of the present invention contains mannitol.
マンニトールとしてはＤ－マンニトールが好ましい。また、マンニトールは数多くの結晶形が存在するが、一般的に使用される結晶形であれば、特に問題ない。好ましくはα型、β型、δ型であり、更に好ましくはβ型マンニトールである。 As 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. Α-type, β-type, and δ-type are preferable, and β-type mannitol is more preferable.
　更に、マンニトールはそれ自体は安定であり、臭いが無く、適度な甘みと清涼感を有するため嗜好性に優れており、本発明の錠剤の賦形剤として好適である。 Furthermore, 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.
　マンニトールの形態は特には限定されるものではないが、粒子の形態にあるものが好ましく、一次粒子（非造粒品）の平均粒子径が１０～２００μｍの範囲内のものがより好ましく、２０～１６０μｍの範囲内のものが更により好ましい。なお、ここでの平均粒子径とは、レーザー回折式粒度分布測定装置を用いて測定した体積基準分布におけるメジアン径を意味する。 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 μm, 20 to Even more preferably within the range of 160 μm. Here, the average particle diameter means a median diameter in a volume reference distribution measured using a laser diffraction particle size distribution measuring apparatus.
　本発明の錠剤に含まれるマンニトールの配合量は特に限定されないが、錠剤の全重量を基準として５．００～６５．００重量％であることが好ましく、６．００～６０．００重量％であることがより好ましい。 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.
［イソマルト］
　本発明の錠剤はイソマルトを含む。 [Isomalt]
The tablet of the present invention contains isomalt.
イソマルトは２つの二糖の等モル混合物であり、それぞれがグルコースとマンニトール（α-D-グルコピラノシド-1,6-マンニトール）及びグルコースとソルビトール（α-D-グルコピラノシド-1,6-マンニトール）及びグルコースとソルビトール（α-D-グルコピラノース-1,6-ソルビトール）からなる。すなわち、イソマルトは、6-O-α-D-Glucopyranosyl-D-sorbitol（1,6-GPS）及び1-O-α-D-Glucopyranosyl-D-mannitol dehydrate（1,1-GPM）の等モル混合組成物である。イソマルトを完全に加水分解すると、グルコース（５０％）、ソルビトール（２５％）、マンニトール（２５％）になる。 Isomalt is an equimolar mixture of two disaccharides, each of glucose and mannitol (α-D-glucopyranoside-1,6-mannitol) and glucose and sorbitol (α-D-glucopyranoside-1,6-mannitol) and glucose And sorbitol (α-D-glucopyranose-1,6-sorbitol). That is, isomalt is equimolar of 6-O-α-D-Glucopyranosyl-D-sorbitol (1,6-GPS) and 1-O-α-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%).
イソマルトは無臭の白色結晶であり、結晶水を含むことができる。結晶水の量は典型的には５重量％以下である。 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.
イソマルトをマンニトールと組み合わせてプレガバリン又はその薬学上許容可能な塩と共に配合することにより、プレガバリンの類縁体の経時的生成を抑制することができる。特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンの類縁体の経時的な生成を抑制可能である。 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.
したがって、本発明によれば、プレガバリンの総類縁体量の経時的な増大を抑制することができ、特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンの総類縁体の経時的な生成を抑制可能である。 Therefore, according to 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.
　一方、本発明の錠剤では、イソマルトをマンニトールと組み合わせてプレガバリン又はその薬学上許容可能な塩と共に配合することによって、高い錠剤硬度を得ることができる。本発明において錠剤硬度は、錠剤破壊強度測定器（例えば、ＴＨ－３０３ＭＰ：富山産業株式会社製）等を使用して測定することが可能である。本発明において錠剤硬度は、製造、運搬、投薬等に際して破損しない程度の硬度を有していればよく、特に限定されるものでない。本発明において錠剤硬度は、３．０ｋｇｆ以上の硬度を有することが好ましく、３．５ｋｇｆ以上の硬度を有することがより好ましく、４．０ｋｇｆ以上の硬度を有することが更により好ましい。本発明の錠剤の硬度は１０．０ｋｇｆ以下が好ましく、９．０ｋｇｆ以下がより好ましく、８．０ｋｇｆ以下が更により好ましい。 On the other hand, in 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. In the present invention, the tablet hardness can be measured using a tablet breaking strength measuring device (for example, TH-303MP: manufactured by Toyama Sangyo Co., Ltd.). In the present invention, 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. In the present invention, 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.
　また、本発明の錠剤に含まれるマンニトールは粒子間の結合性が低く、圧縮成形時に杵、臼等への付着する傾向があるが、本発明の錠剤にイソマルトを配合することにより、その圧縮成形性を向上させることができる。 In addition, 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. By adding isomalt to the tablet of the present invention, the compression molding is performed. Can be improved.
　更に、本発明の錠剤では、イソマルトをマンニトールと組み合わせてプレガバリン又はその薬学上許容可能な塩と共に配合することによって、良好な崩壊性を得ることができる。本発明において、崩壊性は、錠剤の崩壊時間を測定することで評価することが出来る。例えば、日本薬局方に準じた崩壊試験を実施することで、当該崩壊時間の測定が可能である。更に、錠剤が口腔内崩壊錠の場合は、先に示した崩壊試験法の他、例えば、口腔内崩壊錠試験器等を用いて崩壊時間を測定することが可能である。すなわち、本発明の錠剤は口腔内崩壊錠であることができる。本発明の錠剤が、例えば、口腔内崩壊錠である場合、錠剤は口腔内で１２０秒以内に崩壊することが好ましく、６０秒以内に崩壊することがより好ましく、４０秒以内に崩壊することが更により好ましい。 Furthermore, in the tablet of the present invention, good disintegration can be obtained by combining isomalt with mannitol and pregabalin or a pharmaceutically acceptable salt thereof. In the present invention, the disintegration property can be evaluated by measuring the disintegration time of the tablet. For example, the disintegration time can be measured by performing a disintegration test according to the Japanese Pharmacopoeia. Furthermore, when the tablet is an orally disintegrating tablet, 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. When 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.
　硬度と崩壊性は、通常、二律背反的であり、一方を高めると他方が低下する傾向にあるが、本発明の錠剤は優れた硬度と崩壊性を両立することができる。 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.
　イソマルトとしては、例えば、galen IQ（BENEO-Palatinit社製）を使用することができる。イソマルトの形態は特には限定されるものではなく、粉末状又は造粒品のいずれをも使用することができる。 As the 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.
　本発明の錠剤に含まれるイソマルトの配合量は特に限定されないが、錠剤の全重量を基準として１．００～３．００重量％であることが好ましく、１．１０～２．５０重量％であることがより好ましく、１．２０～２．００重量％であることが特に好ましい。 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.
［錠剤］
本発明の錠剤では、プレガバリンのラクタム体のみならずその他の類縁体の経時的な生成をも抑制される。特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンのラクタム体のみならずその他の類縁体の経時的な生成が抑制される。 [tablet]
In the tablet of the present invention, not only the lactam form of pregabalin but also other analogs over time are suppressed. In particular, 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.
したがって、本発明の錠剤では、プレガバリンの総類縁体量の経時的な増大が抑制され、特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンの総類縁体の経時的な生成が抑制される。例えば、本発明の錠剤は、錠剤中の水分が錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上であっても、総類縁体の経時的な生成が抑制される。 Therefore, in the tablet of the present invention, 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. For example, in the tablet of the present invention, 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 generation of the total analog over time is suppressed.
　すなわち、本発明の錠剤中では、特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンの経時安定性が改善される。例えば、本発明の錠剤は、錠剤中の水分が錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上であっても、プレガバリンの経時安定性が改善される。 That is, in the tablet of the present invention, the stability with time of pregabalin is improved, especially in any state where the water content in the tablet is low or high. For example, 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.
本発明の錠剤は長期に亘って、特に、湿度の低い又は高い環境下でも、また、湿度が上下に大きく変動する環境下でも、安定に保存乃至使用することができる。 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.
　本発明の錠剤中の水分は、特に限定されるものではなく、例えば、錠剤の全重量を基準として、０．８０重量％以下であってもよく、０．７０重量％以下であってもよく、０．６０重量％以下であってもよい。また、本発明の錠剤中の水分は、錠剤の全重量を基準として、１．２０重量％以上であってもよく、１．４０重量％以上であってもよく、また、１．６０重量％以上であってもよく、１．８０重量％以上であってもよい。一方、本発明の錠剤中の水分の上限値は、錠剤の全重量を基準として５．０重量％以下が好ましく、４．００重量％以下がより好ましく、３．００重量％以下が更に好ましく、最も好ましくは、２．００重量％以下である。なお、本発明において、錠剤中の水分値は、赤外線水分計（例えば、ＦＤ－２３０：株式会社ケツト科学研究所製）等を用いて測定することが可能である。 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.).
　本発明の錠剤は、本発明の効果を損なわない限りにおいて、必須成分であるマンニトール及びイソマルト以外に、賦形剤、結合剤、崩壊剤、滑沢剤等の固形医薬製剤の分野において汎用の成分を含むことができる。 As long as the effects of the present invention are not impaired, 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.
　賦形剤としては、特には限定されるものではないが、糖質類、デンプン類、セルロース類等が挙げられる。 The excipient is not particularly limited, and examples thereof include carbohydrates, starches, and celluloses.
糖質類としては、固形医薬製剤の分野で使用されている単糖、二糖、及び、糖アルコールが挙げられ、具体的には、乳糖水和物、無水乳糖、白糖、精製白糖、果糖、ブドウ糖、ブドウ糖水和物、ソルビトール、キシリトール、エリスリトール、マルチトール等を挙げることができる。 Examples of 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.
デンプン類としては、トウモロコシ澱粉、小麦澱粉、米澱粉、馬鈴薯澱粉等を挙げることができる。 Examples of starches include corn starch, wheat starch, rice starch, and potato starch.
セルロース類としては、結晶セルロース、粉末セルロース等を挙げることができる。 Examples of celluloses include crystalline cellulose and powdered cellulose.
賦形剤としては、これらのうちの１種以上を使用できるが、２種以上を使用してもよい。賦形剤の配合量は錠剤の全重量を基準として５重量％以上が好ましく、１０重量％以上がより好ましく、１５重量％以上が更により好ましい。賦形剤の配合量は錠剤の全重量を基準として３０重量％以下が好ましく、２５重量％以下がより好ましく、２０重量％以下が更により好ましい。 As 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.
結合剤としては、特には限定されるものではないが、メタケイ酸アルミン酸マグネシウム、合成ケイ酸アルミニウム、軽質無水ケイ酸、ポリビニルアルコール、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム、ポビドン等が挙げられる。 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.
結合剤としては、これらのうちの１種以上を使用できるが、２種以上を使用してもよい。結合剤の配合量は錠剤の全重量を基準として０．１重量％以上、０．５重量％以上、或いは、１．０重量％以上であってもよい。 As 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.
結合剤の配合量は錠剤の全重量を基準として１０．０重量％以下が好ましく、５．０重量％以下がより好ましく、３．０重量％以下が更により好ましい。本発明の錠剤は結合剤を含まないことが特に好ましい。 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.
　崩壊剤としては、特には限定されるものではないが、セルロース系崩壊剤（クロスカルメロースナトリウム、カルメロースカルシウム、カルメロースナトリウム、低置換ヒドロキシプロピルセルロース等）、クロスポビドン、デンプン系崩壊剤（部分アルファー化デンプン、ヒドロキシプロピルスターチ等）等が挙げられる。 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.).
崩壊剤としては、これらのうちの１種以上を使用できるが、２種以上を使用してもよい。崩壊剤の配合量は錠剤の全重量を基準として０．１重量％以上、０．５重量％以上、或いは、１．０重量％以上であってもよい。 As 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.
崩壊剤の配合量は錠剤の全重量を基準として１０．０重量％以下が好ましく、５．０重量％以下がより好ましく、３．０重量％以下が更により好ましい。本発明の錠剤はイソマルト以外の崩壊剤を含まないことが特に好ましい。 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.
滑沢剤としては、特には限定されるものではないが、ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリルアルコール、ステアリン酸、タルク、硬化油、ショ糖脂肪酸エステル、グリセリン脂肪酸エステル等が挙げられる。 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.
滑沢剤としては、これらのうちの１種以上を使用できるが、２種以上を使用してもよい。滑沢剤の配合量は錠剤の全重量を基準として０．１重量％以上が好ましく、０．５重量％以上がより好ましく、１．０重量％以上が更により好ましい。なお、本発明の錠剤はタルクを含まないものであってもよい。 As 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.
　本発明の錠剤は、その他に、発泡剤、香料、着色料、人工甘味料等の固形医薬製剤の分野において汎用の成分を含むことができる。 In addition, 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.
　本発明の錠剤は、セルロース又はその誘導体を含まないことが好ましい。セルロースの誘導体としては、結晶セルロース、粉末セルロース、ヒドロキシプロピルセルロース、ヒプロメロース、カルメロースナトリウム、メチルセルロース等を挙げることができる。 It is preferable that the tablet of the present invention does not contain cellulose or a derivative thereof. Examples of cellulose derivatives include crystalline cellulose, powdered cellulose, hydroxypropylcellulose, hypromellose, carmellose sodium, methylcellulose and the like.
　本発明の錠剤の形状・重量は特には限定されない。例えば、本発明の錠剤は上面及び下面が凸形である略円筒形の形状とすることができる。また、例えば、本発明の錠剤の重量は９０～５４０ｍｇの範囲とすることができる。 The shape and weight of the tablet of the present invention are not particularly limited. For example, the tablet of the present invention can have a substantially cylindrical shape with convex upper and lower surfaces. Further, for example, the weight of the tablet of the present invention can be in the range of 90 to 540 mg.
　本発明の錠剤は、腸溶性コーティング等の表面コーティング層を有さないことが好ましい。 The tablet of the present invention preferably does not have a surface coating layer such as an enteric coating.
［使用］
　本発明は、プレガバリン又はその薬学上許容可能な塩、マンニトール、及び、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含む錠剤の経時安定性向上のためのイソマルトの使用にも関する。 [use]
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.
　上記使用における、プレガバリン又はその薬学上許容可能な塩、マンニトール、イソマルト、及び、錠剤については、本発明の錠剤に関する上記の説明が当てはまる。 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 use.
　本発明の使用では、プレガバリン又はその薬学上許容可能な塩、及び、マンニトールを含む錠剤が、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含む場合であっても、イソマルトの作用により、錠剤の経時安定性が向上する。 In the use of the present invention, 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. However, the stability over time of the tablet is improved by the action of isomalt.
　前記錠剤中の水分は、特に限定されるものではなく、例えば、錠剤の全重量を基準として、０．８０重量％以下であってもよく、０．７０重量％以下であってもよく、０．６０重量％以下であってもよい。また、本発明の錠剤中の水分は、錠剤の全重量を基準として、１．２０重量％以上であってもよく、１．４０重量％以上であってもよく、また、１．６０重量％以上であってもよく、１．８０重量％以上であってもよい。一方、前記錠剤中の水分の上限値は、錠剤の全重量を基準として５．００重量％以下が好ましく、４．００重量％以下がより好ましく、３．００重量％以下が更に好ましく、最も好ましくは、２．００重量％以下である。なお、本発明において、錠剤中の水分値は、赤外線水分計（例えば、ＦＤ－２３０：株式会社ケツト科学研究所製）等を用いて測定することが可能である。 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.).
すなわち、本発明の使用では、錠剤中のプレガバリンのラクタム体のみならずその他の類縁体の経時的な生成が抑制される。特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンのラクタム体のみならずその他の類縁体の経時的な生成が抑制される。 That is, in the use of the present invention, not only the lactam form of pregabalin in the tablet but also other analogs over time are suppressed. In particular, 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.
したがって、本発明の使用では、錠剤中のプレガバリンの総類縁体量の経時的な増大が抑制され、特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンの総類縁体の経時的な生成が抑制される。 Therefore, in the use of the present invention, 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.
　すなわち、本発明の使用では、特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、錠剤中のプレガバリンの経時安定性が改善され、ひいては錠剤の経時安定性が向上する。 That is, in the use of the present invention, 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.
本発明の使用が適用された錠剤は長期に亘って、特に、湿度の低い又は高い環境下でも、また、湿度が上下に大きく変動する環境下でも、安定に保存乃至使用することができる。 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.
［安定性向上方法］
本発明は、プレガバリン又はその薬学上許容可能な塩、マンニトール、及び、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含む錠剤の経時安定性向上方法であって、前記錠剤にイソマルトを配合する方法にも関する。 [Stability improvement method]
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.
　上記安定性向上方法における、プレガバリン又はその薬学上許容可能な塩、マンニトール、イソマルト、及び、錠剤については、本発明の錠剤に関する上記の説明が当てはまる。 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.
　本発明の安定性向上方法では、プレガバリン又はその薬学上許容可能な塩、及び、マンニトールを含む錠剤が、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含む場合であっても、イソマルトの作用により、錠剤の経時安定性が向上する。 In the stability improving method of the present invention, 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.
　前記錠剤中の水分は、特に限定されるものではなく、例えば、錠剤の全重量を基準として、０．８０重量％以下であってもよく、０．７０重量％以下であってもよく、０．６０重量％以下であってもよい。また、本発明の錠剤中の水分は、錠剤の全重量を基準として、１．２０重量％以上であってもよく、１．４０重量％以上であってもよく、また、１．６０重量％以上であってもよく、１．８０重量％以上であってもよい。一方、前記錠剤中の水分の上限値は、錠剤の全重量を基準として５．００重量％以下が好ましく、４．００重量％以下がより好ましく、３．００重量％以下が更に好ましく、最も好ましくは、２．００重量％以下である。なお、本発明において、錠剤中の水分値は、赤外線水分計（例えば、ＦＤ－２３０：株式会社ケツト科学研究所製）等を用いて測定することが可能である。 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.).
すなわち、本発明の安定性向上方法では、錠剤中のプレガバリンのラクタム体のみならずその他の類縁体の経時的な生成が抑制される。特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンのラクタム体のみならずその他の類縁体の経時的な生成が抑制される。 That is, in 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. In particular, 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.
したがって、本発明の安定性向上方法では、錠剤中のプレガバリンの総類縁体量の経時的な増大が抑制され、特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンの総類縁体の経時的な生成が抑制される。 Therefore, in the stability improvement method of the present invention, an increase in the total amount of pregabalin in the tablet over time is suppressed, and in particular, whether the pregabalin content is low or high in the tablet. Generation of total analogs over time is suppressed.
　すなわち、本発明の安定性向上方法では、特に、錠剤中の水分が少ない又は多い状態であっても、錠剤中のプレガバリンの経時安定性が改善され、ひいては錠剤の経時安定性が向上する。 That is, in the stability improving method of the present invention, 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.
本発明の安定性向上方法が適用された錠剤は長期に亘って、特に、湿度の低い又は高い環境下でも、また、湿度が上下に大きく変動する環境下でも、安定に保存乃至使用することができる。 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.
［製造方法］
本発明は、プレガバリン又はその薬学上許容可能な塩及びマンニトールを含む錠剤にイソマルトを配合することを含む、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含有しても経時的に安定な錠剤の製造方法にも関する。 [Production method]
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.
　上記製造方法における、プレガバリン又はその薬学上許容可能な塩、マンニトール、イソマルト、及び、錠剤については、本発明の錠剤に関する説明が当てはまる。 The description regarding the tablet of the present invention applies to pregabalin or a pharmaceutically acceptable salt thereof, mannitol, isomalt and tablet in the above production method.
　本発明の製造方法は常法により実施することができる。例えば、プレガバリン又はその薬学上許容可能な塩及びマンニトールを含む、好ましくは粉末の形態の混合物にイソマルトを添加・混合して得られた混合物を、そのまま、或いは、必要に応じて造粒等の工程を適宜加えた上で、打錠機等の常法により圧縮成形することによって製造することができる。 The production method of the present invention can be carried out by a conventional method. For example, a mixture obtained by adding and mixing isomalt to a mixture containing pregabalin or a pharmaceutically acceptable salt thereof and mannitol, preferably in the form of a powder, as it is, or, if necessary, a step such as granulation Can be produced by compression molding by a conventional method such as a tableting machine.
　本発明において、造粒の手法は特に限定されず、例えば、湿式造粒法、乾式造粒法等を採用することができる。造粒には、例えば、流動層造粒装置、転動型造粒装置、ワースター型造粒装置、攪拌造粒装置等の公知の造粒装置を適宜選択して用いればよい。また本発明において造粒とは、単一又は複数成分からなる粉末原料を、結合剤等を用いて、凝集させることにより、原料より大きな粒状に加工する操作を意味し、被覆造粒等もこれに含まれる。 In the present invention, the granulation method is not particularly limited, and for example, a wet granulation method, a dry granulation method, or the like can be employed. For granulation, for example, 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. In the present invention, 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.
　本発明の上記製造方法によって得られた錠剤では、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含む場合であっても、イソマルトの作用により、錠剤の経時安定性が向上する。 In 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.
　前記錠剤中の水分は、特に限定されるものではなく、例えば、錠剤の全重量を基準として、０．８０重量％以下であってもよく、０．７０重量％以下であってもよく、０．６０重量％以下であってもよい。また、本発明の錠剤中の水分は、錠剤の全重量を基準として、１．２０重量％以上であってもよく、１．４０重量％以上であってもよく、また、１．６０重量％以上であってもよく、１．８０重量％以上であってもよい。一方、前記錠剤中の水分の上限値は、錠剤の全重量を基準として５．００重量％以下が好ましく、４．００重量％以下がより好ましく、３．００重量％以下が更に好ましく、最も好ましくは、２．００重量％以下である。なお、本発明において、錠剤中の水分値は、赤外線水分計（例えば、ＦＤ－２３０：株式会社ケツト科学研究所製）等を用いて測定することが可能である。 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.).
すなわち、本発明の上記製造方法によって得られた錠剤では、錠剤中のプレガバリンのラクタム体のみならずその他の類縁体の経時的な生成が抑制される。特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンのラクタム体のみならずその他の類縁体の経時的な生成が抑制される。 That is, in 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. In particular, 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.
したがって、本発明の上記製造方法によって得られた錠剤では、錠剤中のプレガバリンの総類縁体量の経時的な増大が抑制され、特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンの総類縁体の経時的な生成が抑制される。 Therefore, in the tablet obtained by the above-described production method of the present invention, 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. In addition, the production of pregabalin analogs over time is suppressed.
　すなわち、本発明の上記製造方法では、特に、水分が少ない状態又は多い状態のいずれであっても、錠剤中のプレガバリンの経時安定性が改善され、ひいては錠剤の経時安定性が向上した錠剤を提供することができる。 That is, 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.
本発明の上記製造方法によって得られた錠剤は長期に亘って、特に、湿度の低い又は高い環境下でも、また、湿度が上下に大きく変動する環境下でも、安定に保存乃至使用することができる。 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. .
　また、本発明は、
プレガバリン又はその薬学上許容可能な塩をマンニトールと混合して混合物を得る混合工程、
前記混合物にイソマルトを含む造粒液を噴霧及び乾燥して造粒物を得る造粒工程、及び、
前記造粒物を錠剤化する錠剤化工程
を含む、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含有しても経時的に安定な錠剤の製造方法にも関する。 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.
　本発明の製造方法は常法により実施することができる。 The production method of the present invention can be carried out by a conventional method.
　上記の混合に際して用いることのできる混合機としては、特に限定されず、公知の混合機を用いることができる。 The mixer that can be used for the above mixing is not particularly limited, and a known mixer can be used.
　前記造粒工程は、例えば、流動層造粒装置を使用する流動層造粒法によって、好ましく実施することができる。 The granulation step can be preferably performed, for example, by a fluidized bed granulation method using a fluidized bed granulator.
　前記造粒液は常温・常圧で揮発性の水性媒体を含むことが好ましく、水性媒体としては水、又は、エタノール等の低級アルコールがより好ましく、水が更により好ましい。 The granulating liquid preferably contains a volatile aqueous medium at normal temperature and normal pressure. As the aqueous medium, water or a lower alcohol such as ethanol is more preferred, and water is even more preferred.
　前記造粒液はマンニトールを含むことが好ましい。すなわち、マンニトールの全てを上記混合工程において使用するのではなく、一部を造粒液に配合しておくことが好ましい。これにより、プレガバリン又はその薬学的に許容可能な塩と他の物質との接触をより好適に回避乃至低減することができ、プレガバリン又はその薬学的に許容可能な塩の安定性をより高めることができる。 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. As a result, contact between pregabalin or a pharmaceutically acceptable salt thereof and other substances can be avoided or reduced more suitably, and the stability of pregabalin or a pharmaceutically acceptable salt thereof can be further increased. it can.
　錠剤化に用いられる打錠機についても、特に限定されず、例えば、ロータリー式打錠機、単発打錠機等の公知の打錠機を適宜選択して用いればよい。また錠剤を調製する際の打圧は、本発明の効果を損なわない限りにおいて、特に限定されず、適宜設定することができる。本発明において、錠剤を調製する際の打圧は、３００ｋｇｆ以上が好ましく、５００ｋｇｆ以上がより好ましく、８００ｋｇｆ以上が更に好ましい。本発明において、錠剤を調製する際の打圧は、２４００ｋｇｆ以下が好ましく、２２００ｋｇｆ以下がより好ましく、２０００ｋｇｆ以下が更に好ましい。 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. Further, 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. In the present invention, 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. In the present invention, 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.
　上記製造方法における、プレガバリン又はその薬学上許容可能な塩、マンニトール、イソマルト、及び、錠剤については、本発明の錠剤に関する上記の説明が当てはまる。 In the above production method, the above explanation regarding the tablet of the present invention applies to pregabalin or a pharmaceutically acceptable salt thereof, mannitol, isomalt, and tablet.
　本発明の上記製造方法によって得られた錠剤では、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含む場合であっても、錠剤の経時安定性が向上する。 In the tablet obtained by the above production method of the present invention, 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. .
　前記錠剤中の水分は、特に限定されるものではなく、例えば、錠剤の全重量を基準として、０．８０重量％以下であってもよく、０．７０重量％以下であってもよく、０．６０重量％以下であってもよい。また、本発明の錠剤中の水分は、錠剤の全重量を基準として、１．２０重量％以上であってもよく、１．４０重量％以上であってもよく、また、１．６０重量％以上であってもよく、１．８０重量％以上であってもよい。一方、前記錠剤中の水分の上限値は、錠剤の全重量を基準として５．００重量％以下が好ましく、４．００重量％以下がより好ましく、３．００重量％以下が更に好ましく、最も好ましくは、２．００重量％以下である。なお、本発明において、錠剤中の水分値は、赤外線水分計（例えば、ＦＤ－２３０：株式会社ケツト科学研究所製）等を用いて測定することが可能である。 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.).
すなわち、本発明の上記製造方法によって得られた錠剤では、錠剤中のプレガバリンのラクタム体のみならずその他の類縁体の経時的な生成が抑制される。特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンのラクタム体のみならずその他の類縁体の経時的な生成が抑制される。 That is, in 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. In particular, 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.
したがって、本発明の上記製造方法によって得られた錠剤では、錠剤中のプレガバリンの総類縁体量の経時的な増大が抑制され、特に、錠剤中の水分が少ない状態又は多い状態のいずれであっても、プレガバリンの総類縁体の経時的な生成が抑制される。 Therefore, in the tablet obtained by the above-described production method of the present invention, 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. In addition, the production of pregabalin analogs over time is suppressed.
　すなわち、本発明の上記製造方法では、特に、水分が少ない状態又は多い状態のいずれであっても、錠剤中のプレガバリンの経時安定性が改善され、ひいては錠剤の経時安定性が向上した錠剤を提供することができる。 That is, 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.
本発明の上記製造方法によって得られた錠剤は長期に亘って、特に、湿度の低い又は高い環境下でも、また、湿度が上下に大きく変動する環境下でも、安定に保存乃至使用することができる。 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. .
　更に、本発明の上記のいずれかの製造方法によれば、そのような高い安定性を備えたプレガバリン含有錠剤を容易に製造することができる。 Furthermore, according to any one of the above-described production methods of the present invention, pregabalin-containing tablets having such high stability can be easily produced.
　また、本発明の上記のいずれかの製造方法によって得られた錠剤はプレガバリン又はその薬学上許容可能な塩の錠剤内の分散性が高まり、錠剤中にプレガバリン又はその薬学上許容可能な塩を均一に分散することができる。 In addition, 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.
　本発明の錠剤は、神経障害性疼痛及び線維筋痛症に伴う疼痛の治療に使用することができる。神経障害性疼痛としては、例えば、帯状疱疹後神経痛、糖尿病性末梢神経障害に伴う疼痛、脊髄損傷後疼痛が挙げられる。 The tablet of the present invention can be used for the treatment of pain associated with neuropathic pain and fibromyalgia. Examples of neuropathic pain include postherpetic neuralgia, pain associated with diabetic peripheral neuropathy, and pain after spinal cord injury.
　以下、本発明を実施例及び比較例を用いてより具体的に説明するが、本発明の範囲は実施例に限定されるものではない。 Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples, but the scope of the present invention is not limited to the examples.
［実施例１、比較例１及び比較例２］
　下記表１に記載の処方の口腔内崩壊錠を調製した。表１中の数値は「ｇ」を意味する。 [Example 1, Comparative Example 1 and Comparative Example 2]
Orally disintegrating tablets having the formulations shown in Table 1 below were prepared. The numerical value in Table 1 means “g”.
実施例１では、プレガバリンをＤ－マンニトールと混合し、得られた混合物にＤ－マンニトール、イソマルト及びアセスルファムカリウムを含む水溶液を造粒液として噴霧及び乾燥して流動層造粒法により造粒物を得た。そして、前記造粒物にプレミックス品（Ｄ－マンニトール、トウモロコシデンプン）、スクラロース及び香料を添加・混合し、得られた混合物に更にステアリン酸マグネシウムを添加・混合して、得られた混合物を打錠機を用いて打錠することにより錠剤を調製した。 In 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.
比較例１では、プレガバリンをＤ－マンニトールと混合し、得られた混合物にＤ－マンニトール及びアセスルファムカリウムを含む水溶液を造粒液として噴霧及び乾燥して流動層造粒法により造粒物を得た。そして、前記造粒物にプレミックス品（Ｄ－マンニトール、トウモロコシデンプン）、スクラロース及び香料を添加・混合し、得られた混合物に更にステアリン酸マグネシウムを添加・混合して、得られた混合物を打錠機を用いて打錠することにより錠剤を調製した。 In Comparative Example 1, pregabalin was mixed with D-mannitol, and the resulting mixture was sprayed and dried with an aqueous solution containing D-mannitol and acesulfame potassium as a granulating liquid to obtain a granulated product by a fluidized bed granulating method. . 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.
比較例２では、プレガバリンをＤ－マンニトールと混合し、得られた混合物にＤ－マンニトール、ヒドロキシプロピルメチルセルロース及びアセスルファムカリウムを含む水溶液を造粒液として噴霧及び乾燥して流動層造粒法により造粒物を得た。そして、前記造粒物にプレミックス品（Ｄ－マンニトール、トウモロコシデンプン）、スクラロース及び香料を添加・混合し、得られた混合物に更にステアリン酸マグネシウムを添加・混合して、得られた混合物を打錠機を用いて打錠することにより錠剤を調製した。 In Comparative Example 2, pregabalin was mixed with D-mannitol, and an aqueous solution containing D-mannitol, hydroxypropylmethylcellulose and acesulfame potassium was sprayed and dried as a granulated liquid into the resulting mixture, and granulated by a fluidized bed granulation method. I got a thing. 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.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
［安定性試験１］
　実施例１、比較例１及び比較例２の各錠剤について下記のとおり安定性試験を実施した。 [Stability test 1]
The stability test was performed as follows for each tablet of Example 1, Comparative Example 1 and Comparative Example 2.
（試験製剤の調製）
　下記ａ～ｄの条件で実施例１、比較例１及び比較例２の各錠剤を保管し、錠剤中の水分量が異なる試験製剤を各条件につき４つずつ調製した。各試験製剤の水分量を下記表２に示す。
　条件ａ：錠剤を４０℃で３日間乾燥させる。
　条件ｂ：錠剤を２５℃、相対湿度６０％で３日間吸湿させる。
　条件ｃ：錠剤を２５℃、相対湿度７５％で３日間吸湿させる。
　条件ｄ：条件ａ～ｃのような湿度調整を行わず、錠剤を２５℃の室内で、気密容器に密閉して３日間保管する。 (Preparation of test preparation)
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.
（安定性試験） (Stability test)
　上記４種類の条件で調製した各試験製剤について、それぞれ、７０℃で４日間密封貯蔵した。これら貯蔵後の検体について、ラクタム体及び総類縁体の量を測定した。測定は、EUROPEAN PHARMACOPEIA（ヨーロッパ薬局方）に記載の試験法を基に、高速液体クロマトグラフィ（Ａｌｌｉａｎｃｅ　ＨＰＬＣ：日本ウォーターズ株式会社製）を使用して行った。なお、ラクタム体及び総類縁体の量は、プレガバリンのピーク面積に対するそれぞれの化合物のピーク面積の比率として求めた。各試験製剤の測定結果を下記表２に示す。なお、条件ａ～条件ｄについては、水分量が左から右に多くなる順に並べ替えた。 The 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 | required as a ratio of the peak area of each compound with respect to the peak area of pregabalin. The measurement results of each test preparation are shown in Table 2 below. The conditions a to d were rearranged in order of increasing water content from left to right.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　表２から明らかなように、比較例１及び比較例２の錠剤は比較的低水分量域において不安定であり、特に、総類縁体量が増加した。一方、実施例１の錠剤は比較的低水分域において安定であり、総類縁体量の生成を抑制することができた。 As is apparent from Table 2, the tablets of Comparative Examples 1 and 2 were unstable in a relatively low water content region, and in particular, the total analog amount increased. On the other hand, the tablet of Example 1 was stable in a relatively low moisture region, and the generation of the total analog amount could be suppressed.
［安定性試験２］
　比較例３として、７５ｍｇのプレガバリンを含むリリカＯＤ錠７５ｍｇ（ファイザー（株））について［安定性試験１］と同一の安定性試験を実施した。結果を、表２中の実施例１の結果と共に、下記表３に示す。なお、条件ａ～条件ｄについては、水分量が左から右に多くなる順に並べ替えた。 [Stability test 2]
As Comparative Example 3, the same stability test as [Stability Test 1] was performed on 75 mg of Lyrica OD tablets (Pfizer Inc.) containing 75 mg of pregabalin. The results are shown in Table 3 below together with the results of Example 1 in Table 2. The conditions a to d were rearranged in order of increasing water content from left to right.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
なお、リリカＯＤ錠７５ｍｇに使用されている添加剤は、非特許文献１によると、以下の表４に記載のとおりである。
Figure JPOXMLDOC01-appb-T000006
 In addition, according to Non-Patent Document 1, the additives used in Lyrica OD tablets 75 mg are as shown in Table 4 below.
Figure JPOXMLDOC01-appb-T000006
　表３から明らかなように、比較例３の錠剤は比較的高水分量域において不安定であり、特に、総類縁体量が増加した。一方、実施例１の錠剤は比較的高水分域においても安定であり、総類縁体量の生成を抑制することができた。 As is clear from Table 3, the tablet of Comparative Example 3 was unstable in a relatively high water content region, and in particular, the total analog content increased. On the other hand, 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.
　このように、実施例１の錠剤は比較的低水分域及び比較的高水分域の両方において安定であり、ラクタム体及び総類縁体量の生成を抑制することができ、特に、総類縁体量の生成を抑制することができた。 Thus, 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.
［物性試験］
　実施例１、比較例１及び比較例２の各錠剤について、硬度及び口腔内崩壊性の試験を実施した。結果、実施例１の錠剤は８．０ｋｇｆの優れた硬度を有しており、また口腔内崩壊性についても極めて良好であった。一方、比較例１の錠剤は、その圧縮製造の際において打錠障害が発生した。比較例２の錠剤は口腔内崩壊性に劣っていた。 [Physical property test]
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.
　本発明は、神経障害性疼痛等の治療に使用可能なプレガバリンを含む錠剤においてプレガバリンの安定性を向上させ、また、（特に湿度の低い又は高い環境下でも）長期に亘って使用可能とすることができるため、有用である。 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.

Claims (15)

  1. プレガバリン又はその薬学上許容可能な塩、
    マンニトール、及び、
    イソマルト
    を含む錠剤。     Pregabalin or a pharmaceutically acceptable salt thereof,
    Mannitol and
    Tablet containing isomalt.
  2. 　錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含む場合に７０℃の条件下で４日間密封貯蔵後に錠剤に含まれるプレガバリンの総類縁体量が２．００％以下である、請求項１に記載の錠剤。 When the water content is 0.80% by weight or less or 1.80% by weight or more based on the tablet weight, the total amount of pregabalin contained in the tablet after sealed storage at 70 ° C. for 4 days is 2.00. The tablet according to claim 1, which is not more than%.
  3. 前記プレガバリン又はその薬学的に許容可能な塩の量が錠剤の全重量を基準として２０～３０重量％である、請求項１又は２に記載の錠剤。 The tablet according to claim 1 or 2, wherein the amount of pregabalin or a pharmaceutically acceptable salt thereof is 20 to 30% by weight based on the total weight of the tablet.
  4. 前記マンニトールの量が錠剤の重量を基準として５．００～６５．００重量％である、請求項１～３のいずれかに記載の錠剤。 The tablet according to any one of claims 1 to 3, wherein the amount of mannitol is 5.00 to 65.00 wt% based on the weight of the tablet.
  5. 前記イソマルトの量が錠剤の重量を基準として１．００～３．００重量％である、請求項１～４のいずれかに記載の錠剤。 The tablet according to any one of claims 1 to 4, wherein the amount of the isomalt is 1.00 to 3.00% by weight based on the weight of the tablet.
  6. セルロース又はその誘導体を含まない、請求項１～５のいずれかに記載の錠剤。 The tablet according to any one of claims 1 to 5, which does not contain cellulose or a derivative thereof.
  7. 結合剤を含まない、請求項１～６のいずれかに記載の錠剤。 The tablet according to any one of claims 1 to 6, which does not contain a binder.
  8. 　３．０ｋｇｆ以上の硬度を有する、請求項１～７のいずれかに記載の錠剤。 The tablet according to any one of claims 1 to 7, which has a hardness of 3.0 kgf or more.
  9. 口腔内崩壊錠である、請求項１～８のいずれかに記載の錠剤。 The tablet according to any one of claims 1 to 8, which is an orally disintegrating tablet.
  10. プレガバリン又はその薬学上許容可能な塩、及び、マンニトールを含む錠剤が、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含む場合の、錠剤の経時安定性向上のためのイソマルトの使用。 Improvement of tablet stability over time when a tablet containing pregabalin or a pharmaceutically acceptable salt thereof and mannitol contains water of 0.80% by weight or less or 1.80% by weight or more based on the weight of the tablet. Use of isomalt for.
  11. プレガバリン又はその薬学上許容可能な塩、及び、マンニトールを含む錠剤が、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含む場合の、錠剤の経時安定性向上方法であって、
    前記錠剤にイソマルトを配合する方法。     Improvement of tablet stability over time when a tablet containing pregabalin or a pharmaceutically acceptable salt thereof and mannitol contains water of 0.80% by weight or less or 1.80% by weight or more based on the weight of the tablet. A method,
    A method of blending isomalt with the tablet.
  12. プレガバリン又はその薬学上許容可能な塩及びマンニトールを含む錠剤にイソマルトを配合することを含む、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含有しても経時的に安定な錠剤の製造方法。 Including premavaline or a pharmaceutically acceptable salt thereof and a tablet containing mannitol containing isomalt, even if it contains water of 0.80 wt% or less or 1.80 wt% or more based on the weight of the tablet Method for producing a stable tablet.
  13. プレガバリン又はその薬学上許容可能な塩をマンニトールと混合して混合物を得る混合工程、
    前記混合物にイソマルトを含む造粒液を噴霧及び乾燥して造粒物を得る造粒工程、及び、
    前記造粒物を錠剤化する錠剤化工程
    を含む、錠剤の重量を基準として０．８０重量％以下又は１．８０重量％以上の水分を含有しても経時的に安定な錠剤の製造方法。     A mixing step of mixing pregabalin or a pharmaceutically acceptable salt thereof with mannitol to obtain a mixture;
    A granulation step of spraying and drying a granulation liquid containing isomalt to the mixture to obtain a granulated product; and
    A tablet production method comprising a tableting step for tableting the granulated product, the tablet being 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.
  14. 前記造粒工程が流動層造粒法によって行われる、請求項１３に記載の製造方法。 The production method according to claim 13, wherein the granulation step is performed by a fluidized bed granulation method.
  15. 　前記造粒液が更にマンニトールを含む、請求項１３又は１４に記載の製造方法。 The manufacturing method according to claim 13 or 14, wherein the granulating liquid further contains mannitol.
PCT/JP2018/040873 2018-05-31 2018-11-02 Tablet and production method therefor WO2019230017A1 (en)

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WO2011107812A2 (en) * 2010-03-01 2011-09-09 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Stabilized pharmaceutical composition
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JP2018150287A (en) * 2017-03-15 2018-09-27 武田テバファーマ株式会社 Oral pharmaceutical composition with discomfort taste masked

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JP6496084B2 (en) * 2016-06-16 2019-04-03 東和薬品株式会社 Orally disintegrating tablets

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JP2010524991A (en) * 2007-04-23 2010-07-22 ラシオファルム ゲーエムベーハー Stabilized pharmaceutical composition containing pregabalin
WO2011107812A2 (en) * 2010-03-01 2011-09-09 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Stabilized pharmaceutical composition
WO2017061426A1 (en) * 2015-10-05 2017-04-13 大同化成工業株式会社 Composite granulated product including sugar or sugar alcohol, swelling binder, disintegrating agent and highly absorbent excipient, and method for manufacturing composite granulated product
JP2018118966A (en) * 2017-01-23 2018-08-02 日新製薬株式会社 COMPRESSED SOLID PHARMACEUTICAL COMPOSITION CONTAINING γ-AMINOBUTYRIC ACID DERIVATIVE SUBSTITUTED AT POSITION 3
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