JP2006008676A - Composition for solid preparation - Google Patents
Composition for solid preparation Download PDFInfo
- Publication number
- JP2006008676A JP2006008676A JP2005154761A JP2005154761A JP2006008676A JP 2006008676 A JP2006008676 A JP 2006008676A JP 2005154761 A JP2005154761 A JP 2005154761A JP 2005154761 A JP2005154761 A JP 2005154761A JP 2006008676 A JP2006008676 A JP 2006008676A
- Authority
- JP
- Japan
- Prior art keywords
- tablet
- weight
- pranlukast hydrate
- composition
- capsule
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 87
- 238000002360 preparation method Methods 0.000 title claims abstract description 68
- 239000007787 solid Substances 0.000 title claims abstract description 33
- 229960004583 pranlukast Drugs 0.000 claims abstract description 112
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 26
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- 150000001720 carbohydrates Chemical class 0.000 claims abstract description 18
- UAJUXJSXCLUTNU-UHFFFAOYSA-N pranlukast Chemical compound C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC(C=1)=CC=C(C(C=2)=O)C=1OC=2C=1N=NNN=1 UAJUXJSXCLUTNU-UHFFFAOYSA-N 0.000 claims abstract 22
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- 239000002775 capsule Substances 0.000 claims description 47
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- 230000003247 decreasing effect Effects 0.000 abstract 2
- NBQKINXMPLXUET-UHFFFAOYSA-N Pranlukast Chemical compound C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC1=CC=CC(C(C=2)=O)=C1OC=2C=1N=NNN=1 NBQKINXMPLXUET-UHFFFAOYSA-N 0.000 description 91
- 238000009472 formulation Methods 0.000 description 37
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- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 8
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- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 3
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Landscapes
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Abstract
Description
本発明は、プランルカスト水和物、水溶性セルロース類および糖類を含有する固形製剤用組成物に関する。 The present invention relates to a composition for solid preparations containing pranlukast hydrate, water-soluble celluloses and saccharides.
プランルカスト水和物はロイコトリエン(LT)拮抗剤として知られており(特許文献1参照)、気管支喘息やアレルギー性鼻炎の治療剤として上市されている。プランルカスト水和物が、気管支喘息やアレルギー性鼻炎に対して有効な治療効果を発現するためには、かなりの高用量を必要とするため、朝夕3号カプセルを2カプセルずつ、1日計4カプセル服用することが求められている。このような比較的大きい3号カプセルを一度に2カプセル服用することは、嚥下に困難のある患者、特に小児や老人の患者にとっては問題となることがあり、好ましい投与形態とはいいがたい。従って、患者の服用コンプライアンスを向上させるために、製剤の小型化が望まれていた。しかしながら、プランルカスト水和物は非常に強い付着性を有するため、通常の方法では服用に適した固形製剤を製造することは困難であり、種々の課題を解決した小型製剤を製造するためには、特別な製剤化の方法が必要となる。例えば、付着性を低減する方法として、プランルカスト水和物を糖類と共に噴霧乾燥することで付着性を低減する方法が知られている(特許文献2参照)。しかし、該方法では製剤化工程、得られた製剤の品質(溶出安定性、崩壊性、錠剤の色むら等)等の問題や、高含量の固形製剤を製造することには問題があった。 Pranlukast hydrate is known as a leukotriene (LT) antagonist (see Patent Document 1) and is marketed as a therapeutic agent for bronchial asthma and allergic rhinitis. In order for pranlukast hydrate to exhibit an effective therapeutic effect for bronchial asthma and allergic rhinitis, it requires a very high dose. It is required to take 4 capsules. Taking such a relatively large No. 3 capsule two capsules at a time can be problematic for patients who have difficulty swallowing, especially children and elderly patients, and is not a preferred dosage form. Therefore, it has been desired to reduce the size of the preparation in order to improve patient compliance. However, since pranlukast hydrate has very strong adhesiveness, it is difficult to produce a solid preparation suitable for taking by ordinary methods, and in order to produce a small preparation that solves various problems. Requires special formulation methods. For example, as a method for reducing adhesion, there is known a method for reducing adhesion by spray drying pranlukast hydrate together with sugars (see Patent Document 2). However, this method has problems in the preparation process, the quality of the obtained preparation (elution stability, disintegration, uneven color of tablets, etc.), and the production of a high content solid preparation.
従って、本発明の目的は患者の服用コンプライアンスが向上した小型製剤化が可能な、プランルカスト水和物を含有する新規な固形製剤用組成物を提供することにある。 Accordingly, an object of the present invention is to provide a novel composition for solid preparations containing pranlukast hydrate that can be made into a small preparation with improved patient compliance.
前記課題に鑑み、本発明者らは鋭意検討を行なった結果、現行のプランルカスト水和物を含有するカプセル剤(商品名:オノンカプセル)に含まれる添加物(結合剤)であるポリエチレングリコールを水溶性セルロース類(例えば、ヒドロキシプロピルメチルセルロース等)に変更することによって、驚くべきことに、糖類の含量を減らしても造粒物の付着性を低減できるため、プランルカスト水和物の高含量造粒物を製造することができ、その結果得られた固形製剤の小型化が可能となることを見出した。さらに、得られた造粒物を用いることにより、プランルカスト水和物を高含量に有する固形製剤を得ることにも成功した。このようにして得られた固形製剤(特に錠剤)においては、溶出速度の向上や溶出性の経時安定性が向上することおよび錠剤化成型性、および崩壊速度の安定性も向上することを見出し、本発明を完成した。 In view of the above problems, the present inventors have conducted intensive studies, and as a result, polyethylene glycol, which is an additive (binder) contained in a capsule (trade name: onon capsule) containing the current pranlukast hydrate. Surprisingly, by changing the water content to water-soluble celluloses (for example, hydroxypropylmethylcellulose, etc.) It has been found that a granulated product can be produced and the resulting solid preparation can be miniaturized. Furthermore, by using the obtained granulated material, a solid preparation having a high content of pranlukast hydrate was also successfully obtained. In the solid preparation (particularly tablet) thus obtained, it has been found that the dissolution rate is improved and the dissolution stability over time is improved, and the tableting moldability and the disintegration rate are also improved. The present invention has been completed.
その結果得られた固形製剤(特に錠剤)は、生体内への吸収性、経時安定性に優れ、錠剤同士の付着や色むらがなく、医薬品として提供するのにきわめて有用であることが見出された。すなわち、本発明は
(1)プランルカスト水和物、糖類および水溶性セルロース類を含有することを特徴とする固形製剤用組成物、
(2)水溶性セルロース類がヒドロキシプロピルメチルセルロースである前項(1)記載の組成物、
(3)噴霧乾燥造粒物である前項(2)記載の組成物、
(4)組成物1重量部に対して、プランルカスト水和物が0.70〜0.98重量部である前項(2)記載の組成物、
(5)プランルカスト水和物が0.75〜0.87重量部である前項(4)記載の組成物、
(6)プランルカスト水和物1重量部に対して、糖類が0.05〜0.30重量部、およびヒドロキシプロピルメチルセルロースが0.002〜0.050重量部である前項(2)記載の組成物、
(7)前項(2)記載の組成物を含有する錠剤、
(8)前項(2)記載の組成物を含有するカプセル剤、
(9)1錠剤中、プランルカスト水和物を112.5mg含有する前項(7)記載の錠剤、
(10)1錠剤中、プランルカスト水和物を225mg含有する前項(7)記載の錠剤、
(11)1錠剤1重量部に対して、プランルカスト水和物が0.50〜0.90重量部である前項(7)記載の錠剤、
(12)プランルカスト水和物が0.55〜0.70重量部である前項(11)記載の錠剤、
(13)1錠剤の体積が100〜175mm3である前項(9)記載の錠剤、
(14)1錠剤の体積が200〜350mm3である前項(10)記載の錠剤、
(15)1錠剤の重量が125〜225mgである前項(9)記載の錠剤、
(16)1錠剤の重量が250〜450mgである前項(10)記載の錠剤、
(17)直径7〜8mm、および厚さ2〜4mmの円形錠である前項(9)記載の錠剤、
(18)長径13〜14mm、短径6〜7mm、および厚さ4〜5mmのカプレット錠である前項(10)記載の錠剤、
(19)1カプセル剤中、プランルカスト水和物を225mg含有する前項(8)記載のカプセル剤、
(20)1カプセル剤1重量部に対して、プランルカスト水和物が0.50〜0.90重量部である前項(8)記載のカプセル剤、
(21)カプセルが2号カプセルまたは3号カプセルである前項(20)記載のカプセル剤、
(22)プランルカスト水和物1重量部に対して、糖類を0.20〜0.25重量部、およびヒドロキシプロピルメチルセルロースを0.004〜0.009重量部含有する噴霧乾燥造粒物を含有する錠剤であって、1錠剤中、プランルカスト水和物を112.5mgまたは225mg含有し、1錠剤1重量部に対して、プランルカスト水和物が0.55〜0.70重量部であることを特徴とする、プランルカスト水和物高含量錠剤、
(23)プランルカスト水和物および水溶性セルロース類を含有することを特徴とする固形製剤用組成物、
(24)密封包装されていることを特徴とする前項(7)記載の錠剤、
(25)密封包装されていることを特徴とする前項(7)記載のカプセル剤、
(26)プランルカスト水和物、糖類および水溶性セルロース類を含有することを特徴とする付着凝集性の低減された高含量固形製剤製造のための組成物、
(27)水溶性セルロース類がヒドロキシプロピルメチルセルロースである前項(26)記載の組成物、
(28)噴霧乾燥造粒物である前項(27)記載の組成物、
(29)プランルカスト水和物1重量部に対して、糖類が0.05〜0.30重量部、およびヒドロキシプロピルメチルセルロースが0.002〜0.050重量部であり、組成物1重量部に対して、プランルカスト水和物が0.75〜0.87重量部であることを特徴とする付着性の低減されたプランルカスト水和物高含量組成物、
(30)前項(28)記載の組成物を含有することを特徴とする錠剤、
(31)前項(28)記載の組成物を含有することを特徴とするカプセル剤、
(32)ヒドロキシプロピルメチルセルロースを用いることを特徴とするプランルカスト水和物を含有する高含量製剤の製造方法、
(33)ヒドロキシプロピルメチルセルロースを用いることを特徴とするプランルカスト水和物を含有する製剤の高含量化方法、
(34)ヒドロキシプロピルメチルセルロースを用いることを特徴とするプランルカスト水和物を含有する造粒物の付着凝集性の低減方法および
(35)ヒドロキシプロピルメチルセルロースを用いることを特徴とするプランルカスト水和物を含有する造粒物を含んでなる小型固形製剤の製造方法に関する。
The resulting solid preparations (especially tablets) are found to be extremely useful for providing pharmaceutical products with excellent in vivo absorption and stability over time, without adhesion between tablets and uneven color. It was done. That is, the present invention provides (1) a composition for solid preparations characterized by containing pranlukast hydrate, sugars and water-soluble celluloses,
(2) The composition according to item (1), wherein the water-soluble cellulose is hydroxypropylmethylcellulose;
(3) The composition according to item (2), which is a spray-dried granulated product,
(4) The composition according to item (2), wherein the pranlukast hydrate is 0.70 to 0.98 parts by weight with respect to 1 part by weight of the composition;
(5) The composition according to item (4), wherein the pranlukast hydrate is 0.75 to 0.87 parts by weight,
(6) As described in (2) above, 0.05 to 0.30 parts by weight of saccharide and 0.002 to 0.050 parts by weight of hydroxypropylmethylcellulose with respect to 1 part by weight of pranlukast hydrate Composition,
(7) A tablet containing the composition according to (2) above,
(8) a capsule containing the composition according to item (2),
(9) The tablet according to the above item (7), containing 112.5 mg of pranlukast hydrate in one tablet,
(10) The tablet according to the above item (7), containing 225 mg of pranlukast hydrate in one tablet,
(11) The tablet according to item (7), wherein the pranlukast hydrate is 0.50 to 0.90 parts by weight with respect to 1 part by weight of one tablet,
(12) The tablet according to the above (11), wherein the pranlukast hydrate is 0.55 to 0.70 parts by weight,
(13) The tablet according to (9) above, wherein the volume of one tablet is 100 to 175 mm 3 ;
(14) The tablet according to item (10), wherein the volume of one tablet is 200 to 350 mm 3 ;
(15) The tablet according to the above (9), wherein the weight of one tablet is 125 to 225 mg,
(16) The tablet according to the above (10), wherein the weight of one tablet is 250 to 450 mg,
(17) The tablet according to (9) above, which is a circular tablet having a diameter of 7 to 8 mm and a thickness of 2 to 4 mm,
(18) The tablet according to the above item (10), which is a caplet tablet having a major axis of 13 to 14 mm, a minor axis of 6 to 7 mm, and a thickness of 4 to 5 mm;
(19) The capsule according to (8) above, wherein 225 mg of pranlukast hydrate is contained in one capsule.
(20) The capsule according to the above item (8), wherein the pranlukast hydrate is 0.50 to 0.90 parts by weight per 1 part by weight of the capsule,
(21) The capsule according to the above (20), wherein the capsule is No. 2 capsule or No. 3 capsule;
(22) A spray-dried granulated product containing 0.20 to 0.25 parts by weight of saccharide and 0.004 to 0.009 parts by weight of hydroxypropylmethylcellulose with respect to 1 part by weight of pranlukast hydrate. A tablet containing 112.5 mg or 225 mg of pranlukast hydrate in one tablet, and 0.5 to 0.70 wt.% Of pranlukast hydrate per 1 part by weight of one tablet Pranlukast hydrate high content tablets, characterized in that
(23) A composition for solid preparation, comprising pranlukast hydrate and water-soluble celluloses,
(24) The tablet according to item (7), which is sealed and packaged,
(25) The capsule according to the above item (7), which is sealed and packaged,
(26) A composition for producing a high-content solid preparation with reduced adhesion cohesiveness, comprising pranlukast hydrate, saccharides and water-soluble celluloses,
(27) The composition according to item (26), wherein the water-soluble cellulose is hydroxypropylmethylcellulose;
(28) The composition according to item (27), which is a spray-dried granulated product,
(29) 1 part by weight of pranlukast hydrate is 0.05 to 0.30 part by weight of saccharide and 0.002 to 0.050 part by weight of hydroxypropylmethylcellulose, and 1 part by weight of the composition In contrast, pranlukast hydrate high content composition with reduced adhesion, characterized in that pranlukast hydrate is 0.75 to 0.87 parts by weight,
(30) A tablet comprising the composition described in (28) above,
(31) A capsule comprising the composition described in (28) above,
(32) A method for producing a high-content preparation containing pranlukast hydrate, characterized by using hydroxypropylmethylcellulose;
(33) A method for increasing the content of a preparation containing pranlukast hydrate, characterized by using hydroxypropylmethylcellulose;
(34) A method for reducing the adhesion and cohesiveness of a granulated product containing pranlukast hydrate characterized by using hydroxypropylmethylcellulose and (35) pranlukast water characterized by using hydroxypropylmethylcellulose The present invention relates to a method for producing a small solid preparation comprising a granulated product containing a Japanese product.
本発明に用いられるプランルカスト水和物は式(A) The pranlukast hydrate used in the present invention has the formula (A)
で示される4−オキソ−8−[4−(4−フェニルブトキシ)ベンゾイルアミノ]−2−(テトラゾール−5−イル)−4H−1−ベンゾピラン・1/2水和物である。プランルカスト水和物の製造は、例えば、特開昭61-050977号明細書記載の方法に準じて行なうことができる。 4-oxo-8- [4- (4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran 1/2 hydrate represented by formula (1). The production of pranlukast hydrate can be carried out, for example, according to the method described in JP-A 61-050977.
本発明で用いられる水溶性セルロース類とは、セルロースの水酸基の水素原子の一部をメチル基、エチル基、プロピル基、ヒドロキシプロピル基またはヒドロキシエチル基等で置換することにより、水素結合を消失させた水溶性高分子である。例えば、ヒドロキシメチルセルロース、ヒドロキシメチルエチルセルロース、メチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース(HPC)、ヒドロキシプロピルメチルセルロース(HPMC)、ヒドロキシプロピルメチルセルロースフタレート(HPMCP)、ヒドロキシプロピルメチルセルロースアセテートスクシネート(HPMCAS)等が挙げられる。水溶性セルロース類としてはいずれも好ましいが、特に好ましくはヒドロキシプロピルメチルセルロースである。 The water-soluble celluloses used in the present invention are those in which hydrogen bonds are lost by substituting some of the hydrogen atoms of the hydroxyl groups of cellulose with methyl groups, ethyl groups, propyl groups, hydroxypropyl groups or hydroxyethyl groups. Water-soluble polymer. For example, hydroxymethylcellulose, hydroxymethylethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and the like can be mentioned. . Any water-soluble cellulose is preferable, but hydroxypropylmethylcellulose is particularly preferable.
本発明で用いられるヒドロキシプロピルメチルセルロースのメトキシ基含有率として好ましくは、約19〜30重量%であり、ヒドロキシプロポキシ基含有率として好ましくは、約4〜12重量%であり、粘度として好ましくは、約2.5〜17.5mm2/sである。好適に使用されるヒドロキシプロピルメチルセルロースとしては例えば、ヒドロキシプロピルメチルセルロース2906、ヒドロキシプロピルメチルセルロース2910、ヒドロキシプロピルメチルセルロース2208等が挙げられ、具体的にはメトローズ90SH、メトローズ65SH、メトローズ60SH、Tc−5(信越化学工業(株)製)、メトセルK、メトセルE(ダウケミカル社製)、マーポローズ(松本油脂製薬(株)製)等が挙げられる。Tc−5としては、例えば、Tc−5E、Tc−5Ew、Tc−5R、Tc−5Rw、Tc−5Mw、Tc−5S等が挙げられる。 The methoxy group content of hydroxypropylmethylcellulose used in the present invention is preferably about 19 to 30% by weight, the hydroxypropoxy group content is preferably about 4 to 12% by weight, and the viscosity is preferably about 2.5 to 17.5 mm 2 / s. Examples of hydroxypropylmethylcellulose that can be suitably used include hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose 2208, and the like. Specifically, Metrolose 90SH, Metrolose 65SH, Metrolose 60SH, Tc-5 (Shin-Etsu Chemical) Kogyo Co., Ltd.), Methocel K, Methocel E (Dow Chemical Co., Ltd.), Marporose (Matsumoto Yushi Seiyaku Co., Ltd.) and the like. Examples of Tc-5 include Tc-5E, Tc-5Ew, Tc-5R, Tc-5Rw, Tc-5Mw, Tc-5S, and the like.
本発明における糖類としては、例えば、ぶどう糖、果糖、麦芽糖、乳糖、異性化乳糖、還元乳糖、蔗糖、D−マンニトール、エリスリトール、マルチトール、キシリトール、パラチノース、トレハロース、ソルビトール、トウモロコシデンプン、馬鈴薯デンプン、コムギデンプン、コメデンプン等が挙げられ、好ましくは乳糖である。 Examples of the saccharide in the present invention include glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, corn starch, potato starch, wheat Starch, rice starch and the like can be mentioned, and lactose is preferable.
本発明において、固形製剤用組成物とは、プランルカスト水和物を高含量に含有する錠剤および/またはカプセル剤を製造するための造粒物を表わし、換言すれば、「高含量固形製剤製造のための組成物」である。 In the present invention, the composition for solid preparation represents a granulated product for producing tablets and / or capsules containing a high content of pranlukast hydrate, in other words, “high content solid preparation” “Composition for manufacture”.
また、本発明の固形製剤用組成物には、固形製剤を製造する際に一般的に使用される添加剤(製剤基剤)をさらに含んでいてもよく、例えば、賦形剤、結合剤、滑沢剤、崩壊剤、矯味剤、矯臭剤、界面活性剤、香料、着色剤、抗酸化剤、隠蔽剤、静電気防止剤、流動化剤、湿潤剤、溶出補助剤等を1種または2種以上適宜配合して用いることができる。 Moreover, the composition for solid preparation of the present invention may further contain an additive (formulation base) generally used in producing a solid preparation, for example, an excipient, a binder, One or two types of lubricants, disintegrating agents, flavoring agents, flavoring agents, surfactants, fragrances, coloring agents, antioxidants, masking agents, antistatic agents, fluidizing agents, wetting agents, elution aids, etc. As described above, they can be appropriately blended and used.
本発明の固形製剤用組成物は、例えば、散剤、顆粒剤、錠剤、カプセル剤等の固形製剤として用いるか、前記固形製剤を服用時に溶液または懸濁液として服用する用時溶解/懸濁型製剤(例えば、ドライシロップ剤等)として用いることができる。好ましい製剤形態としては錠剤、またはカプセル剤が挙げられる。 The composition for solid preparation of the present invention is used, for example, as a solid preparation such as powder, granule, tablet, capsule or the like, or dissolved / suspended at the time of taking the solid preparation as a solution or suspension at the time of taking It can be used as a preparation (for example, dry syrup). Preferable preparation forms include tablets or capsules.
本発明の固形製剤用組成物を製剤化する方法は公知であり、例えば、プランルカスト水和物、水溶性セルロース類(例えば、ヒドロキシプロピルメチルセルロース等)、糖類および必要に応じて他の添加剤と混合するか、もしくは公知の造粒法(例えば、押出し造粒法、混合撹拌造粒法、高速混合撹拌造粒法、流動層造粒法、転動撹拌流動層造粒法、転動造粒法、乾式(圧縮)造粒法、破砕造粒法、噴霧乾燥造粒法等)によって得られる造粒物を必要に応じて乾燥、整粒、分級等することにより、散剤や顆粒剤を製造することができる。また、先で得られる造粒物、散剤または顆粒剤と必要に応じて他の添加剤を加えて、打錠またはカプセル充填することにより、錠剤やカプセル剤を製造することができる。また、錠剤は、必要に応じ薬学的に許容され、本発明の効果を妨げない、フィルムコーティング基剤を用いて被覆されても構わない。 Methods for formulating the composition for solid preparations of the present invention are known, for example, pranlukast hydrate, water-soluble celluloses (for example, hydroxypropylmethylcellulose, etc.), saccharides, and other additives as required Or a known granulation method (for example, extrusion granulation method, mixed stirring granulation method, high speed mixed stirring granulation method, fluidized bed granulation method, tumbling stirred fluidized bed granulation method, rolling rolling Granulate, dry (compressed) granulation, crushing granulation, spray-drying granulation, etc.) Can be manufactured. Moreover, a tablet and a capsule can be manufactured by adding the granule, powder, or granule obtained previously and other additives as needed, and tableting or capsule-filling. Moreover, a tablet may be coat | covered using the film coating base which is accept | permitted pharmacologically as needed and does not prevent the effect of this invention.
本発明の効果を妨げないか、または本発明の効果が最小限に得られる限り、他の添加剤(担体)として、いかなるものも加えて構わない。 Any additive (carrier) may be added as long as the effects of the present invention are not disturbed or the effects of the present invention are minimized.
他の添加剤としては、例えば、賦形剤、結合剤、崩壊剤、矯味剤、界面活性剤、香料、滑沢剤、着色剤、抗酸化剤、隠蔽剤、静電気防止剤、流動化剤、湿潤剤、矯臭剤、溶出補助剤等が挙げられ、これらから選択される1種または2種以上を適宜配合して用いてもよい。 Other additives include, for example, excipients, binders, disintegrants, flavoring agents, surfactants, fragrances, lubricants, coloring agents, antioxidants, masking agents, antistatic agents, fluidizing agents, Wetting agents, flavoring agents, elution aids and the like can be mentioned, and one or more selected from these may be used in appropriate combination.
賦形剤としては、例えば、糖類(例えば、ぶどう糖、果糖、麦芽糖、乳糖、異性化乳糖、還元乳糖、蔗糖、D−マンニトール、エリスリトール、マルチトール、キシリトール、パラチノース、トレハロース、ソルビトール、トウモロコシデンプン、馬鈴薯デンプン、コムギデンプン、コメデンプン等)、結晶セルロース、無水ケイ酸、無水リン酸カルシウム、沈降炭酸カルシウム、ケイ酸カルシウム等が挙げられる。結合剤としては、例えば、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、ポビドン、ポリビニルピロリドン、メチルセルロース、ポリビニルアルコール、カルボキシメチルセルロースナトリウム、部分α化デンプン、α化デンプン、アルギン酸ナトリウム、プルラン、アラビアゴム末、ゼラチン等が挙げられる。崩壊剤としては、例えば、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、クロスポビドン、ヒドロキシプロピルスターチ、トウモロコシデンプン等が挙げられる。矯味剤としては、例えば、白糖、D−ソルビトール、キシリトール、クエン酸、アスコルビン酸、酒石酸、リンゴ酸、アスパルテーム、アセスルファムカリウム、ソーマチン、サッカリンナトリウム、グリチルリチン二カリウム、グルタミン酸ナトリウム、5’−イノシン酸ナトリウム、5’−グアニル酸ナトリウム等が挙げられる。界面活性剤としては、例えば、ポリソルベート(例えば、ポリソルベート20、ポリソルベート40、ポリソルベート60、ポリソルベート65、ポリソルベート80等)、ポリオキシエチレン・ポリオキシプロピレン共重合物、ラウリル硫酸ナトリウム等が挙げられる。香料としては、例えば、レモン油、オレンジ油、メントール、はっか油等が挙げられる。滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、蔗糖脂肪酸エステル、フマル酸ステアリルナトリウム、ステアリン酸、タルク、ポリエチレングリコール等が挙げられる。着色剤としては、例えば、酸化チタン、食用黄色5号、食用青色2号、三二酸化鉄、黄色三二酸化鉄等が挙げられる。抗酸化剤としては、例えば、アスコルビン酸ナトリウム、L−システイン、亜硫酸ナトリウム、ビタミンE等が挙げられる。隠蔽剤としては、例えば、酸化チタン等が挙げられる。静電気防止剤としては、例えば、タルク、酸化チタン等が挙げられる。流動化剤としては、例えば、軽質無水ケイ酸、タルク、含水二酸化ケイ素等が挙げられる。湿潤剤としては、例えば、ポリソルベート80、ラウリル酸硫酸ナトリウム、ショ糖脂肪酸エステル、ポリエチレングリコール、ヒドロキシプロピルセルロース(HPC)等が挙げられる。溶出補助剤としては、例えば、乾燥メタクリル酸コポリマーLD、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート等が挙げられる。 Examples of the excipient include sugars (eg, glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, corn starch, potato Starch, wheat starch, rice starch, etc.), crystalline cellulose, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate and the like. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, sodium carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin and the like. Can be mentioned. Examples of the disintegrant include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, hydroxypropyl starch, and corn starch. Examples of the corrigent include sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharine, dipotassium glycyrrhizin, sodium glutamate, 5′-sodium inosinate, 5 '-Sodium guanylate, etc. are mentioned. Examples of the surfactant include polysorbate (for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc.), polyoxyethylene / polyoxypropylene copolymer, sodium lauryl sulfate, and the like. As a fragrance | flavor, lemon oil, orange oil, menthol, brackish oil etc. are mentioned, for example. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol and the like. Examples of the colorant include titanium oxide, food yellow No. 5, food blue No. 2, iron sesquioxide, yellow iron sesquioxide, and the like. Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E and the like. Examples of the concealing agent include titanium oxide. Examples of the antistatic agent include talc and titanium oxide. Examples of the fluidizing agent include light anhydrous silicic acid, talc, hydrous silicon dioxide and the like. Examples of the wetting agent include polysorbate 80, sodium laurate sulfate, sucrose fatty acid ester, polyethylene glycol, hydroxypropyl cellulose (HPC), and the like. Examples of the dissolution aid include dry methacrylic acid copolymer LD, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and the like.
本発明の固形製剤用組成物の造粒物としては、噴霧乾燥造粒物が好ましい。噴霧乾燥造粒物を得る噴霧乾燥造粒法とは、液状物質を気流中に噴霧微粒化し、これを乾燥または凝固、ゲル化によって微細な造粒粒子を得る方法であり、粒子凝集および粉体表面物性の改善、粉体および粉体表面の形状の改善等が可能である。また、他の造粒法と比較し、多孔質となり、毛細管現象による濡れ性の改善、およびなめらかな表面をもつ粒子を得ることができる。さらに乾燥時間が数秒から数十秒と短く、品温も排気温度以上に上がらないため、熱影響が少ない。従って、非常に強い付着性や撥水性を有するプランルカスト水和物には好ましい造粒法である。 As the granulated product of the composition for solid preparation of the present invention, spray-dried granulated product is preferable. The spray-drying granulation method for obtaining a spray-dried granulated product is a method for obtaining a fine granulated particle by spraying and atomizing a liquid substance in an air stream, drying or coagulating it, and gelling. It is possible to improve surface physical properties, improve the shape of the powder and the powder surface, and the like. Further, compared with other granulation methods, it becomes porous, so that wettability is improved by capillary action, and particles having a smooth surface can be obtained. Furthermore, since the drying time is as short as several seconds to several tens of seconds and the product temperature does not rise above the exhaust temperature, there is little heat effect. Therefore, it is a preferred granulation method for pranlukast hydrate having very strong adhesion and water repellency.
本発明の固形製剤用組成物1重量部におけるプランルカスト水和物は約0.70〜0.98重量部が好ましく、さらに好ましくは約0.75〜0.90重量部であり、特に好ましくは約0.75〜0.87重量部である。 The amount of pranlukast hydrate in 1 part by weight of the composition for solid preparations of the present invention is preferably about 0.70 to 0.98 parts by weight, more preferably about 0.75 to 0.90 parts by weight, particularly preferably. Is about 0.75 to 0.87 parts by weight.
また、本発明固形組成物の噴霧乾燥造粒物1重量部における糖類は約0.25重量部以下が好ましく、さらに好ましくは約0.05〜0.20重量部であり、特に好ましくは約0.15〜0.20重量部である。 In addition, the saccharide in 1 part by weight of the spray-dried granulated product of the solid composition of the present invention is preferably about 0.25 part by weight or less, more preferably about 0.05 to 0.20 part by weight, particularly preferably about 0. .15 to 0.20 parts by weight.
本発明の固形製剤用組成物において、プランルカスト水和物1重量部に対して糖類の重量比として好ましくは、約0.05〜0.30重量部であり、さらに好ましくは約0.10〜0.25重量部であり、特に好ましくは約0.2〜0.25重量部である。 In the composition for solid preparation of the present invention, the weight ratio of saccharide to 1 part by weight of pranlukast hydrate is preferably about 0.05 to 0.30 part by weight, more preferably about 0.10. 0.25 parts by weight, particularly preferably about 0.2 to 0.25 parts by weight.
本発明の固形製剤用組成物において、プランルカスト水和物1重量部に対して水溶性セルロース類の重量比として好ましくは、約0.002〜0.050重量部であり、さらに好ましくは約0.004〜0.030重量部であり、特に好ましくは約0.004〜0.009重量部である。 In the composition for solid preparation of the present invention, the weight ratio of the water-soluble cellulose to 1 part by weight of pranlukast hydrate is preferably about 0.002 to 0.050 part by weight, more preferably about The amount is 0.004 to 0.030 parts by weight, particularly preferably about 0.004 to 0.009 parts by weight.
本発明の固形製剤用組成物を錠剤やカプセル剤として用いる場合、該製剤中のプランルカスト水和物含量は、年齢、体重、症状、治療効果、投与方法、処理時間等により異なるが、本発明の所望の効果が得られるように製することが好ましい。例えば、成人1日当たりのプランルカスト水和物の投与量として好ましくは約25〜2500mg、より好ましくは約112.5〜450mg、さらに好ましくは約225〜450mgである。 When the composition for solid preparation of the present invention is used as a tablet or capsule, the content of pranlukast hydrate in the preparation varies depending on age, body weight, symptom, therapeutic effect, administration method, treatment time, etc. It is preferable to manufacture so that the desired effect of invention may be acquired. For example, the dose of pranlukast hydrate per adult is preferably about 25 to 2500 mg, more preferably about 112.5 to 450 mg, and further preferably about 225 to 450 mg.
本発明の固形製剤用組成物を含有する錠剤としては、服用する患者に負担を与えない形状や大きさのものが好ましい。例えば、円形錠や異形錠(例えば、カプレット錠等)等が挙げられ、円形錠であれば直径は約7〜9mm、厚さは約2〜4mmが好ましく、カプレット錠であれば長径は約13〜15mm、短径は約5〜7mm、厚さは約4〜5mmが好ましい。錠剤の形状は特に限定されないが、円柱状で曲率面を有することが好ましい。
また、錠剤に含まれるプランルカスト水和物の含量としては、1錠中、約112.5〜450mgが好ましく、より好ましくは約112.5mgまたは約225mgである。
As a tablet containing the composition for solid preparations of the present invention, a tablet having a shape and a size that does not give a burden to a patient to be taken is preferable. For example, a round tablet, a deformed tablet (for example, caplet tablet etc.), etc. are mentioned. In the case of a round tablet, the diameter is preferably about 7 to 9 mm and the thickness is preferably about 2 to 4 mm. In the case of a caplet tablet, the major axis is about 13 ˜15 mm, the minor axis is preferably about 5 to 7 mm, and the thickness is preferably about 4 to 5 mm. The shape of the tablet is not particularly limited, but is preferably cylindrical and has a curvature surface.
In addition, the content of pranlukast hydrate contained in the tablet is preferably about 112.5 to 450 mg, more preferably about 112.5 mg or about 225 mg per tablet.
本発明における錠剤、すなわち高含量錠剤において、1錠剤1重量部に対して、プランルカスト水和物の含有量は好ましくは約0.50〜0.90重量部であり、より好ましくは約0.50〜0.80重量部であり、特に好ましくは約0.55〜0.70重量部である。 In the tablet of the present invention, that is, the high-content tablet, the content of pranlukast hydrate is preferably about 0.50 to 0.90 parts by weight, more preferably about 0 to 1 part by weight of one tablet. .50 to 0.80 parts by weight, particularly preferably about 0.55 to 0.70 parts by weight.
プランルカスト水和物を約112.5mg含有する錠剤1個の重量として好ましくは、約125〜225mgであり、より好ましくは約140〜225mgであり、特に好ましくは約160〜205mgである。 The weight of a tablet containing about 112.5 mg of pranlukast hydrate is preferably about 125 to 225 mg, more preferably about 140 to 225 mg, and particularly preferably about 160 to 205 mg.
プランルカスト水和物を約225mg含有する錠剤1個の重量として好ましくは、約250〜450mgであり、より好ましくは約280〜450mgであり、特に好ましくは約320〜410mgである。 The weight of one tablet containing about 225 mg of pranlukast hydrate is preferably about 250 to 450 mg, more preferably about 280 to 450 mg, and particularly preferably about 320 to 410 mg.
プランルカスト水和物を約112.5mg含有する錠剤1個の体積として好ましくは、約100〜175mm3であり、より好ましくは約110〜175mm3であり、特に好ましくは約125〜160mm3である。 The volume of one tablet containing about 112.5 mg of pranlukast hydrate is preferably about 100 to 175 mm 3 , more preferably about 110 to 175 mm 3 , and particularly preferably about 125 to 160 mm 3 . is there.
プランルカスト水和物を225mg含有する錠剤1個の体積として好ましくは、約200〜350mm3であり、より好ましくは約220〜350mm3であり、特に好ましくは約250〜320mm3である。 The volume of one tablet containing 225 mg of pranlukast hydrate is preferably about 200 to 350 mm 3 , more preferably about 220 to 350 mm 3 , and particularly preferably about 250 to 320 mm 3 .
本発明の固形組成物を含有するカプセル剤に含まれるプランルカスト水和物の含量としては、1カプセル中、約225〜450mgが好ましく、より好ましくは225mgまたは450mgである。また、カプセルの大きさとしては、1号、2号、3号または4号カプセルが好ましい。例えば、プランルカスト水和物を225mg含有する2号カプセル剤または3号カプセル剤、もしくはプランルカスト水和物を112.5mg含有する4号カプセル剤等が、服用患者のコンプライアンスの観点から好ましい。 The content of pranlukast hydrate contained in the capsule containing the solid composition of the present invention is preferably about 225 to 450 mg, more preferably 225 mg or 450 mg per capsule. As the size of the capsule, No. 1, No. 2, No. 3, or No. 4 capsule is preferable. For example, No. 2 capsule or No. 3 capsule containing 225 mg of pranlukast hydrate or No. 4 capsule containing 112.5 mg of pranlukast hydrate is preferable from the viewpoint of patient compliance. .
本発明におけるカプセル剤、すなわち高含量カプセル剤において、1カプセル剤1重量部に対して、プランルカスト水和物の含有量は好ましくは約0.50〜0.90重量部である。 In the capsule in the present invention, that is, the high content capsule, the content of pranlukast hydrate is preferably about 0.50 to 0.90 parts by weight per 1 part by weight of one capsule.
本発明の固形組成物を含有する錠剤硬度として好ましくは、8.0〜14.6kgであり、例えば、長径13〜15mmで短径5〜7mmである、錠剤硬度10.0〜14.6kgのカプレット錠、直径が7〜9mmである、錠剤硬度8.0〜12.0kgの円形錠が好ましい。 The tablet hardness containing the solid composition of the present invention is preferably 8.0 to 14.6 kg. For example, the major axis is 13 to 15 mm and the minor axis is 5 to 7 mm. The tablet hardness is 10.0 to 14.6 kg. Caplet tablets, preferably round tablets with a tablet hardness of 8.0 to 12.0 kg and a diameter of 7 to 9 mm.
プランルカスト水和物を含有するカプセル剤は無包装状態で放置すると、1週間で溶出性が不安定になることが報告されている(「錠剤・カプセル剤の無包装状態での安定性情報」,改訂3版,医薬ジャーナル社,2003年2月5日,p.136参照)。溶出性が不安定になると、生体内投与後における生物学的利用能の変化が生じることになり、薬効発現が不十分になったり、副作用を伴なったりするおそれがあるが、本発明の固形製剤用組成物を用いることにより、経時的な溶出性が安定になることが明らかとなった。 It has been reported that when a capsule containing pranlukast hydrate is left unpacked, the dissolution property becomes unstable in one week (“Stability information of tablets and capsules in the unpacked state” ", Revised 3rd edition, Pharmaceutical Journal, Feb. 5, 2003, p.136). If the dissolution property becomes unstable, the bioavailability changes after administration in vivo, and there is a possibility that the medicinal effect may be insufficient or may have side effects. It has been clarified that elution with time is stable by using the pharmaceutical composition.
本発明において、経時的な溶出性が安定になるということは、本発明の固形製剤用組成物を用いて製造した製剤(例えば、錠剤、カプセル剤等)を、例えば、加速試験(40℃75%RH)や苛酷試験(60℃)に付しても、試験前の製剤と比して、溶出性の遅延や加速が起こりにくいことを意味する。 In the present invention, the dissolution over time is stable because the preparation (eg, tablet, capsule, etc.) produced using the composition for solid preparation of the present invention is subjected to, for example, an accelerated test (40 ° C. 75 % RH) and a severe test (60 ° C.), it means that dissolution delay and acceleration are less likely to occur as compared to the preparation before the test.
本発明の錠剤および/またはカプセル剤は、前記のように製造された後、所望によって任意の包装が施される。かかる包装は、例えば、個別に包装されていない非単位包装(例えば、バルク包装)等であってもよいが、例えば、熱接着性フィルムで医薬品をシールする、いわゆるヒートシールのような密封包装が好ましい。尚、本発明における密封包装には、例えば、薬局方規定の「気密容器」や「密封容器」を用いての包装も、その意味合いとして含まれる。ヒートシールには、PTP(Press Through Pack)包装やSP(Strip Package)包装等が含まれるが、特に、PTP包装が好ましい。PTP包装の材質としては、PVC(ポリビニルクロライド)、PVDC(ポリビニリデンクロライド)コートPVC(ポリビニルクロライド)、PP(ポリプロピレン)、ポリプロピレン系多層等が挙げられる。PTP包装は、アルミ包装と併用することが好ましい。さらに本発明のカプセルは、PTP包装やSP包装を施した後、その一定数量をポリエチレンやアルミ箔で二次包装(いわゆるピロー包装)してもよい。 After the tablet and / or capsule of the present invention is produced as described above, it is optionally packaged as desired. Such packaging may be, for example, non-unit packaging that is not individually packaged (for example, bulk packaging). For example, sealed packaging such as so-called heat sealing that seals pharmaceuticals with a heat-adhesive film is used. preferable. The sealed packaging in the present invention includes, for example, packaging using a pharmacopoeia-defined “airtight container” or “sealed container”. The heat seal includes PTP (Press Through Pack) packaging, SP (Strip Package) packaging, and the like, and PTP packaging is particularly preferable. Examples of the material for the PTP packaging include PVC (polyvinyl chloride), PVDC (polyvinylidene chloride) -coated PVC (polyvinyl chloride), PP (polypropylene), and polypropylene-based multilayers. PTP packaging is preferably used in combination with aluminum packaging. Further, after the capsule of the present invention is subjected to PTP packaging or SP packaging, a certain amount thereof may be secondarily packaged with polyethylene or aluminum foil (so-called pillow packaging).
本発明の製剤はプランルカスト水和物の物性に基づく付着凝集性を低減することを特徴とするが、付着凝集性を反映するパラメーターとして、引張破断力が用いられる。 The preparation of the present invention is characterized in that it reduces adhesion cohesion based on the physical properties of pranlukast hydrate, and tensile rupture force is used as a parameter reflecting the adhesion cohesion.
付着性を低減した本発明の製剤における引張破断力として好ましくは、約10.0g以下であり、より好ましくは約0.1〜8.0gである。
[医薬品への適用]
本発明の製剤はプランルカスト水和物を有効成分として含有するため、気管支喘息、副鼻腔炎、COPD(慢性閉塞性肺疾患)等の呼吸器疾患、メニエール病、偏頭痛、咳嗽、月経困難症等の種々の疾患等の予防および/または治療薬として有用である。
[毒性]
本発明が提供するプランルカスト水和物を含有する製剤は低毒性であり、医薬として使用するために十分に安全である。
The tensile breaking force in the preparation of the present invention with reduced adhesiveness is preferably about 10.0 g or less, more preferably about 0.1 to 8.0 g.
[Application to pharmaceutical products]
Since the preparation of the present invention contains pranlukast hydrate as an active ingredient, respiratory diseases such as bronchial asthma, sinusitis, COPD (chronic obstructive pulmonary disease), Meniere's disease, migraine, cough, menstrual difficulty It is useful as a prophylactic and / or therapeutic drug for various diseases such as infectious diseases.
[toxicity]
The preparation containing pranlukast hydrate provided by the present invention has low toxicity and is sufficiently safe for use as a medicine.
水溶性セルロース類(例えば、ヒドロキシプロピルメチルセルロース等)を用いることによって、糖類の量を減らしても付着性を低減できるため、小型製剤(特に錠剤)を製造することが可能となった。また、本発明により、製剤化工程における諸問題も解決し、さらに溶出速度の向上や経時的な溶出性も安定になり、また製剤化における成形性も格段に向上した。すなわち、本発明の製剤は、種々の問題点を解決した、プランルカスト水和物を含有する高含量固形製剤である。 By using water-soluble celluloses (for example, hydroxypropylmethylcellulose and the like), the adhesiveness can be reduced even if the amount of saccharide is reduced, so that it is possible to produce a small preparation (especially a tablet). In addition, the present invention has solved various problems in the formulation process, further improves the dissolution rate and stabilizes dissolution over time, and dramatically improves the moldability in formulation. That is, the preparation of the present invention is a high-content solid preparation containing pranlukast hydrate that solves various problems.
以下、実施例によって本発明を詳述するが、本発明をよく理解するためのものであり、本発明はこれらに限定されるものではない。
製剤例1
Tc−5Rw(3g;信越化学工業(株))を精製水(1027mL)に溶解し、さら
に乳糖(100g;NZMP社)およびプランルカスト水和物(450g)を加え、懸濁液とした。この懸濁液をスプレードライヤー(給気(入り口)温度:180℃、排気温度:100〜110℃、送液速度:30〜40g/分、アトマイザー回転速度:12000rpm)で噴霧乾燥し、プランルカスト水和物の噴霧乾燥品を得た。これを0.5mmの篩で篩過し、噴霧乾燥造粒物(SD品)(450g)を得た。得られたSD品(55.8g)に低置換度ヒドロキシプロピルセルロース(L−HPC)(3g;信越化学工業(株))およびステアリン酸マグネシウム(1.2g;太平化学産業(株))を添加・混合して、打錠用末を得た。この打錠用末を打錠機(岡田精工製、Tab−ALL)により、杵径7.5mm、打錠圧750kgfの条件で打錠し、以下の処方である直径7.5mm、厚さ3.1mmのプランルカスト水和物を75.7重量%含有する錠剤1を製造した。
本発明錠剤1の処方(1錠中)
噴霧乾燥造粒物の成分
プランルカスト水和物 112.5mg
乳糖 25.0mg
Tc−5Rw 0.8mg
添加剤
L−HPC 7.4mg
ステアリン酸マグネシウム 3.0mg
計 148.7mg
製剤例2
製剤例1と同様の操作を行なうことにより、以下の処方である直径7.5mm、厚さ2.9mmのプランルカスト水和物を84.0重量%含有する錠剤2を製造した。
本発明錠剤2の処方(1錠中)
噴霧乾燥造粒物の成分
プランルカスト水和物 112.5mg
乳糖 11.3mg
Tc−5Rw 0.8mg
添加剤
L−HPC 6.7mg
ステアリン酸マグネシウム 2.7mg
計 134.0mg
製剤例3
製剤例1と同様の操作を行なうことにより、以下の処方である直径7.5mm、厚さ3.2mmのプランルカスト水和物を74.7重量%含有する錠剤3を製造した。
本発明錠剤3の処方(1錠中)
噴霧乾燥造粒物の成分
プランルカスト水和物 112.5mg
乳糖 25.0mg
Tc−5Rw 2.5mg
添加剤
L−HPC 7.5mg
ステアリン酸マグネシウム 3.0mg
計 150.5mg
製剤例4
Tc−5Rw(5.4g;信越化学工業(株))を精製水(1848.6mL)に溶解し、さらに乳糖(180g;NZMP社)およびプランルカスト水和物(810g)を加え、懸濁液とした。この懸濁液を下記条件下において、スプレードライヤー(給気(入り口)温度:180℃、排気温度:100〜110℃、送液速度:30〜40g/分、アトマイザー回転速度:10000rpm、大川原化工機(株)製、L−8)で噴霧乾燥し、プランルカスト水和物の噴霧乾燥品を得た。これを0.5mmの篩にて篩過し、噴霧乾燥造粒物(SD品)(826.2g)を得た。得られたSD品(760g)に直打用乳糖(スーパータブ)(155g;NZMP社)、乾燥メタクリル酸コポリマーLD(オイドラギット L100−55)(50g;レーム社)、クロスカルメロースナトリウム(Ac−Di−Sol)(25g;旭化成(株))およびステアリン酸マグネシウム(10g;太平化学産業(株))をボーレコンテナーミキサー(寿工業製、MC−2.5)にて30分間混合して、打錠用末を得た。この打錠用末を打錠機((株)菊水製作所製、バーゴ(Virgo))により、杵径8mm、打錠圧1000kgfの条件で打錠し、以下の処方である8mm、厚さ3.41mm、錠剤硬度9.4kgのプランルカスト水和物を61.8%含有する錠剤4を製造した。
本発明錠剤4の処方(1錠中)
噴霧乾燥造粒物の成分
プランルカスト水和物 112.5mg
乳糖 25.0mg
Tc−5Rw 0.8mg
添加剤
オイドラギット L100−55 9.1mg
スーパータブ 28.2mg
Ac−Di−Sol 4.5mg
ステアリン酸マグネシウム 1.8mg
計 181.9mg
製剤例5
Tc−5Rw(5.4g;信越化学工業(株))を精製水(1848.6mL)に溶解し、さらに乳糖(180g;NZMP社)およびプランルカスト水和物(810g)を加え、懸濁液とした。この懸濁液をスプレードライヤー(給気(入り口)温度:180℃、排気温度:100〜110℃、送液速度:30〜40g/分、アトマイザー回転速度:10000rpm、大川原化工機(株)製、L−8)で噴霧乾燥し、プランルカスト水和物の噴霧乾燥品を得た。これを0.5mmの篩にて篩過し、噴霧乾燥造粒物(SD品)(843.2g)を得た。得られたSD品(760g)に直打用乳糖(スーパータブ)(150g;NZMP社)、乾燥メタクリル酸コポリマーLD(オイドラギットL100−55)(50g;レーム社)、Tc−5Rw(30.0g;信越化学工業(株))およびステアリン酸マグネシウム(10g;太平化学産業(株))をボーレコンテナーミキサー(寿工業(株)製、MC−2.5)にて30分間混合して、打錠用末を得た。この打錠用末を打錠機((株)菊水製作所製、バーゴ(Virgo))により、杵直径14mm、短径6mm、打錠圧800kgfの条件で打錠し、以下の処方である14×6mm、厚さ4.86mm、錠剤硬度13.8kgのプランルカスト水和物を61.8%含有するカプレット錠剤(錠剤5)を製造した。
本発明錠剤5の処方(1錠中)
噴霧乾燥造粒物の成分
プランルカスト水和物 225.0mg
乳糖 50.0mg
Tc−5Rw 1.5mg
添加剤
オイドラギット L100−55 18.2mg
スーパータブ 54.6mg
Tc−5Rw 10.9mg
ステアリン酸マグネシウム 3.6mg
計 363.8mg
製剤例6
Tc−5Rw(1.2kg;信越化学工業(株))を精製水(221.2kg)に溶解し、さらに乳糖(40kg;NZMP社)およびプランルカスト水和物(180kg)を加え、懸濁液とした。この懸濁液をスプレードライヤー(給気(入り口)温度:190℃、排気温度:85±5℃、送液速度:100kg/時間、アトマイザー回転速度:16000±100rpm、大川原化工機(株)製、ODA−27)で噴霧乾燥し、プランルカスト水和物の噴霧乾燥品を得た。これを0.85mmの篩にて篩過し、噴霧乾燥造粒物(SD品)(212.3kg)を得た。得られたSD品(47.005kg)に直打用乳糖(スーパータブ)(9.574kg;NZMP社)、乾燥メタクリル酸コポリマーLD(オイドラギットL100−55)(1.53kg;レーム社)、クロスカルメロースナトリウム(キッコレートND−2HS)(1.53kg;ニチリン化学工業(株))、軽質無水ケイ酸(アドソリダー101)(0.52kg;フロイント産業(株))およびステアリン酸マグネシウム(1.04kg;太平化学産業(株))をボーレコンテナーミキサー(寿工業(株)製、MC−150)にて30分間混合して、打錠用末を得た。この打錠用末を打錠機((株)畑鐵工所製、HT−X20)により、杵直径14mm、短径6mm、打錠圧900kgfの条件で打錠し、以下の処方である14×6mm、厚さ4.26mm、錠剤硬度12.64kgのプランルカスト水和物を62.5%含有するカプレット錠剤(錠剤6)を製造した。
本発明錠剤6の処方(1錠中)
噴霧乾燥造粒物の成分
プランルカスト水和物 225.0mg
乳糖 50.0mg
Tc−5Rw 1.5mg
添加剤
オイドラギット L100−55 9.0mg
スーパータブ 56.5mg
キッコレートND−2HS 9.0mg
アドソリダー101 3.0mg
ステアリン酸マグネシウム 6.0mg
計 360.0mg
製剤例7
Tc−5Rw(1.2kg;信越化学工業(株))を精製水(221.2kg)に溶解し、さらに乳糖(40kg;NZMP社)およびプランルカスト水和物(180kg)を加え、懸濁液とした。この懸濁液をスプレードライヤー(給気(入り口)温度:190℃、排気温度:85±5℃、送液速度:100kg/時間、アトマイザー回転速度:16000±100rpm、大川原化工機(株)製、ODA−27)で噴霧乾燥し、プランルカスト水和物の噴霧乾燥品を得た。これを0.85mmの篩にて篩過し、噴霧乾燥造粒物(SD品)(212.3kg)を得た。得られたSD品(47.005kg)に直打用乳糖(スーパータブ)(9.574kg;NZMP社)、乾燥メタクリル酸コポリマーLD(オイドラギットL100−55)(1.53kg;レーム社)、クロスカルメロースナトリウム(キッコレートND−2HS)(1.53kg;ニチリン化学工業(株))、軽質無水ケイ酸(アドソリダー101)(0.52kg;フロイント産業(株))およびステアリン酸マグネシウム(1.04kg;太平化学産業(株))をボーレコンテナーミキサー(寿工業(株)製、MC−150)にて30分間混合して、打錠用末を得た。この打錠用末を打錠機((株)畑鐵工所製、HT−X20)により、杵直径8.0mm、打錠圧700kgfの条件で打錠し、以下の処方である8.0mm、厚さ3.47mm、錠剤硬度9.99kgのプランルカスト水和物を62.5%含有する円形錠剤(錠剤7)を製造した。
本発明錠剤7の処方(1錠中)
噴霧乾燥造粒物の成分
プランルカスト水和物 112.5mg
乳糖 25.0mg
Tc−5Rw 0.75mg
添加剤
オイドラギット L100−55 4.5mg
スーパータブ 28.25mg
キッコレートND−2HS 4.5mg
アドソリダー101 1.5mg
ステアリン酸マグネシウム 3.0mg
計 180.0mg
比較例1
Tc−5Rwの代わりにポリエチレングリコール(PEG)を用いて、製剤例1と同様の操作を行なうことにより、以下の処方である直径7.5mm、厚さ3.78mmのプランルカスト水和物を59.3重量%含有する比較錠剤1を製造した。
比較錠剤1の処方(1錠中)
噴霧乾燥造粒物の成分
プランルカスト水和物 112.5mg
乳糖 52.7mg
PEG 11.3mg
添加剤
L−HPC 9.5mg
ステアリン酸マグネシウム 3.8mg
計 189.8mg
比較例2
Tc−5Rwの代わりにポリエチレングリコール(PEG)を用いて、乳糖を使用しない以外は、製剤例1と同様の操作を行なうことにより、以下の処方である直径7.5mm、厚さ2.91mmのプランルカスト水和物を84.5重量%含有する比較錠剤2を製造した。
比較錠剤2の処方(1錠中)
噴霧乾燥造粒物の成分
プランルカスト水和物 112.5mg
PEG 11.3mg
添加剤
L−HPC 6.7mg
ステアリン酸マグネシウム 2.7mg
計 133.1mg
比較例3
Tc−5Rwの代わりにポリエチレングリコール(PEG)を用いて、乳糖を使用しない以外は、製剤例1と同様の操作を行なうことにより、以下の処方である直径7.5mm、厚さ2.75mmのプランルカスト水和物を92.4重量%含有する比較錠剤3を製造した。
比較錠剤3の処方(1錠中)
噴霧乾燥造粒物の成分
プランルカスト水和物 112.5mg
PEG 0.8mg
添加剤
L−HPC 6.1mg
ステアリン酸マグネシウム 2.4mg
計 121.8mg
比較例4
Tc−5Rwの代わりにポリエチレングリコール(PEG)を用いて、製剤例1と同様の操作を行なうことにより、以下の処方である直径7.5mm、厚さ3.20mmのプランルカスト水和物を75.7重量%含有する比較錠剤4を製造した。
比較錠剤4の処方(1錠中)
噴霧乾燥造粒物の成分
プランルカスト水和物 112.5mg
乳糖 25.0mg
PEG 0.8mg
添加剤
L−HPC 7.4mg
ステアリン酸マグネシウム 3.0mg
計 148.7mg
噴霧乾燥造粒物(SD品)の付着性評価
製剤例1〜3、および比較例1〜4で製造したSD品の付着性を、アグロボット(商品名)にて引張破断力を測定した。アグロボットの測定条件は、セル内径25mm、セル温度25℃、バネ線径1.0mm、圧縮速度0.1mm/秒、最大圧縮力200kgf、圧縮保持時間60秒、引張速度0.04mm/秒、引張サンプリング時間20秒という条件で行なった。結果を表1に示す。なお、*は測定限界値以上の値のため、計測不能であった。
EXAMPLES Hereinafter, although an Example explains this invention in full detail, it is for understanding this invention well and this invention is not limited to these.
Formulation Example 1
Tc-5Rw (3 g; Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (1027 mL), and lactose (100 g; NZMP) and pranlukast hydrate (450 g) were added to form a suspension. This suspension is spray-dried with a spray dryer (air supply (inlet) temperature: 180 ° C., exhaust temperature: 100 to 110 ° C., liquid feed rate: 30 to 40 g / min, atomizer rotational speed: 12000 rpm), and pranlukast A hydrate spray-dried product was obtained. This was sieved with a 0.5 mm sieve to obtain a spray-dried granulated product (SD product) (450 g). Low-substituted hydroxypropylcellulose (L-HPC) (3 g; Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (1.2 g; Taihei Chemical Industry Co., Ltd.) were added to the obtained SD product (55.8 g).・ Mixed to obtain a powder for tableting. This tableting powder was tableted with a tableting machine (Okada Seiko, Tab-ALL) under the conditions of a heel diameter of 7.5 mm and a tableting pressure of 750 kgf. The following prescription is a diameter of 7.5 mm and a thickness of 3 Tablet 1 containing 75.7% by weight of 1 mm pranlukast hydrate was produced.
Formulation of tablet 1 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 25.0mg
Tc-5Rw 0.8mg
Additive L-HPC 7.4 mg
Magnesium stearate 3.0mg
148.7 mg total
Formulation Example 2
By performing the same operation as in Formulation Example 1, tablet 2 containing 84.0% by weight of pranlukast hydrate having a diameter of 7.5 mm and a thickness of 2.9 mm, which is the following formulation, was produced.
Formulation of tablet 2 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 11.3mg
Tc-5Rw 0.8mg
Additive L-HPC 6.7mg
Magnesium stearate 2.7mg
134.0 mg total
Formulation Example 3
By performing the same operation as in Formulation Example 1, tablet 3 containing 74.7% by weight of pranlukast hydrate having a diameter of 7.5 mm and a thickness of 3.2 mm, which is the following formulation, was produced.
Formulation of tablet 3 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 25.0mg
Tc-5Rw 2.5mg
Additive L-HPC 7.5mg
Magnesium stearate 3.0mg
150.5mg total
Formulation Example 4
Tc-5Rw (5.4 g; Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (1848.6 mL), and lactose (180 g; NZMP) and pranlukast hydrate (810 g) were added and suspended. Liquid. Spray suspension (supply air (inlet) temperature: 180 ° C., exhaust temperature: 100 to 110 ° C., liquid feed rate: 30 to 40 g / min, atomizer rotation speed: 10000 rpm, Okawahara Chemical Industries under the following conditions It was spray-dried with L-8), and a spray-dried product of pranlukast hydrate was obtained. This was sieved with a 0.5 mm sieve to obtain a spray-dried granulated product (SD product) (826.2 g). The obtained SD product (760 g) was mixed with lactose for direct compression (super tab) (155 g; NZMP), dried methacrylic acid copolymer LD (Eudragit L100-55) (50 g; Laem), croscarmellose sodium (Ac-Di). -Sol) (25 g; Asahi Kasei Co., Ltd.) and magnesium stearate (10 g; Taihei Chemical Industry Co., Ltd.) were mixed for 30 minutes in a Bole container mixer (manufactured by Kotobuki Kogyo Co., Ltd., MC-2.5). Got the end. This powder for tableting was tableted with a tableting machine (manufactured by Kikusui Seisakusho, Virgo) under the conditions of a diameter of 8 mm and a tableting pressure of 1000 kgf. Tablet 4 containing 61.8% of pranlukast hydrate having a diameter of 41 mm and a tablet hardness of 9.4 kg was produced.
Formulation of tablet 4 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 25.0mg
Tc-5Rw 0.8mg
Additive Eudragit L100-55 9.1 mg
Super Tab 28.2mg
Ac-Di-Sol 4.5mg
Magnesium stearate 1.8mg
Total 181.9mg
Formulation Example 5
Tc-5Rw (5.4 g; Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (1848.6 mL), and lactose (180 g; NZMP) and pranlukast hydrate (810 g) were added and suspended. Liquid. Spray suspension (supply air (inlet) temperature: 180 ° C., exhaust temperature: 100 to 110 ° C., liquid feeding speed: 30 to 40 g / min, atomizer rotation speed: 10,000 rpm, manufactured by Okawara Kako Co., Ltd., A spray-dried product of pranlukast hydrate was obtained by spray drying in L-8). This was sieved with a 0.5 mm sieve to obtain a spray-dried granulated product (SD product) (843.2 g). The obtained SD product (760 g) was used for direct compression lactose (supertab) (150 g; NZMP), dry methacrylic acid copolymer LD (Eudragit L100-55) (50 g; Reem), Tc-5Rw (30.0 g; For tableting, Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (10 g; Taihei Chemical Industry Co., Ltd.) were mixed for 30 minutes in a Boule container mixer (manufactured by Kotobuki Industry Co., Ltd., MC-2.5). I got the end. This powder for tableting was tableted with a tableting machine (Virgo, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a wrinkle diameter of 14 mm, a short diameter of 6 mm, and a tableting pressure of 800 kgf. A caplet tablet (Tablet 5) containing 61.8% pranlukast hydrate having a thickness of 6 mm, a thickness of 4.86 mm and a tablet hardness of 13.8 kg was produced.
Formulation of tablet 5 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 225.0mg
Lactose 50.0mg
Tc-5Rw 1.5mg
Additive Eudragit L100-55 18.2mg
Super Tab 54.6mg
Tc-5Rw 10.9mg
Magnesium stearate 3.6mg
363.8mg total
Formulation Example 6
Tc-5Rw (1.2 kg; Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (221.2 kg), and lactose (40 kg; NZMP) and pranlukast hydrate (180 kg) were added and suspended. Liquid. Spray suspension (supply air (inlet) temperature: 190 ° C., exhaust temperature: 85 ± 5 ° C., liquid feeding speed: 100 kg / hour, atomizer rotation speed: 16000 ± 100 rpm, manufactured by Okawara Kako Co., Ltd., Spray-dried with ODA-27) to obtain a spray-dried product of pranlukast hydrate. This was sieved with a 0.85 mm sieve to obtain a spray-dried granulated product (SD product) (212.3 kg). The obtained SD product (47.005 kg) was directly mixed with lactose (super tab) (9.574 kg; NZMP), dried methacrylic acid copolymer LD (Eudragit L100-55) (1.53 kg; Rohm), Croscalme Loose sodium (Kickolate ND-2HS) (1.53 kg; Nichirin Chemical Industry Co., Ltd.), light anhydrous silicic acid (Adsolider 101) (0.52 kg; Freund Sangyo Co., Ltd.) and magnesium stearate (1.04 kg; Taihei Chemical Industry Co., Ltd.) was mixed for 30 minutes with a Boule Container Mixer (manufactured by Kotobuki Industries Co., Ltd., MC-150) to obtain a tableting powder. This tableting powder was tableted with a tableting machine (manufactured by Hata Seiko Co., Ltd., HT-X20) under the conditions of a wrinkle diameter of 14 mm, a short diameter of 6 mm, and a tableting pressure of 900 kgf. A caplet tablet (tablet 6) containing 62.5% of pranlukast hydrate having a size of 6 mm, a thickness of 4.26 mm, and a tablet hardness of 12.64 kg was produced.
Formulation of tablet 6 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 225.0mg
Lactose 50.0mg
Tc-5Rw 1.5mg
Additive Eudragit L100-55 9.0mg
Super Tab 56.5mg
Kikkolate ND-2HS 9.0mg
ADSOLIDER 101 3.0mg
Magnesium stearate 6.0mg
360.0mg total
Formulation Example 7
Tc-5Rw (1.2 kg; Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (221.2 kg), and lactose (40 kg; NZMP) and pranlukast hydrate (180 kg) were added and suspended. Liquid. Spray suspension (supply air (inlet) temperature: 190 ° C., exhaust temperature: 85 ± 5 ° C., liquid feeding speed: 100 kg / hour, atomizer rotation speed: 16000 ± 100 rpm, manufactured by Okawara Kako Co., Ltd., Spray-dried with ODA-27) to obtain a spray-dried product of pranlukast hydrate. This was sieved with a 0.85 mm sieve to obtain a spray-dried granulated product (SD product) (212.3 kg). The obtained SD product (47.005 kg) was directly mixed with lactose (super tab) (9.574 kg; NZMP), dried methacrylic acid copolymer LD (Eudragit L100-55) (1.53 kg; Rohm), Croscalme Loose sodium (Kickolate ND-2HS) (1.53 kg; Nichirin Chemical Industry Co., Ltd.), light anhydrous silicic acid (Adsolider 101) (0.52 kg; Freund Sangyo Co., Ltd.) and magnesium stearate (1.04 kg; Taihei Chemical Industry Co., Ltd.) was mixed for 30 minutes with a Boule Container Mixer (manufactured by Kotobuki Industries Co., Ltd., MC-150) to obtain a tableting powder. This powder for tableting was tableted with a tableting machine (manufactured by Hata Seiko Co., Ltd., HT-X20) under the conditions of a punch diameter of 8.0 mm and a tableting pressure of 700 kgf, and the following prescription was 8.0 mm. A round tablet (Tablet 7) containing 62.5% of pranlukast hydrate having a thickness of 3.47 mm and a tablet hardness of 9.99 kg was produced.
Formulation of tablet 7 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 25.0mg
Tc-5Rw 0.75mg
Additive Eudragit L100-55 4.5mg
Super tub 28.25mg
Kikkolate ND-2HS 4.5mg
Adsolider 101 1.5mg
Magnesium stearate 3.0mg
180.0mg total
Comparative Example 1
By using polyethylene glycol (PEG) instead of Tc-5Rw and performing the same operation as in Formulation Example 1, the following formulation, pranlukast hydrate having a diameter of 7.5 mm and a thickness of 3.78 mm, was obtained. Comparative tablet 1 containing 59.3% by weight was produced.
Formulation of comparative tablet 1 (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 52.7mg
PEG 11.3mg
Additive L-HPC 9.5 mg
Magnesium stearate 3.8mg
189.8mg total
Comparative Example 2
By using polyethylene glycol (PEG) instead of Tc-5Rw and not using lactose, the same procedure as in Formulation Example 1 was performed, whereby the following prescription was 7.5 mm in diameter and 2.91 mm in thickness. Comparative tablet 2 containing 84.5% by weight of pranlukast hydrate was produced.
Formulation of comparative tablet 2 (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
PEG 11.3mg
Additive L-HPC 6.7mg
Magnesium stearate 2.7mg
Total 133.1mg
Comparative Example 3
By using polyethylene glycol (PEG) instead of Tc-5Rw and not using lactose, the same procedure as in Formulation Example 1 was performed, whereby the following prescription was 7.5 mm in diameter and 2.75 mm in thickness. Comparative tablet 3 containing 92.4% by weight of pranlukast hydrate was produced.
Formulation of comparative tablet 3 (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
PEG 0.8mg
Additive L-HPC 6.1 mg
Magnesium stearate 2.4mg
Total 121.8mg
Comparative Example 4
By using polyethylene glycol (PEG) instead of Tc-5Rw and performing the same operation as in Formulation Example 1, the following formulation, pranlukast hydrate having a diameter of 7.5 mm and a thickness of 3.20 mm, was obtained. Comparative tablet 4 containing 75.7% by weight was produced.
Formulation of comparative tablet 4 (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 25.0mg
PEG 0.8mg
Additive L-HPC 7.4 mg
Magnesium stearate 3.0mg
148.7 mg total
Evaluation of Adhesiveness of Spray-Dried Granulated Product (SD Product) The tensile breaking force of the SD product produced in Formulation Examples 1 to 3 and Comparative Examples 1 to 4 was measured by Agrobot (trade name). The measurement conditions of the Ag robot are: cell inner diameter 25 mm, cell temperature 25 ° C., spring wire diameter 1.0 mm, compression speed 0.1 mm / second, maximum compression force 200 kgf, compression holding time 60 seconds, tensile speed 0.04 mm / second, The tensile sampling time was 20 seconds. The results are shown in Table 1. Note that * cannot be measured because it is greater than the measurement limit value.
上記結果から明らかなように、糖類の含量を少なくした本発明製剤であるSD品は比較例で用いたSD品と比し、圧縮時の付着性が著しい軽減を示している。従って、本発明固形組成物を用いることにより、プランルカスト水和物の高含量化および打錠時の杵への付着に伴なう打錠障害等の抑制を同時に行なうことが可能であることが明らかとなった。 As is clear from the above results, the SD product, which is a preparation of the present invention with a reduced saccharide content, shows a marked reduction in adhesion during compression compared to the SD product used in the comparative examples. Therefore, by using the solid composition of the present invention, it is possible to simultaneously increase the content of pranlukast hydrate and suppress tableting troubles associated with sticking to the punch during tableting. Became clear.
すなわち、本発明の製剤は引張破断力が10.0g以下であり、比較例の製剤と比して付着凝集性が低減されることが明らかである。
溶出性評価1
製剤例1〜3、および比較例1〜4で製造した錠剤について、0.5%ポリソルベート80リン酸緩衝液(pH6.8)における溶出性試験を行なった。試験は第十四改正日本薬局方の一般試験法66溶出試験法・第2法(50rpm)に従って行なった。試験液はpH6.8のリン酸緩衝液(1→2)に0.5%のポリソルベート80を添加した液を用いた。サンプリングした液を吸光度法(測定波長350nm)で測定し、30分後および60分後の溶出率を算出した。
溶出性評価2(経時安定性試験)
製剤例1〜3、および比較例1〜4で製造した錠剤をガラス瓶に詰め、これを(i)密閉状態で60℃の恒温器内または(ii)開封状態で40℃、相対湿度75%条件下の恒温恒湿器内に保存した。16日間保存後、各錠剤を採取し、上記溶出性評価1と同様に溶出率を測定した。溶出性試験1および2の結果を以下の表2に示す。
That is, it is clear that the preparation of the present invention has a tensile breaking force of 10.0 g or less, and the adhesion and aggregation properties are reduced as compared with the preparation of the comparative example.
Dissolution evaluation 1
The tablets produced in Formulation Examples 1 to 3 and Comparative Examples 1 to 4 were subjected to a dissolution test in 0.5% polysorbate 80 phosphate buffer (pH 6.8). The test was conducted in accordance with the 14th revised Japanese Pharmacopoeia General Test Method 66 Dissolution Test Method / Second Method (50 rpm). The test solution used was a solution obtained by adding 0.5% polysorbate 80 to a phosphate buffer solution (1 → 2) having a pH of 6.8. The sampled liquid was measured by the absorbance method (measurement wavelength: 350 nm), and the elution rate after 30 minutes and after 60 minutes was calculated.
Dissolution evaluation 2 (time stability test)
The tablets produced in Formulation Examples 1 to 3 and Comparative Examples 1 to 4 are packed in a glass bottle, and this is either (i) in a thermostatic chamber at 60 ° C. in a sealed state or (ii) 40 ° C. and 75% relative humidity in an opened state. Stored in the lower temperature and humidity chamber. After storage for 16 days, each tablet was collected, and the dissolution rate was measured in the same manner as in the dissolution evaluation 1. The results of dissolution tests 1 and 2 are shown in Table 2 below.
上記結果から明らかなように本発明製剤は比較製剤と比して、おおむね溶出速度の向上が見られている。また、保存後の比較製剤を見ると明らかなように、溶出速度の遅延や加速といった変化が認められる。それに対し、本発明製剤の殆どにおいて溶出速度の変動が非常に小さく、溶出性の制御能力や品質の保存安定性に優れた製剤であることがわかる。 As is clear from the above results, the preparation of the present invention generally has an improved dissolution rate as compared with the comparative preparation. In addition, as is apparent from the comparison preparation after storage, changes such as delay and acceleration of dissolution rate are observed. In contrast, in most of the preparations of the present invention, fluctuations in dissolution rate are very small, indicating that the preparations are excellent in ability to control dissolution and storage stability of quality.
溶出性は、60分後において溶出性評価1における数値と比較して±12%以下であり、かつ60分後において85%以上の溶出率であれば溶出性が安定であるといえる。
崩壊性評価
製剤例1〜3、および比較例1〜4で製造した錠剤を40℃、相対湿度75%の恒温恒湿器内、あるいは60℃の恒温器内に16日保存し、崩壊時間の比較を行なった。崩壊時間の測定は、第十四改正日本薬局方の一般試験法58崩壊試験法に準じて、試験液に水、第1液(pH1.2)および第2液(pH6.8)を用い試験を行なった。40℃、相対湿度75%条件下で保存した錠剤の結果を表3に、60℃条件下で保存した錠剤の結果を表4に示す。なお、変化率(%)とは、例えば、崩壊時間が保存前より保存後が上回った場合、増加(+)の割合を、保存前より保存後が下回った場合、低下(−)の割合を意味する。
It can be said that the dissolution property is stable if the dissolution property is ± 12% or less after 60 minutes as compared with the numerical value in dissolution property evaluation 1 and the dissolution rate is 85% or more after 60 minutes.
The tablets produced in Formulation Examples 1 to 3 and Comparative Examples 1 to 4 for disintegration evaluation were stored for 16 days in a constant temperature and humidity chamber at 40 ° C. and a relative humidity of 75%, or in a constant temperature chamber at 60 ° C. A comparison was made. The disintegration time is measured according to the Japanese Pharmacopoeia General Test Method 58 Disintegration Test Method using water, the first solution (pH 1.2), and the second solution (pH 6.8) as the test solution. Was done. Table 3 shows the results of tablets stored under conditions of 40 ° C. and 75% relative humidity, and Table 4 shows the results of tablets stored under conditions of 60 ° C. Note that the rate of change (%) is, for example, the rate of increase (+) when the decay time is higher after storage than before storage, and the rate of decrease (−) when the time after storage is lower than before storage. means.
上記表3および4から明らかなように、本発明製剤は比較製剤と比して、おおむね向上もしくは同程度の崩壊性を有しており、保存前と保存後の崩壊性の変化率(安定性)を比較した場合、加速試験条件下(40℃75%RH)、苛酷試験条件下(60℃)、両条件下においても本発明製剤の崩壊性の安定性が優れていることが明らかである。
錠剤の成型性試験
製剤例1および2、および比較例1〜4で製造した錠剤の錠剤硬度、錠剤径および錠厚をWHT−2錠剤測定装置(ファルマテスト社製)を用いて測定し、式1に従って引張強度を算出した。比較例1の錠剤の引張強度を100として、他の錠剤の相対引張強度を測定した。結果を表5に示す。
式1:引張強度=(2×錠剤硬度)/(円周率×錠剤径×錠厚)[kg/mm2]
As is apparent from Tables 3 and 4 above, the preparation of the present invention is generally improved or has the same level of disintegration as the comparative preparation, and the rate of change in disintegration before and after storage (stability) ), It is clear that the disintegration stability of the preparation of the present invention is excellent even under accelerated test conditions (40 ° C. 75% RH), severe test conditions (60 ° C.), and both conditions. .
Tablet moldability test The tablet hardness, tablet diameter, and tablet thickness of the tablets produced in Formulation Examples 1 and 2 and Comparative Examples 1 to 4 were measured using a WHT-2 tablet measuring device (Pharma Test Co., Ltd.). The tensile strength was calculated according to 1. With the tensile strength of the tablet of Comparative Example 1 as 100, the relative tensile strength of the other tablets was measured. The results are shown in Table 5.
Formula 1: Tensile strength = (2 × tablet hardness) / (circumference ratio × tablet diameter × tablet thickness) [kg / mm 2 ]
上記から明らかなように、PEGからTc−5Rwに変更した場合、乳糖の含量を少なくしても、引張強度が維持もしくは向上することがわかる。 As is apparent from the above, it can be seen that when the PEG is changed to Tc-5Rw, the tensile strength is maintained or improved even if the lactose content is reduced.
本発明の固形組成物を用いることにより、糖類の含量を少なくしても付着性を低減できるため、安定な品質の製剤や患者のコンプライアンスが改善された小型製剤を提供することができる。
By using the solid composition of the present invention, the adhesiveness can be reduced even if the saccharide content is reduced, so that a stable quality preparation and a small preparation with improved patient compliance can be provided.
Claims (31)
A capsule comprising the composition according to claim 28.
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JP2015052007A (en) * | 2009-05-27 | 2015-03-19 | サムヤン バイオファーマシューティカルズ コーポレイション | Poorly soluble drug containing microsphere with improved bioavailability and method of preparing the same |
WO2022003980A1 (en) * | 2020-07-03 | 2022-01-06 | 富士製薬工業株式会社 | Solid formulation |
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JPH0959156A (en) * | 1995-06-12 | 1997-03-04 | Ono Pharmaceut Co Ltd | Granulate containing pranlukast, its production and improvement in adhering aggregateion of pranlukast |
JP2003534296A (en) * | 2000-05-20 | 2003-11-18 | サン デウク リー | Pranlukast solid dispersion with improved dissolution and method for producing the same |
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JPH0959156A (en) * | 1995-06-12 | 1997-03-04 | Ono Pharmaceut Co Ltd | Granulate containing pranlukast, its production and improvement in adhering aggregateion of pranlukast |
JP2003534296A (en) * | 2000-05-20 | 2003-11-18 | サン デウク リー | Pranlukast solid dispersion with improved dissolution and method for producing the same |
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JP2015052007A (en) * | 2009-05-27 | 2015-03-19 | サムヤン バイオファーマシューティカルズ コーポレイション | Poorly soluble drug containing microsphere with improved bioavailability and method of preparing the same |
US9511026B2 (en) | 2009-05-27 | 2016-12-06 | Samyang Biopharmaceuticals Corporation | Poorly soluble drug containing microspheres with improved bioavailability and method of preparing the same |
WO2022003980A1 (en) * | 2020-07-03 | 2022-01-06 | 富士製薬工業株式会社 | Solid formulation |
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