JP2006143650A - Method for producing tablet containing medicine having high adhesiveness - Google Patents
Method for producing tablet containing medicine having high adhesiveness Download PDFInfo
- Publication number
- JP2006143650A JP2006143650A JP2004336073A JP2004336073A JP2006143650A JP 2006143650 A JP2006143650 A JP 2006143650A JP 2004336073 A JP2004336073 A JP 2004336073A JP 2004336073 A JP2004336073 A JP 2004336073A JP 2006143650 A JP2006143650 A JP 2006143650A
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- JP
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- Prior art keywords
- weight
- parts
- water
- tableting
- drug
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 138
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 23
- 239000000654 additive Substances 0.000 claims abstract description 122
- 230000000996 additive effect Effects 0.000 claims abstract description 112
- 238000000034 method Methods 0.000 claims abstract description 74
- 239000000843 powder Substances 0.000 claims abstract description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 50
- 238000010521 absorption reaction Methods 0.000 claims abstract description 12
- 238000004062 sedimentation Methods 0.000 claims abstract description 9
- 229940079593 drug Drugs 0.000 claims description 134
- 229920002678 cellulose Polymers 0.000 claims description 43
- 239000001913 cellulose Substances 0.000 claims description 43
- 238000002156 mixing Methods 0.000 claims description 34
- 229920000881 Modified starch Polymers 0.000 claims description 32
- 239000000853 adhesive Substances 0.000 claims description 12
- 230000001070 adhesive effect Effects 0.000 claims description 12
- 230000001464 adherent effect Effects 0.000 claims description 7
- 239000013078 crystal Substances 0.000 claims description 6
- 238000002844 melting Methods 0.000 claims description 5
- 230000008018 melting Effects 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000011812 mixed powder Substances 0.000 abstract description 30
- 230000008569 process Effects 0.000 abstract description 10
- 229920002472 Starch Polymers 0.000 abstract description 4
- 235000019698 starch Nutrition 0.000 abstract description 4
- 239000008107 starch Substances 0.000 abstract description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 58
- 238000011156 evaluation Methods 0.000 description 33
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- 229960002373 loxoprofen Drugs 0.000 description 28
- WORCCYVLMMTGFR-UHFFFAOYSA-M loxoprofen sodium Chemical compound [Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 WORCCYVLMMTGFR-UHFFFAOYSA-M 0.000 description 28
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 25
- 230000000052 comparative effect Effects 0.000 description 24
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 18
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 13
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- 230000002745 absorbent Effects 0.000 description 6
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- 239000002253 acid Substances 0.000 description 3
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 3
- 238000013329 compounding Methods 0.000 description 3
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- PARMJFIQRZRMHG-VICXVTCVSA-M flucloxacillin sodium monohydrate Chemical compound O.[Na+].N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl PARMJFIQRZRMHG-VICXVTCVSA-M 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- POUMFISTNHIPTI-BOMBIWCESA-N hydron;(2s,4r)-n-[(1r,2r)-2-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide;chloride Chemical compound Cl.CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 POUMFISTNHIPTI-BOMBIWCESA-N 0.000 description 3
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 3
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- 239000011734 sodium Substances 0.000 description 3
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- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OPSXJNAGCGVGOG-DKWTVANSSA-L Calcium L-aspartate Chemical compound [Ca+2].[O-]C(=O)[C@@H](N)CC([O-])=O OPSXJNAGCGVGOG-DKWTVANSSA-L 0.000 description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
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- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
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- SCLZRKVZRBKZCR-SLINCCQESA-M cloxacillin sodium Chemical compound [Na+].N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl SCLZRKVZRBKZCR-SLINCCQESA-M 0.000 description 2
- 229960003026 cloxacillin sodium Drugs 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
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- VDUVBBMAXXHEQP-ZTRPPZFVSA-M sodium;(2s,6r)-3,3-dimethyl-6-[(5-methyl-3-phenyl-1,2-oxazole-4-carbonyl)amino]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [Na+].N([C@@H]1C(N2[C@H](C(C)(C)SC21)C([O-])=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 VDUVBBMAXXHEQP-ZTRPPZFVSA-M 0.000 description 2
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- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- AJZJIYUOOJLBAU-CEAXSRTFSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;n,n,2-trimethyl-3-phenothiazin-10-ylpropan-1-amine Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC=C2N(CC(CN(C)C)C)C3=CC=CC=C3SC2=C1.C1=CC=C2N(CC(CN(C)C)C)C3=CC=CC=C3SC2=C1 AJZJIYUOOJLBAU-CEAXSRTFSA-N 0.000 description 1
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- PTNZGHXUZDHMIQ-UHFFFAOYSA-N 4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2C(C)C(C(O)C3C(C(O)=C(C(N)=O)C(=O)C3N(C)C)(O)C3=O)C3=C(O)C2=C1O PTNZGHXUZDHMIQ-UHFFFAOYSA-N 0.000 description 1
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- XYGSFNHCFFAJPO-UHFFFAOYSA-N Chlophedianol hydrochloride Chemical compound Cl.C=1C=CC=C(Cl)C=1C(O)(CCN(C)C)C1=CC=CC=C1 XYGSFNHCFFAJPO-UHFFFAOYSA-N 0.000 description 1
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- DBAKFASWICGISY-DASCVMRKSA-N Dexchlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C1([C@H](CCN(C)C)C=2N=CC=CC=2)=CC=C(Cl)C=C1 DBAKFASWICGISY-DASCVMRKSA-N 0.000 description 1
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Abstract
Description
本発明は付着性の高い薬物を含有する錠剤の製造方法に関する。 The present invention relates to a method for producing a tablet containing a highly adhesive drug.
薬物同士や機器、容器に対する付着性の高い薬物の粉末は、特別に配慮した処方でないかぎり固形製剤とすることは困難であった。薬物同士の付着性が強い場合、粉体の流動性が悪くなり、錠剤の製造にあたっては、打錠機への粉体の供給量にばらつきが生じ、錠剤の重量ばらつきを生じさせ、酷い場合にはホッパー内でブリッジを形成し粉体が供給されなくなってしまうという問題が生じる。
また、打錠機に粉体が供給された後も、薬物と打錠機の臼杵への付着性が高い場合には、打錠の際に、打錠機の臼杵等に薬物が付着し、さらに打錠を継続すると臼杵への付着物によって錠剤の刻印が欠けたり、錠剤自体が欠けたり、臼杵の破損を招く、スティッキングという問題が発生する。従来、このような付着性の高い薬物に対する改善処方としては、例えばステアリン酸マグネシウムの様な滑沢剤を多量に使用する処方がある。しかし、この技術を適用すると、該製剤の崩壊性、溶出性さらには生物学的利用能を損ない、錠剤とした場合には、その硬度が著しく低下するという欠点を有する。
It has been difficult to make a drug powder having high adhesion to drugs, devices, and containers into a solid preparation unless it is formulated with special consideration. If the adhesion between drugs is strong, the fluidity of the powder will deteriorate, and in the manufacture of tablets, there will be variations in the amount of powder supplied to the tableting machine, causing tablet weight variations, Causes a problem that a bridge is formed in the hopper and powder is not supplied.
In addition, even after the powder is supplied to the tableting machine, if the drug and the tableting machine have high adhesion to the mortar, the drug adheres to the mortar of the tableting machine, etc. Further, when tableting is continued, there is a problem of sticking, in which a tablet stamp is lost due to an adhering substance to the mortar, the tablet itself is missing, or the mortar is damaged. Conventionally, as an improved formulation for such highly adhesive drugs, there is a formulation that uses a large amount of a lubricant such as magnesium stearate, for example. However, when this technique is applied, the disintegration property, dissolution property and bioavailability of the preparation are impaired, and when it is made into a tablet, its hardness is remarkably reduced.
また、付着性の高い薬物に対しては、一般的に、湿式造粒法あるいは乾式造粒法が用いられる。それは以下のような理由からである。
湿式造粒法とは、薬物粉末を添加剤と水の存在下で結合させて顆粒にした後、乾燥・整粒した顆粒を打錠に用いる方法であり、乾式造粒法とは、薬物粉末と添加剤を混合した後圧縮固化し、破砕、整粒した顆粒を打錠に用いる方法である。
湿式及び乾式造粒法は、粒子を大きくすることにより、打錠粉体の比表面積を小さくし、なおかつ薬物と添加剤を混ぜて造粒することにより、薬物の露出面積を小さくする。したがって、造粒法は、薬物同士や、薬物と杵の接触する確率を減らすことで、打錠時の粉体同士、薬物と打錠臼杵の間の付着性を減らすのに効果がある。ゆえに、付着性の高い薬物に対しては、造粒法が一般的に用いられる。
For drugs with high adhesion, wet granulation or dry granulation is generally used. The reason is as follows.
The wet granulation method is a method in which a drug powder is combined in the presence of an additive and water to form granules, and then dried and sized granules are used for tableting. The dry granulation method is a drug powder. And additives are mixed, and then compressed, solidified, crushed, and sized granules are used for tableting.
In the wet and dry granulation methods, the specific surface area of the tableting powder is reduced by enlarging the particles, and the exposed area of the drug is reduced by granulating the drug and additives. Therefore, the granulation method is effective in reducing the adhesiveness between the powders at the time of tableting and between the drug and the tableting mortar by reducing the probability of contact between the drugs and the drug and the punch. Therefore, granulation is generally used for drugs with high adhesion.
しかしながら、湿式造粒法は、主薬と賦形剤を混合する工程、水または水溶成分を含む水溶液を添加して造粒する工程、乾燥する工程、乾燥後の顆粒を整粒する工程を経た後に、打錠を行う方法であり、多くの工程、装置、エネルギーを必要とする。また工程分のプロセスバリデーションを必要とする。プロセスバリデーションとは、「ある工程において、定められた仕様及び品質特性に一貫して合致する製品を製造することを、高度に保証できるよう文書でその証拠を確立すること」であり、工程が多いほどプロセスバリデーションの数も増えるため、労力及び費用を要する。したがって、湿式打錠法は、これらの理由により、コストがかかるという欠点がある。また、顆粒を圧縮した錠剤は、顆粒までは崩壊しやすいが、粉体にまでは容易に崩壊しない場合が多く、薬物の溶出が遅くなるという欠点や、水で失活する薬物に対して使用できない、等という欠点もある。 However, the wet granulation method is performed after a step of mixing the main agent and excipient, a step of granulating by adding water or an aqueous solution containing a water-soluble component, a step of drying, and a step of sizing the granules after drying. This is a method for tableting, and requires many steps, equipment and energy. Moreover, the process validation for a process is required. Process validation means “establishing evidence in a document so that it can be highly guaranteed to produce a product that consistently meets the specified specifications and quality characteristics in a certain process”. As the number of process validations increases, labor and cost are required. Therefore, the wet tableting method has the disadvantage that it is costly for these reasons. Tablets with compressed granules are easy to disintegrate to granules, but often do not easily disintegrate to powder, and are used for the disadvantage of slow drug elution and drugs that are inactivated by water. There is also a drawback that it is not possible.
乾式造粒法も、主薬と賦形剤を混合する工程、圧縮する工程、粉砕する工程、整粒する工程を経た後に、打錠を行う方法であるため、湿式造粒法と同様、多くの工程及び装置を必要とし、コストがかかるという欠点がある。また、顆粒は一度圧縮を経ることから、顆粒から粉体にまで容易に崩壊せず、薬物の溶出が遅くなるという問題がある。
一方、直接打錠法は、薬物を含む粉体を混合してそのまま打錠機に供給して打錠する方法であるため、湿式及び乾式造粒法に比べて、工程及び装置が少なくなるためコスト面ではかなり有利である。しかしながら、付着性の高い薬物の場合に直接打錠法を用いようとする場合には、薬物は粉体のままであるため、薬物同士の付着性が高く、打錠粉体の流動性が悪いという問題と、薬物と機器との付着性が高く打錠時にスティッキングが発生しやすい等の問題がある。薬物の付着性を抑制するための添加剤を多く配合することも考えられるが、錠剤が大きくなる、もしくは薬物の含有量が減るという問題がある。また付着性を抑制する添加剤を多く配合して直接打錠を行った場合、スティッキングは抑制されるが、添加剤の種類によっては、錠剤にクラックが発生したり、一部が剥離したりするキャッピングという新たな打錠障害が発生するという問題が生じる。
The dry granulation method is a method in which tableting is performed after the steps of mixing the active ingredient and excipient, compressing step, pulverizing step, and sizing step. There is a drawback that it requires a process and an apparatus and is expensive. Further, since the granules are once compressed, there is a problem that the granules are not easily disintegrated from powder to powder, and the dissolution of the drug is delayed.
On the other hand, the direct tableting method is a method in which powder containing a drug is mixed and supplied to a tableting machine as it is for tableting, and therefore, there are fewer steps and equipment compared to wet and dry granulation methods. It is quite advantageous in terms of cost. However, in the case of using a direct tableting method in the case of a drug with high adhesion, since the drug remains in powder form, the adhesion between drugs is high and the flowability of the tableting powder is poor. And the problem of high sticking between the drug and the device and the tendency for sticking to occur during tableting. Although it is conceivable to add many additives for suppressing the adhesion of the drug, there is a problem that the tablet becomes large or the content of the drug decreases. In addition, when tableting is performed directly with many additives that suppress adhesiveness, sticking is suppressed, but depending on the type of additive, cracks may occur in the tablet or some of the tablets may peel off. There arises a problem that a new tableting failure called capping occurs.
薬物表面を表面改質剤で改質して付着性を低減させるという技術もあるが、薬物の表面改質する工程が加わり、かつ表面改質には大きな機械的剪断力を有する、高速攪拌混合造粒機等に代表される、固定容器型混合機を、通常の粉体混合に用いられる低速の回転容器型混合機とは別に必要とする。大きな機械的剪断力を有する固定容器型混合機は、内部に剪断力を発生させるために、容器内に羽根が付いている構造で、その羽根の回転数は数百〜数千ｒｐｍに達する。ゆえに、回転容器型混合機に比べ構造が複雑となり、動力も必要とするために、コストがかかる。さらに、付着性が特に高い薬物の場合、表面を改質しても、薬物が打錠される時に薬物が破砕され、その際に改質されていない面に出現して付着が起こるため、表面改質だけではスティッキングを完全に抑制できないという問題がある。
ゆえに、これまで付着性の高い薬物を、通常の低速の回転容器型混合機による混合と打錠だけで行う、工程の簡略化された直接打錠法にて、スティッキング、キャッピングを起こさずに錠剤を製造することは困難であった。
There is also a technology to reduce the adhesion by modifying the drug surface with a surface modifier, but it adds a process to modify the surface of the drug, and the surface modification has a high mechanical shearing force and is stirred at high speed. A fixed container type mixer represented by a granulator or the like is required separately from a low-speed rotating container type mixer used for normal powder mixing. A fixed container mixer having a large mechanical shear force has a structure in which a blade is provided in the container in order to generate a shear force therein, and the number of rotations of the blade reaches several hundred to several thousand rpm. Therefore, the structure is more complicated than that of the rotary container type mixer, and power is also required, which is expensive. Furthermore, in the case of a drug with particularly high adhesiveness, even if the surface is modified, the drug is crushed when the drug is tableted, and appears on the unmodified surface at that time, resulting in adhesion. There is a problem that sticking cannot be completely suppressed only by reforming.
Therefore, tablets that do not cause sticking and capping in a direct tableting method with a simplified process, in which a drug with high adhesion has been performed only by mixing and tableting using a normal low-speed rotating container mixer. It was difficult to manufacture.
付着性の高い薬物の打錠時の打錠障害を解決する手段として、例えば以下のものが挙げられる。特許文献１には、付着性の高い薬物に対して総吸水能が１.７以上となるよう添加剤を添加する技術が開示され、特許文献２には付着性の高い薬物に対してメタケイ酸アルミン酸マグネシウムを添加する技術が開示されている。しかしながら、これらの技術は打錠の際に湿式造粒法を用いる技術であり、直接打錠法による錠剤の製造を想定した技術ではない。特許文献３から９にも、付着性の高い薬物に添加剤の種類、添加量を規定することにより打錠障害を解決する技術が開示されているが、これらも同様に打錠の際に湿式造粒法を用いるか、さらにその表面に噴霧被覆を行う技術であり、直接打錠法による錠剤の製造を想定した技術ではない。 Examples of means for solving the tableting trouble at the time of tableting of a highly adherent drug include the following. Patent Document 1 discloses a technique in which an additive is added to a drug with high adhesion so that the total water absorption capacity is 1.7 or more, and Patent Document 2 discloses metasilicate for a drug with high adhesion. A technique for adding magnesium aluminate is disclosed. However, these techniques are techniques that use a wet granulation method during tableting, and are not techniques that assume the production of tablets by the direct tableting method. Patent Documents 3 to 9 also disclose technologies for solving tableting troubles by defining the types and amounts of additives in highly adhesive drugs, but these are also wet during tableting. This is a technique of using a granulation method or spray-coating the surface thereof, and is not a technique assuming the production of tablets by the direct tableting method.
一方、薬物と添加剤を組み合わせて直接打錠を行う技術は多く開示されている。例えば、特許文献１０に、薬物を表面改質基剤で表面改質し、崩壊剤として部分アルファー化デンプンを添加して、直接打錠法により速崩壊錠を製造する技術が開示されている。しかしながら、当該技術においては、表面改質基剤は薬物の表面を改質して薬物の流動性を改善する目的で添加されており、直接打錠法においての薬物の付着性、打錠障害の改善を目的としていない。また、表面改質においては、表面改質装置、高速混合機、高速攪拌混合機造粒機、万能練合機等の機械的攪拌力を与える強い装置で、薬物の表面に表面改質基剤を物理的に付着させる必要がある。また部分アルファー化デンプンは錠剤の崩壊性を付与するために、崩壊剤として添加されており、薬物の付着性、打錠障害を改善する目的の記載はない。 On the other hand, many techniques for directly compressing tablets by combining drugs and additives have been disclosed. For example, Patent Document 10 discloses a technique in which a drug is surface-modified with a surface-modifying base, and partially pregelatinized starch is added as a disintegrant to produce a quick disintegrating tablet by a direct tableting method. However, in this technique, the surface modifying base is added for the purpose of modifying the surface of the drug and improving the fluidity of the drug. Not aimed at improvement. In surface modification, the surface modification base is applied to the surface of the drug with a strong device that gives mechanical agitation such as a surface modification device, a high-speed mixer, a high-speed stirring mixer / granulator, and a universal kneader. Need to be physically attached. Further, partially pregelatinized starch is added as a disintegrating agent in order to impart disintegration property of the tablet, and there is no description for the purpose of improving the adhesiveness of the drug and the tableting trouble.
本発明の目的は、付着性の高い薬物を含む粉末を、工程が簡略化された方法で、打錠障害を起こすことなく、錠剤化する製造方法を提供することである。 An object of the present invention is to provide a production method for tableting a powder containing a highly adherent drug without causing any tableting troubles by a method with a simplified process.
本発明者らは、付着性の高い薬物の、打錠時の付着性・流動性等の打錠障害を直接打錠法において解決する手段について、鋭意研究を重ねた結果、付着性の高い薬物と、該薬物１００重量部に対して２０〜１００重量部の吸水性添加剤と１０〜２００重量部の冷水可溶分が１０％以下である部分アルファー化デンプンを含む粉体であって、該吸水性添加剤が、比表面積１００ｍ２／ｇ以上かつ吸水量１．０ｇ／ｍｌ以上の吸水性添加剤Ａと比表面積２ｍ２／ｇ以下かつ沈降体積１４ｍｌ以上の吸水性添加剤Ｂからなり、配合比率が吸水性添加剤Ａ：吸水性添加剤Ｂ＝１：１〜１：８である該粉体を、低速の回転容器型混合機で混合した後、混合した粉体をそのまま回転式打錠機に供給して打錠する製造方法において、スティッキング、キャッピングの打錠障害の問題を起こすことなく、錠剤を得ることができることを見出し、付着性の高い薬物を含む錠剤を直接打錠法において打錠障害なく得るための製造方法を確立した。 As a result of intensive research on means for directly solving tableting problems such as adhesion and fluidity at the time of tableting in a direct tableting method, a highly adhesive drug has been obtained. A powder containing partially pregelatinized starch having 20 to 100 parts by weight of a water-absorbing additive and 10 to 200 parts by weight of cold water soluble content of 10% or less based on 100 parts by weight of the drug, The water-absorbing additive comprises a water-absorbing additive A having a specific surface area of 100 m 2 / g or more and a water absorption amount of 1.0 g / ml or more and a water-absorbing additive B having a specific surface area of 2 m 2 / g or less and a sedimentation volume of 14 ml or more, After mixing the powder having a mixing ratio of water-absorbing additive A: water-absorbing additive B = 1: 1 to 1: 8 with a low-speed rotating container mixer, the mixed powder is directly rotated. In a manufacturing method in which a tablet is supplied and tableted, sticking and The present inventors have found that tablets can be obtained without causing the problem of tableting troubles in papping, and have established a production method for obtaining tablets containing a highly adhesive drug in the direct tableting method without tableting troubles.
すなわち、本発明は以下の通りである。
（１）付着性の高い薬物と、該薬物１００重量部に対して２０〜１００重量部の吸水性添加剤と１０〜２００重量部の冷水可溶分が１０％以下である部分アルファー化デンプンを含む粉体であって、該吸水性添加剤が、比表面積１００ｍ２／ｇ以上かつ吸水量１．０ｇ／ｍｌ以上の吸水性添加剤Ａと比表面積２ｍ２／ｇ以下かつ沈降体積１４ｍｌ以上の吸水性添加剤Ｂからなり、配合比率が吸水性添加剤Ａ：吸水性添加剤Ｂ＝１：１〜１：８である該粉体を、低速の回転容器型混合機で混合した後、混合した粉体をそのまま回転式打錠機に供給して打錠する、付着性の高い薬物を含む錠剤を直接打錠法において打錠障害なく得るための製造方法。
（２）付着性の高い薬物が、薬物１ｇまたは１ｍｌを溶かすのに必要な量が１００ｇ未満であることを特徴とする（１）の製造方法。
（３）付着性の高い薬物が、結晶水を有する薬物であることを特徴とする（１）の製造方法。
（４）付着性の高い薬物が、融点の低い薬物であることを特徴とする（１）の製造方法。
（５）粉末が薬物１００重量部に対して１０〜１５０重量部の結晶セルロース含むことを特徴とする（１）〜（４）記載の錠剤の製造方法。
（６）（１）〜（５）記載の製造方法で製造される錠剤。
That is, the present invention is as follows.
(1) a highly adhesive drug, 20 to 100 parts by weight of a water-absorbing additive and 10 to 200 parts by weight of a partially pregelatinized starch having a cold water soluble content of 10% or less based on 100 parts by weight of the drug The water-absorbing additive comprises a water-absorbing additive A having a specific surface area of 100 m 2 / g or more and a water absorption of 1.0 g / ml or more, and a water-absorbing additive having a specific surface area of 2 m 2 / g or less and a sedimentation volume of 14 ml or more. The powder having a mixing ratio B of water-absorbing additive A: water-absorbing additive B = 1: 1 to 1: 8 was mixed in a low-speed rotating container mixer and then mixed. A production method for obtaining a tablet containing a highly adherent drug by directly supplying a powder to a rotary tableting machine without any obstruction in tableting in the direct tableting method.
(2) The production method of (1), wherein the amount of the drug having high adhesiveness required to dissolve 1 g or 1 ml of the drug is less than 100 g.
(3) The method according to (1), wherein the drug with high adhesion is a drug having crystal water.
(4) The method according to (1), wherein the drug having high adhesion is a drug having a low melting point.
(5) The method for producing a tablet according to (1) to (4), wherein the powder contains 10 to 150 parts by weight of crystalline cellulose with respect to 100 parts by weight of the drug.
(6) A tablet produced by the production method described in (1) to (5).
付着性の高い薬物を含有する錠剤を、従来技術では難しかった直接打錠法を用いて製造する場合においても、付着性、錠剤の重量ばらつきという打錠障害の問題を解決し、付着性の高い薬物を含む粉末を、工程が簡略化された方法で、打錠障害を起こすことなく、錠剤化する製造方法を提供することが可能となった。 Even when tablets containing highly adhesive drugs are manufactured using the direct tableting method, which was difficult with the prior art, the problem of tableting problems such as adhesiveness and tablet weight variation is solved, and high adhesiveness is achieved. It has become possible to provide a production method in which a powder containing a drug is tableted by a method with a simplified process without causing tableting trouble.
以下、本発明について、具体的に説明する。
本発明において用いられる付着性の高い薬物とは、溶質１ｇまたは１ｍLを溶かすのに必要な水の量が１００ｇ未満である薬物、結晶水を含有する薬物、あるいは融点の低い薬物の少なくともいずれか１つに分類される薬物である。
溶質１ｇまたは１ｍLを溶かすのに必要な水の量が１００ｇ未満である薬物としては、サリチル酸ナトリウム、アスコルビン酸、サリチル酸コリン、アミノピリン、スルピリン、ロキソプロフェン・ナトリウム、塩酸チアラミド、メシル酸ジメトチアジン、ミグレニン、リン酸コデイン、リン酸ジヒドロコデイン、クエン酸ペントキシベリン、ｄｌ−塩酸メチルエフェドリン、酒石酸アリメマジン、トラネキサム酸、塩酸フェニルプロパノールアミン、塩酸ジフェンヒドラミン、プロメタジン、塩酸プロメタジン、塩酸トリプロリジン、ｄ−マレイン酸クロルフェニラミン、ｄｌ−マレイン酸クロルフェニラミン、塩酸レナンピリジン、塩酸クロブチノール、塩酸クロフェダノール、塩酸Ｌ−エチルシステイン、塩酸Ｌ−メチルシステイン、塩酸エフェドリン、ｄｌ−塩酸エピネフリン、塩酸クロルプレナリン、硫酸オシルプレナリン、硫酸サルブタモール、クエン酸イソアミニル、クロペラスチン、Ｌ−アスパラギン酸カルシウム、ペンジルペニシリンカリウム、フェニルメチルペニシリンンカリウム、プロピシリンカリウム、オキサシリンナトリウム、クロキサシリンナトリウム、フルクロキサシリンナトリウム、ヘタシリンカリウム、塩酸レナンピシリン、塩酸ドキシサイクリン、塩酸リンコマイシン等が挙げられる。
Hereinafter, the present invention will be specifically described.
The highly adhesive drug used in the present invention is at least one of a drug whose amount of water required to dissolve 1 g or 1 mL of solute is less than 100 g, a drug containing crystal water, or a drug having a low melting point. It is a drug classified into two.
Drugs whose amount of water required to dissolve 1 g or 1 mL of solute is less than 100 g include sodium salicylate, ascorbic acid, choline salicylate, aminopyrine, sulpyrine, loxoprofen sodium, tiaramid hydrochloride, dimethothiazine mesylate, migrenin, phosphoric acid Codeine, dihydrocodeine phosphate, pentoxyberine citrate, dl-methylephedrine hydrochloride, alimemazine tartrate, tranexamic acid, phenylpropanolamine hydrochloride, diphenhydramine hydrochloride, promethazine, promethazine hydrochloride, triprolidine d-chlorpheniramine maleate, dl -Chlorpheniramine maleate, lennanpyridine hydrochloride, clobutinol hydrochloride, clofedanol hydrochloride, L-ethylcysteine hydrochloride, L-methylcysteine hydrochloride, salt Acid ephedrine, dl-epinephrine hydrochloride, chlorprenalin hydrochloride, osylprenalin sulfate, salbutamol sulfate, isoaminyl citrate, cloperastine, calcium L-aspartate, potassium pendylpenicillin, potassium phenylmethylpenicillin, potassium propicillin, oxacillin sodium, chloro Xacillin sodium, flucloxacillin sodium, hetacillin potassium, lenampicillin hydrochloride, doxycycline hydrochloride, lincomycin hydrochloride and the like can be mentioned.
結晶水を含有する薬物としては、スルピリン、塩酸メクリジン、塩酸トリプロリジン、リン酸コデイン、ロキソプロフェン・ナトリウム、オキシフェンブタゾン、クロフェゾン、クエン酸イソアミニル、塩酸トリメトキノール、Ｌ−アスパラギン酸カルシウム、オキサシリンナトリウム、クロキサシリンナトリウム、ジクロキサシリンナトリウム、アンモキシリン、フルクロキサシリンナトリウム、塩酸リンコマイシン等が挙げられる。
融点の低い薬物は、融点が１００℃以下である薬物であり、アルクロフェナク、イブプロフェン、ケトプロフェン、メピリゾール、ブコローム、エモルファゾン、チアプロフェン酸、ナブメトン、アリルイソプロピルアセチル尿素、ブロムワレリル尿素、生薬エキス末等が挙げられる。
Drugs containing water of crystallization include sulpyrine, meclizine hydrochloride, triprolidine hydrochloride, codeine phosphate, loxoprofen sodium, oxyphenbutazone, clofaezone, isoaminyl citrate, trimethquinol hydrochloride, calcium L-aspartate, oxacillin sodium , Cloxacillin sodium, dicloxacillin sodium, amoxiline, flucloxacillin sodium, lincomycin hydrochloride and the like.
A drug having a low melting point is a drug having a melting point of 100 ° C. or lower, and examples thereof include alclofenac, ibuprofen, ketoprofen, mepyrazole, bucolome, emorphazone, thiaprofenic acid, nabumetone, allylisopropylacetylurea, bromvalerylurea, and herbal extract powder.
これらの付着性の高い薬物は、３つに分類したものの中から、同じ種類に分類される薬物を２種以上組み合わせても良いし、異なる種類に分類される薬物を２種以上組み合わせても良い。さらに、付着性の高い薬物と、付着性の高い薬物として分類されない薬物を２種以上組み合わせても良い。
これらの付着性の高い薬物のうち、本発明の効果が高く得られるのは、溶質１ｇまたは１ｍLを溶かすのに必要な水の量が１００ｇ未満である薬物、または、結晶水を有する薬物であり、最も効果が高く得られるのは、溶質１ｇまたは１ｍLを溶かすのに必要な水の量が１００ｇ未満である薬物であり、かつ結晶水を有する薬物である。そのような薬物としては、スルピリン、リン酸コデイン、ロキソプロフェン・ナトリウム、塩酸リンコマイシン、クロキサシリンナトリウム、フルクロキサシリンナトリウム等が挙げられる。
錠剤１錠中の薬物の含有量は、特に規定されるものではないが、錠剤１錠あたり０．１〜７０重量％含有することが好ましい。
These highly adherent drugs may be a combination of two or more drugs classified into the same type, or a combination of two or more drugs classified into different types among those classified into three categories. . Further, two or more kinds of drugs having high adhesion and drugs not classified as drugs having high adhesion may be combined.
Among these highly adherent drugs, the effect of the present invention is highly obtained for drugs whose amount of water required to dissolve 1 g or 1 mL of solute is less than 100 g, or drugs having crystal water. The drug that has the highest effect is a drug whose amount of water required to dissolve 1 g or 1 mL of the solute is less than 100 g and that has crystal water. Such drugs include sulpyrine, codeine phosphate, loxoprofen sodium, lincomycin hydrochloride, cloxacillin sodium, flucloxacillin sodium and the like.
The content of the drug in one tablet is not particularly specified, but it is preferably 0.1 to 70% by weight per tablet.
本発明に用いられる吸水性添加剤は、その配合量が少なすぎる場合、付着性を改善する効果が得られないため好ましくない。逆に多すぎる場合、粉体の流動性を悪化させたり、錠剤にクラックが発生したり、一部が剥離したりするキャッピングが起こるため好ましくない。吸水性添加剤の配合量は、薬物１００重量部に対して２０〜１００重量部、好ましくは２０〜７０重量部である。 The water-absorbing additive used in the present invention is not preferable if the blending amount is too small because the effect of improving adhesion cannot be obtained. On the other hand, when the amount is too large, capping that deteriorates the fluidity of the powder, causes cracks in the tablets, or partially peels off is not preferable. The amount of the water-absorbing additive is 20 to 100 parts by weight, preferably 20 to 70 parts by weight, based on 100 parts by weight of the drug.
本発明の吸水性添加剤は、２種類の吸水性添加剤Ａと吸水性添加剤Ｂからなる。
本発明に用いられる吸水性添加剤Ａは、比表面積が１００ｍ２／ｇ以上、かつ吸水量が１．０ｍｌ／ｇである添加剤である。比表面積が１００ｍ２／ｇ以上であっても、吸水量が１．０ｍｌ／ｇ未満の場合、また吸水量が１．０ｍｌ／ｇ以上であっても、比表面積が１００ｍ２／ｇ未満である場合は、付着性を充分に抑制できないため好ましくない。
The water absorbing additive of the present invention comprises two types of water absorbing additive A and water absorbing additive B.
The water-absorbing additive A used in the present invention is an additive having a specific surface area of 100 m 2 / g or more and a water absorption amount of 1.0 ml / g. Also the specific surface area is not more 100 m 2 / g or more, when the water absorption amount is less than 1.0 ml / g, also water absorption even 1.0 ml / g or more, the specific surface area is less than 100 m 2 / g In such a case, it is not preferable because adhesion cannot be sufficiently suppressed.
吸水性添加剤Ａである添加剤として、具体的には、メタケイ酸アルミン酸マグネシウム、軽質無水ケイ酸、ケイ酸カルシウム等が挙げられ、市販品としては、それぞれノイシリン（富士化学工業（株））製、アエロジル（日本アエロジル（株））製、フローライト（（株）トクヤマ製）等が挙げられる。吸水性添加剤Ａは、比表面積が大きいほど付着性を抑制する効果が高いため好ましく、また、吸水量が大きいほど付着性を抑制する効果が高いため好ましい。この点において、吸水性添加剤Ａの中では、メタケイ酸アルミン酸マグネシウムが好ましい。また、これらの吸水性添加剤Ａは、単独で使用しても良いし、２種以上を使用しても良い。 Specific examples of the water-absorbing additive A include magnesium aluminate metasilicate, light anhydrous silicic acid, calcium silicate, and the like. Manufactured, Aerosil (Nippon Aerosil Co., Ltd.), Florite (Tokuyama Co., Ltd.), and the like. The water-absorbing additive A is preferable because the effect of suppressing the adhesion is higher as the specific surface area is larger, and the effect of suppressing the adhesion is higher as the water absorption amount is larger. In this respect, among the water absorbing additive A, magnesium aluminate metasilicate is preferable. Moreover, these water absorbing additives A may be used independently and may use 2 or more types.
吸水性添加剤Ａは、付着性の高い薬物、吸水性添加剤Ｂ、部分アルファー化デンプン、結晶セルロース、及びその他添加剤の全ての成分と一括して混合しても良いし、吸水性添加剤Ａを１種以上の特定の成分に混合した後に、残りの成分を混合する、いわゆる前処理混合に使用しても良い。吸水性添加剤Ａを分割して、前処理混合を複数の成分に対して行い、それらを混合しても良い。吸水性添加剤Ａの添加量は、薬物１００重量部に対して、５〜２０重量部であること好ましい。 The water-absorbing additive A may be mixed together with all the ingredients of the highly adhesive drug, the water-absorbing additive B, the partially pregelatinized starch, the crystalline cellulose, and other additives, or the water-absorbing additive. A may be used for so-called pretreatment mixing in which A is mixed with one or more specific components and then the remaining components are mixed. The water-absorbing additive A may be divided, and pretreatment mixing may be performed on a plurality of components and then mixed. The amount of the water-absorbing additive A added is preferably 5 to 20 parts by weight with respect to 100 parts by weight of the drug.
本発明に用いられる吸水性添加剤Ｂは、比表面積が２ｍ２／ｇ以下、かつ沈降体積が１４ｍｌ以上である添加剤である。沈降体積が１４ｍｌ未満の場合は、比表面積に関わらず付着性を充分に抑制できないため好ましくない。比表面積が２ｍ２／ｇより大きい場合、粉体の流動性悪化、キャッピング発生につながり好ましくない。
吸水性添加剤Ｂである添加剤として、具体的には、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、低置換度ヒドロキシプロピルセルロース等が挙げられる。これらは単独で使用しても良いし、２種以上使用しても良い。
The water-absorbing additive B used in the present invention is an additive having a specific surface area of 2 m 2 / g or less and a sedimentation volume of 14 ml or more. A sedimentation volume of less than 14 ml is not preferable because the adhesion cannot be sufficiently suppressed regardless of the specific surface area. When the specific surface area is larger than 2 m 2 / g, it is not preferable because the fluidity of the powder is deteriorated and capping occurs.
Specific examples of the additive that is the water-absorbing additive B include croscarmellose sodium, sodium carboxymethyl starch, and low-substituted hydroxypropylcellulose. These may be used alone or in combination of two or more.
本発明においては、比表面積の大きく異なる吸水性添加剤Ａと吸水性添加剤Ｂの配合量、及び配合比率を規定することで、直接打錠時のスティッキングとキャッピングを同時に抑制することができる。
吸水性添加剤Ａと吸水性添加剤Ｂの配合比率については、吸水性添加剤Ａの量に対して吸水性添加剤Ｂが同量より少ない場合、付着性を改善する効果が充分に得られないため好ましくない。吸水性添加剤Ａに対して、吸水性添加剤Ｂが多すぎる場合は、粉体の流動性を悪化させたり、錠剤にクラックが発生したり、一部が剥離したりするキャッピングが起こったりするため好ましくない。吸水性添加剤Ａと吸水性添加剤Ｂの配合比率は吸水性添加剤Ａ：吸水性添加剤Ｂ＝１：１〜１：８、好ましくは１：１〜1：５である。
In the present invention, by defining the blending amount and blending ratio of the water-absorbing additive A and the water-absorbing additive B having greatly different specific surface areas, sticking and capping during direct tableting can be suppressed at the same time.
As for the blending ratio of the water-absorbing additive A and the water-absorbing additive B, when the water-absorbing additive B is less than the same amount with respect to the amount of the water-absorbing additive A, the effect of improving the adhesion is sufficiently obtained. It is not preferable because it is not. When the water-absorbing additive B is too much compared to the water-absorbing additive A, capping that deteriorates the fluidity of the powder, causes cracks in the tablet, or partially peels off occurs. Therefore, it is not preferable. The mixing ratio of the water-absorbing additive A and the water-absorbing additive B is water-absorbing additive A: water-absorbing additive B = 1: 1 to 1: 8, preferably 1: 1 to 1: 5.
本発明に用いられる部分アルファー化デンプンは、冷水可溶分が多い場合には充分に付着性を抑制することができないため好ましくない。付着性改善効果を得るためには、冷水可溶分は１０％以下であり、さらに５％以下が好ましい。具体的には、ＰＣＳ（旭化成ケミカルズ（株）製）が好ましい。部分アルファー化デンプンの配合量は少なすぎると薬物の付着性を充分に抑制できず、打錠時の流動性、付着性を改善できないため好ましくない。配合量が多い分については付着性、流動性に特に問題を与えるものではないが、多すぎると、薬物、吸水性添加剤、結晶セルロース等の１錠中の含有量を確保できない。また、錠剤の成形性が不足しキャッピングを起こすため好ましくない。部分アルファー化デンプンの配合量は、薬物１００重量部に対して、１０〜２００重量部、好ましくは２０〜１５０重量部、さらに好ましくは３０〜１００重量部である。 The partially pregelatinized starch used in the present invention is not preferable because the adhesiveness cannot be sufficiently suppressed when there is a large amount of cold water soluble matter. In order to obtain the adhesion improving effect, the cold water soluble content is 10% or less, and preferably 5% or less. Specifically, PCS (manufactured by Asahi Kasei Chemicals Corporation) is preferable. If the amount of the partially pregelatinized starch is too small, it is not preferable because the adhesiveness of the drug cannot be sufficiently suppressed and the fluidity and adhesiveness at the time of tableting cannot be improved. The amount added is not particularly problematic for adhesion and fluidity, but if it is too much, the content in one tablet such as drug, water-absorbing additive, crystalline cellulose, etc. cannot be ensured. Moreover, it is not preferable because the moldability of the tablet is insufficient and capping occurs. The amount of the partially pregelatinized starch is 10 to 200 parts by weight, preferably 20 to 150 parts by weight, and more preferably 30 to 100 parts by weight with respect to 100 parts by weight of the drug.
本発明においては、さらに結晶セルロースを配合する。結晶セルロースは、薬物を含む粉体の付着性、流動性をさらに改善し、錠剤の成形性を向上させる効果がある。結晶セルロースは、医薬品添加剤として使用される物であれば特に制限はなく、いくつかの性質の異なる種類の結晶セルロースのうちの１種類を単独で用いても良いし、２つ以上の種類の混合物を用いても良いが、結晶セルロースの中でも、平均重合度が１５０−４５０、２５０μｍオン１０％以下、７５μｍ以下の粒子Ｌ／Ｄが２.０−４.５、見掛け比容積４．０−７．０ｃｍ３／ｇ、安息角５５度以下の結晶セルロースを使用することが、結晶セルロースの添加効果が大きく得られるため、好ましい。結晶セルロースの配合量としては、その配合量が少なすぎる場合、その効果が得られないため好ましくない。また、配合量が多い場合、薬物、吸水性添加剤、部分アルファー化デンプンの配合量を確保できないため好ましくない。結晶セルロースの配合量は、薬物１００重量部に対して、１０〜１５０重量部、好ましくは３０〜１２０重量部である。 In the present invention, crystalline cellulose is further blended. Crystalline cellulose has the effect of further improving the adherence and fluidity of the powder containing the drug and improving the moldability of the tablet. The crystalline cellulose is not particularly limited as long as it is a product used as a pharmaceutical additive, and one of several types of crystalline cellulose having different properties may be used alone, or two or more types of crystalline cellulose may be used. A mixture may be used, but among crystalline cellulose, the average degree of polymerization is 150-450, 250 μm on 10% or less, particle L / D of 75 μm or less is 2.0-4.5, apparent specific volume 4.0- It is preferable to use crystalline cellulose having 7.0 cm 3 / g and an angle of repose of 55 degrees or less because the effect of adding crystalline cellulose can be greatly obtained. As the blending amount of crystalline cellulose, if the blending amount is too small, the effect cannot be obtained, which is not preferable. Moreover, when there are many compounding quantities, since the compounding quantity of a drug, a water absorbing additive, and a partially pregelatinized starch cannot be ensured, it is not preferable. The compounding amount of the crystalline cellulose is 10 to 150 parts by weight, preferably 30 to 120 parts by weight with respect to 100 parts by weight of the drug.
本発明においては、上記の成分以外にさらに薬学的に許容される添加剤を配合してもよく、結晶乳糖、造粒乳糖等の乳糖類、Ｄ−マンニトール、白糖、エリスリトール、トレハロース等の糖類及び糖アルコール類、トウモロコシデンプン、バレイショデンプン等のデンプン類、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシメチルエチルセルロース、カルボキシメチルセルロースカルシウム、カルボキシメチルセルロースナトリウム等のセルロース誘導体、三二酸化鉄等の着色剤、アステルパーム等の甘味剤、等が挙げられる。 In the present invention, in addition to the above components, pharmaceutically acceptable additives may be further blended, and lactose such as crystalline lactose and granulated lactose, saccharides such as D-mannitol, sucrose, erythritol, and trehalose, and Sugar alcohols, starches such as corn starch, potato starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as sodium carboxymethylcellulose, colorants such as iron sesquioxide, astel Sweetening agents such as palm, etc. can be mentioned.
これらの粉体の混合には、低速の回転容器型混合機を用いる。低速の回転容器型混合機とは、容器に取り付けられた軸を中心として、容器自体が回転することで粉体を持ち上げ、粉体が重力により落下することで混合を行う混合機であり、粉体の混合が主に移動混合、拡散混合により行われる混合機である。回転容器型混合機の種類としては、Ｖ型混合機、二重円錐型混合機、タンブラー型混合機、水平円筒型混合機、傾斜円筒型混合機、正立法型混合機、円錐型混合機、Ｙコーン型混合機等がある。 For mixing these powders, a low-speed rotating container type mixer is used. A low-speed rotating container mixer is a mixer that lifts powder by rotating the container itself around an axis attached to the container, and performs mixing when the powder falls by gravity. This is a mixer in which body mixing is performed mainly by moving mixing and diffusion mixing. The types of rotary container mixers include V mixers, double cone mixers, tumbler mixers, horizontal cylindrical mixers, tilted cylindrical mixers, upright mixers, cone mixers, There are Y cone type mixers.
混合機の大きさは、打錠機に供給する量に合わせて任意に決定することができる。また、その回転速度については、混合機の種類や大きさにより、最適な回転速度があるが、その回転速度は、式（１）に示される最適回転速度の算定式（田村晃一、「工場操作シリーズ 攪拌・捏和・混合編」、別冊ケミカルエンジニヤリング、化学工業社、昭和４３年４月、第２巻、第１号、ｐ．４０−４２）により決定される回転速度とすることが好ましい。
Ａ＝ω２＊Ｒmax／ｇ （１）
（Ａ：混合機の種類により決められる値、ω：角速度［ｒａｄ／ｓ］、Ｒmax：装置最大回転半径［ｍ］、ｇ：重力加速度［ｍ２／ｓ］）
The size of the mixer can be arbitrarily determined according to the amount supplied to the tablet press. In addition, the rotation speed has an optimum rotation speed depending on the type and size of the mixer, but the rotation speed is calculated by an equation for calculating the optimum rotation speed shown in Equation (1) (Keiichi Tamura, “Factory Operation”). It is preferable that the rotation speed is determined by “Series Stirring / Mixing / Mixing”, separate volume Chemical Engineering, Kagaku Kogyosha, April 1968, Vol. 2, No. 1, p. 40-42). .
A = ω 2 * Rmax / g (1)
(A: Value determined by the type of mixer, ω: angular velocity [rad / s], Rmax: device maximum turning radius [m], g: gravitational acceleration [m 2 / s])
例えば、Ｖ型混合機の場合、装入率３０％において、Ａ＝０．３〜０．４［ω２＊Ｒmax／ｇ］と示されており、混合機の装置最大半径が０．４８ｍのＶ型混合機（内容積５Ｌ）に当てはめると、３．７８〜４．０４ｒａｄ／ｓ、すなわち３３．０〜３８．６ｒｐｍが最適回転速度となる。装置が大きくなる場合、Ｒmax値は大ききなるため、ωは小さくなる。すなわち、最適回転速度はより小さくて済む。他の回転容器型混合機の場合におけるＡの値も開示されており、混合機の種類に応じたのＡ値、混合機の半径によって、混合の回転速度を決定すれば良い。 For example, in the case of a V-type mixer, A = 0.3 to 0.4 [ω 2 * Rmax / g] is shown at a charging rate of 30%, and the maximum radius of the mixer is 0.48 m. When applied to a V-type mixer (internal volume 5 L), 3.78 to 4.04 rad / s, that is, 33.0 to 38.6 rpm is the optimum rotation speed. When the device becomes larger, the Rmax value becomes larger, so ω becomes smaller. That is, the optimum rotation speed may be smaller. The value of A in the case of other rotary container type mixers is also disclosed, and the rotational speed of mixing may be determined by the A value corresponding to the type of the mixer and the radius of the mixer.
粉体の混合時間は、通常粉体を混合するために必要な時間であれば良く、５〜３０分程度が好ましい。
上に記した付着性の高い薬物、吸水性添加剤、部分アルファー化デンプンを含む粉体、又は該粉体に加えて結晶セルロース、及びその他許容される添加剤を配合した粉体を回転容器型混合機にて所定の時間混合した粉体に、さらに別に混合した粉体、もしくは造粒した顆粒を配合して混合しても良い。これらの配合可能な粉体及び顆粒は公知の製造方法で得られるもので良い。これらの混合についても、低速の容器回転型混合機で行うことができる。
このようにして得られた粉体に、滑沢剤を添加し、さらに回転容器型混合機にて混合を行う。滑沢剤は、特に限定されるものではなく、従来公知の滑沢剤を用いることができるが、具体的にはステアリン酸マグネシウム、ショ糖脂肪酸エステル等を用いることが好ましい。また、滑沢剤の添加量は、打錠圧、用いる滑沢剤の種類等に応じて適宜選定することができるが、ステアリン酸マグネシウムを用いる場合には、滑沢剤を添加する前の粉体１００重量部に対して、０．５〜４重量部とすることが好ましい。滑沢剤の混合時間は、１〜１５分程度が好ましい。
The mixing time of the powder is usually a time required for mixing the powder, and is preferably about 5 to 30 minutes.
The above-mentioned highly adhesive drug, water-absorbing additive, powder containing partially pregelatinized starch, or powder containing crystalline cellulose and other acceptable additives in addition to the powder is a rotating container type. You may mix and mix the powder mixed separately with the powder mixed for the predetermined time with the mixer, or the granulated granule. These compoundable powders and granules may be obtained by a known production method. These mixing can also be performed with a low-speed container rotating mixer.
A lubricant is added to the powder obtained as described above, and the mixture is further mixed in a rotating container mixer. The lubricant is not particularly limited, and a conventionally known lubricant can be used. Specifically, magnesium stearate, sucrose fatty acid ester, and the like are preferably used. The amount of lubricant added can be appropriately selected depending on the tableting pressure, the type of lubricant used, etc., but when using magnesium stearate, the powder before adding the lubricant is used. The amount is preferably 0.5 to 4 parts by weight with respect to 100 parts by weight of the body. The mixing time of the lubricant is preferably about 1 to 15 minutes.
本発明では、以上の手順により、回転容器式混合機にて混合して得た粉体を、そのまま打錠機のホッパーに充填し、直接打錠を行う。
本発明における直接打錠には、回転式打錠機を使用する。回転式打錠機は、ターンテーブル上に臼杵が同心円状に均等に配置され、ターンテーブルが回転することにより、ホッパーからの粉体の充填、粉体の圧縮、錠剤の排出が連続的に行われる機構を備えた打錠機である。その中でも圧縮が予圧、本圧の２段階で行う、２段圧縮式の打錠機が好ましい。 また、予圧を２回以上又は連続で行う、多段圧縮打錠機等を使用しても良い。また、回転盤が１周する間に充填・圧縮・排出のサイクルを１回行うシングル式打錠機でも良いし、１周する間にサイクルを２回行うダブル式打錠機でも良い。
回転式打錠機の杵の本数、回転盤回転数等は、実用的に製造を行う機械において使用される範囲であれば特に制限はないが、製造の生産性を考慮した場合、杵の本数は１０本以上が好ましく、回転盤の回転数は２５ｒｐｍ以上とすることが好ましい。杵の本数が多くなるほど、回転盤の回転数が速くなるほど生産性は向上するが、一方で、杵の本数を多くしすぎたり、回転盤の回転速度を速くしすぎたりした場合、薬物の性質を問わず、また直接打錠法・湿式造粒法を問わず、機械の構造的な制約により、打錠障害が起こりやすくなるため好ましくない。ゆえに、杵の本数や回転速度等については、これらの範囲を逸脱しない条件とすることが好ましい。
In the present invention, the powder obtained by mixing in the rotary container type mixer is filled in the hopper of the tableting machine as it is by the above procedure, and directly tableted.
A rotary tableting machine is used for direct tableting in the present invention. In rotary tablet presses, mortars are arranged evenly and concentrically on the turntable, and the turntable rotates to continuously fill the powder from the hopper, compress the powder, and discharge the tablet. This is a tableting machine equipped with a mechanism. Among these, a two-stage compression tableting machine in which compression is performed in two stages of preload and main pressure is preferable. Moreover, you may use the multistage compression tableting machine etc. which perform preload twice or more continuously. Moreover, a single type tableting machine that performs a filling / compression / discharge cycle once while the rotating disk makes one revolution may be used, or a double type tableting machine that performs two cycles during one revolution.
There are no particular restrictions on the number of punches of the rotary tableting machine, the number of rotations of the rotating disk, etc. as long as they are within the range of practical use, but the number of punches is considered when manufacturing productivity is considered. Is preferably 10 or more, and the rotation speed of the rotating disk is preferably 25 rpm or more. The productivity increases as the number of cocoons increases and the rotation speed of the rotating disk increases. On the other hand, if the number of cocoons is increased too much or the rotation speed of the rotating disk is increased too much, the properties of the drug Regardless of the direct compression method or the wet granulation method, it is not preferable because a tableting failure is likely to occur due to structural limitations of the machine. Therefore, it is preferable that the number of ridges, the rotation speed, and the like are set so as not to depart from these ranges.
本発明の製造方法に用いられる臼杵の形状には、特に制限はなく、円型、楕円型、三角型、四角型、五角型、六角型、星型等が選択されうるが、使用時の扱いやすさの観点から円状が特に好ましい。また円状の場合打錠機の臼及び杵の径は通常の医薬品錠剤を製造する大きさであれば良く、６〜２０ｍｍであることが好ましく、６〜１０ｍｍがさらに好ましい。また、杵の打錠面の形状についても、通常の医薬品錠剤を製造する形状であれば良く、平杵、R杵、２段R杵、割線杵等が使用できる。また、刻印を付与する杵であっても良い。杵の材質は通常使用される材質であれば良く、打錠面はクロム等の金属メッキを施したり、研磨剤で磨いたりしたものを使用しても良い。また、打錠する錠剤の重量についても、通常の医薬品錠剤の範囲であれば良く、１００〜５００ｍｇであることが好ましい。 The shape of the mortar used in the production method of the present invention is not particularly limited, and a circular shape, an elliptical shape, a triangular shape, a quadrangular shape, a pentagonal shape, a hexagonal shape, a star shape, and the like can be selected. A circular shape is particularly preferable from the viewpoint of ease. In the case of a circle, the diameter of the die and punch of the tableting machine may be any size as long as it can produce a normal pharmaceutical tablet, preferably 6 to 20 mm, more preferably 6 to 10 mm. Moreover, the shape of the tableting surface of the punch may be any shape as long as it can produce ordinary pharmaceutical tablets, and flat punches, R punches, two-stage R punches, secant punches, and the like can be used. Further, it may be a ridge that gives a stamp. The material of the punches may be any material that is normally used, and the tableting surface may be plated with a metal such as chromium or polished with an abrasive. Further, the weight of the tablet to be tableted may be in the range of a normal pharmaceutical tablet, and is preferably 100 to 500 mg.
本発明により製造された錠剤は、そのまま使用しても良いし、外観の改善、防湿、防酸素、薬物の溶出速度調節（例えば、徐放性、腸溶性）、薬物の臭いや苦味マスキング等の目的で、錠剤に水系や溶媒系のコーティングをさらに施しても良い。
本発明を用いることで、付着性の高い薬物を含む錠剤を、従来技術では難しかった直接打錠法を用いても、打錠障害を起こすことなく、製造する方法が見出され、付着性の高い薬物を含む錠剤を工程の簡素化された直接打錠法で提供することが見出された。
The tablet produced according to the present invention may be used as it is, such as improvement in appearance, moisture prevention, oxygen prevention, drug elution rate adjustment (for example, sustained release, enteric), drug odor and bitterness masking, etc. For the purpose, an aqueous or solvent-based coating may be further applied to the tablet.
By using the present invention, a method for producing a tablet containing a highly adherent drug without causing any tableting trouble even when using a direct tableting method, which was difficult in the prior art, has been found. It has been found that tablets with high drug content are provided by a direct compression method with a simplified process.
以下に実施例及び比較例を挙げて本発明を詳しく説明するが、本発明はこれらに限定されるものではない。
これまでに説明していない、物性の測定方法を説明する。
・比表面積
試料を１０５℃の通風乾燥機（（株）タバイエスペック社製）で６時間乾燥後、自動比表面積測定装置（ＴｒｉＳｔａｒ３０００、（株）島津製作所製）を使用して、ＢＥＴ法（窒素）により求めた。
・吸水量
粉末試料を乳鉢に入れ、これに水を加えて乳鉢を用いて練合する場合において、パサパサの状態の粉末が、添加量の増加とともにネバネバの状態へ移行する、このネバネバの状態に移行する直前の吸水量を粉体の単位重量当たりに換算にした値により求めた。
・沈降体積
１００ｍｌの共栓メスシリンダーに水７５ｍｌを入れ、試料１．５ｇを０．５ｇずつ激しく振り混ぜながら加える。水を加えて１００ｍｌとし、均一に分散するまで良く振り混ぜた後、４時間放置したときの、メスシリンダーから読み取った試料の沈降体積から求めた。
Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.
A method for measuring physical properties that has not been described so far will be described.
Specific surface area The sample was dried for 6 hours with a ventilator at 105 ° C. (made by Tabai Espec Co., Ltd.), and then the BET method (nitrogen was used) using an automatic specific surface area measuring device (TriStar 3000, made by Shimadzu Corporation). ).
・ Water absorption amount When a powder sample is put in a mortar, and water is added to the mortar and kneaded using a mortar, the powder in the papasa state transitions to the sticky state as the amount added increases. The amount of water absorption immediately before the transfer was determined from a value converted per unit weight of the powder.
-Sedimentation volume Put 75 ml of water into a 100 ml stoppered measuring cylinder and add 1.5 g of sample 0.5 g at a time while shaking vigorously. Water was added to make 100 ml, and after shaking well until uniformly dispersed, it was determined from the sediment volume of the sample read from the graduated cylinder when left for 4 hours.
・打錠障害評価法
本発明における打錠障害評価法は、以下に示す装置及び条件により混合・打錠される錠剤を用いて、以下に示す評価方法にて実施するものと定義する。
（混合機条件）
Ｖ型混合機（ＭＩＸ ＷＥＬＬ ＢＬＥＮＤＥＲ Ｖ−５、有効容積５Ｌ、３５ｒｐｍ、（株）徳寿製作所製）
（打錠機条件）
回転式打錠機（クリーンプレスコレクト１２ＨＵＫ、（株）菊水製作所製）
ターンテーブル：臼回転半径２２０ｍｍ、回転数５４ｒｐｍ
杵本数：１２本立て
杵形状：２段Ｒ刻印錠（刻印「ＡＳＡＨＩ」））、杵面クロムメッキ付き
錠剤形状：直径８ｍｍ円型、重量２００ｍｇ
打錠数：５０００錠
打錠圧：予圧：５ｋＮ、本圧：１０ｋＮ
-Tableting failure evaluation method The tableting failure evaluation method in the present invention is defined to be carried out by the following evaluation method using tablets mixed and tableted by the following apparatus and conditions.
(Mixer conditions)
V-type mixer (MIX WELL BLENDER V-5, effective volume 5L, 35rpm, manufactured by Tokuju Seisakusho Co., Ltd.)
(Tabletting machine conditions)
Rotary tableting machine (Clean Press Collect 12HUK, manufactured by Kikusui Seisakusho)
Turntable: mortar rotation radius 220mm, rotation speed 54rpm
Number of ridges: 12 ridges 杵 shape: 2-stage R engraved tablet (engraved “ASAHI”)), with chrome plating on the side surface Tablet shape: 8 mm diameter circle, weight 200 mg
Number of tableting: 5000 tablets Tableting pressure: Preload: 5 kN, Main pressure: 10 kN
（評価方法）
本発明では、上記の打錠条件で打錠を行った錠剤について（１）スティッキング率、（２）キャッピング率、（３）重量ＣＶ値の３つを評価指標にて、打錠障害を評価する。以下にその詳細を記す。この３つの評価指標のうち、１つでも打錠障害ありと判断された場合は、打錠障害があると判断する。
（１）スティッキング率
打錠される錠剤のうち、５００錠をサンプリングし、次の○、△、×の３つのレベルに分ける。
○・・・外観に問題なし
△・・・外観にやや曇りは見られるものの、表面の欠損はなく、製品としては問題なし
×・・・表面に欠損があり、製品として問題がある
錠剤を以上の３レベルで錠剤を分けた際に、×のレベルをスティッキングとし、５００錠中のスティッキング率が０．５％より大きい場合に、打錠障害があると判断した。
(Evaluation methods)
In the present invention, a tablet that has been tableted under the above tableting conditions is evaluated for tableting failure using three evaluation indices: (1) sticking rate, (2) capping rate, and (3) weight CV value. . The details are described below. If at least one of these three evaluation indices is determined to have a tableting failure, it is determined that there is a tableting failure.
(1) Sticking rate Out of tablets to be tableted, 500 tablets are sampled and divided into the following three levels: ○, Δ, ×.
○ ・ ・ ・ There is no problem in the appearance △ ・ ・ ・ Although the appearance is slightly cloudy, there is no defect on the surface and there is no problem as a product × ・ ・ ・ There is a defect on the surface and there is a problem as a product When the tablets were divided into three levels, the level of x was regarded as sticking, and when the sticking rate in 500 tablets was larger than 0.5%, it was judged that there was a tableting failure.
（２）キャッピング率
キャッピングとは錠剤を圧縮成形する際に、錠剤にクラックが発生したり、一部が剥離したりする現象である。打錠される５０００錠中、１０００錠をサンプリングしたとき、キャッピングを起こす錠剤の確率が０．１％より大きい場合に、打錠障害があると判断した。
（３）重量ＣＶ値
重量ＣＶ値は、打錠後の錠剤１０個を任意にサンプリングしたものの重量を測定し、その測定値の平均値及び標準偏差より、
重量ＣＶ値＝（標準偏差／平均値）＊１００ [％]
で定義する。
重量ＣＶ値が大きいと、重量バラツキが大きく、薬物の含量バラツキ増加、製品収率の低下につながる。本発明においては、重量ＣＶ値が２．０％よりも大きい場合、打錠障害があると判断した。
(2) Capping rate
Capping is a phenomenon in which a tablet is cracked or partly peeled when the tablet is compressed. When 1000 tablets were sampled out of 5000 tablets to be tableted, it was judged that there was a tableting failure when the probability of the tablets causing capping was greater than 0.1%.
(3) Weight CV value The weight CV value is obtained by measuring the weight of an arbitrary sample of 10 tablets after tableting. From the average value and standard deviation of the measured values,
Weight CV value = (standard deviation / average value) * 100 [%]
Define in.
When the weight CV value is large, the weight variation is large, which leads to an increase in drug content variation and a decrease in product yield. In the present invention, when the weight CV value is larger than 2.0%, it is determined that there is a tableting failure.
［実施例１］
薬物としてロキソプロフェン・ナトリウム（ＬＸＰ、大原薬品工業（株）製）１００重量部、吸水性添加剤Ａとしてメタケイ酸アルミン酸マグネシウム「ノイシリン」ＵＦＬ２（富士化学工業（株）製、比表面積３００ｍ２／ｇ、吸水量１.９ｍｌ／ｇ） １４．７重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１（信越化学（株）製、比表面積０.４７ｍ２／ｇ、沈降体積２４ｍｌ）１４．７重量部、部分アルファー化デンプンとして「ＰＣＳ」（旭化成ケミカルズ（株）製、冷水可溶分１.２％）５５．７重量部、結晶セルロースとして「セオラス」ＫＧ−８０２（旭化成ケミカルズ（株）製）５８．７重量部、「セオラス」ＰＨ−３０２ ４１．１重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム（太平化学産業（株）製）を８．８重量部投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表１に示す。スティッキング率は０％、キャッピング率は０％、錠剤の重量ＣＶ値は、０．９１％であり、直接打錠法において、打錠障害を起こすことなく、錠剤を得ることができた。
[Example 1]
100 parts by weight of loxoprofen sodium (LXP, manufactured by Ohara Pharmaceutical Co., Ltd.) as a drug, and magnesium aluminometasilicate “Neusilin” UFL2 (manufactured by Fuji Chemical Industry Co., Ltd., specific surface area 300 m 2 / g) as a water-absorbing additive A 14.7 parts by weight, water-absorbing additive B as low-substituted hydroxypropylcellulose LH-B1 (manufactured by Shin-Etsu Chemical Co., Ltd., specific surface area 0.47 m 2 / g, sedimentation volume 24 ml) 14.7 parts by weight, “PCS” as partially pregelatinized starch (produced by Asahi Kasei Chemicals Co., Ltd., cold water soluble content 1.2%) 55.7 parts by weight, “Ceolus” KG-802 (Asahi Kasei Chemicals) as crystalline cellulose 58.7 parts by weight, manufactured by Co., Ltd., and 41.1 parts by weight of “Theolas” PH-302 were put into a V-type mixer and mixed for 15 minutes. 8.8 parts by weight of magnesium acid (manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed for another 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 1. The sticking rate was 0%, the capping rate was 0%, and the tablet weight CV value was 0.91%. In the direct tableting method, tablets could be obtained without causing any tableting trouble.
［実施例２］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａ「ノイシリン」ＵＦＬ２ ４．４重量部をＶ型混合機に投入し、２０分間前処理混合を行った後取り出し、前処理粉体（Ｉ）を得た。次に、結晶セルロース「セオラス」ＫＧ−８０２ ５８．７重量部、吸水性添加剤Ａ「ノイシリン」ＵＦＬ２ ４．４重量部をＶ型混合機に投入し、２０分間前処理混合を行い、前処理粉体（ＩＩ）を得た。Ｖ型混合機中の前処理粉体（ＩＩ）に、前処理粉体（Ｉ）、及び吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １４．７重量部、部分アルファー化デンプン「ＰＣＳ」６１．５重量部、結晶セルロース「セオラス」ＰＨ−３０２ ４１．１重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表１に示す。スティッキング率は０％、キャッピング率は０％、錠剤の重量ＣＶ値は、０．６１％であり、直接打錠法において、打錠障害を起こすことなく、錠剤を得ることができた。
[Example 2]
100 parts by weight of loxoprofen sodium and 4.4 parts by weight of a water-absorbing additive A “Neucillin” UFL2 are put into a V-type mixer as a drug, pretreated and mixed for 20 minutes, taken out, and pretreated powder (I) Got. Next, 58.7 parts by weight of crystalline cellulose “Theolas” KG-802 and 4.4 parts by weight of water-absorbing additive A “Neucillin” UFL2 were put into a V-type mixer, pretreated and mixed for 20 minutes, and pretreated. Powder (II) was obtained. In the pretreated powder (II) in the V-type mixer, the pretreated powder (I) and low substituted hydroxypropylcellulose LH-B1 14.7 parts by weight as the water-absorbing additive B, partially pregelatinized starch “ 61.5 parts by weight of PCS and 41.1 parts by weight of crystalline cellulose “Theolas” PH-302 are put into a V-type mixer, mixed for 15 minutes, and then mixed with 8.8 parts by weight of magnesium stearate and further mixed for 5 minutes. did.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 1. The sticking rate was 0%, the capping rate was 0%, and the tablet weight CV value was 0.61%. In the direct tableting method, tablets could be obtained without causing any tableting problems.
［実施例３］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ １４．７重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １４．７重量部、部分アルファー化デンプンとして「ＰＣＳ」５５．７重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ５８．７重量部、造粒乳糖「ＳＵＰＥＲ−ＴＡＢ」（旭化成ケミカルズ（株）販売）４１．１重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表１に示す。スティッキング率は０％、キャッピング率は０％、錠剤の重量ＣＶ値は、１.０２％であり、直接打錠法において、打錠障害を起こすことなく、錠剤を得ることができた。
[Example 3]
100 parts by weight of loxoprofen sodium as a drug, 14.7 parts by weight of “Neusilin” UFL2 as a water-absorbing additive A, 14.7 parts by weight of low-substituted hydroxypropylcellulose LH-B1 as a water-absorbing additive B, partially pregelatinized starch "PCS" as 55.7 parts by weight, Crystalline cellulose as "Seolas" KG-802 58.7 parts by weight, granulated lactose "SUPER-TAB" (sales by Asahi Kasei Chemicals) 41.1 parts by weight After putting into the machine and mixing for 15 minutes, 8.8 parts by weight of magnesium stearate was added and further mixed for 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 1. The sticking rate was 0%, the capping rate was 0%, and the tablet weight CV value was 1.02%. In the direct tableting method, tablets could be obtained without causing any tableting problems.
［実施例４］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ １４．７重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １４．７重量部、部分アルファー化デンプンとして「ＰＣＳ」５５．７重量部、結晶セルロースとして「セオラス」ＰＨ−１０１ ５８．７重量部、造粒乳糖「ＳＵＰＥＲ−ＴＡＢ」４１．１重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表１に示す。スティッキング率は０．２％、キャッピング率は０％、錠剤の重量ＣＶ値は、０．７５％であり、直接打錠法において、打錠障害を起こすことなく、錠剤を得ることができた。
[Example 4]
100 parts by weight of loxoprofen sodium as a drug, 14.7 parts by weight of “Neusilin” UFL2 as a water-absorbing additive A, 14.7 parts by weight of low-substituted hydroxypropylcellulose LH-B1 as a water-absorbing additive B, partially pregelatinized starch "PCS" 55.7 parts by weight, crystalline cellulose "Ceorus" PH-101 58.7 parts by weight, granulated lactose "SUPER-TAB" 41.1 parts by weight into a V-type mixer and mixed for 15 minutes Thereafter, 8.8 parts by weight of magnesium stearate was added and further mixed for 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 1. The sticking rate was 0.2%, the capping rate was 0%, and the tablet weight CV value was 0.75%. In the direct tableting method, tablets could be obtained without causing any tableting problems.
［実施例５］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ １４．７重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １４．７重量部、部分アルファー化デンプンとして「ＰＣＳ」５７．７重量部、造粒乳糖「ＳＵＰＥＲ−ＴＡＢ」１００重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表１に示す。スティッキング率は０．４％、キャッピング率は０％、錠剤の重量ＣＶ値は、１．２２％であり、直接打錠法において、打錠障害を起こすことなく、錠剤を得ることができた。
[Example 5]
100 parts by weight of loxoprofen sodium as a drug, 14.7 parts by weight of “Neusilin” UFL2 as a water-absorbing additive A, 14.7 parts by weight of low-substituted hydroxypropylcellulose LH-B1 as a water-absorbing additive B, partially pregelatinized starch "PCS" 57.7 parts by weight and granulated lactose "SUPER-TAB" 100 parts by weight are mixed in a V-type mixer for 15 minutes, and then 8.8 parts by weight of magnesium stearate is added for another 5 minutes. Mixed.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 1. The sticking rate was 0.4%, the capping rate was 0%, and the tablet weight CV value was 1.22%. In the direct tableting method, tablets could be obtained without causing any tableting problems.
［実施例６］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａ「ノイシリン」ＵＦＬ２ ４．４重量部をＶ型混合機に投入し、２０分間前処理混合を行った後取り出し、前処理粉体（Ｉ）を得た。次に、結晶セルロース「セオラス」ＫＧ−８０２ ５８．７重量部、吸水性添加剤Ａ「ノイシリン」ＵＦＬ２ ２．９重量部をＶ型混合機に投入し、２０分間前処理混合を行い、前処理粉体（ＩＩ）を得た。Ｖ型混合機中の前処理粉体（ＩＩ）に、前処理粉体（Ｉ）、及び吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １４．７重量部、部分アルファー化デンプン「ＰＣＳ」６３．０重量部、結晶セルロース「セオラス」ＰＨ−３０２ ４１．１重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表２に示す。スティッキング率は０．４％、キャッピング率は０％、錠剤の重量ＣＶ値は、０．５４％であり、直接打錠法において、打錠障害を起こすことなく、錠剤を得ることができた。
[Example 6]
100 parts by weight of loxoprofen sodium and 4.4 parts by weight of a water-absorbing additive A “Neucillin” UFL2 are put into a V-type mixer as a drug, pretreated and mixed for 20 minutes, taken out, and pretreated powder (I) Got. Next, 58.7 parts by weight of crystalline cellulose “Theolas” KG-802 and 2.9 parts by weight of water-absorbing additive A “Neusilin” UFL2 were put into a V-type mixer, pretreated and mixed for 20 minutes, and pretreated. Powder (II) was obtained. In the pretreated powder (II) in the V-type mixer, the pretreated powder (I) and low substituted hydroxypropylcellulose LH-B1 14.7 parts by weight as the water-absorbing additive B, partially pregelatinized starch “ 63.0 parts by weight of PCS and 41.1 parts by weight of crystalline cellulose “Theolas” PH-302 are put into a V-type mixer, mixed for 15 minutes, and then mixed with 8.8 parts by weight of magnesium stearate and further mixed for 5 minutes. did.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 2. The sticking rate was 0.4%, the capping rate was 0%, and the tablet weight CV value was 0.54%. In the direct tableting method, tablets could be obtained without causing any tableting problems.
［実施例７］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ ７．３重量部、及びケイ酸カルシウム「フローライト」ＲＥ（（株）トクヤマ製、比表面積１００ｍ２／ｇ、吸水量１.２ｍｌ／ｇ）７．３重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １４．７重量部、部分アルファー化デンプンとして「ＰＣＳ」６３．０重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ５８．７重量部、ＰＨ−３０２ ４１．１重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表２に示す。スティッキング率は０％、キャッピング率は０％、錠剤の重量ＣＶ値は、０．８４％であり、直接打錠法において、打錠障害を起こすことなく、錠剤を得ることができた。
[Example 7]
100 parts by weight of loxoprofen sodium as a drug, 7.3 parts by weight of “Neusilin” UFL2 as a water-absorbing additive A, and calcium silicate “Flolite” RE (manufactured by Tokuyama Corporation, specific surface area 100 m 2 / g, water absorption 1.2 ml / g) 7.3 parts by weight, low substituted hydroxypropylcellulose LH-B1 14.7 parts by weight as water-absorbing additive B, 63.0 parts by weight “PCS” as partially pregelatinized starch, as crystalline cellulose "Theorus" KG-802 58.7 parts by weight and PH-302 41.1 parts by weight were put into a V-type mixer and mixed for 15 minutes, then 8.8 parts by weight of magnesium stearate was added and mixed for another 5 minutes. did.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 2. The sticking rate was 0%, the capping rate was 0%, and the tablet weight CV value was 0.84%. In the direct tableting method, tablets could be obtained without causing any tableting problems.
［実施例８］
薬物としてスルピリン（メルク・ホエイ（株）製）１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ １４．７重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １４．７重量部、部分アルファー化デンプンとして「ＰＣＳ」５５．７重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ５８．７重量部、ＰＨ−３０２ ４１．１重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表２に示す。スティッキング率は０％、キャッピング率は０％、錠剤の重量ＣＶ値は、１．０７％であり、直接打錠法において、打錠障害を起こすことなく、錠剤を得ることができた。
[Example 8]
100 parts by weight of sulpyrine (manufactured by Merck Whey Co., Ltd.) as the drug, 14.7 parts by weight of “Neusilin” UFL2 as the water-absorbing additive A, and low substituted hydroxypropylcellulose LH-B1 14.7 as the water-absorbing additive B 1 part by weight, 55.7 parts by weight of “PCS” as partially pregelatinized starch, 58.7 parts by weight of “Theolas” KG-802 as crystalline cellulose, and 41.1 parts by weight of PH-302 are introduced into a V-type mixer. After mixing for 8 minutes, 8.8 parts by weight of magnesium stearate was added and further mixed for 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 2. The sticking rate was 0%, the capping rate was 0%, and the tablet weight CV value was 1.07%. In the direct tableting method, tablets could be obtained without causing any tableting problems.
［実施例９］
薬物としてイブプロフェン（（株）エーピーアイコーポレーション製）１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ １４．７重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １４．７重量部、部分アルファー化デンプンとして「ＰＣＳ」５５．７重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ５８．７重量部、ＰＨ−３０２ ４１．１重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表２に示す。スティッキング率は０％、キャッピング率は０％、錠剤の重量ＣＶ値は、０．８７％であり、直接打錠法において、打錠障害を起こすことなく、錠剤を得ることができた。
[Example 9]
100 parts by weight of ibuprofen (manufactured by API Corporation) as the drug, 14.7 parts by weight of “Neusilin” UFL2 as the water-absorbing additive A, and low substituted hydroxypropylcellulose LH-B1 14.7 as the water-absorbing additive B 1 part by weight, 55.7 parts by weight of “PCS” as partially pregelatinized starch, 58.7 parts by weight of “Theolas” KG-802 as crystalline cellulose, and 41.1 parts by weight of PH-302 are introduced into a V-type mixer. After mixing for 8 minutes, 8.8 parts by weight of magnesium stearate was added and further mixed for 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 2. The sticking rate was 0%, the capping rate was 0%, and the tablet weight CV value was 0.87%. In the direct tableting method, tablets could be obtained without causing any tableting problems.
［実施例１０］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ ８．８重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ ４４．１重量部、部分アルファー化デンプンとして「ＰＣＳ」５５．７重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ３５．２重量部、ＰＨ−３０２ ４１．１重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表２に示す。スティッキング率は０％、キャッピング率は０％、錠剤の重量ＣＶ値は１．４５％であり、直接打錠法において、打錠障害を起こすことなく、錠剤を得ることができた。
[Example 10]
100 parts by weight of loxoprofen sodium as a drug, 8.8 parts by weight of “Neusilin” UFL2 as a water absorbing additive A, 44.1 parts by weight of low substituted hydroxypropylcellulose LH-B1 as a water absorbing additive B, partially pregelatinized starch "PCS" 55.7 parts by weight, crystalline cellulose "Theorus" KG-802 35.2 parts by weight, PH-302 41.1 parts by weight into a V-type mixer, mixed for 15 minutes, then magnesium stearate 8.8 parts by weight were added and mixed for another 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 2. The sticking rate was 0%, the capping rate was 0%, and the tablet weight CV value was 1.45%. In the direct tableting method, tablets could be obtained without causing any tableting trouble.
［実施例１１］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ ８．８重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ ２９．４重量部及びクロスカルメロースナトリウム「キッコレート」ＮＤ−２ＨＳ（比表面積０．６５ｍ２／ｇ、沈降体積２３．５ｍｌ、旭化成ケミカルズ（株）販売） ３５．２重量部、部分アルファー化デンプンとして「ＰＣＳ」３５．２重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ３５．２重量部、ＰＨ−３０２ ４１．１重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表２に示す。スティッキング率は０．０４％、キャッピング率は０％、錠剤の重量ＣＶ値は１．７７％であり、直接打錠法において、打錠障害を起こすことなく、錠剤を得ることができた。
[Example 11]
Loxoprofen sodium 100 parts by weight as drug, “Noiselin” UFL2 8.8 parts by weight as water absorbent additive A, low substituted hydroxypropylcellulose LH-B1 29.4 parts by weight as water absorbent additive B and croscarmellose sodium “Kickolate” ND-2HS (specific surface area 0.65 m 2 / g, sedimentation volume 23.5 ml, sold by Asahi Kasei Chemicals) 35.2 parts by weight, “PCS” 35.2 parts by weight as partially pregelatinized starch, crystals As cellulose, 35.2 parts by weight of “Seolas” KG-802 and 41.1 parts by weight of PH-302 were added to a V-type mixer, mixed for 15 minutes, and then further charged with 8.8 parts by weight of magnesium stearate and further 5 Mixed for minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 2. The sticking rate was 0.04%, the capping rate was 0%, and the tablet weight CV value was 1.77%. In the direct tableting method, tablets could be obtained without causing any tableting problems.
［実施例１２］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ １４．７重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ ３６．７重量部及びクロスカルメロースナトリウム「キッコレート」ＮＤ−２ＨＳ ３６．７重量部、部分アルファー化デンプンとして「ＰＣＳ」３５．２重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ２９．４重量部、ＰＨ−３０２ ３２．３重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表２に示す。スティッキング率は０％、キャッピング率は０．０６％、錠剤の重量ＣＶ値は１．８６％であり、直接打錠法において、打錠障害を起こすことなく、錠剤を得ることができた。
[Example 12]
Loxoprofen sodium 100 parts by weight as drug, "Noiselin" UFL2 14.7 parts by weight as water-absorbing additive A, low-substituted hydroxypropylcellulose LH-B1 36.7 parts by weight as water-absorbing additive B and croscarmellose sodium “Kickolate” ND-2HS 36.7 parts by weight, partially pregelatinized starch “PCS” 35.2 parts by weight, crystalline cellulose “Seolus” KG-802 29.4 parts by weight, PH-302 32.3 parts by weight The mixture was put into a V-type mixer and mixed for 15 minutes, and then 8.8 parts by weight of magnesium stearate was added and mixed for another 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 2. The sticking rate was 0%, the capping rate was 0.06%, and the weight CV value of the tablet was 1.86%. In the direct tableting method, tablets could be obtained without causing any tableting trouble.
［比較例１］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ ４．４重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １４．７重量部、部分アルファー化デンプンとして「ＰＣＳ」６５．９重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ５８．７重量部、ＰＨ−３０２ ４１．１重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表３に示す。結果を表３に示す。スティッキング率が１３．２％であり、打錠障害が認められた。
[Comparative Example 1]
Loxoprofen sodium 100 parts by weight as drug, "Noiselin" UFL2 4.4 parts by weight as water-absorbing additive A, low substituted hydroxypropylcellulose LH-B1 14.7 parts by weight as water-absorbing additive B, partially pregelatinized starch "PCS" 65.9 parts by weight, crystalline cellulose "Ceorus" KG-802 58.7 parts by weight, PH-302 41.1 parts by weight into a V-type mixer, mixed for 15 minutes, magnesium stearate 8.8 parts by weight were added and mixed for another 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 3. The results are shown in Table 3. The sticking rate was 13.2%, and a tableting failure was observed.
［比較例２］
比較例１でスティッキングが発生した原因として、打錠圧の不足が考えられたため、打錠圧を１０ｋＮから１５ｋＮへ上げた以外は、比較例１と同様に実施した。
結果を表３に示す。キャッピング率が３．４％、スティッキング率が８．８％であり、打錠障害が認められた。
[Comparative Example 2]
Since the cause of sticking in Comparative Example 1 was thought to be due to insufficient tableting pressure, it was carried out in the same manner as Comparative Example 1 except that the tableting pressure was increased from 10 kN to 15 kN.
The results are shown in Table 3. The capping rate was 3.4%, the sticking rate was 8.8%, and a tableting failure was observed.
［比較例３］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ ７．３重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １０．３重量部、部分アルファー化デンプンとして「ＰＣＳ」６７．４重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ５８．７重量部、ＰＨ−３０２ ４１．１重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表３に示す。結果を表３に示す。スティッキング率が２０．６％であり、打錠障害が認められた。
[Comparative Example 3]
Loxoprofen sodium 100 parts by weight as drug, “Neusilin” UFL2 7.3 parts by weight as water absorbent additive A, low substituted hydroxypropylcellulose LH-B1 10.3 parts by weight as water absorbent additive B, partially pregelatinized starch “PCS” as 67.4 parts by weight, crystalline cellulose as “Seolas” KG-802 58.7 parts by weight, PH-302 41.1 parts by weight into a V-type mixer and mixed for 15 minutes, then magnesium stearate 8.8 parts by weight were added and mixed for another 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 3. The results are shown in Table 3. The sticking rate was 20.6%, and a tableting failure was observed.
［比較例４］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ １４．７重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ ４４．１重量部及びクロスカルメロースナトリウム「キッコレート」ＮＤ−２ＨＳ ４４．１重量部、部分アルファー化デンプンとして「ＰＣＳ」２３．３重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ２９．４重量部、ＰＨ−３０２ ２９．４重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表３に示す。結果を表３に示す。キャッピング率が５５．８％であり、打錠障害が認められた。
[Comparative Example 4]
100 parts by weight of loxoprofen sodium as a drug, 14.7 parts by weight of “Neusilin” UFL2 as a water absorbing additive A, 44.1 parts by weight of low substituted hydroxypropylcellulose LH-B1 as a water absorbing additive B and croscarmellose sodium “Kickolate” ND-2HS 44.1 parts by weight, partially pregelatinized starch “PCS” 23.3 parts by weight, crystalline cellulose “Seorasu” KG-802 29.4 parts by weight, PH-302 29.4 parts by weight The mixture was put into a V-type mixer and mixed for 15 minutes, and then 8.8 parts by weight of magnesium stearate was added and mixed for another 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 3. The results are shown in Table 3. The capping rate was 55.8%, and tableting trouble was observed.
［比較例５］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ １１．７重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １０．３重量部、部分アルファー化デンプンとして「ＰＣＳ」５５．７重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ５８．７重量部、ＰＨ−３０２ ４８．５重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表４に示す。結果を表３に示す。スティッキング率が２．４％であり、打錠障害が認められた。
[Comparative Example 5]
Loxoprofen sodium 100 parts by weight as drug, "Noiselin" UFL2 11.7 parts by weight as water-absorbing additive A, low-substituted hydroxypropylcellulose LH-B1 10.3 parts by weight as water-absorbing additive B, partially pregelatinized starch "PCS" 55.7 parts by weight, crystalline cellulose "Theorus" KG-802 58.7 parts by weight, PH-302 48.5 parts by weight in a V-type mixer, mixed for 15 minutes, magnesium stearate 8.8 parts by weight were added and mixed for another 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 4. The results are shown in Table 3. The sticking rate was 2.4%, and tableting trouble was observed.
［比較例６］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ １７．６重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １１．７重量部、部分アルファー化デンプンとして「ＰＣＳ」５５．７重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ５８．７重量部、ＰＨ−３０２ ４８．５重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表４に示す。結果を表３に示す。スティッキング率が１．６％であり、打錠障害が認められた。
[Comparative Example 6]
Loxoprofen sodium 100 parts by weight as drug, “Neusilin” UFL2 17.6 parts by weight as water absorbent additive A, low substituted hydroxypropylcellulose LH-B1 11.7 parts by weight as water absorbent additive B, partially pregelatinized starch "PCS" 55.7 parts by weight, crystalline cellulose "Theorus" KG-802 58.7 parts by weight, PH-302 48.5 parts by weight in a V-type mixer, mixed for 15 minutes, magnesium stearate 8.8 parts by weight were added and mixed for another 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 4. The results are shown in Table 3. The sticking rate was 1.6%, and tableting trouble was observed.
［比較例７］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ ８．８重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ ３９．６重量部及びクロスカルメロースナトリウム「キッコレート」ＮＤ−２ＨＳ ３９．６重量部、部分アルファー化デンプンとして「ＰＣＳ」３８．０重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ２９．４重量部、ＰＨ−３０２ ２９．４重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表４に示す。結果を表３に示す。キャッピング率が４２．２％であり、打錠障害が認められた。
[Comparative Example 7]
100 parts by weight of loxoprofen sodium as a drug, 8.8 parts by weight of “Neusilin” UFL2 as a water-absorbing additive A, 39.6 parts by weight of low-substituted hydroxypropylcellulose LH-B1 as a water-absorbing additive B, and croscarmellose sodium “Cickolate” ND-2HS 39.6 parts by weight, partially pregelatinized starch “PCS” 38.0 parts by weight, crystalline cellulose “Seolus” KG-802 29.4 parts by weight, PH-302 29.4 parts by weight The mixture was put into a V-type mixer and mixed for 15 minutes, and then 8.8 parts by weight of magnesium stearate was added and mixed for another 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 4. The results are shown in Table 3. The capping rate was 42.2% and a tableting failure was observed.
［比較例８］
比較例７でキャッピングが発生した原因として、打錠圧が高すぎることが考えられたため、打錠圧を１０ｋＮから５ｋＮに落とした以外は、比較例７と同様に実施した。
結果を表４に示す。スティッキング率が１０．６％であり、打錠障害が認められた。
[Comparative Example 8]
The reason why capping occurred in Comparative Example 7 was considered that the tableting pressure was too high. Therefore, the same procedure as in Comparative Example 7 was performed except that the tableting pressure was reduced from 10 kN to 5 kN.
The results are shown in Table 4. The sticking rate was 10.6%, and a tableting failure was observed.
［比較例９］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ １４．７重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １４．７重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ５８．７重量部、ＰＨ−３０２ ９６．８重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表５に示す。結果を表３に示す。スティッキング率が２２．４％であり、打錠障害が認められた。
[Comparative Example 9]
Loxoprofen sodium 100 parts by weight as drug, “Neusilin” UFL2 14.7 parts by weight as water-absorbing additive A, low-substituted hydroxypropylcellulose LH-B1 14.7 parts by weight as water-absorbing additive B, crystalline cellulose “ "Seolus" KG-802 58.7 parts by weight and PH-302 96.8 parts by weight were put into a V-type mixer and mixed for 15 minutes, then 8.8 parts by weight of magnesium stearate was added and mixed for another 5 minutes. .
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 5. The results are shown in Table 3. The sticking rate was 22.4%, and tableting trouble was observed.
［比較例１０］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ １４．７重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ ７０．３重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ５８．７重量部、ＰＨ−３０２ ４１．１重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表５に示す。結果を表５に示す。キャッピング率が６８．８％、スティッキング率が２．２％であり、打錠障害が認められた。
[Comparative Example 10]
Loxoprofen sodium 100 parts by weight as drug, “Noiselin” UFL2 14.7 parts by weight as water-absorbing additive A, low-substituted hydroxypropylcellulose LH-B1 70.3 parts by weight as water-absorbing additive B, crystalline cellulose “ "Seolas" KG-802 58.7 parts by weight and PH-302 41.1 parts by weight were put into a V-type mixer and mixed for 15 minutes, then 8.8 parts by weight of magnesium stearate was added and mixed for another 5 minutes. .
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 5. The results are shown in Table 5. The capping rate was 68.8%, the sticking rate was 2.2%, and a tableting failure was observed.
［比較例１１］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ １０．７重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ １０．７重量部、部分アルファー化デンプンとして「ＰＣＳ」２１０．７重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ １０．７重量部をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表５に示す。結果を表５に示す。キャッピング率が５４．２％、スティッキング率が４．５％であり、打錠障害が認められた。
[Comparative Example 11]
100 parts by weight of loxoprofen sodium as a drug, 10.7 parts by weight of “Neusilin” UFL2 as a water-absorbing additive A, 10.7 parts by weight of low-substituted hydroxypropylcellulose LH-B1 as a water-absorbing additive B, partially pregelatinized starch "PCS" 210.7 parts by weight and crystalline cellulose "Ceorus" KG-802 10.7 parts by weight were added to a V-type mixer for 15 minutes, and then 8.8 parts by weight of magnesium stearate was added. Mix for another 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 5. The results are shown in Table 5. The capping rate was 54.2%, the sticking rate was 4.5%, and tableting trouble was observed.
［比較例１２］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ ６９．５重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ５８．７重量部、「ＳＵＰＥＲ−ＴＡＢ」 ６４重量部、をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表６に示す。キャッピング率が４２．２％、スティッキング率が３．２％であり、打錠障害が認められた。
[Comparative Example 12]
Loxoprofen sodium as a drug 100 parts by weight, water-absorbing additive B as low-substituted hydroxypropylcellulose LH-B1 69.5 parts by weight, crystalline cellulose as “Seolas” KG-802 58.7 parts by weight, “SUPER-TAB” 64 parts by weight was charged into a V-type mixer and mixed for 15 minutes, and then 8.8 parts by weight of magnesium stearate was charged and mixed for another 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 6. The capping rate was 42.2%, the sticking rate was 3.2%, and a tableting failure was observed.
［比較例１３］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＮＳ２Ｎ（富士化学工業（株）製） ５１．４重量部、吸水性添加剤Ｂとしてカルボキシメチルスターチナトリウム「Ｐｒｉｍｏｊｅｌ」 １００重量部、コーンスターチ（ＳＴ−Ｃ、日澱化学（株）製）２３．５重量部、「ＳＵＰＥＲ−ＴＡＢ」 ９９．７をＶ型混合機に投入して１５分間混合後、タルク（和光純薬（株）製）２．９重量部、ステアリン酸マグネシウム１．５重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表６に示す。キャッピング率が６８．６％であり、打錠障害が認められた。
[Comparative Example 13]
100 parts by weight of loxoprofen sodium as a drug, 51.4 parts by weight of “Noiselin” NS2N (Fuji Chemical Industry Co., Ltd.) as a water-absorbing additive A, 100 parts by weight of sodium carboxymethyl starch “Primojel” as a water-absorbing additive B Corn starch (ST-C, manufactured by Nissho Chemical Co., Ltd.) 23.5 parts by weight, “SUPER-TAB” 99.7 was put into a V-type mixer, mixed for 15 minutes, and then talc (Wako Pure Chemical Industries, Ltd.). )) 2.9 parts by weight and 1.5 parts by weight of magnesium stearate were added and further mixed for 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 6. The capping rate was 68.6%, and tableting trouble was observed.
［比較例１４］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ ６９．５重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ５８．７重量部、「ＳＵＰＥＲ−ＴＡＢ」 ６４重量部、をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表６に示す。キャッピング率が７２．２％、スティッキング率が３．２％であり、打錠障害が認められた。
[Comparative Example 14]
Loxoprofen sodium as a drug 100 parts by weight, water-absorbing additive B as low-substituted hydroxypropylcellulose LH-B1 69.5 parts by weight, crystalline cellulose as “Seolas” KG-802 58.7 parts by weight, “SUPER-TAB” 64 parts by weight was charged into a V-type mixer and mixed for 15 minutes, and then 8.8 parts by weight of magnesium stearate was charged and mixed for another 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 6. The capping rate was 72.2%, the sticking rate was 3.2%, and a tableting failure was observed.
［比較例１５］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ−２ １４．７重量部、吸水性添加剤Ｂとして低置換度ヒドロキシプロピルセルロース ＬＨ−Ｂ１ ５４．８重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ５８．７重量部、「ＳＵＰＥＲ−ＴＡＢ」 ６４重量部、をＶ型混合機に投入して１５分間混合後、ステアリン酸マグネシウム８．８重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表６に示す。キャッピング率が１８．６％であり、打錠障害が認められた。
[Comparative Example 15]
Loxoprofen sodium 100 parts by weight as drug, "Noiselin" UFL-2 14.7 parts by weight as water-absorbing additive A, low-substituted hydroxypropylcellulose LH-B1 54.8 parts by weight as water-absorbing additive B, crystalline cellulose As follows, “Theolas” KG-802 58.7 parts by weight and “SUPER-TAB” 64 parts by weight were put into a V-type mixer and mixed for 15 minutes, then 8.8 parts by weight of magnesium stearate was added and further 5 Mixed for minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 6. The capping rate was 18.6%, and tableting trouble was observed.
［比較例１６］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして軽質無水ケイ酸（「アエロジル」２００、日本アエロジル（株）製）１重量部を、高速攪拌造粒機（バーチカルグラニュレータ ＶＧ−１０、（株）パウレック製）に入れ、ブレード回転数３００ｒｐｍ、クロススクリュー回転数１５００ｒｐｍの条件で２５分間混合した。次に酸化チタン（ＡＨ−Ｒ、フロイント産業（株）製）３重量部を加え、同条件で５分間混合し、表面改質処理品（Ｉ）を得た。
表面改質処理品（Ｉ）及び、部分アルファー化デンプンとして「ＰＣＳ」１１９．６重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ４７．６重量部、クエン酸（和光純薬工業（株）製）１７．１重量部をＶ型混合機に投入して１５分間混合後、タルク６重量部、ステアリン酸マグネシウム６重量部を投入してさらに５分間混合した。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表７に示す。スティッキング率が２８．６％であり、打錠障害が認められた。
[Comparative Example 16]
100 parts by weight of loxoprofen sodium as a drug, 1 part by weight of light anhydrous silicic acid (“Aerosil” 200, manufactured by Nippon Aerosil Co., Ltd.) as a water-absorbing additive A, a high-speed stirring granulator (Vertical Granulator VG-10, And mixed for 25 minutes under the conditions of a blade rotation speed of 300 rpm and a cross screw rotation speed of 1500 rpm. Next, 3 parts by weight of titanium oxide (AH-R, Freund Sangyo Co., Ltd.) was added and mixed for 5 minutes under the same conditions to obtain a surface-modified product (I).
Surface-modified product (I), 119.6 parts by weight of “PCS” as partially pregelatinized starch, 47.6 parts by weight of “Seolas” KG-802 as crystalline cellulose, citric acid (manufactured by Wako Pure Chemical Industries, Ltd.) ) 17.1 parts by weight was put into a V-type mixer and mixed for 15 minutes, and then 6 parts by weight of talc and 6 parts by weight of magnesium stearate were added and mixed for another 5 minutes.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 7. The sticking rate was 28.6%, and tableting trouble was observed.
［比較例１７］
吸水性添加剤Ａとして、軽質無水ケイ酸を「ノイシリン」ＵＦＬ−２に変更した以外は、比較例１５と同様に混合を行った。
混合後の粉体を、回転式打錠機により打錠し、打錠障害評価法により評価した。
結果を表７に示す。スティッキング率が２１．８％であり、打錠障害が認められた。
[Comparative Example 17]
As water-absorbing additive A, mixing was performed in the same manner as in Comparative Example 15 except that light anhydrous silicic acid was changed to “Neusilin” UFL-2.
The mixed powder was tableted by a rotary tableting machine and evaluated by a tableting failure evaluation method.
The results are shown in Table 7. The sticking rate was 21.8%, and a tableting failure was observed.
［比較例１８］
薬物としてロキソプロフェン・ナトリウム１００重量部、吸水性添加剤Ａとして「ノイシリン」ＵＦＬ２ １重量部、部分アルファー化デンプンとして「ＰＣＳ」１１９．６重量部、結晶セルロースとして「セオラス」ＫＧ−８０２ ４７．６重量部、酸化チタン３重量部、クエン酸１７．１重量部をＶ型混合機に投入して１５分間混合後、タルク６重量部、ステアリン酸マグネシウム６重量部を投入してさらに５分間混合した。
混合後の粉体を、上記の条件で、回転式打錠機により打錠した。
結果を表７に示す。スティッキング率が４１．２％であり、打錠障害が認められた。
[Comparative Example 18]
100 parts by weight of loxoprofen sodium as a drug, 1 part by weight of “Neucillin” UFL2 as a water-absorbing additive A, 119.6 parts by weight of “PCS” as partially pregelatinized starch, and 47.6 parts by weight of “Seolus” KG-802 as crystalline cellulose Parts, 3 parts by weight of titanium oxide and 17.1 parts by weight of citric acid were added to a V-type mixer and mixed for 15 minutes, and then 6 parts by weight of talc and 6 parts by weight of magnesium stearate were added and further mixed for 5 minutes.
The mixed powder was tableted with a rotary tableting machine under the above conditions.
The results are shown in Table 7. The sticking rate was 41.2%, and a tableting failure was observed.
本発明は、付着性の高い薬物を含む錠剤を、工程が簡略化された方法で、打錠障害を起こすことなく、製造することができる。 INDUSTRIAL APPLICABILITY The present invention can produce a tablet containing a highly adhesive drug by a method with a simplified process without causing any tableting trouble.
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| JP2016508124A (en) * | 2012-12-14 | 2016-03-17 | エスアイ・グループ・インコーポレイテッドSi Group, Inc. | High content of ibuprofen sodium granules, their preparation, and their use in the preparation of non-foaming solid dosage forms |
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| JP2016222648A (en) * | 2015-05-26 | 2016-12-28 | 大正製薬株式会社 | Solid preparation |
| JP2017019688A (en) * | 2015-07-10 | 2017-01-26 | 株式会社合同資源 | Manufacturing method of metal iodide tablet |
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