TWI572360B - Tiny cellulose powder - Google Patents
Tiny cellulose powder Download PDFInfo
- Publication number
- TWI572360B TWI572360B TW104125454A TW104125454A TWI572360B TW I572360 B TWI572360 B TW I572360B TW 104125454 A TW104125454 A TW 104125454A TW 104125454 A TW104125454 A TW 104125454A TW I572360 B TWI572360 B TW I572360B
- Authority
- TW
- Taiwan
- Prior art keywords
- cellulose powder
- tablet
- cellulose
- powder
- active ingredient
- Prior art date
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 title claims description 147
- 239000002245 particle Substances 0.000 claims description 87
- 239000004480 active ingredient Substances 0.000 claims description 75
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 57
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- 238000006116 polymerization reaction Methods 0.000 claims description 21
- 229920001223 polyethylene glycol Polymers 0.000 claims description 19
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
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- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000010018 saw palmetto extract Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229940048730 senega Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 229940082787 spirulina Drugs 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- VACCAVUAMIDAGB-UHFFFAOYSA-N sulfamethizole Chemical compound S1C(C)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 VACCAVUAMIDAGB-UHFFFAOYSA-N 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960000658 sumatriptan succinate Drugs 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 229950006156 teprenone Drugs 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
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- 235000019364 tetracycline Nutrition 0.000 description 1
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- 238000009283 thermal hydrolysis Methods 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 229960000344 thiamine hydrochloride Drugs 0.000 description 1
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 1
- 239000011747 thiamine hydrochloride Substances 0.000 description 1
- 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 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 description 1
- ZCIHMQAPACOQHT-ZGMPDRQDSA-N trans-isorenieratene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/c1c(C)ccc(C)c1C)C=CC=C(/C)C=Cc2c(C)ccc(C)c2C ZCIHMQAPACOQHT-ZGMPDRQDSA-N 0.000 description 1
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 235000013976 turmeric Nutrition 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 208000022934 urinary frequency Diseases 0.000 description 1
- 230000036318 urination frequency Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- WCTNXGFHEZQHDR-UHFFFAOYSA-N valencene Natural products C1CC(C)(C)C2(C)CC(C(=C)C)CCC2=C1 WCTNXGFHEZQHDR-UHFFFAOYSA-N 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 229960000744 vinpocetine Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- 229960005111 zolpidem tartrate Drugs 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/12—Powdering or granulating
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- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
- C08J2301/02—Cellulose; Modified cellulose
Description
本發明係關於一種纖維素粉末及包含該纖維素粉末與一種以上之活性成分之組合物。該纖維素粉末係於醫藥、食品、其他化學工業領域中使用,尤其是作為醫藥品用錠劑之賦形劑有用。又,使用該組合物所製備之粉末、顆粒、及包含該粉末、顆粒之錠劑對於即便無水亦可服用之口腔內崩解錠亦有用。
先前,於醫藥品、健康食品、食品、其他化學工業領域,藉由使用纖維素粉末作為賦形劑,而製備為含有活性成分之成型體、例如錠劑等之情況已廣為人知。尤其關於最近之錠劑,無水便可服用之口腔內崩解錠成為主流,其係於醫藥製劑領域中大力發展之劑型。近年來,口腔內崩解錠亦利用並非特別製法之與普通錠同樣之製法而製造,但原本係基於為了獲得實用之錠劑硬度與作為口腔內崩解錠之令人滿意之崩解性或服用感,採用多種多樣之添加劑或賦形劑之調配比率而完成之技術者。基於此種技術之製劑作為高附加價值製劑,除了提高患者之QOL(Quality Of Life,生活質量)以外,於製品之PLCM(Product Life Cycle Management,產品生命週期管理)方面亦逐漸變得重要。進而,於迅速向老齡化社會發展之背景下,以唾液或少量之水而迅速崩解之口腔內崩解錠作為即便老年人或兒童等吞咽力較弱之患者亦容易服用之劑型,對於醫療現場之便利性或患者之服用性等依從性(adherence)或順從性(compliance)之提昇有較大助益。然
而,口腔內崩解錠之歷史較短,亦存在確保口腔內之崩解時間或服用感、製造或流通時不會破裂或磨損之錠劑之硬度的技術性問題。其中,關於服用感,患者僅用口腔內之唾液使錠劑崩解時所感受到之粉體之粗澀或乾澀作為不適感而殘留,而無法獲得令人滿意之服用感之實例較多。
因此,期望開發出具有適當之硬度、迅速之崩解性及不會感到粗澀或乾澀而令人滿意之服用感的口腔內速崩解錠之製造技術,且期待完成度更高之口腔內崩解錠技術。
專利文獻1中記載有藉由將纖維素粉末之粉體物性控制為特定範圍,而使壓縮成形性及液狀成分保持性提高之纖維素粉末。藉由使用該纖維素粉末,於進行錠劑化時,以較低之打錠壓力而製作較高硬度之錠劑,亦可抑制液狀成分自錠劑表面之滲出,亦有助於防止打錠損傷。尤其於平均聚合度為150~450、平均粒徑為30~250μm、及表觀比容超過7cm3/g、分子量400之聚乙二醇保持率為190%以上之特定範圍內進行控制,但完全未提及作為口腔內崩解錠之崩解性及服用感。
專利文獻2中記載有如下纖維素微晶凝聚物,該纖維素微晶凝聚物係平均穩定聚合度為15~375、表觀比容為1.84~8.92cm3/g(表觀密度為7~34lb/ft3)、粒度為300μm以下者。
專利文獻3中記載有如下醫藥品組合物,該醫藥品組合物包含平均聚合度為75~375、表觀比容為1.6~3.1cc/g、200目以上之成分為2~80重量%之纖維素粉與藥效成分及其他添加劑。
專利文獻4中記載有如下纖維素粉末,該纖維素粉末係平均聚合度為150~450、75μm以下之粒子之平均L/D(long diameter/short diameter,長徑/短徑)為2.0~4.5、平均粒徑為20~250μm、表觀比容為4.0~7.0cm3/g、輕敲表觀比容為2.4~4.5cm3/g、靜止角為55°以下者。
藉由該等專利文獻2~4所揭示之方法所獲得之纖維素粉末存在如下問題:由於壓縮成形性較低,故而有錠劑之成形性不足,無法獲得實用之錠劑硬度之情況,又,完全未提及作為口腔內崩解錠之崩解性及服用感。
[專利文獻1]國際公開第2004/106416號說明書
[專利文獻2]日本專利特公昭40-26274號公報
[專利文獻3]日本專利特公昭56-2047號公報
[專利文獻4]國際公開第2002/02643號說明書
關於專利文獻1所揭示之纖維素粉末,分子量400之聚乙二醇之保持率為190%以上。一般而言,關於調配有15%以上之粉末纖維素之口腔內崩解錠,據稱吸水性良好之粉末纖維素會吸取唾液,於口腔內產生粉之乾澀感,而服用感不良。又,據稱於口腔內感到粒子之粗澀之大小為100μm以上。專利文獻1之實施例中係使用平均粒徑為100μm以上者,錠劑組成之纖維素粉末比率亦為10%以上。考慮到該等情況,可推測專利文獻1所記載之纖維素粉末於用於口腔內崩解錠之情形時,唾液之吸水性亦較高,口腔內之唾液被粉末吸收,與粗澀一起亦產生乾澀,服用感出現問題之可能性較高。
專利文獻2~4所揭示之纖維素粉末由於壓縮成形性較低,故而於進行錠劑化時需要較高之打錠壓力,結果無法獲得迅速之崩解性,非常難以製成口腔內崩解錠。
為了同時實現錠劑硬度與崩解速度,必須使結晶纖維素之含量較多,另一方面,為了改善服用感(粗澀、乾澀),必須使結晶纖維素
之含量較少,因此難以同時滿足該等3個條件。
因而,專利文獻1~4所記載之纖維素粉末於滿足作為錠劑所需之硬度之基礎上,無法製造出作為口腔內崩解錠而崩解性、服用感令人滿意者。
因此,本發明之目的在於提供一種口腔內崩解錠,其係壓縮成形性優異,且取得錠劑之成形性與崩解性之平衡者,並且係於口腔內不會感到粗澀或乾澀而可獲得良好之服用感的令人滿意者。
本發明者等人為了解決上述課題而進行努力研究,結果發現:將平均聚合度為150~450之纖維素粉末藉由特定方法進行噴霧乾燥或粉碎並錠劑化時之吸水能力令人驚訝的是較將通常之未進行噴霧乾燥或粉碎之纖維素粉末進行錠劑化時有所降低,而使作為纖維素粉末之課題之口腔內崩解錠之服用感得以顯著改善。研究結果發現:若平均粒徑為10~100μm,一次粒子率為50%以上,則即便纖維素粉末之錠劑調配率較多,亦可達成上述目的,從而完成本發明。
即,本發明如下所述。
1.一種纖維素粉末,其平均聚合度為150~450,平均粒徑為10μm以上且未達100μm,一次粒子率為50%以上。
2.如上述之纖維素粉末,其中纖維素粉末粒子之長徑/短徑(L/D)之比為1.8~2.8。
3.如上述之纖維素粉末,其中平均分子量400之聚乙二醇保持率未達190%,錠劑硬度60N之錠劑吸水能力為170%以下,2.0kN打錠壓力之錠劑硬度為130N以上。
4.一種如上述任一項之纖維素粉末之用途,其係用於口腔內崩解錠用賦形劑。
5.一種口腔內崩解錠之製造方法,其特徵在於:將如上述任一項
之纖維素粉末3~99質量%、與包含藥物或有效成分、賦形劑、結合劑、崩解劑、及潤滑劑中之至少藥物或有效成分之1種以上之成分1~97質量%進行混合,並進行壓縮成形。
本發明之纖維素粉末可製造如下口腔內崩解錠,該口腔內崩解錠兼具壓縮成形性、速崩解性之各物性,即便為大量含有該纖維素粉末之錠劑,作為口腔內崩解錠亦不會感到粗澀或乾澀,錠劑之硬度或崩解性令人滿意。
以下,對用以實施本發明之最佳形態(以下,簡稱為「本實施形態」)進行詳細說明。再者,本發明並不限定於以下之實施形態,可於其主旨之範圍內進行各種變化而實施。
(纖維素粉末)
本發明之纖維素粉末之平均聚合度較佳為150~450。平均聚合度具有如下傾向:若為150以上,則壓縮成形性變高,故而較佳,又,若為450以下,則纖維素之水解充分,不會大量含有纖維素之非晶質部分,不會強烈顯現纖維性而變得容易彈性恢復,從而成形性優異。
本發明之纖維素粉末之平均粒徑較佳為10μm以上且未達100μm,更佳為10μm以上且未達70μm,進而較佳為10μm以上且未達50μm。若平均粒徑為10μm以上,則於進行微粒化時,粒子表面過度受到衝擊而使纖維素粒子凝聚之情況較少,因此與活性成分混合時,活性成分均勻地分散,藉此,所獲得之錠劑之活性成分含量之不均減小,故而較佳。又,若平均粒徑為100μm以上,則於口腔內感到粒子
之粗澀而無法獲得令人滿意之服用感。
於本發明之纖維素粉末之粒子構成中,一次粒子率較佳為50%以上,更佳為60%以上,進而較佳為70%以上。
一次粒子率係相對於粒子之總數而表示一次粒子數之比率者。具體而言,根據下述測定方法而規定。
一次粒子係自外表之幾何學形態而認為是單位粒子者。將一次粒子凝聚而成者稱為二次粒子(aggregate,agglomerate)。若一次粒子率未達50%,則二次粒子之粒子形狀產生影響,於口腔內使錠劑崩解之情形時,感到纖維素粉末之乾澀,而無法獲得滿意之服用感。具體而言,二次粒子成為構成該二次粒子之一次粒子間之空隙較多之結構,水或液體成分容易進入該空隙中。其結果為,認為於口腔內使錠劑崩解後,唾液被纖維素粉末吸收,唾液變得不足,口腔內乾澀,服用感變差。
本發明之纖維素粉末中,平均分子量400之聚乙二醇保持率較佳為未達190%,更佳為180%以下。若未達190%,則於口腔內使錠劑崩解時被纖維素粉末吸收之唾液較少,而抑制口腔內之乾澀、服用感之惡化。再者,於本發明之纖維素粉末中,平均分子量400之聚乙二醇保持率之下限並無特別限定,通常較佳為100%以上。
所謂聚乙二醇保持率係將纖維素粉末所保持之聚乙二醇之飽和量以相對於纖維素粉末之重量%進行表示之值。又,聚乙二醇之平均分子量係藉由如下方法進行測定,該方法係依據日本藥典第14修訂版(以下,有簡稱為日局之情況)之聚乙二醇4000之平均分子量之測定方法。
再者,一次粒子率與平均分子量400之聚乙二醇保持率為不同概念。具體而言,於一次粒子率較低之纖維素粉末中,存在平均分子量400之聚乙二醇保持率較低者與較高者。認為前者對應於構成二次粒
子之一次粒子間之空隙較少之結構(aggregate),後者對應於構成二次粒子之一次粒子間之空隙較多之結構(agglomerate)。
關於本發明之纖維素粉末,將該纖維素粉末以錠劑硬度成為60N之打錠壓力所成形之錠劑之吸水能力較佳為170%以下,更佳為50%以上且170%以下,進而較佳為50%以上且160%以下。若該吸水能力為170%以下,則與上述同樣地,於口腔內使錠劑崩解時被纖維素粉末吸收之唾液較少,口腔內之乾澀、服用感之惡化得以抑制。若為50%以上,則錠劑之吸水性優異,可獲得作為口腔內崩解錠而適合之崩解性。
所謂錠劑之吸水能力係吸收有飽和量之水之錠劑相對於乾燥錠劑之重量%。
關於本發明之纖維素粉末,其2.0kN打錠壓力之錠劑硬度較佳為130N以上,更佳為150N以上,進而較佳為200N以上。若錠劑硬度為130N以上,則於輸送或保管時錠劑會缺損、或破裂,產生製品品質上之問題之可能性較小。再者,錠劑硬度根據錠劑直徑、錠劑重量、壓縮方法而大幅度變動,只要無解釋性說明,則於本說明書中,表示將纖維素粉末0.5g放入臼中,使用直徑1.13cm之圓形平面杵,以打錠壓力2kN保持10秒鐘之錠劑硬度。
(纖維素粉末之製造方法)
以下,對本發明之纖維素粉末之製造方法進行記述。
本發明之纖維素粉末例如係藉由如下方式獲得:對將經水解處理之天然纖維素系物質分散至適當介質中而獲得之纖維素分散液進行乾燥。於該情形時,可對如下分散液進行乾燥,該分散液係將包含經水解處理之纖維素系物質之固形物成分自藉由水解處理所獲得之水解反應溶液單離,另外使其分散至適當介質中而製備者,又,於同水解溶液之狀態下直接形成纖維素分散液之情形時,亦可直接對該分散液
進行乾燥。
天然纖維素系物質可為植物性亦可為動物性,為源自例如木材、竹子、棉花、苧麻、海鞘、蔗渣、洋麻、細菌纖維素等含有纖維素之天然物的纖維質物質,較佳為具有纖維素I型之結晶結構。作為原料,可使用上述中之1種天然纖維素質物質,亦可使用將2種以上混合而獲得者。又,較佳為於精製紙漿之形態下使用,紙漿之精製方法並無特別限制,可使用溶解紙漿、牛皮紙漿、NBKP(needle bleached kraft pulp,漂白硫酸鹽針葉木漿)等中之任一紙漿。
水解方法可為酸水解,亦可為鹼性氧化分解、熱水解、蒸氣爆裂(steam explosion)等,可單獨使用任一方法,亦可併用2種。
於上述製法中,作為使包含經水解處理之纖維素系物質之固形物成分於其後分散至適當介質中之情形時所使用之介質,只要為工業上使用者,則無特別限制,例如可使用水及/或有機溶劑。作為有機溶劑,例如可列舉:甲醇、乙醇、異丙醇、丁醇、2-甲基丁醇、苄醇等醇類,戊烷、己烷、庚烷、環己烷等烴類,丙酮、甲基乙基酮等酮類等。有機溶劑尤佳為用於醫藥品者,可列舉於「醫藥品添加劑事典2007」(藥事日報社(股份)發行)中被分類為溶劑者。關於水及有機溶劑,可自由地將其單獨使用或併用2種以上,亦可暫時分散至1種介質中之後,去除該介質,再分散至不同介質中。
如此而獲得之纖維素分散液中存在之纖維素分散粒子之平均粒徑較佳為50μm以上。於平均粒徑為50μm以上之情形時,藉由對纖維素分散液進行乾燥,可獲得表觀比容較大,壓縮成形性、液狀成分保持性優異之本案發明之纖維素粉末。尤其是平均粒徑未達50μm之纖維素分散液包含相對大量之纖維素分散微粒子成分,但該微粒子成分於進行微粒化時,粒子表面會過度受到衝擊,導致表面結構發生變化,因此於使大量包含微粒子成分之分散液乾燥之情形時,難以獲得
液狀成分之保持性較高之纖維素粉末。
為了自上述纖維素分散液獲得平均粒徑成為50μm以上之纖維素分散粒子,例如針對乾燥前之纖維素分散液,進行使用傾析器之傾析,使水分被吸收,以水分含量成為40%以上之方式進行控制,一次性地進行脫水精製,藉此可製成較大之粒子。或者,作為其他方法,亦可使藉由篩分而篩選出之平均粒徑50μm以上之纖維素分散粒子另外分散至適當介質中。
又,可單獨使用任一方法,亦可併用而使用。
關於乾燥方法,亦無特別限制,例如可使用冷凍乾燥、噴霧乾燥、轉筒乾燥、擱架乾燥、氣流乾燥、真空乾燥中之任一者,可單獨使用1種,亦可併用2種以上。進行噴霧乾燥時之噴霧方法可為圓片式、加壓噴嘴、加壓二流體噴嘴、加壓四流體噴嘴等中之任一噴霧方法,可單獨使用1種,亦可併用2種以上。就經濟性之觀點而言,較佳為噴霧乾燥。
於進行上述噴霧乾燥時,亦可為了降低分散液之表面張力而添加微量之水溶性高分子、界面活性劑,亦可為了促進介質之氣化速度而將發泡劑、或氣體添加至分散液中。
於噴射纖維素分散液之噴霧乾燥機內之噴嘴(噴嘴方式)或圓片(旋轉噴霧器方式)之種類有加壓二流體噴嘴、二流體噴嘴、雙噴嘴(twin-jet nozzle)、圓片式噴嘴(disk nozzle)、低容量(low capacity)噴嘴,就提高一次粒子率之方面而言,較佳為加壓二流體噴嘴、二流體噴嘴。
噴霧乾燥機一般稱為噴霧乾燥器,使用使纖維素分散液瞬間乾燥而成為粒子之乾燥裝置(大川原化工機製造、Matsubo、GEA Process Engineering、Powdering Japan、日本化學機械、藤崎電機)之裝置。
若纖維素粒子彼此強力凝聚,則於下述粉碎步驟中,難以達成一次粒子率為50%以上。纖維素粒子之凝聚狀態大致取決於噴霧乾燥條件,因此較佳為於纖維素粒子彼此不強力凝聚之條件下實施噴霧乾燥步驟。具體而言,欲噴霧之纖維素分散液之固形物成分濃度較佳為20%以下,更佳為15%以下,進而較佳為10%以下。若欲噴霧之纖維素分散液之固形物成分濃度較低,則有纖維素粒子之凝聚力變小之傾向。
噴霧乾燥後之纖維素粉末較佳為平均粒徑為30~150μm。即便平均粒徑大於100μm之情形時,藉由供給至下述粉碎步驟,亦能夠將平均粒徑調整為10~未達100μm。
(粉碎步驟)
於乾燥步驟後之纖維素粉末之一次粒子率未達50%之情形時、或平均粒徑大於100μm之情形時,較佳為於噴霧乾燥後進行粉碎。該粉碎可藉由利用如下粉碎機進行粉碎而實施:超離心粉碎機(ZM-200,Retsch製造)、噴射磨機(STJ-200,清新企業製造)或鎚碎機(beater mill)(H-12,Hosokawa Micron製造)、小型磨機(bantam mill)(AP-B,Hosokawa Micron製造)、針磨機(160Z,Powrex製造)、篩網式粉碎機(Feather Mill)(FM,Hosokawa Micron)、錘磨機(hammer mill)(HM-600,奈良機械製作所)、快速粉碎機(FL-250N,DALTON)、球磨機(Emax,Retsch)、振動球磨機(2C,TRU)、過篩之篩磨機(U30,Powrex)等。尤其是,噴射研磨粉碎機(STJ-200,清新企業製造)係一面於較高之氣壓下使粒子彼此碰撞一面進行粉碎之氣流式粉碎機,由於使二次粒子破碎而容易進行一次粒子化,故而尤佳。
噴射研磨粉碎機之粉碎條件中,重要的是粉末之供給量與粉碎壓力,使用噴射研磨粉碎機(STJ-200,清新企業製造)之情形時之供給量較佳為10~20kg/h,進而較佳為15~20kg/h。又,粉碎壓力較佳
為0.15~0.70MPa,進而較佳為0.30~0.50MPa。若粉末之供給量與粉碎壓力為上述範圍,則有容易控制為平均粒徑為10μm以上且未達100μm且一次粒子率為50%以上之傾向。
又,藉由上述方法所製作之纖維素粉末粒子之長徑/短徑(L/D)之比較佳為1.8~2.8。若L/D之比為上述範圍,則服用感得以改善,可用作口腔內崩解錠之藥品之種類增加。
長徑(L)及短徑(D)可利用顯微鏡進行測定。對100個粒子進行觀察,測定各自之長徑及短徑,算出L/D之比後,將100個粒子之平均值設為纖維素粉末之L/D。再者,長徑係利用顯微鏡觀察之粒子之最長方向上之長度,短徑係與長徑垂直之方向上最長部分之長度。若粉碎條件過強,則有使一次粒子過度破碎,而L/D變小之傾向。又,若粉碎條件過弱,則有細長之粒子不會被粉碎,而L/D變大之傾向。為了使L/D為1.8~2.8之範圍,需要適當地設定粉碎條件,但只要為上述之粉末之供給量與粉碎壓力,則有大致能將L/D調節為1.8~2.8之範圍之傾向。若相反於L/D超出1.8~2.8之範圍之情形時,藉由適當調節粉末之供給量與粉碎壓力,便可控制為適當範圍。
(口腔內崩解錠)
本發明中所述之口腔內崩解錠含有1種以上之藥物或有效成分(以下,亦稱為「活性成分」)與本發明之纖維素粉末。作為製造該口腔內崩解錠之方法,可藉由各成分之混合、攪拌、造粒、整粒、打錠等公知方法而實施。
於本發明之口腔內崩解錠中,上述本發明之纖維素粉末之添加率較佳為3質量%以上,更佳為10質量%以上,進而較佳為15質量%以上。若為3質量%以上之添加率,則錠劑之成形性變得良好,獲得實用之錠劑硬度,故而較佳。再者,於本發明之口腔內崩解錠中,本發明之纖維素粉末之添加率較佳為99質量%以下。
本發明之口腔內崩解錠中之活性成分包含醫藥品藥效成分、食品成分、健康食品成分。再者,亦能夠將本發明之纖維素粉末與化妝品成分、色素、香料、觸媒、界面活性劑混合而使用。活性成分之形態可為粉體狀、結晶狀、油狀、液狀、半固體狀等中之任一形態。又,亦可為了控制溶出、降低苦味等而實施包衣。活性成分可單獨使用,亦可併用2種以上。
例如作為活性成分中之醫藥品藥效成分,對象為如下經口投予者:抗癲癇藥、解熱鎮痛消炎藥、精神神經用藥、骨骼肌鬆弛藥、催眠鎮靜藥、防瞌睡藥、抗眩暈藥、小兒鎮痛藥、健胃藥、制酸藥、消化藥、強心劑、心律不整用藥、降壓藥、血管擴張藥、利尿藥、抗潰瘍藥、整腸藥、骨質疏鬆症治療用藥、止咳祛痰藥、抗哮喘藥、抗菌劑、尿頻改善劑、營養強化劑、維生素劑等。關於藥效成分,可自由地將其單獨使用,或併用2種以上。具體而言,例如可列舉:抗癲癇藥(苯妥英、乙醯苯丁醯脲、三甲雙酮、苯巴比妥、撲米酮、硝西泮、丙戊酸鈉、舒噻美等)、解熱鎮痛消炎藥(乙醯胺酚、苯基乙醯基甘胺酸甲基醯胺、甲芬那酸、雙氯芬酸鈉、夫洛非寧、阿司匹林、阿司匹林鋁、乙水楊胺、羥保泰松、舒爾必寧、苯基丁氮酮、布洛芬、阿氯芬酸、那若松(naloxone)、酮洛芬、鹽酸替諾立定、鹽酸芐達明、鹽酸噻拉米特、吲哚美辛、吡羅昔康、水楊醯胺等)、抗眩暈藥(茶苯海明、鹽酸美克洛、鹽酸地芬尼多等)、麻醉藥(鹽酸鴉片鹼(opium alkaloid hydrochloride)、鹽酸嗎啡、磷酸可待因、磷酸二氫可待因、羥甲嗎啡(Oxymethebanol)等)、精神神經用藥(鹽酸氯丙、馬來酸左美丙、馬來酸甲哌丙、哌氰、羥哌氯丙、氯普噻噸、氟哌啶醇、二氮平、去甲羥基安定、奧沙唑侖、美沙唑侖、阿普唑侖、佐替平等)、骨骼肌鬆弛藥(氯唑沙宗、胺基甲酸氯苯甘醚、氯苯甲酮、甲磺酸普力諾、鹽酸乙哌立松等)、自主神經用藥(氯貝膽鹼、溴新斯的
明、溴吡斯的明等)、鎮痙劑(硫酸阿托品、溴丁托品、丁溴東莨菪鹼、溴丙胺太林、鹽酸罌粟鹼等)、抗帕金森藥(鹽酸比哌立登、鹽酸苯海索、鹽酸金剛烷胺、左旋多巴等)、抗組織胺劑(鹽酸苯海拉明、dl-馬來酸氯苯那敏、普敏太定、過敏美奎錠、富馬酸氯馬斯汀等)、強心劑(胺茶鹼、咖啡因、dl-鹽酸異丙腎上腺素、鹽酸依替福林、鹽酸去甲苯福林(nonfenerin hydrochloride)、癸烯醌等)、心律不整用藥(鹽酸普魯卡因胺、品多洛爾、酒石酸美托洛爾、丙吡胺(disopyramide)等)、利尿藥(氯化鉀、環戊噻、氫氯噻、胺苯喋啶、乙醯唑胺、利尿磺胺等)、降壓藥(溴化六羥季銨、鹽酸聯胺肼、血壓果平、利血平、鹽酸普萘洛爾(propranolol hydrochloride)、卡托普利、甲基多巴等)、血管收縮藥(甲磺雙氫麥角胺等)、血管擴張藥(鹽酸依他苯酮、鹽酸地爾硫卓、鹽酸卡波羅孟、季戊四醇四硝酸酯、雙嘧達莫、硝酸異山梨酯、硝苯地平、檸檬酸尼卡密特、環扁桃酯、辛那伶等)、動脈硬化用藥(亞麻油酸乙酯、卵磷脂、安妥明等)、循環器官用藥(鹽酸尼卡地平、鹽酸甲氯芬酯、細胞色素C、吡啶醇胺基甲酸酯(pyridinol carbamate)、長春西汀(vinpocetine)、胡泮酸鈣、己酮可可鹼、艾地苯醌等)、呼吸促進藥(鹽酸二甲弗林等)、止咳祛痰藥(磷酸可待因、磷酸二氫可待因、氫溴酸右美沙芬、那可汀、L-半胱胺酸甲酯鹽酸鹽、鹽酸溴己新、茶鹼、鹽酸麻黃鹼、胺來呫諾等)、利膽藥(柳胺酚、苯丙醇、羥甲香豆素等)、整腸藥(氯化黃連素、鹽酸洛哌丁胺等)、消化器官用藥(氯普胺(metoclopramide)、苯戊醇、多潘立酮等)、維生素劑(乙酸視黃醇酯、二氫速固醇、依曲替酯、鹽酸硫胺、硝酸硫胺、呋喃硫胺、奧托硫胺、賽可硫胺、核黃素、鹽酸吡哆醇、磷酸吡哆醛、菸鹼酸、泛硫乙胺、氰鈷胺素、生物素、抗壞血酸、植物甲萘醌、四烯甲萘醌等)、抗生素(苄星青黴素、阿莫西林、安比西林、環己西林、頭孢可若、頭孢胺苄(cefalexin)、頭孢呋辛酯、紅黴素、北里黴
素、交沙黴素、氯黴素、四環素、灰黃黴素、頭孢唑喃鈉等)、化學療法藥(磺胺甲噁唑、異菸酸酊、乙硫異菸醯胺、磺基塞唑、呋喃妥因、依諾沙星、氧氟沙星、諾氟沙星等)。
作為其他活性成分,可列舉:咖啡因、蘭索拉唑、法莫替丁、奧美拉唑、檸檬酸莫沙必利(mosapride citrate)、伏格列波糖、酒石酸唑吡坦、氯雷他定、鹽酸咪達普利、咪唑立賓、鹽酸頭孢卡品酯、左氧氟沙星、利培酮、琥珀酸舒馬曲坦、富馬酸喹硫平、琥珀酸素立芬新、葡萄糖胺、鹽酸葡萄糖胺、N-乙醯基葡萄糖胺、輔酶Q10、武靴葉、巴西蘑菇、膠原蛋白、洋車前子殼粉、軟骨素、硫酸軟骨素、薑黃、海藻酸、海藻酸鈉、海藻酸酯、海藻酸鋅、海藻酸鉀、海藻酸鈣、海藻酸銨、防風通聖散、明日葉、蝦紅素、α-硫辛酸、銀杏樹葉、彈力蛋白、L-肉鹼、殼聚糖、綠藻、螺旋藻、腦醯胺、鋸葉棕(saw palmetto)、玻尿酸、山桑、β-葡聚醣、瑪卡、松樹皮萃取物、葉黃素、非洲芒果、柑橘系水果萃取物、蘑菇殼聚糖(mushroom chitosan)、野葛花萃取物、綠咖啡豆萃取物、南非博士綠茶(green rooibos)、黑醋、鳥胺酸、胺基酸、橄欖、薑黃素、巴西蘑菇、靈芝等真菌類、磷脂質、寡乳酸、阿魏酸、青大豆粉、乳糖醛酸、貓爪草、多酚等。
作為其他油狀、液狀活性成分,例如可列舉:替普瑞酮、吲哚美辛法尼酯、矽靈、四烯甲萘醌、植物甲萘醌、維生素A油、苯戊醇、維生素D、維生素E等維生素類、DHA(docosahexaenoic acid,二十二碳六烯酸)、EPA(eicosapentaenoic acid,二十碳五烯酸)、肝油等高級不飽和脂肪酸類、輔酶Q類、甜橙油、檸檬油、薄荷油等油溶性香味料等於「日本藥典第16修訂版」(廣川書店股份有限公司發行)、「局外基」、「USP26」、「NF21」(均由美國藥典會有限公司發行)、「EP」中所記載之醫藥品藥效成分等。維生素E中存在各種同族體、
衍生物,只要於常溫下為液狀,則無特別限定。例如可列舉dl-α-生育酚、dl-α-生育酚乙酸酯、d-α-生育酚、d-α-生育酚乙酸酯等,可自由地將選自上述中之1種單獨使用,或併用2種以上。
作為半固體狀活性成分,例如可列舉:地龍、甘草、桂皮、牡丹根、牡丹皮、纈草、山椒、生薑、陳皮、麻黃、天竺子、黃砷、遠志、桔梗、車前子、車前草、石蒜、美遠志(senega)、貝母、茴香、黃柏、黃連、莪述、洋甘菊、龍膽、牛黃、動物膽、珊瑚菜、生薑、蒼術、丁香、陳皮、白術、竹節人參、人參、葛根湯、桂枝湯、香蘇散、紫胡桂枝湯、小紫胡湯、小青龍湯、麥門冬湯、半夏厚朴湯、麻黃湯等中藥或天然藥萃取類、牡蠣肉萃取物、蜂膠及蜂膠萃取物、輔酶Q類等,可自由地將選自上述中之1種單獨使用,或併用2種以上。
本發明之口腔內崩解錠除活性成分、纖維素粉末以外,亦可視需要含有崩解劑、結合劑、塑化劑、賦形劑、潤滑劑、矯味劑、香料、著色劑、甜味劑、高甜味劑等其他成分。該等成分與活性成分之合計較佳為1~97質量%,更佳為1~90質量%。又,於本發明之口腔內崩解錠中,包含藥物或有效成分(活性成分)、賦形劑、結合劑、崩解劑、及潤滑劑中之至少活性成分之1種以上之成分之添加率較佳為1~97質量%。
作為崩解劑,可列舉:交聯羧甲基纖維素鈉、羧甲基纖維素、羧甲基纖維素鈣、羧甲基纖維素鈉、低取代度羥丙基纖維素等纖維素類,羧甲基澱粉鈉、羥丙基澱粉、米澱粉、小麥澱粉、玉米澱粉、馬鈴薯澱粉、部分α化澱粉等澱粉類,交聯聚維酮、交聯聚維酮共聚物等合成高分子等於「醫藥品添加物事典2000」(藥事日報社(股份)發行)中被分類為崩解劑者或其他添加劑等能夠用於製劑或食品等之成分,可自由地將選自上述中之1種單獨使用,或併用2種以上。
作為結合劑或糖類,可列舉:白糖、葡萄糖、乳糖、果糖等糖
類,甘露糖醇、木糖醇、麥芽糖醇、赤藻糖醇、山梨糖醇等糖醇類,明膠、聚三葡萄糖、鹿角菜膠、刺槐豆膠、瓊脂、葡甘露聚醣、三仙膠、羅望子膠、果膠、海藻酸鈉、阿拉伯膠等水溶性多糖類,結晶纖維素、粉末纖維素、羥丙基纖維素、甲基纖維素等纖維素類,α化澱粉、澱粉糊等澱粉類,聚乙烯吡咯啶酮、羧基乙烯基聚合物、聚乙烯醇等合成高分子類,磷酸氫鈣、碳酸鈣、合成水滑石、鋁矽酸鎂等無機化合物類等於「醫藥品添加物事典2007」(藥事日報社(股份)發行)中被分類為結合劑者。可自由地將選自上述中之1種單獨使用,或併用2種以上。
作為塑化劑,可列舉:含水二氧化矽、輕質無水矽酸等矽化物類等於「醫藥品添加物事典2007」(藥事日報社(股份)發行)中被分類為塑化劑者。可自由地將選自上述中之1種單獨使用,或併用2種以上。
作為潤滑劑,可列舉:硬脂酸鎂、硬脂酸鈣、硬脂酸、蔗糖脂肪酸酯、滑石等於「醫藥品添加物事典2007」(藥事日報社(股份)發行)中被分類為潤滑劑者。可自由地將選自上述中之1種單獨使用,或併用2種以上。
作為矯味劑,可列舉:麩胺酸、富馬酸、琥珀酸、檸檬酸、檸檬酸鈉、酒石酸、蘋果酸、抗壞血酸、氯化鈉、l-薄荷腦等於「醫藥品添加物事典2007」(藥事日報社(股份)發行)中被分類為矯味劑者。可自由地將選自上述中之1種單獨使用,或併用2種以上。
作為香料,可列舉:柳橙、香草、草莓、酸乳酪、薄荷腦、茴香油、桂皮油、苦橙油、薄荷油等油類、綠茶末等於「醫藥品添加物事典2007」(藥事日報社(股份)發行)中被分類為調味劑、香料者。可自由地將選自上述中之1種單獨使用,或併用2種以上。
作為著色劑,可列舉:食用色素紅色3號、食用色素黃色5號、
食用色素藍色1號等食用色素、葉綠素銅鈉、氧化鈦、核黃素等於「醫藥品添加物事典2007」(藥事日報社(股份)發行)中被分類為著色劑者。可自由地將選自上述中之1種單獨使用,或併用2種以上。
作為甜味劑、高甜味劑,可列舉:阿斯巴甜、糖精、甘草酸二鉀、甜菊、麥芽糖、麥芽糖醇、蔗糖素、果糖、木糖醇、飴糖、甘茶末等於「醫藥品添加物事典2007」(藥事日報社(股份)發行)中被分類為甜味劑者。可自由地將選自上述中之1種單獨使用,或併用2種以上。
(口腔內崩解錠之製造方法)
本發明之口腔內崩解錠係包含本發明之纖維素粉末、1種以上之活性成分及視需要添加之其他添加劑之組合物,係指藉由壓縮成形所獲得之錠劑。本發明之口腔內崩解錠之製造方法較佳為將本發明之纖維素粉末、1種以上之活性成分、及視需要添加之其他添加物混合,並將所獲得之混合物壓縮成形而成者,更具體而言,更佳為將本發明之纖維素粉末3~99質量%、與包含藥物或有效成分、賦形劑、結合劑、崩解劑、及潤滑劑中之至少藥物或有效成分之1種以上之成分1~97質量%進行混合,並進行壓縮成形而成者。
調配有本發明之纖維素粉末之錠劑尤其為不經過複雜步驟而利用如直接打錠法之簡便方法獲得實用硬度者,可使用乾式顆粒壓縮法、濕式顆粒壓縮法、後末法、以預先已壓縮成形之錠劑為內核之多核片之製造方法等中之任一製造方法。
以下,對以1種以上之活性成分與本發明之纖維素粉末為主成分之錠劑組合物之製造方法進行記述,作為一例,本發明之製造方法並不限制於以下之方法。此處所述之活性成分可為固形狀、液狀、半固體狀中之任一形態,可將活性成分單獨使用,亦可將活性成分於介質中溶解、懸浮、乳化而使用。
作為製造方法,例如可列舉以下之方法。
i)將本發明之纖維素粉末與單一活性成分混合並壓縮成形之製造方法,
ii)將使活性成分預先溶解或分散於水而獲得者與本發明之纖維素粉末混合並壓縮成形之製造方法,
iii)將使活性成分預先溶解於少量之有機溶劑後分散於水而獲得者與本發明之纖維素粉末混合並壓縮成形之製造方法,
iv)將使活性成分預先溶解或分散於水溶性高分子或水溶性高分子水溶液而獲得者與本發明之纖維素粉末混合並壓縮成形之製造方法,
v)將使活性成分預先溶解或分散於油脂而獲得者與本發明之纖維素粉末混合並壓縮成形之製造方法
又,亦可將使活性成分預先溶解於大量之有機溶劑而獲得者與本發明之纖維素粉末混合,並利用公知之方法進行壓縮成形。但是,於使用該製造方法時,為了使其脫有機溶劑,而必須對所獲得之錠劑進行乾燥。
於上述製造方法中,i)所示之將本發明之纖維素粉末與單一活性成分混合並壓縮成形之製造方法之情形時,亦可於進行混合時除本發明之纖維素粉末與活性成分以外,視需要添加界面活性劑、油脂等所謂溶解改善劑、崩解劑、結合劑、塑化劑、潤滑劑、矯味劑、香料、著色劑、甜味劑等其他成分。該等成分可單獨使用1種,亦可併用2種以上。各成分之添加/混合之順序並無限制,可向本發明之纖維素粉末中添加/混合活性成分,可向活性成分中添加/混合本發明之纖維素粉末,亦可將兩者一起添加/混合。於除本發明之纖維素粉末、活性成分以外添加其他成分之情形時,可向預先與活性成分混合而獲得者中添加/混合本發明之纖維素粉末,可向預先與本發明之纖維素粉末
混合而獲得者中添加/混合活性成分,可向預先將本發明之纖維素粉末與活性成分混合而獲得者中添加/混合,亦可將各成分一次性添加/混合。
活性成分之添加方法只要為通常進行之方法,則無特別限制,可使用小型吸引輸送裝置、空氣輸送裝置、鬥式輸送機、壓送式輸送裝置、真空輸送機、振動式定量進料機、噴霧器、漏斗等連續地添加,亦可一次性投入。
混合方法只要為通常進行之方法,則無特別限制,可使用V型、W型、雙錐型、罐容器(container tank)型混合機等容器旋轉式混合機、或者高速攪拌型、萬能攪拌型、帶型、攪拌型、諾塔型混合機等攪拌式混合機、高速流動式混合機、轉筒式混合機、流動層式混合機。又,亦可使用振盪器等容器振動式混合機。
組合物之壓縮成形方法只要為通常進行之方法,則無特別限制,可為使用臼與杵壓縮成形為所需形狀之方法、預先壓縮成形為片狀後切斷為所需形狀之方法。作為壓縮成形機,例如可使用靜壓壓力機、壓塊輥(briquetting roller)型壓力機、平滑輥型壓力機等輥式壓力機、單衝壓片打錠機、旋轉打錠機等壓縮機。
於上述製造方法中,ii)將使活性成分預先溶解或分散於水而獲得者與本發明之纖維素粉末混合並壓縮成形之製造方法之情形時,於作為預處理使活性成分溶解或分散於水時,亦自由地視需要加入界面活性劑、油脂等所謂溶解改善劑等。該等成分可單獨使用1種,亦可併用2種以上。關於進行溶解或分散時之各成分之添加/混合之順序,並無特別限制,可向水中添加/混合活性成分,可向活性成分中添加/混合水,亦可一起添加/混合。於添加溶解助劑時,可將活性成分與溶解助劑之混合物向水中添加/混合,可向使溶解助劑溶解或分散於水中而獲得者中添加/混合活性成分,亦可將各成分一次性添加/混合。
作為溶解或分散方法,只要為通常進行之溶解、分散方法,則無特別限制,可使用可攜式攪拌器、立體攪拌器、側面攪拌器等1方向旋轉式、多軸旋轉式、往復反轉式、上下移動式、旋轉+上下移動式、管路式等之使用攪拌翼之攪拌混合方法、管線攪拌器等噴流式攪拌混合方法、氣體吹入式攪拌混合方法、使用高剪切均質器、高壓均質器、超音波均質器等之混合方法,亦可使用利用振盪器之容器振動式混合方法等。
於將藉由上述方法所獲得之溶液或分散液與本發明之纖維素粉末混合時,亦可添加崩解劑、結合劑、塑化劑、潤滑劑、矯味劑、香料、著色劑、甜味劑、溶解助劑等其他成分。該等成分可單獨使用1種,亦可併用2種以上。各成分之添加/混合之順序並無限制,可向本發明之纖維素粉末中添加/混合活性成分溶液或分散液,亦可向活性成分溶液或分散液中添加/混合本發明之纖維素粉末。又,於除本發明之纖維素粉末、活性成分溶液或分散液以外亦添加其他成分時,可向將該成分預先與本發明之纖維素粉末混合而獲得者中添加/混合活性成分溶液或分散液,可向將該成分預先與活性成分溶液或分散液混合而獲得者中添加/混合本發明之纖維素粉末,可向預先將本發明之纖維素粉末與活性成分溶液或分散液混合而獲得者中添加/混合該成分,亦可將各成分一次性添加/混合。
關於此時之添加方法、混合方法、壓縮成形方法,只要為通常使用之方法,則無特別限制,可使用i)之製造方法中作為一例而列舉之方法。
作為製造方法,於iii)將使活性成分預先溶解於少量有機溶劑後分散於水而獲得者與本發明之纖維素粉末混合並壓縮成形之製造方法之情形時,於作為預處理使活性成分溶解於少量有機溶劑時,添加順序並無特別限制,可向有機溶劑中添加/混合活性成分,可向活性成
分中添加/混合有機溶劑,亦可將兩者一起添加/混合。於使該活性成分溶液分散於水時,可併用1種以上之溶解助劑。此時之添加順序亦無特別限制,可將活性成分溶液與溶解助劑之混合物向水中添加/混合,可向使溶解助劑溶解或分散於水而獲得者中添加/混合活性成分溶液,可向將水與活性成分溶液混合而獲得者中添加/混合溶解助劑,亦可將各成分一次性添加混合。
作為溶解或分散方法,只要為通常進行之溶解、分散方法,則無特別限制,可使用ii)之製造方法中作為一例而列舉之溶解或分散方法。於將藉由上述方法所獲得之活性成分溶液或分散液與本發明之纖維素粉末混合時,可視需要添加崩解劑、結合劑、塑化劑、潤滑劑、矯味劑、香料、著色劑、甜味劑、溶解助劑等。該等成分可單獨使用1種,亦可併用2種以上。此時之添加、混合、壓縮成形方法並無特別限制,可使用i)之製造方法中作為一例而列舉之方法。
作為製造方法,於iv)將使活性成分預先溶解或分散於水溶性高分子或水溶性高分子水溶液而獲得者與本發明之纖維素粉末混合並壓縮成形之製造方法之情形時,於作為預處理使活性成分溶解或分散於水溶性高分子或水溶性高分子水溶液時,可視需要添加溶解助劑。各成分之添加順序並無特別限制,例如可向水溶性高分子或水溶性高分子水溶液中添加/混合活性成分,可向活性成分中添加/混合水溶性高分子或水溶性高分子水溶液,亦可將兩者一起添加/混合。於添加溶解助劑時,添加順序亦無特別限制,可將活性成分與溶解助劑之混合物向水溶性高分子或水溶性高分子水溶液中添加/混合,可將水溶性高分子或水溶性高分子水溶液與溶解助劑之混合物向活性成分中添加/混合,可將活性成分與水溶性高分子或水溶性高分子溶液之混合物向溶解助劑中添加/混合,亦可將各成分一次性添加/混合。
於將藉由上述方法所獲得之活性成分溶液或分散液與本發明之
纖維素粉末混合時,可視需要添加崩解劑、結合劑、塑化劑、潤滑劑、矯味劑、香料、著色劑、甜味劑、溶解助劑等。該等成分可單獨使用1種,亦可併用2種以上。此時之添加、混合、壓縮成形方法並無特別限制,可使用i)之製造方法中作為一例而列舉之方法。
作為製造方法,於v)將使活性成分預先溶解或分散於油脂而獲得者與本發明之纖維素粉末混合並壓縮成形之製造方法之情形時,於作為預處理使活性成分溶解或分散於油脂時,可添加溶解助劑。各成分之添加、溶解或分散方法並無特別限制,可使用i)之製造方法中作為一例而列舉之方法。於將所獲得之溶液或分散液與本發明之纖維素粉末混合時,可視需要添加崩解劑、結合劑、塑化劑、潤滑劑、矯味劑、香料、著色劑、甜味劑、溶解助劑等。該等成分可單獨使用1種,亦可併用2種以上。此時之添加、混合、壓縮成形方法並無特別限制,可使用i)之製造方法中作為一例而列舉之方法。
於該等製造方法中,尤其於活性成分難溶於水之情形時,藉由使用添加溶解助劑之i)~v)之製造方法、不添加溶解助劑之iii)、iv)、v)之製造方法,所獲得之組合物可改善活性成分於水中之溶解性或分散性。又,此時,於使用各種聚乙二醇作為溶解助劑之情形時,其亦作為藥物之保護成分而發揮作用,故而可抑制藥物於體內之分解,而改善藥效持續性。
作為上述製造方法中使用之有機溶劑,只要為醫藥品所使用者,則無特別限制,例如可列舉:甲醇、乙醇等醇類、丙酮等酮類等於「醫藥品添加劑事典2007」(藥事日報社(股份)發行)中被分類為溶劑者,可自由地將其單獨使用,或併用2種以上。
作為水溶性高分子,例如可列舉:羥丙基纖維素、羥丙基甲基纖維素、聚丙烯酸、羧基乙烯基聚合物、聚乙二醇、聚乙烯醇、聚乙烯吡咯啶酮、甲基纖維素、乙基纖維素、阿拉伯膠、澱粉糊等「醫藥
品添加劑事典2007」(藥事日報社(股份)發行)所記載之水溶性高分子,可自由地將其單獨使用,或併用2種以上。
作為油脂,例如可列舉:硬脂酸單甘油酯、硬脂酸三甘油酯、硬脂酸蔗糖酯等硬脂酸類、液態石蠟等石蠟類、巴西棕櫚蠟、氫化蓖麻油等硬化油類、蓖麻油、硬脂酸、硬脂醇、聚乙二醇等「醫藥品添加劑事典2007」(藥事日報社(股份)發行)所記載之油脂,可自由地將其單獨使用,或併用2種以上。
作為界面活性劑,例如可列舉:磷脂質、甘油脂肪酸酯、聚乙二醇脂肪酸酯、山梨糖醇酐脂肪酸酯、聚氧乙烯氫化蓖麻油、聚氧乙烯鯨蠟醚、聚氧乙烯硬脂醚、聚氧乙烯壬基苯基醚、聚氧乙烯聚氧丙烯二醇、聚氧乙烯山梨糖醇酐單月桂酸酯、聚山梨糖醇酯、山梨糖醇酐單油酸酯、單硬脂酸甘油酯、單氧乙烯山梨糖醇酐單棕櫚酸酯、單氧乙烯山梨糖醇酐單硬脂酸酯、聚氧乙烯山梨糖醇酐單油酸酯、山梨糖醇酐單棕櫚酸酯、月桂基硫酸鈉等於「醫藥品添加劑事典2007」(藥事日報社(股份)發行)中被分類為界面活性劑者,可自由地將其單獨使用,或併用2種以上。除如上所述般進行壓縮成形製成錠劑而使用以外,本發明之錠劑用組合物由於液狀成分之保持性優異,故而亦可為了改善尤其是流動性、耐黏連性、耐凝聚性而以顆粒劑或散劑之形式使用。
對本發明之口腔內崩解錠之具體之打錠方法進行說明。
例如可列舉如下方法:將活性成分與纖維素粉末、包含糖或糖醇等之添加劑利用適當之混合機混合而製備打錠用粉末後,進行打錠而製造。打錠例如可利用旋轉打錠機、單銃打錠機等公知打錠裝置進行製造。較理想為打錠時之壓力儘量低,較佳為20kN以下,更佳為15kN以下,進而較佳為10kN以下。打錠壓力及錠劑之崩解性係與錠劑內之空隙率及水浸透性相關,故而為了確保作為口腔內崩解錠之崩
解性,亦較佳為打錠壓力較低。
口腔內崩解錠之錠劑硬度較佳為50N以上且未達200N,更佳為50N以上且未達150N,進而較佳為50N以上且未達100N。若錠劑硬度為50N以上,則於輸送或保管中,錠劑側面難以缺損、或破裂,故而較佳。另一方面,若未達200N,則錠劑之崩解性不會變慢,而獲得作為口腔內崩解錠之令人滿意之崩解性。
口腔內崩解錠為即便無水亦可服用之醫藥品及健康食品製劑等,例如依據日本藥典第16修訂版、普通試驗法「崩解試驗法」而實施之錠劑之崩解時間較佳為未達60秒,更佳為30秒以內。
又,於將錠劑實際放入人口中僅用唾液使其崩解之口腔內崩解試驗中,較佳為未達60秒便崩解,更佳為30秒以內。
[實施例]
以下,列舉實施例及比較例對本發明進行詳細說明,但本發明並不限定於此。
本發明中所使用之物性之測定方法及條件如下所述。
<平均聚合度>
設為藉由日本藥典第16修訂版、結晶纖維素之確認試驗(3)所記載之銅乙二胺溶液黏度法所測得之值。
<粒子之平均粒徑[μm]>
使用雷射繞射散射粒度分佈計(堀場製作所(股份)製造,LA-910)進行測定。平均粒徑係以體積頻率之平均數之形式算出。
<表觀鬆密度[g/ml]>
於100ml之量筒中讀取疏鬆填充有粒子30g之粒子層之容積,算出除以30之值。重複次數為3,取其平均值。
<平均分子量400之聚乙二醇(PEG)保持率[重量%]>
將纖維素粉末2.0g放置於玻璃盤上,一面自滴定管滴下聚乙二
醇(三洋化成股份有限公司製造,Macrogol 400),一面隨時利用刮勺(spatula)進行混練,將聚乙二醇滲出至粉體表面之點設為終點,由聚乙二醇重量g×100/纖維素粉末量(2.0g)算出飽和保持率。
<一次粒子率>
使用乾式圖像解析裝置(Malvern Morphorogi G3S),對約1萬個左右之粒子進行拍照、圖像解析,求出各粒子之面積圓當量之粒徑與縱橫比。根據其結果,自處於面積圓當量之粒徑之平均值±5μm之範圍與縱橫比之平均值±0.1之範圍之粒子中,任意地抽取1000個粒子圖像。再者,於處於上述範圍之粒子不足1000個之情形時,則使用所有粒子圖像。
逐一目視確認所抽取之粒子圖像中之粒子形狀,將粒子單獨體判定為一次粒子,將粒子凝聚而成者判定為2次粒子,算出1000個中之一次粒子數之比率作為一次粒子率。
作為簡易方法,亦可將各個抽取之粒子圖像之亮度分散值設為1~X之範圍而選擇者設為一次粒子,將設為X~100之範圍而選擇者設為二次粒子,並根據一次粒子數/全部粒子數×100,算出一次粒子率(%)。該方法係以與藉由上述目視方法所測得之一次粒子率最為一致之方式實驗性地於1~100之範圍內規定X者,於本實施例中採用X=30。
此處,「面積圓當量之粒徑」係將經3維處理之粒子圖像轉換為2維,出現與其面積相同之圓面積之圓,將圓之直徑設為粒徑之方法。「縱橫比」係以粒子之短徑/粒子之長徑所求出之比。
「亮度分散值」意指0~255之灰度等級所表示之像素之亮度之標準偏差,由數1所示之式表示。成為該值越大,粒子內之白~黑之對比度越強,越小則對比度越低之粒子。成為二次粒子後,粒子彼此重合,故而粒子之對比度變強,亮度分散值變大。
Ii:像素(i)之強度之值。
N:粒子內之像素之合計數。
<長徑/短徑(L/D)>
將使用數位顯微鏡(VH-7000型,基恩斯製造,使用VH-501鏡頭)進行拍照所獲得之圖像以1360×1024像素、TIFF檔案之形式保存,使用圖像處理解析軟體(Image HyperII,Digimo製造),測定100個粒子之短徑與長徑,算出L/D之比,取100個粒子之L/D之平均值。
<錠劑之硬度>
利用一般使用之錠劑硬度測定器(Tablet Tester 8M/DR.,索鈮格(Schleuniger)製造),測定錠劑之硬度。針對每1片測定錠劑硬度,算出20片之錠劑硬度之平均值。
<錠劑之崩解試驗>
依據日本藥典第16修訂版、普通試驗法「崩解試驗法」進行實施。試驗液係使用水。
<粉末之吸水能力>
依據JIS K5101所記載之吸油量之測定,使用純水代替油,對纖維素系核粒子10g加入純水30ml,於室溫下放置1小時後,進行濾取,將粒子表面之附著水用濾紙等輕輕拭去後,測定重量,根據重量之增加量算出含水量後,除以10g。
<錠劑之吸水能力>
於培養皿上放置錠劑,測定錠劑之重量,向錠劑底部側利用滴管緩慢地滴下水,測定錠劑不吸水之時間點之重量,根據(錠劑重量
+所吸之水重量)/錠劑重量×100而算出錠劑之吸水能力。
<錠劑之口腔內崩解試驗>
以3名健康成年男子為被試驗者,測定以口腔內之唾液使錠劑完全崩解之時間。每人測定2次,算出3人之平均值。
<服用感>
以3名健康成年男子為官能檢查員,官能性地評價口腔內之錠劑之服用感。將錠劑之味道或口感無問題之情形判定為「良好」,將感到粉感之情形判定為「有乾澀感」,將感到顆粒等之粗澀之情形判定為「有不適感」。每人測定2次,僅於2次均為「良好」之情形,將該被試驗者之服用感之評價判定為「良好」。而且,例如針對乾澀感,於官能檢查員第1次無任何感受,第2次感到乾澀感之情形時,將該官能檢查員之評價判定為「有乾澀感」,同樣地即便感到1次顆粒等之粗澀之情形時亦判定為「有不適感」。
[實施例1]
將對市售之紙漿(聚合度790)進行切碎而獲得者2kg、與4N之鹽酸水溶液30L裝入低速型攪拌機(池袋琺瑯工業(股份)製造,30LGL反應器,翼徑約30cm)中,一面以攪拌速度5rpm進行攪拌,一面於40℃下水解24小時,而獲得平均聚合度310之酸不溶性殘渣。對所獲得之酸不溶性殘渣使用布氏漏斗,以固形物成分成為40質量%之方式進行過濾,進而利用純水將過濾殘渣洗淨,利用氨水進行中和後,裝入90L之塑膠桶中,加入純水,利用三一馬達(HEIDON製造,類型1200G,8M/M,攪拌翼徑5cm),以攪拌速度5rpm進行攪拌,藉此製成固形物成分濃度為10質量%之纖維素分散液。對其進行噴霧乾燥(分散液供給速度6L/hr,入口溫度180~220℃,出口溫度50~70℃),使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型),以粉碎壓力0.4MPa、粉體供給速度10kg/h進行粉碎,而獲得纖
維素粉末A。將纖維素粉末A之粉體物性示於表1。
[實施例2]
除使用市售之紙漿(聚合度840),將水解條件設為5N鹽酸水溶液、40℃、60小時以外,進行與實施例1相同之操作,而獲得平均聚合度160之酸不溶性殘渣。不對所獲得之酸不溶性殘渣進行過濾,利用純水洗淨後進行中和,不進行攪拌,使用網眼38μm之篩,去除過篩部分,而獲得固形物成分濃度為10質量%之纖維素分散液。對所獲得之纖維素分散液進行與實施例1相同之操作,進行噴霧乾燥,使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型),以粉碎壓力0.4MPa、粉體供給速度10kg/h進行粉碎,而獲得纖維素粉末B。將纖維素粉末B之粉體物性示於表1。
[實施例3]
除使用市售之紙漿(聚合度790),將水解條件設為5N鹽酸水溶液、40℃、4小時、攪拌速度30rpm以外,進行與實施例1相同之操作,而獲得平均聚合度440之酸不溶性殘渣。對所獲得之酸不溶性殘渣進行與實施例1相同之操作,進行過濾、中和後,以攪拌速度500rpm進行攪拌,而獲得固形物成分濃度為17質量%之纖維素分散液。對所獲得之纖維素分散液利用轉筒乾燥機(楠木製作所(股份)製造,KDD-1型,蒸氣壓力0.35MPa,轉筒表面溫度136℃,轉筒轉數2rpm,積存部分溫度100℃)進行乾燥後,使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型),以粉碎壓力0.4MPa、粉體供給速度10kg/h進行粉碎,而獲得纖維素粉末C。將纖維素粉末C之粉體物性示於表1。
[實施例4]
使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型)以粉碎壓力0.4MPa、粉體供給速度10kg/h將市售之結晶纖維素
(Ceolus KG-1000:旭化成化學製造)粉碎,而獲得纖維素粉末D。將纖維素粉末D之粉體物性示於表1。
[實施例5]
使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型)以粉碎壓力0.4MPa、粉體供給速度10kg/h將市售之結晶纖維素(Ceolus PH-302:旭化成化學製造)粉碎,而獲得纖維素粉末E。將纖維素粉末E之粉體物性示於表1。
[實施例6]
使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型)以粉碎壓力0.6MPa、粉體供給速度10kg/h將市售之結晶纖維素(Ceolus KG-1000:旭化成化學製造)粉碎,而獲得纖維素粉末F。將纖維素粉末F之粉體物性示於表1。
[實施例7]
使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型)以粉碎壓力0.25MPa、粉體供給速度10kg/h將市售之結晶纖維素(Ceolus KG-1000:旭化成化學製造)粉碎,而獲得纖維素粉末G。將纖維素粉末G之粉體物性示於表1。
[實施例8]
使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型)以粉碎壓力0.8MPa、粉體供給速度10kg/h將市售之結晶纖維素(Ceolus PH-302:旭化成化學製造)粉碎,而獲得纖維素粉末H。將纖維素粉末H之粉體物性示於表1。
[實施例9]
使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型)以粉碎壓力0.2MPa、粉體供給速度10kg/h將市售之結晶纖維素(Ceolus PH-302:旭化成化學製造)粉碎,而獲得纖維素粉末I。將纖
維素粉末I之粉體物性示於表1。
[比較例1]
除將水解條件設為3N鹽酸水溶液、40℃、20小時、將反應中之攪拌速度設為20rpm以外,藉由與實施例1相同之操作進行水解,而獲得平均聚合度440之酸不溶性殘渣。對所獲得之酸不溶性殘渣使用布氏漏斗,以固形物成分成為70質量%之方式進行過濾。進而利用純水將所獲得之過濾殘渣洗淨,利用氨水進行中和後,放入90L之塑膠桶中,加入純水,利用與實施例1相同之操作,以攪拌速度100rpm進行攪拌,而製成固形物成分濃度為6質量%之纖維素分散液。將所獲得之纖維素分散液利用與實施例1相同之操作進行噴霧乾燥,而獲得纖維素粉末J。將纖維素粉末J之粉體物性示於表1。
[比較例2]
除將水解條件設為0.14N鹽酸水溶液、121℃、1小時、將反應中之攪拌速度設為30rpm以外,藉由與實施例1相同之操作進行水解,而獲得平均聚合度220之酸不溶性殘渣。對所獲得之酸不溶性殘渣使用布氏漏斗,以固形物成分成為70質量%之方式進行過濾。進而利用純水將所獲得之過濾殘渣洗淨,利用氨水進行中和後,放入90L之塑膠桶中,加入純水,利用與實施例1相同之操作,以攪拌速度500rpm進行攪拌,而製成固形物成分濃度為17質量%之纖維素分散液。將所獲得之纖維素分散液利用與實施例1相同之操作進行噴霧乾燥之後,利用網眼325目之篩除去粗大粒子,而獲得纖維素粉末K。將纖維素粉末K之粉體物性示於表1。
[比較例3]
使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型)以粉碎壓力0.4MPa、粉體供給速度10kg/h將市售之結晶纖維素(Ceolus PH-101:旭化成化學製造)粉碎,而獲得纖維素粉末L。將纖
維素粉末L之粉體物性示於表1。
[比較例4]
使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型)以粉碎壓力0.4MPa、粉體供給速度10kg/h將市售之結晶纖維素(Ceolus PH-102:旭化成化學製造)粉碎,而獲得纖維素粉末M。將纖維素粉末M之粉體物性示於表1。
[比較例5]
使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型)以粉碎壓力0.4MPa、粉體供給速度10kg/h將市售之纖維素粉末(商品名:KC Flock,日本製紙化學製造)粉碎,而獲得纖維素粉末N。將纖維素粉末N之粉體物性示於表1。
[比較例6]
除使用將市售之紙漿(聚合度1030)切碎而成者2kg以外,進行與實施例1相同之操作,而獲得纖維素粉末O。將纖維素粉末O之粉體物性示於表1。
[比較例7]
將對市售之紙漿(聚合度790)進行切碎而成者2kg、與0.14N之鹽酸水溶液30L放入低速型攪拌機(池袋琺瑯工業(股份)製造,30LGL反應器,翼徑約30cm)中,一面以攪拌速度30rpm進行攪拌,一面於121℃下水解1小時,而獲得平均聚合度220之酸不溶性殘渣。對所獲得之酸不溶性殘渣使用布氏漏斗,以固形物成分成為70質量%之方式進行過濾,進而利用純水將過濾殘渣洗淨,利用氨水進行中和後,放入90L之塑膠桶中,加入純水,利用三一馬達(HEIDON製造,類型1200G,8M/M,攪拌翼徑5cm),以攪拌速度500rpm進行攪拌,藉此製成固形物成分濃度為17質量%之纖維素分散液。對其進行噴霧乾燥(分散液供給速度6L/hr,入口溫度180~220℃,出口溫度50~70
℃),使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型)以粉碎壓力0.8MPa、粉體供給速度5kg/h進行粉碎,而獲得纖維素粉末P。將纖維素粉末P之粉體物性示於表1。
[比較例8]
使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型)以粉碎壓力0.8MPa、粉體供給速度5kg/h將市售之結晶纖維素(Ceolus KG-1000:旭化成化學製造)粉碎,而獲得纖維素粉末Q。將纖維素粉末Q之粉體物性示於表1。
[比較例9]
使用氣流式粉碎機(清新企業(股份)製造,單軌噴射磨機STJ-200型)以粉碎壓力0.10MPa、粉體供給速度20kg/h將市售之結晶纖維素(Ceolus KG-1000:旭化成化學製造)粉碎,而獲得纖維素粉末R。將纖維素粉末R之粉體物性示於表1。
[實施例10]
使用實施例1~9中所獲得之各纖維素粉末0.5g,放入臼(菊水製作所製造,使用材質SUK2、3)中,利用直徑1.13cm之圓形平面杵(菊水製作所製造,使用材質SUK2、3)以打錠壓力2.0kN進行壓縮。將該壓力保持10秒鐘,而製作錠劑(壓縮機係使用Aikoh Engineering製造之PCM-1A)。將所獲得之錠劑之硬度示於表2。
[比較例10]
使用比較例1~9中所獲得之各纖維素粉末0.5g,放入臼(菊水製作所製造,使用材質SUK2、3)中,利用直徑1.13cm之圓形平面杵(菊水製作所製造,使用材質SUK2、3)以打錠壓力2kN進行壓縮。將該壓力保持10秒鐘,而製作錠劑(壓縮機係使用Aikoh Engineering製造
之、PCM-1A)。將所獲得之錠劑之硬度示於表2。
[實施例11]
與實施例10同樣地使用實施例1~9中所獲得之各纖維素粉末0.5g,放入臼(菊水製作所製造,使用材質SUK2、3)中,利用直徑1.13cm之圓形平面杵(菊水製作所製造,使用材質SUK2、3),使打錠壓力低於實施例10,而製作錠劑硬度為60N左右之錠劑。將所獲得之錠劑之吸水能力示於表3。
[比較例11]
與比較例10同樣地使用比較例1~9中所獲得之各纖維素粉末0.5g,放入臼(菊水製作所製造,使用材質SUK2、3)中,利用直徑1.13cm之圓形平面杵(菊水製作所製造,使用材質SUK2、3),使打錠壓力低於比較例6,而製作錠劑硬度為60N左右之錠劑。將所獲得之錠劑
之吸水能力示於表3。
[實施例12]
將赤藻糖醇(Cargill Japan)1.12kg、實施例1~9中所獲得之各纖維素粉末0.48kg及N-乙醯基葡萄糖胺(燒津水產)1.60kg添加至滾筒混合機(TM-50S型,DALTON)中,混合20分鐘後取出,投入至高速攪拌造粒機(立式造粒機VG-10,Powrex)中進行造粒。造粒條件如下所述。
(1)葉片轉數:500rpm
(2)切碎機轉數:1500rpm
(3)造粒時間:3分鐘
(4)水添加量:0.24kg
取出造粒顆粒,添加至流動層乾燥機中,使顆粒乾燥。乾燥條
件如下所述。
(A)使用裝置:Multiplex(商品名),MP-01型,Powrex(股份)、
(B)風量:7m3/min
(C)供氣溫度:70~75℃
(D)停止排氣溫度:45℃
取出已乾燥之顆粒,以篩網710μm進行整粒後,測定顆粒之粒度分佈,而獲得平均粒徑。將顆粒之平均粒徑示於表4。
對該顆粒1200g加入α化澱粉(商品名SWELSTAR FD-1:旭化成化學)36g、抗壞血酸(武田藥品工業)14g,添加至滾筒混合機(TM-50S型,DALTON)中混合20分鐘後,加入12g硬脂酸鈣(太平化學工業),進而混合3分鐘並取出。該混合粉體之纖維素粉末之重量比率為28.5%,添加至打錠機(LIBRA 2(商品名),菊水製作所)中,而製作錠劑。打錠條件如下所述。能夠於完全無打錠損傷之情況下進行打錠,口腔內之服用感亦無粗澀或乾澀感,獲得了作為口腔內崩解錠而言充分之結果。將所獲得之錠劑之物性及評價結果示於表5。
(A)錠劑重量:280mg
(B)錠劑直徑:8mm,12R
(C)轉子轉數:45rpm
(D)進料機種類:敞開式進料機(open feeder)
(E)打錠壓力:5kN
(F)打錠時間:10分鐘
(G)臼杵根數:12根
[實施例13]
加入赤藻糖醇(Cargill Japan)0.42kg、實施例1~9中所獲得之各纖維素粉末0.18kg、N-乙醯基葡萄糖胺(燒津水產)0.60kg、SWELSTAR FD-1(商品名)(旭化成化學)36g、及抗壞血酸(武田藥品工業)14g,添加至滾筒混合機(TM-50S型,DALTON)中混合20分鐘後,加入12g硬脂酸鈣(太平化學工業),進而混合3分鐘並取出。該混合粉體之纖維素粉末之重量比率為14.3%,添加至打錠機(LIBRA2(商品名),菊水製作所)中,而製作錠劑。打錠條件如下所述。能夠於完全無打錠損傷之情況下進行打錠,口腔內之服用感亦無粗澀或乾澀感,獲得了作為口腔內崩解錠而言充分之結果。將所獲得之錠劑之物性及
評價結果示於表6。
(A)錠劑重量:280mg
(B)錠劑直徑:8mm,12R
(C)轉子轉數:45rpm
(D)進料機種類:敞開式進料機
(E)打錠壓力:5kN
(F)打錠時間:10分鐘
(G)臼杵根數:12根
[比較例12]
將赤藻糖醇(Cargill Japan)1.12kg、比較例1~9中所獲得之各纖維素粉末0.48kg及N-乙醯基葡萄糖胺(燒津水產)1.60kg添加至滾筒混合機(TM-50S型,DALTON)中,混合20分鐘後取出,投入至高速攪拌造粒機(立式造粒機VG-10,Powrex)中進行造粒。造粒條件如下所述。
(1)葉片轉數:500rpm
(2)切碎機轉數:1500rpm
(3)造粒時間:3分鐘
(4)水添加量:0.24kg
取出造粒顆粒,添加至流動層乾燥機中,使顆粒乾燥。乾燥條件如下所述。
(A)使用裝置:Multiplex(商品名),MP-01型,Powrex(股份)、
(B)風量:7m3/min
(C)供氣溫度:70~75℃
(D)停止排氣溫度:45℃
取出已乾燥之顆粒,以篩網710μm進行整粒後,測定顆粒之粒度分佈,而獲得平均粒徑。將顆粒之平均粒徑示於表7。
對該顆粒1200g加入SWELSTAR FD-1(商品名)(旭化成化學)36g、抗壞血酸(武田藥品工業)14g,添加至滾筒混合機(TM-50S型,DALTON)中混合20分鐘後,加入12g硬脂酸鈣(太平化學工業),進而混合3分鐘並取出。該混合粉體之纖維素粉末之重量比率為28.5%,添加至打錠機(LIBRA2(商品名),菊水製作所)中,而製作錠劑。打錠條件如下所述。雖然能夠於完全無打錠損傷之情況下進行打錠,但關於口腔內之服用感,感到粗澀或乾澀感,而未能獲得作為口腔內崩解錠
而言充分之結果。將所獲得之錠劑之物性及評價結果示於表8。
(A)錠劑重量:280mg
(B)錠劑直徑:8mm,12R
(C)轉子轉數:45rpm
(D)進料機種類:敞開式進料機
(E)打錠壓力:5kN
(F)打錠時間:10分鐘
(G)臼杵根數:12根
[比較例13]
加入赤藻糖醇(Cargill Japan)0.42kg、比較例1~9中所獲得之各纖維素粉末0.18kg、N-乙醯基葡萄糖胺(燒津水產)0.60kg、SWELSTAR FD-1(商品名)(旭化成化學)36g、及抗壞血酸(武田藥品工
業)14g,添加至滾筒混合機(TM-50S型,DALTON)中混合20分鐘後,加入12g硬脂酸鈣(太平化學工業),進而混合3分鐘並取出。該混合粉體之纖維素粉末之重量比率為14.3%,添加至打錠機(LIBRA2(商品名),菊水製作所)中,而製作錠劑。打錠條件如下所述。能夠於完全無打錠損傷之情況下進行打錠,關於口腔內之服用感,感到粗澀或乾澀,而無法獲得作為口腔內崩解錠而言充分之結果。將所獲得之錠劑之物性及評價結果示於表9。
(A)錠劑重量:280mg
(B)錠劑直徑:8mm,12R
(C)轉子轉數:45rpm
(D)進料機種類:敞開式進料機
(E)打錠壓力:5kN
(F)打錠時間:10分鐘
(G)臼杵根數:12根
[參考例]
加入赤藻糖醇(Cargill Japan)0.62kg、實施例1~9中所獲得之各纖維素粉末0.18kg、薑黃素末0.40kg、SWELSTAR FD-1(商品名)(旭化成化學)36g、及抗壞血酸(武田藥品工業)14g,添加至滾筒混合機(TM-50S型,DALTON)中混合20分鐘後,加入12g硬脂酸鈣(太平化學工業),進而混合3分鐘並取出。該混合粉體之纖維素粉末之重量比率為14.3%,添加至打錠機(LIBRA2(商品名),菊水製作所)中,而製作錠劑。打錠條件如下所述。雖然能夠於完全無打錠損傷之情況下進行打錠,但關於實施例8及9之纖維素粉末之口腔內之服用感,感到粗澀或乾澀,而未能獲得作為口腔內崩解錠而言充分之結果。將所獲得之錠劑之物性及評價結果示於表10。
(A)錠劑重量:280mg
(B)錠劑直徑:8mm,12R
(C)轉子轉數:45rpm
(D)進料機種類:敞開式進料機
(E)打錠壓力:5kN
(F)打錠時間:10分鐘
(G)臼杵根數:12根
[產業上之可利用性]
本發明能夠適宜地用於含有醫藥品藥物之醫藥品製劑、健康食品及食品之領域。由於具有尤其優異之崩解性,故而能夠作為無水便可服用之崩解性固形製劑、較佳為口腔內速崩解性之固形製劑(錠劑)而利用。
Claims (5)
- 一種纖維素粉末,其平均聚合度為150~450,平均粒徑為10μm以上且未達100μm,一次粒子率為50%以上。
- 如請求項1之纖維素粉末,其中纖維素粉末粒子之長徑/短徑(L/D)之比為1.8~2.8。
- 如請求項1或2之纖維素粉末,其中平均分子量400之聚乙二醇保持率未達190%,錠劑硬度60N之錠劑吸水能力為170%以下,2.0kN打錠壓力之錠劑硬度為130N以上。
- 一種如請求項1至3中任一項之纖維素粉末之用途,其係用於口腔內崩解錠用賦形劑。
- 一種口腔內崩解錠之製造方法,其特徵在於:將如請求項1至3中任一項之纖維素粉末3~99質量%、與包含藥物或有效成分、賦形劑、結合劑、崩解劑、及潤滑劑中之至少藥物或有效成分之1種以上之成分1~97質量%進行混合,並進行壓縮成形。
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