JP6834080B2 - 加熱溶融押出によるやや難溶な化合物の製剤 - Google Patents
加熱溶融押出によるやや難溶な化合物の製剤 Download PDFInfo
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- JP6834080B2 JP6834080B2 JP2016529898A JP2016529898A JP6834080B2 JP 6834080 B2 JP6834080 B2 JP 6834080B2 JP 2016529898 A JP2016529898 A JP 2016529898A JP 2016529898 A JP2016529898 A JP 2016529898A JP 6834080 B2 JP6834080 B2 JP 6834080B2
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- 229920002472 Starch Polymers 0.000 description 2
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- 229940072056 alginate Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
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- 150000001280 alpha hydroxy acids Chemical class 0.000 description 2
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- 150000001746 carotenes Chemical class 0.000 description 2
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- 239000000969 carrier Substances 0.000 description 2
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- 235000005822 corn Nutrition 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 2
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 2
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- 239000000665 guar gum Substances 0.000 description 2
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- 229960002154 guar gum Drugs 0.000 description 2
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- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
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- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 2
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
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- 229920005615 natural polymer Polymers 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
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- 229920001277 pectin Polymers 0.000 description 2
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- 235000010987 pectin Nutrition 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000010773 plant oil Substances 0.000 description 2
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- 239000004632 polycaprolactone Substances 0.000 description 2
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- 239000004626 polylactic acid Substances 0.000 description 2
- 229920000098 polyolefin Polymers 0.000 description 2
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- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 239000011118 polyvinyl acetate Substances 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
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- 239000000243 solution Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- DMXBZAANBCMUMR-UHFFFAOYSA-N 2-oxo-2-propoxyacetic acid Chemical compound CCCOC(=O)C(O)=O DMXBZAANBCMUMR-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 241000612182 Rexea solandri Species 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003042 alpha-carotene group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 125000001409 beta-carotene group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- FDSDTBUPSURDBL-DKLMTRRASA-N canthaxanthin Chemical compound CC=1C(=O)CCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C(=O)CCC1(C)C FDSDTBUPSURDBL-DKLMTRRASA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229920003174 cellulose-based polymer Polymers 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical group CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000000576 food coloring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- QJQZEJFUIOWFMS-UHFFFAOYSA-N formaldehyde;sulfanediol Chemical compound O=C.OSO QJQZEJFUIOWFMS-UHFFFAOYSA-N 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000011164 primary particle Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 235000019529 tetraterpenoid Nutrition 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
- 235000008210 xanthophylls Nutrition 0.000 description 1
- 150000003735 xanthophylls Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/01—Hydrocarbons
- A61K31/015—Hydrocarbons carbocyclic
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/179—Colouring agents, e.g. pigmenting or dyeing agents
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K40/00—Shaping or working-up of animal feeding-stuffs
- A23K40/25—Shaping or working-up of animal feeding-stuffs by extrusion
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/035—Organic compounds containing oxygen as heteroatom
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P30/00—Shaping or working of foodstuffs characterised by the process or apparatus
- A23P30/20—Extruding
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
- A23L5/40—Colouring or decolouring of foods
- A23L5/42—Addition of dyes or pigments, e.g. in combination with optical brighteners
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Nutrition Science (AREA)
- Animal Husbandry (AREA)
- Manufacturing & Machinery (AREA)
- Mycology (AREA)
- Medicinal Preparation (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Fodder In General (AREA)
Description
(i)加熱溶融押出製剤の総重量に基づくと、0.5〜50重量%(wt−%)、好ましくは5〜20重量%、より好ましくは5〜10重量%の、低透過性及び低溶解性を有する少なくとも1種の化合物、及び
(ii)加熱溶融押出製剤の総重量に基づくと、50〜99.5重量%、好ましくは80〜95重量%、より好ましくは90〜95重量%の、少なくとも1種の高分子担体材料、
を含む加熱溶融押出製剤(HEF)に関する。
(i)(特に水に)低透過性及び低溶解性を有する化合物がこの製剤によって生体利用可能にされる、及び
(ii)このような製剤は食品及び飼料製品並びに栄養補助食品中において安定性がある、及び
(iii)製造プロセスは連続的な手法で実施される、及び
(iv)製造プロセスはいかなる溶媒なしに運ばれる、及び
(v)このような製剤はカロテノイドでは知られていない。
生物薬剤学分類システムは、薬物をその溶解性及び透過性に基づき区別するためのシステムである。
クラスI−高透過性、高溶解性
クラスII−高透過性、低溶解性
クラスIII−低透過性、高溶解性
クラスIV−低透過性、低溶解性
例:ヒドロクロロチアジド
BCSにおいて、この薬物は以下のパラメータに基づいて分類される。
1.溶解性
2.透過性
3.溶出性
(i)加熱溶融押出製剤の総重量に基づくと、0.5〜50重量%(wt−%)、好ましくは5〜20重量%、より好ましくは5〜10重量%の、低透過性及び低溶解性を有する少なくとも1種の化合物と、
(ii)加熱溶融押出製剤の総重量に基づくと、50〜99.5重量%、好ましくは80〜95重量%、より好ましくは90〜95重量%の、少なくとも1種の高分子担体材料と、が、
溶媒がまったくない状態で加熱溶融押出しされる、加熱溶融押出製剤の製造のための加熱溶融押出プロセス(HEP)に関する。
[実施例1]
Xplore 5cc円錐型同時回転2軸スクリュー式マイクロコンパウンダーを用いてβ−カロテンの加熱溶融押出(HME)プロセスを実施した。ヒドロキシプロピルメチルセルロース(HPMC;ダウケミカル社(Dow Chemicals)のMethocel E5又はMethocel E19)、ポリエチレングリコール(シグマアルドリッチ社(Sigma Aldrich)のPEG200)及び結晶β−カロテン(DSMニュートリショナルプロダクツリミテッド(DSM Nutritional Products Ltd.))を、それぞれ59.4/39.6/1重量%の割合で、手動で予め混合した。プレミックスを、水平ピストンを用いて、窒素パージした押出機に供給した。すべてのバレルの温度を160℃に設定した。250rpmの初期スクリュー速度を2分間選択し、続いて、400rpmを8分間選択した。押出成形物を、その後、押出機の底部にあるバルブを開くことによって、150rpmの低下したスクリュー速度で回収した。押出成形物を水中に溶解させ、β−カロテンの分散粒度は、レーザー回折(マルバーンインスツルメンツ社(Malvern Instruments)マスターサイザー3000(Mastersizer 3000))により決定した。得られた分散粒度分布は単峰性であり、平均粒度d10=0.457μm、d50=0.637μm及びd90=0.901μmであった。
Xplore 5cc円錐型同時回転2軸スクリュー式マイクロコンパウンダーを用いてβ−カロテンの加熱溶融押出(HME)プロセスを実施した。ポリビニルカプロラクタム−ポリ酢酸ビニル−ポリエチレングリコールグラフトコポリマー(BASF社のソルプラス)と結晶β−カロテン(DSMニュートリショナルプロダクツリミテッド)とを手動で予め混合した。β−カロテン含有量は1重量%であった。プレミックスを、水平ピストンを用いて、窒素パージした押出機に供給した。すべてのバレルの温度を160℃に設定した。250rpmのスクリュー速度を選択し、5分間混合を行った。スクリュー速度を、その後、50rpmに低下し、バルブを回すことによって底部開口部から混合物を押し出した。押出されたストランドを室温まで冷却した。押出成形物を水中に溶解させ、β−カロテンの分散粒度を光相関分光法(ベックマンコールター社(Beckman Coulter)Delsa Nano S粒子分析器)によって測定した。細かい単峰性の分布が得られ、平均粒度d10=43.9nm、d50=62.8nm及びd90=91.1nmであった。2重量%のβ−カロテンを含有する押出成形物の分散粒度は、d10=50.1nm、d50=57.5nm及びd90=66.1nmであり、類似していた。HME前及びHME後のβ−カロテンの結晶化度を示差走査熱量測定(DSC)によって測定した。試料を蓋に穴のある50μLの密閉アルミニウム皿に入れて量り、5℃/分で20℃から195℃に加熱した。純粋結晶β−カロテンのDSC溶解ピークは182℃以下であった。β−カロテン溶解ピークはHME後にもはや視認できず、HMEによる結晶化度の喪失を示した。
β−カロテンの連続的な加熱溶融押出(HME)を同時回転2軸スクリュー式押出機(サーモサイエンティフィック社のHaake Polylab OS Rheodrive7、Haake Rheomex OS PTW16)で実施した。β−カロテンとHPMC(ダウケミカル社のMethocel E19)とのプレミックスをふるいにかけた粉末を20分間窒素下でブレンドすることによって調製した。このプレミックスを、押出機の第1のバレルに重量測定フィーダ(ブラベンダーテクノロジー社(Brabender Technologie))を用いて502g/hで加えた。PEG200(シグマアルドリッチ社)を、液体ポンプ(HNP Mikrosystem)により329g/hで下流の次のバレルに供給した。押出成形物の組成は、したがって、HPMC、PEG200及びβ−カロテンがそれぞれ、59.4/39.6/1重量%であった。全バレルを160℃まで加熱し、450rpmのスクリュー速度を選択した。直径1mmのダイを押出機のヘッドに取り付け、押出成形物のストランドをコンベヤベルト上で室温まで冷却させた。β−カロテンの分散粒度を実施例1に記載したレーザー回折によって決定した。単峰性の粒度分布が得られ、平均粒度d10=0.407μm、d50=0.548μm及びd90=0.734μmであった。連続的なHMEの前及び後のβ−カロテンの結晶化度を実施例2に記載したDSCによって測定した。β−カロテンの吸熱溶解ピークは押出成形物のDSC曲線において検出されなかった。
Claims (12)
- 加熱溶融押出製剤であって、
(i)前記加熱溶融押出製剤の総重量に基づくと、0.5〜20重量%の、α−カロテン、β−カロテン、8’−アポ−β−カロテナール、8’−アポ−β−カロテン酸エステル、カンタキサンチン、アスタキサンチン、リコペン、ルテイン、ゼアキサンチン及びクロセチンからなる群より選択される、低腸管透過性及び水に対する低溶解性を有する少なくとも1種の化合物と、
(ii)前記加熱溶融押出製剤の総重量に基づくと、50〜95重量%の、ポリビニルカプロラクタム−ポリ酢酸ビニル−ポリエチレングリコールグラフトコポリマーからなる高分子担体材料と、
(iii)前記加熱溶融押出製剤の総重量に基づくと、40重量%以下の、エチレングリコール、1,2−ブチレングリコール、2,3−ブチレングリコール、スチレングリコール、ジエチレングリコール、トリエチレングリコール、テトラエチレングリコール、モノプロピレングリコールモノイソプロピルエーテル、プロピレングリコールモノエチルエーテル、エチレングリコールモノエチルエーテル、ジエチレングリコールモノエチルエーテル、ソルビトールラクテート、乳酸エチル、乳酸ブチル、グリコール酸エチル、セバシン酸ジブチル、クエン酸アセチルトリブチル、クエン酸トリエチル、クエン酸アセチルトリエチル、クエン酸トリブチル及びグリコール酸アリルからなる群より選択される、少なくとも1種の可塑剤と、
を含む、加熱溶融押出製剤。 - 前記低腸管透過性及び水に対する低溶解性を有する少なくとも1種の化合物が非晶質形態である、請求項1に記載の加熱溶融押出製剤。
- 前記少なくとも1種の可塑剤の含有割合が10〜40重量%である、請求項1又は2に記載の加熱溶融押出製剤。
- 少なくとも1種の酸化防止剤を含む、請求項1〜3のいずれか一項に記載の加熱溶融押出製剤。
- 前記少なくとも1種の酸化防止剤が、アスコルビン酸、アスコルビン酸パルミテート、ブチルヒドロキシアニソール、ブチルヒドロキシトルエン、次亜リン酸、モノチオグリセロール、アスコルビン酸ナトリウム、ホルムアルデヒドスルホキシル酸ナトリウム、メタ重亜硫酸ナトリウム、BHT、BHA、重亜硫酸ナトリウム、ビタミンE及びその誘導体、及び没食子酸プロピルからなる群より選択される、請求項4に記載の加熱溶融押出製剤。
- 前記加熱溶融押出製剤の総重量に基づくと、5重量%以下の前記少なくとも1種の酸化防止剤を含む、請求項4又は5に記載の加熱溶融押出製剤。
- 前記低腸管透過性及び水に対する低溶解性を有する少なくとも1種の化合物の含有割合が0.5〜10重量%であり、前記高分子担体材料の含有割合が80〜95重量%である、請求項1〜6のいずれか一項に記載の加熱溶融押出製剤。
- 請求項1〜7のいずれか一項に記載の加熱溶融押出製剤を含む食品製品、飼料製品及び/又は栄養補助食品。
- 請求項1〜7のいずれか一項に記載の加熱溶融押出製剤を含む、食品製品、飼料製品及び/又は栄養補助食品のプレミックス。
- 加熱溶融押出製剤を製造するための加熱溶融押出方法であって、
(i)前記加熱溶融押出製剤の総重量に基づくと、0.5〜20重量%の、α−カロテン、β−カロテン、8’−アポ−β−カロテナール、8’−アポ−β−カロテン酸エステル、カンタキサンチン、アスタキサンチン、リコペン、ルテイン、ゼアキサンチン及びクロセチンからなる群より選択される、低腸管透過性及び水に対する低溶解性を有する少なくとも1種の化合物と、
(ii)前記加熱溶融押出製剤の総重量に基づくと、50〜95重量%の、ポリビニルカプロラクタム−ポリ酢酸ビニル−ポリエチレングリコールグラフトコポリマーからなる高分子担体材料と、
(iii)前記加熱溶融押出製剤の総重量に基づくと、40重量%以下の、エチレングリコール、1,2−ブチレングリコール、2,3−ブチレングリコール、スチレングリコール、ジエチレングリコール、トリエチレングリコール、テトラエチレングリコール、モノプロピレングリコールモノイソプロピルエーテル、プロピレングリコールモノエチルエーテル、エチレングリコールモノエチルエーテル、ジエチレングリコールモノエチルエーテル、ソルビトールラクテート、乳酸エチル、乳酸ブチル、グリコール酸エチル、セバシン酸ジブチル、クエン酸アセチルトリブチル、クエン酸トリエチル、クエン酸アセチルトリエチル、クエン酸トリブチル及びグリコール酸アリルからなる群より選択される、少なくとも1種の可塑剤と、
を含む成分を、溶媒がまったくない状態で加熱溶融押出しすることを含む、加熱溶融押出方法。 - 前記低腸管透過性及び水に対する低溶解性を有する少なくとも1種の化合物の含有割合が0.5〜10重量%であり、前記高分子担体材料の含有割合が80〜95重量%である、請求項10に記載の加熱溶融押出方法。
- 前記少なくとも1種の可塑剤の含有割合が10〜40重量%である、請求項10に記載の加熱溶融押出方法。
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