JP2020180101A - Method for Producing Levetiracetam-Containing Pharmaceutical Composition - Google Patents
Method for Producing Levetiracetam-Containing Pharmaceutical Composition Download PDFInfo
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- JP2020180101A JP2020180101A JP2019086101A JP2019086101A JP2020180101A JP 2020180101 A JP2020180101 A JP 2020180101A JP 2019086101 A JP2019086101 A JP 2019086101A JP 2019086101 A JP2019086101 A JP 2019086101A JP 2020180101 A JP2020180101 A JP 2020180101A
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- Prior art keywords
- levetiracetam
- pharmaceutical composition
- granulation
- water content
- composition containing
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 28
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 claims abstract description 61
- 229960004002 levetiracetam Drugs 0.000 claims abstract description 61
- 239000000203 mixture Substances 0.000 claims abstract description 35
- 238000010828 elution Methods 0.000 claims abstract description 17
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- 238000000034 method Methods 0.000 claims description 19
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Abstract
Description
本発明は、優れた溶出性を備えたレベチラセタム含有医薬組成物の製造方法、並びに、当該組成物を含む医薬固形製剤に関する。 The present invention relates to a method for producing a levetiracetam-containing pharmaceutical composition having excellent dissolution property, and a pharmaceutical solid preparation containing the composition.
レベチラセタムは、化学名(−)−(S)−エチル−(2−オキソ−1−ピロリジン)アセトアミドであり(分子式C8H14N2O2、分子量170.21)、下記化学式(1)で表される化合物である。 Levetiracetam has the chemical name (-) - with a (2-oxo-1-pyrrolidine) acetamide (molecular formula C 8 H 14 N 2 O 2 , molecular weight 170.21), the following chemical formula (1) - (S) - ethyl It is a compound represented.
レベチラセタムは白色から淡灰白色の結晶性の粉末で、極めて高い水溶性を示す。 Levetiracetam is a white to pale grayish white crystalline powder that exhibits extremely high water solubility.
レベチラセタムは、てんかんの治療・予防薬として用いられており、てんかん患者の部分発作(二次性全般化発作を含む)に対して効能を有する。また、他の抗てんかん薬と併用して使用されることもある。 Levetiracetam is used as a therapeutic / prophylactic agent for epilepsy and is effective for partial seizures (including secondary generalized seizures) in epilepsy patients. It may also be used in combination with other antiepileptic drugs.
レベチラセタムを含む医薬製剤(錠剤、顆粒等)の製造方法としては、レベチラセタムを含む組成物に、結合剤を添加して造粒する工程(以下、「造粒工程」とも称す)を含む製造方法が知られている(特許文献1〜5)。 As a method for producing a pharmaceutical preparation (tablets, granules, etc.) containing levetiracetam, a production method including a step of adding a binder to a composition containing levetiracetam to granulate (hereinafter, also referred to as “granulation step”) is used. It is known (Patent Documents 1 to 5).
レベチラセタムを含む医薬製剤においては、時間の経過に伴って生じるレベチラセタムの溶出遅延が問題となることがある。 In pharmaceutical preparations containing levetiracetam, the delay in elution of levetiracetam that occurs over time can be a problem.
このような課題への解決策として、これまでに、レベチラセタムを含む医薬製剤にポリビニルポリピロリドン及びクロスカルメロースナトリウムからなる群から選択される崩壊剤等を所定の割合で配合する方法(例えば、特許文献1)、遅延防止剤としてヒドロキシプロピルセルロースを配合する方法(例えば、特許文献4)、フマル酸ステアリルナトリウムを配合する方法(例えば、特許文献5)などが報告されている。 As a solution to such a problem, a method of blending a pharmaceutical preparation containing levetiracetam with a disintegrant selected from the group consisting of polyvinylpolypyrrolidone and croscarmellose sodium in a predetermined ratio (for example, patent). Document 1), a method of blending hydroxypropyl cellulose as a delay inhibitor (for example, Patent Document 4), a method of blending sodium stearyl fumarate (for example, Patent Document 5), and the like have been reported.
しかし、レベチラセタムを含む医薬製剤では、上述したような各種添加剤を配合しても、その医薬製剤の製法方法によっては、溶出遅延の抑制効果が十分に発揮されず、製造後、時間の経過に伴って十分な溶出性が得られなくなってしまうおそれがある。 However, in a pharmaceutical preparation containing levetiracetam, even if various additives as described above are blended, the effect of suppressing elution delay is not sufficiently exhibited depending on the manufacturing method of the pharmaceutical preparation, and the time elapses after the production. As a result, sufficient elution property may not be obtained.
本発明は上記の点に鑑みてなされたものであり、溶出遅延が十分に抑制されており、優れた溶出性を備えたレベチラセタム含有医薬組成物を製造する方法を提供することを主な目的とする。 The present invention has been made in view of the above points, and an object of the present invention is to provide a method for producing a levetiracetam-containing pharmaceutical composition having sufficiently suppressed elution delay and excellent elution property. To do.
本発明の一態様に係る、レベチラセタムを含む医薬組成物の製造方法は、レベチラセタムを含む組成物を、この組成物中の水分量を実質的に0.5%以下に維持する条件下で造粒する工程を含むことを特徴とする。 The method for producing a pharmaceutical composition containing levetiracetam according to one aspect of the present invention is to granulate a composition containing levetiracetam under conditions in which the water content in the composition is substantially maintained at 0.5% or less. It is characterized by including a step of performing.
前記製造方法において、前記レベチラセタムを含む組成物が賦形剤を含有していることが好ましい。 In the production method, it is preferable that the composition containing levetiracetam contains an excipient.
さらに、前記賦形剤が、糖、糖アルコール、及び結晶セルロースからなる群から選択される少なくとも1つであることが好ましい。 Further, it is preferable that the excipient is at least one selected from the group consisting of sugar, sugar alcohol, and crystalline cellulose.
また、前記製造方法は、得られるレベチラセタムを含む医薬組成物において、40℃、75%RHの条件で2週間保存後、日本薬局方記載の溶出試験のパドル法に従い10分間溶出させた時のレベチラセタムの溶出率が90%以上であることが好ましい。 In addition, the production method is that levetiracetam is obtained when the pharmaceutical composition containing levetiracetam is stored for 2 weeks under the conditions of 40 ° C. and 75% RH and then eluted for 10 minutes according to the paddle method of the dissolution test described in the Japanese Pharmacopoeia. The elution rate of is preferably 90% or more.
本発明によれば、優れた溶出性を備える、レベチラセタム含有医薬組成物を製造する方法を提供することができる。 According to the present invention, it is possible to provide a method for producing a levetiracetam-containing pharmaceutical composition having excellent dissolution property.
以下、本発明に係る実施形態について説明するが、本発明は、これらに限定されるものではない。 Hereinafter, embodiments according to the present invention will be described, but the present invention is not limited thereto.
本実施形態のレベチラセタムを含む医薬組成物の製造方法は、レベチラセタムを含む組成物を、この組成物中の水分量を実質的に0.5%以下に維持する条件下で造粒する工程を含むことを特徴とする。 The method for producing a pharmaceutical composition containing levetiracetam of the present embodiment includes a step of granulating the composition containing levetiracetam under conditions in which the water content in the composition is substantially maintained at 0.5% or less. It is characterized by that.
本実施形態の医薬組成物の製造方法は、前記造粒工程を含んでいれば、その他の工程については特に限定されるものではない。 The method for producing the pharmaceutical composition of the present embodiment is not particularly limited to other steps as long as it includes the granulation step.
本実施形態の造粒工程に供するレベチラセタムを含む組成物には、有効成分であるレベチラセタムが含まれている。レベチラセタムとは、下記式(1)で表される(−)−(S)−エチル−(2−オキソ−1−ピロリジン)アセトアミドの化学名を有する化合物である。 The composition containing levetiracetam to be used in the granulation step of the present embodiment contains levetiracetam as an active ingredient. Levetiracetam is a compound having a chemical name of (-)-(S) -ethyl- (2-oxo-1-pyrrolidin) acetamide represented by the following formula (1).
このレベチラセタムは、製品名を「イーケプラ(登録商標)ドライシップ50%」又は「イーケプラ(登録商標)錠250mg/イーケプラ(登録商標)錠500mg」とし、抗てんかん剤として、日本で販売されている。 This levetiracetam has a product name of "Ekepla (registered trademark) Dryship 50%" or "Ekepla (registered trademark) tablet 250 mg / Ekepra (registered trademark) tablet 500 mg" and is sold in Japan as an antiepileptic agent.
本実施形態の製造方法で製造する医薬組成物におけるレベチラセタムの配合量は、ヒト患者に対するレベチラセタムの日用量が、通常、1日300〜3000mg(1回に又は分割して)程度となるような配合量にすることが好ましい。 The amount of levetiracetam to be blended in the pharmaceutical composition produced by the production method of the present embodiment is such that the daily dose of levetiracetam to a human patient is usually about 300 to 3000 mg (in a single dose or divided). The amount is preferable.
よって、剤型などによっても異なるが、本実施形態の医薬組成物には、通常150〜1500mg、好ましくは150〜1000mgのレベチラセタムが含まれる。なお、各患者にとって適切な実際の用量は、その患者の年齢、体重及び症状などによって適宜設定することが可能である。 Therefore, although it depends on the dosage form and the like, the pharmaceutical composition of the present embodiment usually contains 150 to 1500 mg, preferably 150 to 1000 mg of levetiracetam. The actual dose appropriate for each patient can be appropriately set according to the patient's age, body weight, symptoms, and the like.
本実施形態で使用するレベチラセタムの粒度は、特に限定されず、例えば、粒子径(D50)が100〜300μmのレベチラセタムを使用可能である。上記の粒子径(D50)の測定方法としては、レーザー回折式粒度分布測定法が挙げられ、具体例としてはレーザー回折散乱式粒度分布測定装置(マルバーン社製 マスターサイザー3000)を用いる方法などが挙げられる。 The particle size of levetiracetam used in the present embodiment is not particularly limited, and for example, levetiracetam having a particle size (D50) of 100 to 300 μm can be used. Examples of the method for measuring the particle size (D50) include a laser diffraction type particle size distribution measuring method, and specific examples thereof include a method using a laser diffraction scattering type particle size distribution measuring device (Mastersizer 3000 manufactured by Malvern). Be done.
本実施形態の造粒工程に供するレベチラセタムを含む組成物には、前記レベチラセタム以外に、造粒に使用する各種添加剤(賦形剤など)が含まれていてもよい。 The composition containing levetiracetam to be used in the granulation step of the present embodiment may contain various additives (excipients and the like) used for granulation in addition to the levetiracetam.
賦形剤としては、通常、ドライシロップや錠剤等に使用される賦形剤であれば特に限定はされず、例えば、糖、糖アルコール、結晶セルロース、デキストリン、トウモロコシデンプン、無水リン酸水素カルシウム等を使用することができる。これらは1種単独で用いてもよいし、2種以上を組み合わせて使用することも可能である。 The excipient is not particularly limited as long as it is an excipient usually used for dry syrup, tablets and the like, and for example, sugar, sugar alcohol, crystalline cellulose, dextrin, corn starch, anhydrous calcium hydrogen phosphate and the like can be used. Can be used. These may be used individually by 1 type, or may be used in combination of 2 or more type.
特に、前記賦形剤が、糖、糖アルコール、及び結晶セルロースからなる群から選択される少なくとも1つであることが好ましい。なかでも、マンニトール、乳糖水和物、及び結晶セルロースからなる群から選択される少なくとも1つを本実施形態の賦形剤として使用することが好ましい。 In particular, it is preferable that the excipient is at least one selected from the group consisting of sugar, sugar alcohol, and crystalline cellulose. Among them, it is preferable to use at least one selected from the group consisting of mannitol, lactose hydrate, and crystalline cellulose as the excipient of the present embodiment.
本実施形態の医薬組成物中における賦形剤の含有量は、剤型によって異なるが、例えば、ドライシロップ製剤の場合、原薬(レベチラセタム)と賦形剤の合計量を100質量%とすると、5〜90質量%であることが好ましく、5〜70質量%であることがより好ましい。また、錠剤の場合には、錠剤用顆粒において、原薬(レベチラセタム)と賦形剤の合計量を100質量%とすると、5〜90質量%であることが好ましく、5〜70質量%であることがより好ましい。 The content of the excipient in the pharmaceutical composition of the present embodiment varies depending on the dosage form. For example, in the case of a dry syrup preparation, assuming that the total amount of the drug substance (levetiracetam) and the excipient is 100% by mass, 5 It is preferably ~ 90% by mass, and more preferably 5 to 70% by mass. Further, in the case of tablets, when the total amount of the drug substance (levetiracetam) and the excipient is 100% by mass in the granules for tablets, it is preferably 5 to 90% by mass, preferably 5 to 70% by mass. Is more preferable.
本実施形態の医薬組成物には、有効成分である前記レベチラセタムおよび前記賦形剤以外に、薬学的に許容される添加剤を、本発明の効果を損なわない範囲内で、必要に応じて適宜配合することができる。 In the pharmaceutical composition of the present embodiment, in addition to the active ingredient levetiracetam and the excipient, pharmaceutically acceptable additives may be appropriately added as necessary within a range not impairing the effects of the present invention. Can be blended.
具体的な添加剤としては、例えば、アルファー化デンプン、カルメロースナトリウム、ヒドロキシプロピルセルロース、ポリビニルアルコール、アルギン酸塩、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、マクロゴール、メチルセルロース等の結合剤等;軽質無水ケイ酸、含水二酸化ケイ酸、メタケイ酸アルミン酸マグネシウム、タルク、ステアリン酸カルシウム等の流動化剤;デンプン、クロスポビドン、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウム、部分アルファー化デンプン等の崩壊剤;アステルパーム、アセスルファムカリウム、サッカリン、スクラロース、ステビア、白糖等の甘味料;I−メントール、ヨーグルトミクロン、パイナップルミクロン、ペパーミントミクロン、レモンミクロン、オレンジミクロン等の香料;酸化チタン、食用黄色4号、食用黄色4号アルミニウムレーキ、食用黄色5号、食用赤色2号、食用赤色3号、食用赤色102号、黒酸化鉄、三二酸化鉄、黄色三二酸化鉄、青色2号アルミニウムレーキ等の着色剤・遮光剤;ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸、ケイ酸マグネシウム、酸化マグネシウム、ショ糖脂肪酸エステル、ベヘン酸グリセリル及びタルクのような滑沢剤;ショ糖、ゼラチン等の顆粒化結合剤等を配合することができる。 Specific additives include, for example, binders such as pregelatinized starch, carmellose sodium, hydroxypropyl cellulose, polyvinyl alcohol, alginate, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, macrogol, methyl cellulose, etc .; light silicic acid anhydride, Flooding agents such as hydrous silicic acid dioxide, magnesium aluminometasilicate, talc, calcium stearate; starch, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, partial Disintegrants such as alcoholized starch; sweeteners such as astelpalm, acesulfam potassium, saccharin, scullose, stevia, sucrose; fragrances such as I-menthol, yogurt micron, pineapple micron, peppermint micron, lemon micron, orange micron; titanium oxide , Edible Yellow No. 4, Edible Yellow No. 4 Aluminum Lake, Edible Yellow No. 5, Edible Red No. 2, Edible Red No. 3, Edible Red No. 102, Black Iron Oxide, Iron Dioxide, Yellow Iron Dioxide, Blue No. 2 Aluminum Coloring agents and light-shielding agents such as lakes; lubricants such as magnesium stearate, calcium stearate, stearic acid, magnesium silicate, magnesium oxide, sucrose fatty acid esters, glyceryl behenate and talc; granules such as sucrose and gelatin A chemical binder or the like can be blended.
本実施形態の医薬組成物の製造方法は、上述の通り、前記造粒工程を含んでいる限り、その他の工程については特に限定されるものではないが、以下に、錠剤とドライシロップ製剤を具体例として挙げて説明する。 As described above, the method for producing the pharmaceutical composition of the present embodiment is not particularly limited to other steps as long as the granulation step is included, but the following are specific examples of tablets and dry syrup preparations. It will be described as.
まず、本実施形態の医薬組成物が錠剤である場合について説明する。錠剤は、例えば、レベチラセタムを、賦形剤及び必要に応じてその他添加剤等を用いて、造粒し、乾燥させ、整粒することによって、整粒末(顆粒)を得る。なお、造粒方法としては、例えば、流動層造粒法、撹拌造粒法等を挙げることができ、好ましくは、流動層造粒法が挙げられる。 First, a case where the pharmaceutical composition of the present embodiment is a tablet will be described. Tablets are obtained by granulating, drying, and sizing levetiracetam, for example, using excipients and other additives as necessary to obtain sized powder (granule). Examples of the granulation method include a fluidized bed granulation method, a stirring granulation method, and the like, and a fluidized bed granulation method is preferable.
この造粒工程において、レベチラセタムを含む組成物の水分量を実質的に0.5%以下に維持する条件下で造粒することが重要であり、このような造粒工程を経ることによって、製造後、時間の経過に伴って生じうる溶出遅延が十分に抑制された(特に、加湿保存後も十分な溶出性も備えた)レベチラセタム含有医薬組成物を得ることができる。 In this granulation step, it is important to granulate under the condition that the water content of the composition containing levetiracetam is substantially maintained at 0.5% or less, and it is produced by going through such a granulation step. Later, it is possible to obtain a levetiracetam-containing pharmaceutical composition in which the elution delay that may occur with the passage of time is sufficiently suppressed (particularly, the elution property is also sufficient even after humidified storage).
なお、本実施形態において、前記「水分量」は、造粒物を80℃の温度条件下で30秒間乾燥した際の乾燥減量を、電子式水分計を用いて測定した値であり、測定前の造粒物質量を100%として算出した値(質量%)である。 In the present embodiment, the "moisture content" is a value obtained by measuring the weight loss when the granulated product is dried under a temperature condition of 80 ° C. for 30 seconds using an electronic moisture meter, and before the measurement. It is a value (mass%) calculated by assuming that the amount of granulated substance of is 100%.
前記水分量を実質的に0.5%以下に維持する条件については、特に限定はされず、使用する造粒装置等の各パラメーターを適宜設定し、前記水分量を調整する。例えば、流動層造粒法で造粒する場合は、流動層造粒装置における送液速度を遅くしたり、給気温度を上げたりすることによって、水分量を調節することができる。送液速度や給気温度の調節は、組成物の製造量や造粒に使用する設備によって、適宜設定する。よって、造粒工程中における、レベチラセタムを含む組成物の水分量は定期的に測定し、その測定数値によって送液速度や給気温度を調整する。なお、使用する造粒装置において、前記水分量を実質的に0.5%以下に維持する条件(送液速度、給気温度など)を見出した後は、その条件を適用して、水分量の定期的な測定を実施することなく、造粒工程を実施することも可能であり、本発明において、「水分量を実質的に0.5%以下に維持する条件下で造粒する」ことは、造粒中に水分量測定を実施することに限定されない。 The conditions for maintaining the water content substantially at 0.5% or less are not particularly limited, and each parameter of the granulator to be used or the like is appropriately set to adjust the water content. For example, in the case of granulating by the fluidized bed granulation method, the amount of water can be adjusted by slowing the liquid feeding speed in the fluidized bed granulator or raising the air supply temperature. The liquid feeding rate and the air supply temperature are appropriately set according to the production amount of the composition and the equipment used for granulation. Therefore, the water content of the composition containing levetiracetam during the granulation process is periodically measured, and the liquid feeding rate and the air supply temperature are adjusted according to the measured values. After finding the conditions (liquid feeding rate, air supply temperature, etc.) for maintaining the water content substantially at 0.5% or less in the granulator to be used, apply the conditions to the water content. It is also possible to carry out the granulation step without carrying out the periodic measurement of, and in the present invention, "granulation under the condition that the water content is substantially maintained at 0.5% or less". Is not limited to performing water content measurement during granulation.
錠剤は、上記のようにして得られた顆粒に外添剤を混合し、打錠することによって製造することができる。また、打錠して得られた錠剤(素錠)に、フィルムコーティングを施し、フィルムコーティング錠としてもよい。 Tablets can be produced by mixing an external preparation with the granules obtained as described above and tableting. Further, a tablet (uncoated tablet) obtained by tableting may be film-coated to obtain a film-coated tablet.
打錠は圧縮成形によって行うことが好ましく、例えば、錠剤の成形に使用する打錠用臼、打錠用上杵及び下杵を用い、油圧式ハンドプレス機、単発式打錠機又はロータリー式打錠機等を利用することができる。打錠圧力は、製造する錠剤としての錠剤重量に応じて、適宜設定することができる。 The tableting is preferably performed by compression molding. For example, a hydraulic hand press machine, a single-shot tableting machine or a rotary type tableting machine is used using a tableting mortar, a tableting upper punch and a lower punch used for tablet molding. A lock machine or the like can be used. The tableting pressure can be appropriately set according to the weight of the tablet to be produced.
前記では錠剤について説明したが、本実施形態の製造方法によって得られる医薬組成物の剤型は特に限定されず、ドライシロップ製剤、散剤、顆粒、錠剤、カプセル剤等であってもよい。好ましくは、錠剤またはドライシロップ製剤である。 Although tablets have been described above, the dosage form of the pharmaceutical composition obtained by the production method of the present embodiment is not particularly limited, and may be dry syrup preparations, powders, granules, tablets, capsules and the like. Preferably, it is a tablet or a dry syrup preparation.
また、上記造粒中の水分量を調節する必要はあるが、本実施形態の製造方法によって最終的に得られる医薬組成物中における水分量は特に限定されず、例えば、3.0%以下であることが好ましく、1.0%以下であることがより好ましい。 Further, although it is necessary to adjust the water content during the granulation, the water content in the pharmaceutical composition finally obtained by the production method of the present embodiment is not particularly limited, and is, for example, 3.0% or less. It is preferably present, and more preferably 1.0% or less.
本実施形態の製造方法で得られるレベチラセタム含有医薬組成物は、40℃、75%RHの条件で2週間保存後、日本薬局方記載の溶出試験のパドル法に従い10分間溶出させた時のレベチラセタムの溶出率が90%以上であることが好ましく、本発明には、当該組成物を含む医薬固形製剤も包含される。 The levetiracetam-containing pharmaceutical composition obtained by the production method of the present embodiment is obtained from levetiracetam when it is stored at 40 ° C. and 75% RH for 2 weeks and then eluted for 10 minutes according to the paddle method of the dissolution test described in the Japanese Pharmacopoeia. The dissolution rate is preferably 90% or more, and the present invention also includes pharmaceutical solid preparations containing the composition.
すなわち、本実施形態の医薬固形製剤は、レベチラセタムを含む組成物の造粒工程における水分量が0.5%以下である組成物を含む、医薬固形製剤である。 That is, the pharmaceutical solid preparation of the present embodiment is a pharmaceutical solid preparation containing a composition having a water content of 0.5% or less in the granulation step of the composition containing levetiracetam.
本実施形態のレベチラセタム含有医薬組成物は、抗てんかん剤として、有効に用いることができる。また、本実施形態のレベチラセタム含有医薬組成物は、製造後、時間が経過しても(具体的には、40℃、75%RHの条件での2週間保存後も)十分な溶出性が得られるため、長期保存が可能である。 The levetiracetam-containing pharmaceutical composition of the present embodiment can be effectively used as an antiepileptic agent. In addition, the levetiracetam-containing pharmaceutical composition of the present embodiment has sufficient elution property even after a lapse of time after production (specifically, even after storage for 2 weeks at 40 ° C. and 75% RH). Therefore, long-term storage is possible.
本実施形態の錠剤の形状は、特に限定されないが、円盤状、ドーナツ状、多角形板状、球状、楕円状等の形状とすることが可能である。 The shape of the tablet of the present embodiment is not particularly limited, but can be a disk shape, a donut shape, a polygonal plate shape, a spherical shape, an elliptical shape, or the like.
また、錠剤の硬度は、特に限定されないが、素錠の場合は、例えば、70N〜200N程度であることが好ましく、フィルムコーティング錠の場合は、例えば、120N〜300N程度であることが好ましい。 The hardness of the tablet is not particularly limited, but in the case of an uncoated tablet, it is preferably about 70N to 200N, and in the case of a film-coated tablet, it is preferably about 120N to 300N.
以下に、実施例により本発明を更に具体的に説明するが、本発明の範囲はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited thereto.
まず、本実施例で使用した各試薬について示す。
・結晶セルロース:旭化成株式会社製のセオラス(登録商標)
・低置換度ヒドロキシプロピルセルロース:信越化学工業株式会社製
・低置換度ヒドロキシプロピルセルロース:信越化学工業株式会社製
・ボビドン:BASFジャパン株式会社製のコリドン30
・ステアリン酸マグネシウム:日東化成工業株式会社製
・ステアリン酸マグネシウム:太平化学工業株式会社製
・ヒプロメロース:信越化学工業株式会社製
・ヒドロキシプロピルセルロース:日本曹達株式会社製
・タルク:林化成株式会社製のタルカンハヤシ(登録商標)
・青色2号アルミニウムレーキ:癸巳化成株式会社製
・黄色三二酸化鉄:癸巳化成株式会社製
・三二酸化鉄:癸巳化成株式会社製
First, each reagent used in this example will be shown.
-Crystalline cellulose: Theoras (registered trademark) manufactured by Asahi Kasei Corporation
・ Low-substituted hydroxypropyl cellulose: manufactured by Shin-Etsu Chemical Co., Ltd. ・ Low-substituted hydroxypropyl cellulose: manufactured by Shin-Etsu Chemical Co., Ltd. ・ Bobidone: Corridon 30 manufactured by BASF Japan Ltd.
・ Magnesium stearate: Nitto Kasei Kogyo Co., Ltd. ・ Magnesium stearate: Taihei Kasei Kogyo Co., Ltd. ・ Hypromellose: Shin-Etsu Chemical Co., Ltd. ・ Hydroxypropyl cellulose: Nippon Soda Co., Ltd. ・ Talc: Hayashi Kasei Co., Ltd. Talkan Hayashi (registered trademark)
・ Blue No. 2 aluminum lake: manufactured by Indigo Kasei Co., Ltd. ・ Yellow iron sesquioxide: manufactured by Indigo Kasei Co., Ltd. ・ Iron sesquioxide: manufactured by Indigo Kasei Co., Ltd.
<フィルムコーティング(FC)錠の製造>
(実施例1:FC錠 500mg錠)
レベチラセタム500.0g、低置換度ヒドロキシプロピルセルロース31.0gを流動層造粒装置((株)パウレック製のMP−01)に投入し、混合した。次に、ポビドン5.0gを含む1.0質量%水溶液を結合剤液として別途調製し、この結合剤液505.0gを混合物に噴霧しながら造粒した(造粒条件:給気温度75℃、送液速度4.5〜5.5g/分)。なお、この造粒工程では、造粒末の水分量(後述する水分量測定方法で得た乾燥減量値)が造粒工程中0.5質量%以下となるように造粒条件を上記の通り調整した。また、造粒合計時間100分に対し、造粒開始から10分毎に、造粒末(造粒される組成物)の水分量を測定したところ、最大の水分量は0.35%であった。
<Manufacturing of film coating (FC) tablets>
(Example 1: FC tablet 500 mg tablet)
500.0 g of levetiracetam and 31.0 g of low-substituted hydroxypropyl cellulose were put into a fluidized bed granulator (MP-01 manufactured by Paulec Co., Ltd.) and mixed. Next, a 1.0 mass% aqueous solution containing 5.0 g of povidone was separately prepared as a binder solution, and 505.0 g of this binder solution was sprayed onto the mixture for granulation (granulation conditions: supply air temperature 75 ° C.). , Liquid feeding rate 4.5-5.5 g / min). In this granulation step, the granulation conditions are set as described above so that the water content at the granulation powder (dry weight loss value obtained by the water content measurement method described later) is 0.5% by mass or less during the granulation step. It was adjusted. Further, when the water content of the granulated powder (composition to be granulated) was measured every 10 minutes from the start of granulation with respect to the total granulation time of 100 minutes, the maximum water content was 0.35%. It was.
次いで、造粒後、排気温度が50℃以上となるように流動層造粒装置にて乾燥した(乾燥条件:給気温度70℃、給気風量約1.0m3/分)。乾燥時間は3分を要した。 Then, after granulation, the mixture was dried in a fluidized bed granulator so that the exhaust temperature was 50 ° C. or higher (drying conditions: air supply temperature 70 ° C., air supply air volume about 1.0 m 3 / min). The drying time took 3 minutes.
得られた造粒物を目開き500μmの篩にて篩過することで整粒した。得られた造粒物に、この造粒物に対して0.37質量%の量のステアリン酸マグネシウムを添加して袋混合した。 The obtained granules were sized by sieving with a sieve having an opening of 500 μm. To the obtained granules, magnesium stearate in an amount of 0.37% by mass was added to the granules and mixed in a bag.
得られた混合物をロータリー打錠機((株)菊水製作所製のVIRGO)において、打錠圧18kNにて打錠して、1錠あたり538.0mgの素錠を製造した。 The obtained mixture was locked with a rotary locking machine (VIRGO manufactured by Kikusuiseisaku Seisakusho Co., Ltd.) at a locking pressure of 18 kN to produce 538.0 mg of uncoated tablets per tablet.
そして、得られた素錠を、錠剤コーティング機(フロイント産業(株)製のHCT−LABO)に投入し、ヒプメロース112.01g、ヒドロキシプロピルセルロース14.0010g、タルク14.0008g、黄色三二酸化鉄0.3000g、三二酸化鉄0.0150g及び精製水1200.08gを含むフィルムコーティング液121.8gを噴霧し、1錠あたり552mgのフィルムコーティング錠を得た。 Then, the obtained uncoated tablets were put into a tablet coating machine (HCT-LABO manufactured by Freund Sangyo Co., Ltd.), and Hypmerose 112.01 g, hydroxypropyl cellulose 14.0010 g, talc 14.0008 g, and yellow iron sesquioxide 0. 121.8 g of a film coating solution containing 3000 g, 0.0150 g of iron sesquioxide and 1200.08 g of purified water was sprayed to obtain 552 mg of film-coated tablets per tablet.
(実施例2:FC錠 500mg)
工程1
レベチラセタム25.00kg、低置換度ヒドロキシプロピルセルロース1270g、結晶セルロース270.0gを流動層造粒装置((株)フロイント社製のFLO−30)に投入し、混合した。次に、ポビドン250.0gを含む1.0質量%水溶液を結合剤液として別途調製し、この結合剤液25.25kgを混合物に噴霧しながら造粒した(給気温度:73℃、送液速度:60.0〜70.0g/分)。なお、この造粒工程では、造粒末の水分含量(後述する水分量測定方法で得た乾燥減量値)が造粒工程中0.5質量%以下となるように造粒条件を上記の通り調整した。また、造粒合計時間390分に対し、造粒開始から60分毎に、造粒末(造粒される組成物)の水分量を測定したところ、最大の水分量は0.16%であった。
(Example 2: FC tablet 500 mg)
Process 1
25.00 kg of levetiracetam, 1270 g of low-substituted hydroxypropyl cellulose, and 270.0 g of crystalline cellulose were put into a fluidized bed granulator (FLO-30 manufactured by Freund Co., Ltd.) and mixed. Next, a 1.0 mass% aqueous solution containing 250.0 g of povidone was separately prepared as a binder solution, and 25.25 kg of this binder solution was granulated while spraying on the mixture (supply air temperature: 73 ° C., liquid feed). Speed: 60.0-70.0 g / min). In this granulation step, the granulation conditions are set as described above so that the water content at the granulation powder (dry weight loss value obtained by the water content measurement method described later) is 0.5% by mass or less during the granulation step. It was adjusted. Further, when the water content of the granulated powder (composition to be granulated) was measured every 60 minutes from the start of granulation with respect to the total granulation time of 390 minutes, the maximum water content was 0.16%. It was.
次いで、造粒後、排気温度が50℃以上となるように流動層造粒装置にて乾燥した(乾燥条件:給気温度75℃、給気風量約8.1Nm3/分)。乾燥時間は4分を要した。上記工程1の操作を2回行い、合わせて造粒物とした。 Then, after granulation, the mixture was dried in a fluidized bed granulator so that the exhaust temperature was 50 ° C. or higher (drying conditions: supply air temperature 75 ° C., supply air volume about 8.1 Nm 3 / min). The drying time took 4 minutes. The operation of the above step 1 was performed twice to obtain a granulated product.
得られた造粒物を整粒機((株)パウレック社製のQC−197S)にて整粒した。得られた造粒物に、この造粒物に対して0.37質量%の量のステアリン酸マグネシウムを拡散式混合機((株)キット社製のCB-200)に投入し混合した。 The obtained granulated product was sized with a sizing machine (QC-197S manufactured by Paulec Co., Ltd.). Magnesium stearate in an amount of 0.37% by mass with respect to the granulated product was put into a diffusion type mixer (CB-200 manufactured by Kit Co., Ltd.) and mixed with the obtained granulated product.
得られた混合物をステアリン酸マグネシウムとともにロータリー打錠機((株)菊水製作所製のVIRGO)において、打錠圧20kNにて打錠して、1錠あたり538.0mgの素錠を製造した。 The obtained mixture was locked together with magnesium stearate in a rotary locking machine (VIRGO manufactured by Kikusui Seisakusho Co., Ltd.) at a locking pressure of 20 kN to produce 538.0 mg of uncoated tablets per tablet.
得られた素錠を、錠剤コーティング機(フロイント産業(株)製のFZ−100)に投入し、ヒプメロース2240.03g、ヒドロキシプロピルセルロース280.05g、タルク280.09g、黄色三二酸化鉄6.000g、三二酸化鉄0.301g及び精製水32.00kgを含むフィルムコーティング液16.64kgを噴霧し、1錠あたり552mgのフィルムコーティング錠を得た。 The obtained uncoated tablets were put into a tablet coating machine (FZ-100 manufactured by Freund Industries, Ltd.), and hypmerose 2240.03 g, hydroxypropyl cellulose 280.05 g, talc 280.09 g, and yellow iron sesquioxide 6.000 g. , 16.64 kg of film coating liquid containing 0.301 g of iron sesquioxide and 32.00 kg of purified water was sprayed to obtain 552 mg of film-coated tablets per tablet.
(実施例3:FC錠 250mg)
レベチラセタム25.00kg、低置換度ヒドロキシプロピルセルロース1270g、結晶セルロース270.0gを流動層造粒装置((株)フロイント社製のFLO−30)に投入し、混合した。次に、ポビドン250.0gを含む1.0質量%水溶液を結合剤液として別途調製し、この結合剤液25.25kgを混合物に噴霧しながら造粒した(造粒条件:給気温度73℃、送液速度60.0〜70.0g/分)。なお、この造粒工程では、造粒末の水分含量(後述する水分量測定方法で得た乾燥減量値)が造粒工程中0.5質量%以下となるように造粒条件を上記の通り調整した。また、造粒合計時間390分に対し、造粒開始から60分毎に、造粒末(造粒される組成物)の水分量を測定したところ、最大の水分量は0.39%であった。
(Example 3: FC tablet 250 mg)
25.00 kg of levetiracetam, 1270 g of low-substituted hydroxypropyl cellulose, and 270.0 g of crystalline cellulose were put into a fluidized bed granulator (FLO-30 manufactured by Freund Co., Ltd.) and mixed. Next, a 1.0 mass% aqueous solution containing 250.0 g of povidone was separately prepared as a binder solution, and 25.25 kg of this binder solution was sprayed onto the mixture for granulation (granulation conditions: supply air temperature 73 ° C.). , Liquid feeding rate 60.0 to 70.0 g / min). In this granulation step, the granulation conditions are set as described above so that the water content at the granulation powder (dry weight loss value obtained by the water content measurement method described later) is 0.5% by mass or less during the granulation step. It was adjusted. Further, when the water content of the granulated powder (composition to be granulated) was measured every 60 minutes from the start of granulation with respect to the total granulation time of 390 minutes, the maximum water content was 0.39%. It was.
次いで、造粒後、排気温度が50℃以上となるように流動層造粒装置にて乾燥した(乾燥条件:給気温度75℃、給気風量約8.1Nm3/分)。乾燥時間は4分を要した。 Then, after granulation, the mixture was dried in a fluidized bed granulator so that the exhaust temperature was 50 ° C. or higher (drying conditions: supply air temperature 75 ° C., supply air volume about 8.1 Nm 3 / min). The drying time took 4 minutes.
得られた造粒物を整粒機((株)パウレック社製のQC−197S)にて整粒した。得られた造粒物に、この造粒物に対して0.37質量%の量のステアリン酸マグネシウムを拡散式混合機((株)広島メタル&マシナリー社製のPM-100)に投入し混合した。 The obtained granulated product was sized with a sizing machine (QC-197S manufactured by Paulec Co., Ltd.). In the obtained granules, 0.37% by mass of magnesium stearate with respect to the granules was put into a diffusion mixer (PM-100 manufactured by Hiroshima Metal & Machinery Co., Ltd.) and mixed. did.
得られた混合物をステアリン酸マグネシウムとともにロータリー打錠機((株)菊水製作所製のVIRGO)において、打錠圧20kNにて打錠して、1錠あたり269.0mgの素錠を製造した。 The obtained mixture was locked together with magnesium stearate in a rotary locking machine (VIRGO manufactured by Kikusui Seisakusho Co., Ltd.) at a locking pressure of 20 kN to produce 269.0 mg of uncoated tablets per tablet.
得られた素錠を、錠剤コーティング機(フロイント産業(株)製のHCT−80N)に投入し、ヒプメロース1280.01g、ヒドロキシプロピルセルロース160.01g、タルク160.00g、青色2号アルミニウムレーキ3.001g及び精製水18000gを含むフィルムコーティング液7940gを噴霧し、1錠あたり277mgのフィルムコーティング錠を得た。 The obtained uncoated tablets were put into a tablet coating machine (HCT-80N manufactured by Freund Sangyo Co., Ltd.), and Hypmerose 1280.01 g, hydroxypropyl cellulose 160.01 g, talc 160.00 g, and blue No. 2 aluminum lake 3. 7940 g of a film coating solution containing 001 g and 18,000 g of purified water was sprayed to obtain 277 mg of film-coated tablets per tablet.
(比較例1:FC錠 500mg錠)
造粒条件を、給気温度65℃、送液速度9.5〜10.5g/分に変更し、造粒末の水分含量(後述する水分量測定方法で得た乾燥減量値)が造粒工程中0.5質量%を上回るように調整した以外は、実施例1と同様にして、1錠あたり552mgのフィルムコーティング錠を得た。なお、造粒合計時間50分に対し、造粒工程において、造粒開始から10分毎に、造粒末(造粒される組成物)の水分量を測定したところ、最大の水分量は1.12%であった。
(Comparative Example 1: FC Tablets 500 mg Tablets)
The granulation conditions were changed to an air supply temperature of 65 ° C. and a liquid feeding rate of 9.5 to 10.5 g / min, and the water content of the granulated powder (dry weight loss value obtained by the water content measuring method described later) was granulated. A film-coated tablet of 552 mg per tablet was obtained in the same manner as in Example 1 except that the content was adjusted to exceed 0.5% by mass during the step. When the water content of the granulated powder (composition to be granulated) was measured every 10 minutes from the start of granulation in the granulation step with respect to the total granulation time of 50 minutes, the maximum water content was 1. It was .12%.
各実施例の処方分量(質量%)を表1にまとめる。 Table 1 summarizes the prescribed amounts (% by mass) of each example.
<評価方法>
(溶出試験)
第17改正日本薬局方の溶出試験法(パドル法/即放性製剤)に準じ、試験液として水900mLを用いて溶出試験を実施した。詳細は以下の通りである。
<Evaluation method>
(Dissolution test)
According to the 17th revised Japanese Pharmacopoeia dissolution test method (paddle method / immediate release preparation), the dissolution test was carried out using 900 mL of water as the test solution. The details are as follows.
溶出試験装置に上記試験液を入れた容器をセットした後、試験対象の錠剤1個を投入して、50rpmの回転速度で装置を作動させ、規定された時間(0分、5分、10分、15分)毎に試験液を採取した。 After setting the container containing the above test solution in the dissolution test device, one tablet to be tested is put in and the device is operated at a rotation speed of 50 rpm for a specified time (0 minutes, 5 minutes, 10 minutes). , 15 minutes), the test solution was collected every time.
採取した試験液中のレベチラセタム量を、高速液体クロマトグラフィー(HPLC)を用いて測定し、表示量(表1に記載のレベチラセタム量)に対する百分率を溶出率(%)として求めた。 The amount of levetiracetam in the collected test solution was measured by high performance liquid chromatography (HPLC), and the percentage with respect to the displayed amount (the amount of levetiracetam shown in Table 1) was determined as the elution rate (%).
なお、本溶出試験は、Initial(初期状態)及び加湿条件下(温度40℃、湿度75%RH、オープン)で2週間(2W)放置後の各錠剤に対して実施した。 This dissolution test was carried out on each tablet after being left for 2 weeks (2 W) under Initial (initial state) and humidified conditions (temperature 40 ° C., humidity 75% RH, open).
(崩壊試験)
崩壊性は、第17改正日本薬局方の崩壊試験法に準じ、補助盤なしで評価した。詳細は以下の通りである。
(Collapse test)
The disintegration property was evaluated according to the 17th revised Japanese Pharmacopoeia disintegration test method without an auxiliary board. The details are as follows.
試験器の6本のガラス管にそれぞれ試料1個ずつ入れ、補助盤を使用せず、試験液(水)にて、37±2℃で試験器を作動させた。そして、試料の残留物がガラス管内部から確認できなくなった時間を崩壊時間とした。試料は、加湿条件下(温度40℃、湿度75%RH、オープン)で、Initial、3日(3D)、1週間(1W)、および2週間(2W)、放置した後の錠剤をそれぞれ用いた。 One sample was placed in each of the six glass tubes of the tester, and the tester was operated at 37 ± 2 ° C. with the test solution (water) without using the auxiliary plate. Then, the time when the residue of the sample could not be confirmed from the inside of the glass tube was defined as the disintegration time. Samples used were tablets after being left to stand for 3 days (3D), 1 week (1W), and 2 weeks (2W) under humidified conditions (temperature 40 ° C., humidity 75% RH, open). ..
(水分量測定)
造粒末の水分含量は、造粒末約5.0gを80℃の条件下で乾燥した際の乾燥減量を、電子式水分計を用いて測定した値であり、測定前の造粒末質量を100%として算出した値(質量%)である。
(Measurement of water content)
The water content of the granulated powder is a value obtained by measuring the drying weight loss when about 5.0 g of the granulated powder is dried under the condition of 80 ° C. using an electronic moisture meter, and the mass of the granulated powder before the measurement. Is a value (mass%) calculated with 100%.
試験方法:熱重量分析法
約5gの検体を測定器の試験皿に均等に広がるように乗せた。設定温度にて熱をかけ続け、検体重量の変化率が0.05%以下になった時点で測定を終了した。重量の変化が全て水分の蒸発によるものと仮定して、水分量を算出した。
Test method: Thermogravimetric analysis A sample of about 5 g was placed on the test plate of the measuring instrument so as to spread evenly. Heat was continuously applied at the set temperature, and the measurement was terminated when the rate of change in the sample weight became 0.05% or less. The amount of water was calculated on the assumption that all changes in weight were due to evaporation of water.
水分測定条件:
・水分測定器:MOC−120H
・検体重量:5g±0.25g
・設定温度:80℃
・終了条件:30秒間の変化量が0.05%以下
Moisture measurement conditions:
・ Moisture measuring instrument: MOC-120H
-Sample weight: 5 g ± 0.25 g
・ Set temperature: 80 ℃
・ Termination condition: Change amount for 30 seconds is 0.05% or less
<結果と考察>
上記溶出試験の結果について、実施例1および比較例1については、表2(Initial)および表3(温度40℃、湿度75%RHにて2週間放置後)に示す。
<Results and discussion>
The results of the dissolution test are shown in Table 2 (Initial) and Table 3 (after being left at a temperature of 40 ° C. and a humidity of 75% RH for 2 weeks) for Example 1 and Comparative Example 1.
表2および表3の結果比較により、同じ処方であっても、造粒工程中の水分量が0.5%を上回っていた比較例1のFC錠では溶出遅延傾向があり、特に加湿保存後(温度40℃、湿度75%RHにて2週間放置後)は溶出遅延が顕著に起こっていることがわかる。一方、造粒工程中の水分量が0.5%以下であった実施例1のFC錠は、比較例1のFC錠よりも溶出性に優れ、加湿保存後においても、10分以内に錠剤中のレベチラセタムが90%以上溶出する優れた溶出性を備えていることが確かめられた。 According to the comparison of the results in Tables 2 and 3, even with the same formulation, the FC tablets of Comparative Example 1 in which the water content during the granulation step exceeded 0.5% tended to delay elution, especially after humidified storage. (After leaving for 2 weeks at a temperature of 40 ° C. and a humidity of 75% RH), it can be seen that the elution delay is remarkable. On the other hand, the FC tablet of Example 1 in which the water content during the granulation step was 0.5% or less was superior to the FC tablet of Comparative Example 1, and the tablet was within 10 minutes even after humidified storage. It was confirmed that levetiracetam in the medium had an excellent elution property of 90% or more.
次に、実施例2および3の溶出試験結果(10分、15分)を表4に示す。 Next, the dissolution test results (10 minutes, 15 minutes) of Examples 2 and 3 are shown in Table 4.
表4の結果から、実施例1とは異なる処方の実施例2および実施例3のFC錠においても、造粒工程中の水分量が0.5%以下であったため、加湿保存後(温度40℃、湿度75%RHにて2週間放置後)も、10分以内に錠剤中のレベチラセタムが90%以上溶出し、優れた溶出性を示すことが明らかとなった。 From the results in Table 4, even in the FC tablets of Example 2 and Example 3 having different formulations from Example 1, the water content during the granulation step was 0.5% or less, so that after humidification and storage (temperature 40). It was revealed that 90% or more of levetiracetam in the tablet was eluted within 10 minutes even after being left at ℃ and humidity of 75% RH for 2 weeks), showing excellent dissolution property.
次に、崩壊性について、実施例1および比較例1の試験結果を表5に、実施例2の試験結果を表6に、実施例3の試験結果を表7示す。 Next, regarding the disintegration property, the test results of Example 1 and Comparative Example 1 are shown in Table 5, the test results of Example 2 are shown in Table 6, and the test results of Example 3 are shown in Table 7.
表5〜7の結果より、造粒工程中の水分量を0.5%以下とすることにより、FC錠の崩壊遅延も抑制(温度40℃、湿度75%RHにて2週間放置後の崩壊時間が、Initialにおける崩壊時間の±1分以内)できることも明らかとなった。 From the results in Tables 5 to 7, by setting the water content during the granulation process to 0.5% or less, the delay in disintegration of FC tablets is also suppressed (disintegration after leaving at a temperature of 40 ° C. and a humidity of 75% RH for 2 weeks. It was also clarified that the time can be (within ± 1 minute of the decay time in Initial).
以上より、本発明の製造方法によって、溶出遅延が十分に抑制されており、溶出性に優れたレベチラセタム含有医薬組成物が得られることが確認できた。 From the above, it was confirmed that the production method of the present invention sufficiently suppresses the elution delay, and a levetiracetam-containing pharmaceutical composition having excellent elution property can be obtained.
Claims (4)
40℃、75%RHの条件で2週間保存後、日本薬局方記載の溶出試験のパドル法に従い10分間溶出させた時のレベチラセタムの溶出率が90%以上である、請求項1〜3のいずれかに記載のレベチラセタムを含む医薬組成物の製造方法。 In the resulting pharmaceutical composition containing levetiracetam,
Any of claims 1 to 3, wherein the elution rate of levetiracetam is 90% or more when it is stored for 2 weeks under the conditions of 40 ° C. and 75% RH and then eluted for 10 minutes according to the paddle method of the dissolution test described in the Japanese Pharmacopoeia. A method for producing a pharmaceutical composition containing levetiracetam according to the above.
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