JP6112765B2 - Solid preparation containing loxoprofen sodium and dl-methylephedrine hydrochloride - Google Patents
Solid preparation containing loxoprofen sodium and dl-methylephedrine hydrochloride Download PDFInfo
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- JP6112765B2 JP6112765B2 JP2011271599A JP2011271599A JP6112765B2 JP 6112765 B2 JP6112765 B2 JP 6112765B2 JP 2011271599 A JP2011271599 A JP 2011271599A JP 2011271599 A JP2011271599 A JP 2011271599A JP 6112765 B2 JP6112765 B2 JP 6112765B2
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- Prior art keywords
- loxoprofen sodium
- solid preparation
- hydrate
- methylephedrine hydrochloride
- granule
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- 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.)
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- 238000002360 preparation method Methods 0.000 title claims description 60
- NTCYWJCEOILKNG-ROLPUNSJSA-N [(1r,2s)-1-hydroxy-1-phenylpropan-2-yl]-dimethylazanium;chloride Chemical compound Cl.CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 NTCYWJCEOILKNG-ROLPUNSJSA-N 0.000 title claims description 45
- 229940073563 dl- methylephedrine hydrochloride Drugs 0.000 title claims description 44
- 239000007787 solid Substances 0.000 title claims description 43
- 229960002373 loxoprofen Drugs 0.000 title claims description 42
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 title description 35
- 239000008187 granular material Substances 0.000 claims description 43
- 239000001913 cellulose Substances 0.000 claims description 19
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 claims description 19
- 229920002678 cellulose Polymers 0.000 claims description 18
- 229960004211 loxoprofen sodium dihydrate Drugs 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 description 28
- 239000000203 mixture Substances 0.000 description 21
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- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 16
- 238000009472 formulation Methods 0.000 description 16
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- 239000003814 drug Substances 0.000 description 13
- 239000000654 additive Substances 0.000 description 12
- 230000000996 additive effect Effects 0.000 description 10
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 10
- 229960000920 dihydrocodeine Drugs 0.000 description 10
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 description 10
- 238000002845 discoloration Methods 0.000 description 10
- 229960001948 caffeine Drugs 0.000 description 9
- PMGQWSIVQFOFOQ-BDUVBVHRSA-N (e)-but-2-enedioic acid;(2r)-2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound OC(=O)\C=C\C(O)=O.CN1CCC[C@@H]1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PMGQWSIVQFOFOQ-BDUVBVHRSA-N 0.000 description 8
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 229960002689 clemastine fumarate Drugs 0.000 description 8
- 235000019192 riboflavin Nutrition 0.000 description 8
- 239000002151 riboflavin Substances 0.000 description 8
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- 238000003860 storage Methods 0.000 description 7
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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 5
- 229960002873 benfotiamine Drugs 0.000 description 5
- BTNNPSLJPBRMLZ-LGMDPLHJSA-N benfotiamine Chemical compound C=1C=CC=CC=1C(=O)SC(/CCOP(O)(O)=O)=C(/C)N(C=O)CC1=CN=C(C)N=C1N BTNNPSLJPBRMLZ-LGMDPLHJSA-N 0.000 description 5
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- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 4
- 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 4
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 description 4
- 239000003205 fragrance Substances 0.000 description 4
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 4
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- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 3
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- 229960001681 croscarmellose sodium Drugs 0.000 description 3
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- 239000004615 ingredient Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 3
- 229960000401 tranexamic acid Drugs 0.000 description 3
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-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
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229960000985 ambroxol hydrochloride Drugs 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 230000000954 anitussive effect Effects 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 239000003434 antitussive agent Substances 0.000 description 2
- 229940108858 belladonna total alkaloid Drugs 0.000 description 2
- 229960002335 bromhexine hydrochloride Drugs 0.000 description 2
- UCDKONUHZNTQPY-UHFFFAOYSA-N bromhexine hydrochloride Chemical compound Cl.C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N UCDKONUHZNTQPY-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
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- 239000007884 disintegrant Substances 0.000 description 2
- -1 disintegration aids Substances 0.000 description 2
- YRSGDLIATOURQO-UHFFFAOYSA-N ethyl 4-acetyl-5-oxohexanoate Chemical compound CCOC(=O)CCC(C(C)=O)C(C)=O YRSGDLIATOURQO-UHFFFAOYSA-N 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
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- 239000012530 fluid Substances 0.000 description 2
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- 235000003599 food sweetener Nutrition 0.000 description 2
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- 239000003112 inhibitor Substances 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
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- 239000003765 sweetening agent Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- UIERGBJEBXXIGO-UHFFFAOYSA-N thiamine mononitrate Chemical compound [O-][N+]([O-])=O.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UIERGBJEBXXIGO-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- YQSHYGCCYVPRDI-UHFFFAOYSA-N (4-propan-2-ylphenyl)methanamine Chemical compound CC(C)C1=CC=C(CN)C=C1 YQSHYGCCYVPRDI-UHFFFAOYSA-N 0.000 description 1
- CDQGZJGHIVUWQA-UHFFFAOYSA-N 4-[2-(4-hydroxy-3,5-dimethylphenyl)butan-2-yl]-2,6-dimethylphenol Chemical compound C=1C(C)=C(O)C(C)=CC=1C(C)(CC)C1=CC(C)=C(O)C(C)=C1 CDQGZJGHIVUWQA-UHFFFAOYSA-N 0.000 description 1
- 241001106067 Atropa Species 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 description 1
- YPZUZOLGGMJZJO-UHFFFAOYSA-N ambrofix Natural products C1CC2C(C)(C)CCCC2(C)C2C1(C)OCC2 YPZUZOLGGMJZJO-UHFFFAOYSA-N 0.000 description 1
- YPZUZOLGGMJZJO-LQKXBSAESA-N ambroxan Chemical compound CC([C@@H]1CC2)(C)CCC[C@]1(C)[C@@H]1[C@]2(C)OCC1 YPZUZOLGGMJZJO-LQKXBSAESA-N 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 235000010376 calcium ascorbate Nutrition 0.000 description 1
- 229940047036 calcium ascorbate Drugs 0.000 description 1
- 239000011692 calcium ascorbate Substances 0.000 description 1
- BLORRZQTHNGFTI-ZZMNMWMASA-L calcium-L-ascorbate Chemical compound [Ca+2].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] BLORRZQTHNGFTI-ZZMNMWMASA-L 0.000 description 1
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 1
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- 239000011248 coating agent Substances 0.000 description 1
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- 230000003247 decreasing effect Effects 0.000 description 1
- 229960003782 dextromethorphan hydrobromide Drugs 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
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- 235000013355 food flavoring agent Nutrition 0.000 description 1
- JTLXCMOFVBXEKD-FOWTUZBSSA-N fursultiamine Chemical compound C1CCOC1CSSC(\CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N JTLXCMOFVBXEKD-FOWTUZBSSA-N 0.000 description 1
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
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- 230000003993 interaction Effects 0.000 description 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229960005042 mequitazine Drugs 0.000 description 1
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- 229940051020 methylephedrine hydrochloride Drugs 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
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- 206010039083 rhinitis Diseases 0.000 description 1
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- WTGQALLALWYDJH-MOUKNHLCSA-N scopolamine hydrobromide (anhydrous) Chemical compound Br.C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 WTGQALLALWYDJH-MOUKNHLCSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、安定性に優れたロキソプロフェンナトリウムを含有する固形製剤に関する。 The present invention relates to a solid preparation containing loxoprofen sodium having excellent stability.
現在、総合感冒薬や解熱鎮痛剤等については、複数の薬効成分を配合した製剤が広く使用されている。例えば、総合感冒薬においては、解熱鎮痛薬、鎮咳去痰薬、鼻炎薬など多くの成分が配合されていることが知られている。これらの薬剤は、一般用医薬品として広く販売されており、有効性及び安全性の観点から、製剤としての安定性に優れている必要がある。 Currently, for general cold medicines and antipyretic analgesics, preparations containing a plurality of medicinal ingredients are widely used. For example, it is known that many components such as antipyretic analgesics, antitussive expectorants, rhinitis drugs are blended in the common cold medicine. These drugs are widely sold as over-the-counter drugs, and are required to have excellent stability as a preparation from the viewpoint of efficacy and safety.
ロキソプロフェンナトリウム又はその水和物は、非ステロイド系解熱鎮痛薬として臨床で広く使用されている。また、dl−メチルエフェドリン塩酸塩は、咳を鎮める鎮咳薬として知られており、総合感冒薬の有効成分として配合されている。 Loxoprofen sodium or its hydrate is widely used clinically as a non-steroidal antipyretic analgesic. In addition, dl-methylephedrine hydrochloride is known as an antitussive agent that suppresses cough, and is blended as an active ingredient of a general cold medicine.
ロキソプロフェンナトリウム又はその水和物と、dl−メチルエフェドリン塩酸塩との併用や、それらを組み合わせた医薬組成物については、すでに報告があるが(特許文献1参照)、この文献には、ロキソプロフェンナトリウム又はその水和物とdl−メチルエフェドリン塩酸塩の配合変化等に関する記載がないことから、ロキソプロフェンナトリウム又はその水和物と、dl−メチルエフェドリン塩酸塩とを配合した製剤の安定性については知られていない。 There has already been reported a combination of loxoprofen sodium or a hydrate thereof with dl-methylephedrine hydrochloride and a pharmaceutical composition in which they are combined (see Patent Document 1). In this document, loxoprofen sodium or Since there is no description about the mixing change of the hydrate and dl-methylephedrine hydrochloride, it is known about the stability of the formulation containing loxoprofen sodium or its hydrate and dl-methylephedrine hydrochloride. Absent.
本発明者らは、ロキソプロフェンナトリウム又はその水和物とdl−メチルエフェドリン塩酸塩を含む物理混合物を調製後、これを保存した際、経時的に色調の変化及び性状の変化が発生する問題があることを見出した。したがって、本発明の課題は、ロキソプロフェンナトリウム又はその水和物とdl−メチルエフェドリン塩酸塩を含有する固形製剤において、変色や含量低下等がなく安定性に優れた固形製剤を提供することである。 The present inventors have a problem that when a physical mixture containing loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride is prepared and then stored, changes in color and properties occur over time. I found out. Accordingly, an object of the present invention is to provide a solid preparation excellent in stability without discoloration or content reduction in a solid preparation containing loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride.
本発明者らは、上記課題を解決すべく製剤の試行錯誤を重ねた結果、ロキソプロフェンナトリウム又はその水和物とdl−メチルエフェドリン塩酸塩を、製剤中で実質的に接触することなく存在するように配合することによって、安定した製剤が得られることを見出し、本発明を完成させた。 As a result of repeated trial and error of the preparation to solve the above-mentioned problems, the present inventors have found that loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride are present in the preparation without substantial contact. It was found that a stable preparation could be obtained by blending into the above, and the present invention was completed.
すなわち、本発明は以下の(1)〜(8)を提供する。
(1):ロキソプロフェンナトリウム又はその水和物、及びdl−メチルエフェドリン塩酸塩を含有する固形製剤において、
ロキソプロフェンナトリウム又はその水和物、及びdl−メチルエフェドリン塩酸塩が、製剤中で実質的に接触することなく存在することを特徴とする固形製剤。
(2):ロキソプロフェンナトリウム又はその水和物を含む顆粒a、及びdl−メチルエフェドリン塩酸塩を含む顆粒bを含有することにより、ロキソプロフェンナトリウム又はその水和物、及びdl−メチルエフェドリン塩酸塩が、製剤中で実質的に接触することなく存在する(1)に記載の固形製剤。
(3):顆粒a及び顆粒bが、セルロース誘導体を含むものである(2)に記載の固形製剤
(4):ロキソプロフェンナトリウム又はその水和物が、ロキソプロフェンナトリウム2水和物である(1)〜(3)のいずれか1に記載の固形製剤。
(5):固形製剤が、顆粒剤、散剤、カプセル剤、丸剤又は錠剤である(1)〜(4)のいずれか1に記載の固形製剤。
(6):固形製剤が錠剤である(1)〜(4)のいずれか1に記載の固形製剤。
(7):少なくとも、ロキソプロフェンナトリウム又はその水和物を含む層aと、dl−メチルエフェドリン塩酸塩を含む層bの2層以上からなる多層錠であり、ロキソプロフェンナトリウム又はその水和物、及びdl−メチルエフェドリン塩酸塩が、製剤中で実質的に接触することなく存在する(6)に記載の固形製剤。
(8):ロキソプロフェンナトリウム又はその水和物、及びdl−メチルエフェドリン塩酸塩を含有する固形製剤の製造方法において、
ロキソプロフェンナトリウム又はその水和物、及びdl−メチルエフェドリン塩酸塩が、製剤中で実質的に接触することなく存在することを特徴とするとする固形製剤の製造方法。
That is, the present invention provides the following (1) to (8).
(1): In a solid preparation containing loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride,
A solid preparation, characterized in that loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride are present in the preparation without substantial contact.
(2): By containing granule a containing loxoprofen sodium or hydrate thereof and granule b containing dl-methylephedrine hydrochloride, loxoprofen sodium or hydrate thereof and dl-methylephedrine hydrochloride are The solid preparation according to (1), which exists in the preparation without substantial contact.
(3): The solid preparation (4) according to (2), wherein the granule a and the granule b contain a cellulose derivative: (1) to (1), wherein loxoprofen sodium or a hydrate thereof is loxoprofen sodium dihydrate. The solid preparation according to any one of 3).
(5): The solid preparation according to any one of (1) to (4), wherein the solid preparation is a granule, powder, capsule, pill, or tablet.
(6): The solid preparation according to any one of (1) to (4), wherein the solid preparation is a tablet.
(7): a multi-layered tablet comprising at least two layers of a layer a containing loxoprofen sodium or a hydrate thereof and a layer b containing dl-methylephedrine hydrochloride, loxoprofen sodium or a hydrate thereof, and dl -The solid formulation according to (6), wherein the methylephedrine hydrochloride is present in the formulation without substantial contact.
(8): In a method for producing a solid preparation containing loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride,
A method for producing a solid preparation, characterized in that loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride are present in the preparation without substantial contact.
本発明により、ロキソプロフェンナトリウム又はその水和物と、dl−メチルエフェドリン塩酸塩を含有し、保存安定性に優れた固形製剤を提供することができる。 According to the present invention, a solid preparation containing loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride and excellent in storage stability can be provided.
本発明における「ロキソプロフェンナトリウム又はその水和物」は、ロキソプロフェンナトリウム、ロキソプロフェンナトリウム1水和物、ロキソプロフェンナトリウム2水和物を含む。ロキソプロフェンナトリウム2水和物は、ロキソプロフェンナトリウム水和物として、第15改正日本薬局方に収載されており、容易に入手可能である。 “Loxoprofen sodium or a hydrate thereof” in the present invention includes loxoprofen sodium, loxoprofen sodium monohydrate, and loxoprofen sodium dihydrate. Loxoprofen sodium dihydrate is listed in the 15th revision Japanese Pharmacopoeia as loxoprofen sodium hydrate and is readily available.
本発明における「dl−メチルエフェドリン塩酸塩」は、第15改正日本薬局方に収載されており、容易に入手可能である。 “Dl-Methylephedrine hydrochloride” in the present invention is listed in the 15th revised Japanese Pharmacopoeia and is easily available.
本発明において、ロキソプロフェンナトリウム又はその水和物、及びdl−メチルエフェドリン塩酸塩の含有比は、本発明の効果に影響がない限り特に限定されないが、ロキソプロフェンナトリウム2水和物1重量部に対し、dl−メチルエフェドリン塩酸塩の含有比率は、0.01〜1重量部が好ましく、0.05〜0.5重量部がより好ましい。 In the present invention, the content ratio of loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride is not particularly limited as long as the effect of the present invention is not affected, but with respect to 1 part by weight of loxoprofen sodium dihydrate, The content ratio of dl-methylephedrine hydrochloride is preferably 0.01 to 1 part by weight, and more preferably 0.05 to 0.5 part by weight.
本発明の「固形製剤」としては、具体的には、第15改正日本薬局方に記載されている顆粒剤、散剤、カプセル剤、錠剤、又は丸剤等を挙げることができる。本発明の「固形製剤」は、好適には、顆粒剤、散剤、カプセル剤又は錠剤であり、より好適には、錠剤を挙げることができる。 Specific examples of the “solid preparation” of the present invention include granules, powders, capsules, tablets, or pills described in the 15th revised Japanese Pharmacopoeia. The “solid preparation” of the present invention is preferably a granule, powder, capsule or tablet, and more preferably a tablet.
また、本発明の顆粒剤又は錠剤の態様として、水溶性の高分子などで製剤をコーティングしたものや、糖で錠剤をコーティングしたものも好適である。すなわち、フィルムコーティング顆粒、フィルムコーティング錠、糖衣錠等が好ましい顆粒剤及び錠剤の態様として挙げることができる。 Further, as the granule or tablet of the present invention, those in which the preparation is coated with a water-soluble polymer and those in which the tablet is coated with sugar are also suitable. That is, film-coated granules, film-coated tablets, sugar-coated tablets and the like can be mentioned as preferred granule and tablet embodiments.
本発明の固形製剤が錠剤の場合、組成の異なる粉末又は顆粒を2層又は3層以上に積み重ねて圧縮成型した多層錠も好ましい態様として挙げることができる。 When the solid preparation of the present invention is a tablet, a multilayer tablet obtained by compressing and molding powders or granules having different compositions in two layers or three or more layers can also be mentioned as a preferred embodiment.
本発明の「製剤中で実質的に接触することなく存在する」とは、固形製剤中に複数の薬剤等が存在する場合に、共存が好ましくない薬剤が均一に混合して存在することがなく、すなわち当該薬剤同士が直接接触して相互作用をすることなく、同一の固形製剤中に存在する状態をいう。例えば、当該薬剤の間に結合剤や賦形剤等の薬剤と反応しない不活性添加物質が存在したり、当該薬剤が異なる顆粒中に存在する複数の顆粒として存在したり、或いは当該薬剤が異なる層に存在する多層錠の形態を有する固形製剤が挙げられる。具体的な態様としては、ロキソプロフェンナトリウム又はその水和物とdl−メチルエフェドリン塩酸塩を、各々別の顆粒に配合し混合した顆粒剤や、当該顆粒を圧縮成型した錠剤でもよく、また、本発明の固形製剤が錠剤であって多層錠や有核錠の場合、ロキソプロフェンナトリウム又はその水和物を含む層aとdl−メチルエフェドリン塩酸塩を含む層bとに、分けて配合した錠剤であってもよい。 In the present invention, “exist substantially without contact in the preparation” means that when a plurality of drugs are present in the solid preparation, there is no presence of uniformly mixed drugs that are not preferred to coexist. That is, it refers to a state where the drugs are present in the same solid preparation without direct contact and interaction. For example, an inert additive substance that does not react with a drug such as a binder or excipient exists between the drugs, the drug exists as a plurality of granules existing in different granules, or the drugs are different. A solid preparation having the form of a multilayer tablet existing in the layer can be mentioned. As specific embodiments, a granule in which loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride are mixed and mixed in separate granules, or a tablet in which the granules are compression-molded may be used. In the case where the solid preparation is a multi-layer tablet or a dry-coated tablet, it is a tablet that is divided into a layer a containing loxoprofen sodium or a hydrate thereof and a layer b containing dl-methylephedrine hydrochloride, Also good.
このように薬剤が「製剤中で実質的に接触することなく存在する」ことにより、複数の薬剤が同一の固形製剤中に存在しても、当該薬剤同士の相互作用によって、固形製剤の変色や有効成分の含量低下を抑制することができる。 As described above, since the drug “exists substantially without contact in the preparation”, even if a plurality of drugs exist in the same solid preparation, discoloration of the solid preparation or A decrease in the content of the active ingredient can be suppressed.
本発明の固形製剤の調製方法としては特に限定されず、ロキソプロフェンナトリウム又はその水和物を含む顆粒と、dl−メチルエフェドリン塩酸塩を含む顆粒を個別に調製する際には、必要により、各々の顆粒に他の薬効成分を配合し、さらに必要に応じて製剤添加剤を添加して、常法に従って調製すればよい。 The method for preparing the solid preparation of the present invention is not particularly limited, and when separately preparing a granule containing sodium loxoprofen or a hydrate thereof and a granule containing dl-methylephedrine hydrochloride, if necessary, What is necessary is just to mix | blend another medicinal ingredient with a granule, and also add a formulation additive as needed, and to prepare according to a conventional method.
例えば、ロキソプロフェンナトリウム又はその水和物含む顆粒と、dl−メチルエフェドリン塩酸塩を含む顆粒を分離して配合されたフィルムコーティング錠を調製する方法としては、ロキソプロフェンナトリウム又はその水和物及び製剤添加剤を含む顆粒と、トラネキサム酸及び製剤添加剤を含む顆粒を調製し、各々の顆粒と滑沢剤を混合後に打錠し錠剤を調製する。錠剤の調製後にフィルムコーティング機に投入、フィルムコーティング液を噴霧しフィルムコーティング錠を調製すればよい。 For example, as a method of preparing a film-coated tablet in which a granule containing sodium loxoprofen or a hydrate thereof and a granule containing dl-methylephedrine hydrochloride are blended separately, loxoprofen sodium or a hydrate thereof and a preparation additive are used. And a granule containing tranexamic acid and a formulation additive are prepared, and each granule and lubricant are mixed and then tableted to prepare a tablet. After preparation of the tablet, it may be put into a film coating machine and sprayed with a film coating solution to prepare a film coated tablet.
ここで、固形製剤の製剤化に使用される製剤添加剤としては、薬学的に許容される担体、例えば賦形剤、結合剤、崩壊剤、崩壊補助剤、滑沢剤、流動化剤、光沢化剤、発泡剤、防湿剤、界面活性剤、安定化剤、乳化剤、抗酸化剤、充填剤、防腐剤、保存剤、甘味剤、矯味剤、清涼化剤、香料、芳香剤、着色剤、コーティング剤、分散剤、消泡剤等が挙げられ、従来公知の固形製剤に使用しうる製剤添加剤を上記の目的で使用しうる。 Here, preparation additives used for the preparation of solid preparations include pharmaceutically acceptable carriers such as excipients, binders, disintegrants, disintegration aids, lubricants, fluidizing agents, glossy agents. Agent, foaming agent, moisture-proofing agent, surfactant, stabilizer, emulsifier, antioxidant, filler, preservative, preservative, sweetener, flavoring agent, refreshing agent, fragrance, fragrance, colorant, A coating agent, a dispersing agent, an antifoaming agent, etc. are mentioned, The formulation additive which can be used for a conventionally well-known solid formulation can be used for said objective.
本発明において、ロキソプロフェンナトリウム又はその水和物を含む顆粒と、dl−メチルエフェドリン塩酸塩を含む顆粒bに使用される製剤添加剤としては、賦形剤、結合剤、崩壊剤、崩壊補助剤、流動化剤、発泡剤、防湿剤、界面活性剤、安定化剤、抗酸化剤、甘味剤、矯味剤、清涼化剤、香料、芳香剤、着色剤、等が挙げられる。 In the present invention, as a formulation additive used for granules containing loxoprofen sodium or a hydrate thereof and granules b containing dl-methylephedrine hydrochloride, excipients, binders, disintegrants, disintegration aids, Examples thereof include a fluidizing agent, a foaming agent, a moisture-proofing agent, a surfactant, a stabilizer, an antioxidant, a sweetener, a corrigent, a refreshing agent, a fragrance, a fragrance, and a coloring agent.
特に本発明において、ロキソプロフェンナトリウム又はその水和物を含む顆粒aと、dl−メチルエフェドリン塩酸塩を含む顆粒bに使用される製剤添加剤としては賦形剤を含有することが好ましく、賦形剤としては、好ましくはセルロース誘導体から選ばれる1種又は2種以上が好ましい。ここで、セルロース誘導体としては、例えば、カルボキシメチルエチルセルロース、カルメロース、カルメロースカルシウム、カルメロースナトリウム、クロスカルメロースナトリウム、結晶セルロース、微結晶セルロース、結晶セルロース(微粒子)、結晶セルロース(粒)、粉末セルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシエチルメチルセルロース、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2208、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、メチルセルロース、及びエチルセルロース等から選ばれる1種又は2種以上を挙げることができ;カルメロースカルシウム、カルメロースナトリウム、クロスカルメロースナトリウム、結晶セルロース、微結晶セルロース、結晶セルロース(微粒子)、結晶セルロース(粒)、低置換度ヒドロキシプロピルセルロース、及びヒドロキシプロピルセルロースから選ばれる1種又は2種以上が好ましい。 In particular, in the present invention, it is preferable that the formulation additive used for the granule a containing loxoprofen sodium or a hydrate thereof and the granule b containing dl-methylephedrine hydrochloride contains an excipient, Is preferably one or more selected from cellulose derivatives. Here, as the cellulose derivative, for example, carboxymethyl ethyl cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, crystalline cellulose, microcrystalline cellulose, crystalline cellulose (fine particles), crystalline cellulose (particles), powdered cellulose , Low substituted hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methylcellulose, ethylcellulose, etc. 1 or 2 Carmellose calcium, carmellose sodium, croscarmellose sodium, crystalline cellulose, microcrystalline cellulose, crystalline cellulose (fine particles), crystalline cellulose (grains), low-substituted hydroxypropyl cellulose, and hydroxypropyl cellulose 1 type or 2 types or more chosen from are preferable.
本発明においては、ロキソプロフェンナトリウム又はその水和物及びセルロース誘導体を含む顆粒a、ならびにdl−メチルエフェドリン塩酸塩及びセルロース誘導体を含む顆粒bを含有する固形製剤を調製することが好ましく、ロキソプロフェンナトリウム又はその水和物及び結晶セルロースを含む顆粒、ならびにdl−メチルエフェドリン塩酸塩及び結晶セルロースを含む顆粒を含有する固形製剤を調製することがより好ましい。 In the present invention, it is preferable to prepare a solid preparation containing granule a containing loxoprofen sodium or a hydrate thereof and a cellulose derivative, and granule b containing dl-methylephedrine hydrochloride and a cellulose derivative. It is more preferred to prepare a solid formulation containing granules containing hydrate and crystalline cellulose, and granules containing dl-methylephedrine hydrochloride and crystalline cellulose.
本発明に配合される製剤添加物の配合量については、ロキソプロフェンナトリウム又はその水和物と、dl−メチルエフェドリン塩酸塩が、製剤中において互いに境界を介して存在すれば、特に限定されないが、製剤添加物がセルロース誘導体の場合、ロキソプロフェンナトリウム又はその水和物1重量部に対して、セルロース誘導体を0.05〜100重量部を配合するのが好ましく、0.1〜50重量部配合するのがより好ましく、0.1〜10重量部配合するのがさらに好ましい。 The blending amount of the formulation additive blended in the present invention is not particularly limited as long as loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride are present through a boundary in the formulation. When an additive is a cellulose derivative, it is preferable to mix | blend 0.05-100 weight part of cellulose derivatives with respect to 1 weight part of loxoprofen sodium or its hydrate, and it mix | blends 0.1-50 weight part. More preferably, 0.1 to 10 parts by weight is further blended.
本発明の固形製剤に配合できる、ロキソプロフェンナトリウム又はその水和物、及びdl−メチルエフェドリン塩酸塩以外の薬効成分としては、クロルフェニラミンマイレン酸塩、クレマスチンフマル酸塩、メキタジン等の抗ヒスタミン剤、アンブロキソール塩酸塩、ブロムヘキシン塩酸塩等の去痰剤、ベラドンナ総アルカロイド、ベラドンナエキス、スコポラミン臭化水素酸塩等の副交感神経抑制剤、ジヒドロコデインリン酸塩、デキストロメトルファン臭化水素酸塩、ノスカピン等の鎮咳薬、トラネキサム酸等の抗炎症薬、無水カフェイン、カフェイン等の中枢神経抑制剤、チアミン硝化物、ベンフォチアミン、フルスルチアミン、リボフラビン、アスコルビン酸、アスコルビン酸カルシウム等のビタミン剤等を挙げることができる。 Examples of medicinal ingredients other than loxoprofen sodium or hydrate and dl-methylephedrine hydrochloride that can be blended in the solid preparation of the present invention include antihistamines such as chlorpheniramine maleate, clemastine fumarate and mequitazine, ambrox Molecules such as sole hydrochloride, bromhexine hydrochloride, parasympathetic nerve inhibitors such as belladonna total alkaloids, belladonna extract, scopolamine hydrobromide, antitussives such as dihydrocodeine phosphate, dextromethorphan hydrobromide, noscapine, etc. Drugs, anti-inflammatory drugs such as tranexamic acid, central nervous inhibitors such as anhydrous caffeine and caffeine, thiamine nitrate, benfotiamine, fursultiamine, vitamins such as riboflavin, ascorbic acid, calcium ascorbate, etc. be able to.
本発明をより詳細に説明するため、以下に実施例及び比較例を記載するが、本発明はこれになんら限定されるものではない。 In order to describe the present invention in more detail, examples and comparative examples are described below, but the present invention is not limited thereto.
試験例1:配合成分の物理混合物での配合変化試験
1.比較サンプルの調製
(比較例1)
ロキソプロフェンナトリウム2水和物(第一三共プロファーマ株式会社製)2.0gとdl−メチルエフェドリン塩酸塩(アルプル薬品工業株式会社製)3.0gをポリ袋にて混合した後に、混合末を篩(20号)にて篩過し、物理混合物としてサンプルを調製した。
Test Example 1: Blending change test with physical mixture of blending components Preparation of comparative sample (Comparative Example 1)
After mixing 2.0 g of loxoprofen sodium dihydrate (Daiichi Sankyo Propharma Co., Ltd.) and 3.0 g of dl-methylephedrine hydrochloride (Alpur Yakuhin Kogyo Co., Ltd.) in a plastic bag, The sample was prepared as a physical mixture by sieving with a sieve (No. 20).
2.試験方法
比較例1の物理混合物をガラス瓶(1k規格瓶)に充填し50℃開放で2ヶ月間保存した。保管後に冷蔵庫保存品を対照として色調変化、性状変化を確認した。
2. Test Method The physical mixture of Comparative Example 1 was filled in a glass bottle (1k standard bottle) and stored at 50 ° C. for 2 months. After storage, the color change and property change were confirmed using the refrigerator stored product as a control.
色調変化は;A:変色なし、B:わずかな変色、C:変色あり、D:著しい変色、の4段階で評価した。 The change in color tone was evaluated in four stages: A: no discoloration, B: slight discoloration, C: discoloration, D: significant discoloration
性状変化は;A:変化なし、B:わずかな変化、C:変化あり、D:著しい変化、の4段階で評価した。 The change in properties was evaluated in four stages: A: no change, B: slight change, C: change, D: significant change.
また、保存後のdl−メチルエフェドリン塩酸塩の含量を測定した。 Further, the content of dl-methylephedrine hydrochloride after storage was measured.
3.試験結果
ロキソプロフェンナトリウム2水和物とdl−メチルエフェドリン塩酸塩を含む物理混合物は色調変化「D」及び性状変化「D」が発生した。また、保存後のdl−メチルエフェドリン塩酸塩の残存率を測定したところ、83.3%であった。
3. Test Results A physical mixture containing loxoprofen sodium dihydrate and dl-methylephedrine hydrochloride produced a color change “D” and a property change “D”. Further, the residual ratio of dl-methylephedrine hydrochloride after storage was measured and found to be 83.3%.
試験例2:錠剤での比較試験
1.錠剤の調製方法
下記の(A)〜(C)の工程により、錠剤を製造した。
(A)顆粒aの製造:流動層造粒機にロキソプロフェンナトリウム2水和物(第一三共プロファーマ株式会社製)102.9g、下記の実施例に記載された(薬効成分A)、製剤添加剤としての結晶セルロース(旭化成ケミカルズ株式会社製)適量、及びD−マンニトール(三菱商事フードテック株式会社製)適量を投入・混合し、ヒドロキシプロピルセルロース(日本曹達株式会社製)の水溶液を噴霧し顆粒aを得た。
(B)顆粒bの製造:流動層造粒機にdl−メチルエフェドリン塩酸塩(アルプル薬品工業株式会社製)30.0g、下記の製剤例に記載された(薬効成分B)、及び製剤添加剤としての結晶セルロース適量を投入・混合し、ヒドロキシプロピルセルロース水溶液を噴霧し顆粒bを得た。
(C)錠剤の製造:該顆粒a、bとクロスカルメロースナトリウム(旭化成ケミカルズ株式会社製)、及びステアリン酸マグネシウム(メルクジャパン株式会社製)を混合後、打錠して錠剤を得た。
Test Example 2: Comparative test with tablets Tablet Preparation Method Tablets were produced by the following steps (A) to (C).
(A) Manufacture of granules a: Loxoprofen sodium dihydrate (Daiichi Sankyo Propharma Co., Ltd.) 102.9 g in a fluid bed granulator, described in the following examples (medicinal component A), formulation An appropriate amount of crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd.) and an appropriate amount of D-mannitol (manufactured by Mitsubishi Corporation Foodtech Co., Ltd.) are added and mixed as an additive, and an aqueous solution of hydroxypropylcellulose (manufactured by Nippon Soda Co., Ltd.) is sprayed Granule a was obtained.
(B) Manufacture of granule b: 30.0 g of dl-methylephedrine hydrochloride (manufactured by Alpur Yakuhin Kogyo Co., Ltd.) in a fluid bed granulator, described in the following formulation examples (medicinal component B), and formulation additives An appropriate amount of crystalline cellulose was added and mixed, and an aqueous hydroxypropylcellulose solution was sprayed to obtain granules b.
(C) Manufacture of tablets: The granules a and b, croscarmellose sodium (manufactured by Asahi Kasei Chemicals Corporation), and magnesium stearate (manufactured by Merck Japan Co., Ltd.) were mixed and then tableted to obtain tablets.
上述の錠剤の調整方法にて、下記の実施例1〜7の錠剤を製造した。 The tablets of Examples 1 to 7 below were produced by the above-described tablet adjustment method.
(実施例1)
(薬効成分A):ノスカピン24.0g、結晶セルロース120.0g。
(薬効成分B):ブロムヘキシン塩酸塩6.0g、クレマスチンフマル酸塩0.67g、無水カフェイン37.5g。
Example 1
(Medicinal component A): 24.0 g of noscapine, 120.0 g of crystalline cellulose.
(Medicinal component B): Bromohexine hydrochloride 6.0 g, clemastine fumarate 0.67 g, anhydrous caffeine 37.5 g.
(実施例2)
(A):ジヒドロコデインリン酸塩6.0g。
(薬効成分B):クレマスチンフマル酸塩0.67g、ジヒドロコデインリン酸塩6.0g、無水カフェイン37.5g。
(Example 2)
(A): 6.0 g of dihydrocodeine phosphate.
(Medicinal component B): Clemastine fumarate 0.67 g, dihydrocodeine phosphate 6.0 g, anhydrous caffeine 37.5 g.
(実施例3)
(薬効成分A):ジヒドロコデインリン酸塩6.0g、ベラドンナ総アルカロイド0.15g、リボフラビン3.0g。
(薬効成分B):アンブロキソール塩酸塩10.0g、クレマスチンフマル酸塩0.67g、ジヒドロコデインリン酸塩6.0g、ノスカピン24.0g、無水カフェイン37.5g、ベンフォチアミン12.5g、リボフラビン3.0g。
(Example 3)
(Medical component A): Dihydrocodeine phosphate 6.0 g, Belladonna total alkaloid 0.15 g, Riboflavin 3.0 g.
(Medicine component B): Ambroxol hydrochloride 10.0 g, clemastine fumarate 0.67 g, dihydrocodeine phosphate 6.0 g, noscapine 24.0 g, anhydrous caffeine 37.5 g, benfotiamine 12.5 g, Riboflavin 3.0 g.
(実施例4)
(薬効成分A):無水カフェイン37.5g。
(薬効成分B):トラネキサム酸375.0g、ブロムヘキシン塩酸塩6.0g、クレマスチンフマル酸塩0.67g、ジヒドロコデインリン酸塩12.0g、ベンフォチアミン12.5g、リボフラビン6.0g。
Example 4
(Medicinal component A): 37.5 g of anhydrous caffeine.
(Medicinal component B): tranexamic acid 375.0 g, bromhexine hydrochloride 6.0 g, clemastine fumarate 0.67 g, dihydrocodeine phosphate 12.0 g, benfotiamine 12.5 g, riboflavin 6.0 g.
(実施例5)
(薬効成分A):ジヒドロコデインリン酸塩6.0g、リボフラビン3.0g。
(薬効成分B):アンブロキソール塩酸塩10.0g、クレマスチンフマル酸塩0.67g、ジヒドロコデインリン酸塩6.0g、無水カフェイン37.5g、ベンフォチアミン12.5g、リボフラビン3.0g。
(Example 5)
(Medicinal component A): 6.0 g of dihydrocodeine phosphate, 3.0 g of riboflavin.
(Medicinal component B): 10.0 g of ambroxol hydrochloride, 0.67 g of clemastine fumarate, 6.0 g of dihydrocodeine phosphate, 37.5 g of anhydrous caffeine, 12.5 g of benfotiamine, and 3.0 g of riboflavin.
(実施例6)
(薬効成分A):ノスカピン24.0g、結晶セルロース120.0g、D−マンニトール適量、ヒドロキシプロピルセルロース水溶液。
(薬効成分B):ブロムヘキシン塩酸塩6.0g、クレマスチンフマル酸塩0.67g、無水カフェイン37.5g、チアミン硝化物12.5g。
(Example 6)
(Medicinal component A): 24.0 g of noscapine, 120.0 g of crystalline cellulose, an appropriate amount of D-mannitol, an aqueous hydroxypropylcellulose solution.
(Medicinal component B): Bromohexine hydrochloride 6.0 g, clemastine fumarate 0.67 g, anhydrous caffeine 37.5 g, thiamine nitrate 12.5 g.
(実施例7)
(薬効成分A):ジヒドロコデインリン酸塩6.0g、リボフラビン3.0g。
(薬効成分B):クレマスチンフマル酸塩0.67g、ジヒドロコデインリン酸塩6.0g、無水カフェイン37.5g、ベンフォチアミン12.5g、リボフラビン3.0g。
(Example 7)
(Medicinal component A): 6.0 g of dihydrocodeine phosphate, 3.0 g of riboflavin.
(Medicinal component B): Clemastine fumarate 0.67 g, dihydrocodeine phosphate 6.0 g, anhydrous caffeine 37.5 g, benfotiamine 12.5 g, riboflavin 3.0 g.
2.試験方法
実施例1の錠剤を各々ガラス瓶(6k規格瓶)に充填し60℃密栓、50℃密栓の条件で2週間放置した。保管後に冷蔵庫保存品を対照としてロキソプロフェンナトリウム2水和物及びdl−メチルエフェドリン塩酸塩の含量、錠剤外観の色調変化、及び性状変化を確認した。
2. Test Method Each tablet of Example 1 was filled in a glass bottle (6k standard bottle) and allowed to stand for 2 weeks under conditions of 60 ° C. sealed cap and 50 ° C. sealed cap. After storage, the contents of loxoprofen sodium dihydrate and dl-methylephedrine hydrochloride, the change in color of the tablet appearance, and the change in properties were confirmed using the refrigerator stored product as a control.
色調変化は;A:変色なし、B:わずかな変色、C:変色あり、D:著しい変色、の4段階で評価した。 The change in color tone was evaluated in four stages: A: no discoloration, B: slight discoloration, C: discoloration, D: significant discoloration
性状変化は;A:変化なし、B:わずかな変化、C:変化あり、D:著しい変化、の4段階で評価した。 The change in properties was evaluated in four stages: A: no change, B: slight change, C: change, D: significant change.
3.試験結果
実施例の製造方法で製造した製剤例処方の錠剤は、50℃密栓及び60℃密栓という苛酷条件下で2週間保存しても、色調や性状にほぼ変化は認められなかった(色調変化:A、性状変化:A)。また、ロキソプロフェンナトリウム2水和物及びdl−メチルエフェドリン塩酸塩の含量低下も認められなかった。この結果より、ロキソプロフェンナトリウム2水和物とdl−メチルエフェドリン塩酸塩を含有する、2種の顆粒を配合した錠剤は、保存安定性に優れていることがわかった。
3. Test results The tablets of the formulation of the preparations prepared by the production method of the Examples showed almost no change in color tone or properties even when stored for 2 weeks under severe conditions of 50 ° C. and 60 ° C. : A, property change: A). In addition, the contents of loxoprofen sodium dihydrate and dl-methylephedrine hydrochloride were not decreased. From this result, it was found that a tablet containing two types of granules containing loxoprofen sodium dihydrate and dl-methylephedrine hydrochloride was excellent in storage stability.
本発明により、保存安定性に優れたロキソプロフェンナトリウム2水和物及びdl−メチルエフェドリン塩酸塩を含有した固形製剤を提供することができ、総合感冒薬、又はかぜ薬として有用である。 According to the present invention, a solid preparation containing loxoprofen sodium dihydrate excellent in storage stability and dl-methylephedrine hydrochloride can be provided, and it is useful as a general cold medicine or a cold medicine.
Claims (6)
ロキソプロフェンナトリウム又はその水和物を含む顆粒a、及びdl−メチルエフェドリン塩酸塩を含む顆粒bを含有することにより、ロキソプロフェンナトリウム又はその水和物、及びdl−メチルエフェドリン塩酸塩が、製剤中で実質的に接触することなく存在することを特徴とする固形製剤。 In a solid preparation containing loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride,
By containing granule a containing loxoprofen sodium or a hydrate thereof and granule b containing dl-methylephedrine hydrochloride, loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride are substantially contained in the preparation. A solid preparation characterized by existing without contact.
ロキソプロフェンナトリウム又はその水和物を含む顆粒a、及びdl−メチルエフェドリン塩酸塩を含む顆粒bを含有することにより、ロキソプロフェンナトリウム又はその水和物、及びdl−メチルエフェドリン塩酸塩が、製剤中で実質的に接触することなく存在することを特徴とする固形製剤の製造方法。By containing granule a containing loxoprofen sodium or a hydrate thereof and granule b containing dl-methylephedrine hydrochloride, loxoprofen sodium or a hydrate thereof and dl-methylephedrine hydrochloride are substantially contained in the preparation. A method for producing a solid preparation, characterized by existing without contact.
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