JP2020069470A - Method for manufacturing liposome and method for manufacturing liposome containing liquid - Google Patents
Method for manufacturing liposome and method for manufacturing liposome containing liquid Download PDFInfo
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- 239000002502 liposome Substances 0.000 title claims abstract description 126
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 26
- 239000007788 liquid Substances 0.000 title claims description 50
- 238000000034 method Methods 0.000 title abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 54
- 239000000243 solution Substances 0.000 claims abstract description 47
- 239000012530 fluid Substances 0.000 claims abstract description 19
- 150000002632 lipids Chemical class 0.000 claims abstract description 16
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 16
- 239000012528 membrane Substances 0.000 claims abstract description 15
- 238000004090 dissolution Methods 0.000 claims abstract description 14
- 239000000463 material Substances 0.000 claims abstract description 13
- 239000012670 alkaline solution Substances 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 230000007935 neutral effect Effects 0.000 claims abstract description 6
- 239000003381 stabilizer Substances 0.000 claims description 13
- 230000008719 thickening Effects 0.000 claims description 12
- 239000003929 acidic solution Substances 0.000 claims description 10
- 230000002378 acidificating effect Effects 0.000 claims description 7
- 238000010979 pH adjustment Methods 0.000 abstract description 4
- 239000002198 insoluble material Substances 0.000 abstract 3
- 239000002253 acid Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000003960 organic solvent Substances 0.000 description 9
- 239000011701 zinc Substances 0.000 description 9
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- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 7
- 238000012546 transfer Methods 0.000 description 7
- 229910052725 zinc Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 2
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
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- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
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- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 235000013402 health food Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
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- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000019155 vitamin A Nutrition 0.000 description 2
- 239000011719 vitamin A Substances 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002567 Chondroitin Polymers 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
- 235000000069 L-ascorbic acid Nutrition 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 240000004584 Tamarindus indica Species 0.000 description 1
- 235000004298 Tamarindus indica Nutrition 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
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- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 description 1
- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
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- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
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- 238000000265 homogenisation Methods 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
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- 230000000887 hydrating effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 235000014413 iron hydroxide Nutrition 0.000 description 1
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
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- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- DDOVBCWVTOHGCU-QMXMISKISA-N n-[(e,2s,3r)-3-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxynonadec-4-en-2-yl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)N[C@H]([C@H](O)\C=C\CCCCCCCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O DDOVBCWVTOHGCU-QMXMISKISA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
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- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 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
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- Coloring Foods And Improving Nutritive Qualities (AREA)
- General Preparation And Processing Of Foods (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
- Manufacturing Of Micro-Capsules (AREA)
Abstract
Description
本発明は、リポソーム又はリポソーム含有液の製造方法に関する。 The present invention relates to a method for producing a liposome or a liposome-containing liquid.
リポソームは、脂質分子により形成される少なくとも１つの脂質二重層により囲まれた小胞（例えば、１０〜１００μｍの小胞）である。近年、健康食品、化粧品、医薬品などの様々な分野で、リポソームの研究や開発が行われている。 Liposomes are vesicles (eg, 10-100 μm vesicles) surrounded by at least one lipid bilayer formed by lipid molecules. In recent years, research and development of liposomes have been conducted in various fields such as health foods, cosmetics, and pharmaceuticals.
特許文献１には、リポソーム膜中にビタミンＡ類を含有するリポソーム水懸濁液が記載されている。このリポソーム水懸濁液は、公知の方法に従い、リポソームの膜成分並びに膜中に配合する薬物及び添加物（ビタミンＡ類、ビタミンＥアセテート、ＢＨＴなど）を有機溶媒に溶解し、有機溶媒を留去して膜質膜を形成させた後、水溶性成分を溶解した溶液で水和することによりリポソーム水懸濁液を調製する。 Patent Document 1 describes a liposome aqueous suspension containing vitamins A in a liposome membrane. This liposome aqueous suspension is prepared by dissolving a liposome membrane component and drugs and additives (vitamin A, vitamin E acetate, BHT, etc.) to be incorporated into the membrane in an organic solvent according to a known method and distilling the organic solvent. After leaving it to form a membranous film, a liposome aqueous suspension is prepared by hydrating with a solution in which a water-soluble component is dissolved.
ところで、従来は、水に溶ける水溶性物質又は有機溶媒に溶ける脂溶性物質を原料として用いて、リポソームに内包させる流動性物質（液体など）を得ている。従来は、リポソームに内包させる流動性物質における主成分の原料として、難溶性物質は用いられていない。 By the way, conventionally, a water-soluble substance soluble in water or a fat-soluble substance soluble in an organic solvent is used as a raw material to obtain a fluid substance (liquid or the like) to be encapsulated in liposomes. Conventionally, a poorly soluble substance has not been used as a raw material for the main component of a fluid substance to be encapsulated in liposomes.
本発明は、このような事情に鑑みてなされたものであり、リポソームに内包させる流動性物質における主成分の原料として難溶性物質を用いたリポソームの製造方法を提供することを目的とする。 The present invention has been made in view of such circumstances, and an object thereof is to provide a method for producing a liposome using a poorly soluble substance as a raw material of a main component of a fluid substance to be encapsulated in a liposome.
上述の課題を解決するべく、第１の発明は、酸性又はアルカリ性の溶液に、リポソームに内包させる流動性物質における主成分の原料として難溶性物質を溶解させる溶解工程と、溶解工程により難溶性物質が溶解した溶液に、その溶液を中性側に調整するためのｐＨ調節剤を加えるｐＨ調節工程と、ｐＨ調節工程後の溶液とリポソームの膜材料となる脂質とを混ぜ合せ、溶液を内包するリポソームを製造するリポソーム化工程とを含む、リポソームの製造方法である。 In order to solve the above-mentioned problems, the first invention is a dissolution step of dissolving a hardly soluble substance as a main component raw material of a fluid substance to be encapsulated in liposomes in an acidic or alkaline solution, and a hardly soluble substance by the dissolution step. The pH adjusting step of adding a pH adjusting agent for adjusting the solution to the neutral side, and the solution after the pH adjusting step and the lipid to be the membrane material of the liposome are mixed to encapsulate the solution. A method for producing liposomes, which comprises a liposome forming step of producing liposomes.
第２の発明は、第１の発明におけるリポソーム化工程により製造された多数のリポソームと、多数のリポソームを浸漬させる液体とを含むリポソーム含有液を製造する、リポソーム含有液の製造方法である。 A second invention is a method for producing a liposome-containing liquid, which comprises producing a liposome-containing liquid containing a large number of liposomes produced by the liposome-forming step of the first invention and a liquid in which a large number of liposomes are dipped.
第３の発明は、リポソームに内包させる溶液とリポソームの膜材料となる脂質とを混ぜ合わせ、溶液を内包するリポソームを製造するリポソーム化工程と、リポソーム化工程により製造された多数のリポソームと、多数のリポソームを浸漬させる液体と、液体中において多数のリポソームを分散状態に維持するための増粘安定剤とを含むリポソーム含有液を製造する調整工程とを含む、リポソーム含有液の製造方法である。 A third aspect of the invention is a liposome-forming step of producing a solution-encapsulating liposome by mixing a solution to be encapsulated in the liposome with a lipid serving as a liposome membrane material, a large number of liposomes produced by the liposome-forming step, and a large number of liposomes. The method for producing a liposome-containing liquid, which comprises the step of producing a liposome-containing solution containing a liquid for immersing liposomes and a thickening stabilizer for maintaining a large number of liposomes in a dispersed state in the liquid.
本発明では、酸性又はアルカリ性の溶液を用いた溶解工程と、溶解工程により難溶性物質が溶解した溶液を中性側に調整するｐＨ調節工程とを行うため、リポソームに内包させる流動性物質における主成分の原料として、難溶性物質を用いることができる。 In the present invention, since the dissolution step using an acidic or alkaline solution and the pH adjustment step of adjusting the solution in which the hardly soluble substance is dissolved to the neutral side by the dissolution step are performed, it is mainly used in the fluid substance to be encapsulated in the liposome. A poorly soluble substance can be used as a raw material for the components.
以下、本発明の実施形態を詳細に説明する。なお、以下の実施形態は、本発明の一例であって、本発明、その適用物、あるいはその用途の範囲を制限することを意図するものではない。 Hereinafter, embodiments of the present invention will be described in detail. The following embodiments are examples of the present invention, and are not intended to limit the scope of the present invention, its application, or its application.
［リポソームの製造方法］
本実施形態は、リポソームに内包させる流動性物質（液体、ゾル等）における主成分の原料として難溶性物質を用いたリポソームの製造方法（以下、「本製造方法」という。）である。本製造方法は、酸性又はアルカリ性の溶液に難溶性物質を溶解させる溶解工程と、溶解工程により難溶性物質が溶解した溶液に、その溶液を中性側に調整するためのｐＨ調節剤（溶解工程後の溶液とは逆の極性を有するｐＨ調節剤）を加えるｐＨ調節工程と、ｐＨ調節工程後の溶液とリポソームの膜材料となる脂質とを混ぜ合せ、溶液を内包するリポソームを製造するリポソーム化工程とを、この順番で行う。
[Method for producing liposome]
The present embodiment is a method for producing liposomes (hereinafter, referred to as “present production method”) using a sparingly soluble substance as a main component material of a fluid substance (liquid, sol, etc.) to be encapsulated in liposomes. This production method is a dissolution step of dissolving a hardly soluble substance in an acidic or alkaline solution, a solution in which the hardly soluble substance is dissolved in the dissolution step, a pH adjuster for adjusting the solution to the neutral side (dissolution step A pH adjusting step of adding a pH adjusting agent having a polarity opposite to that of the latter solution, and the solution after the pH adjusting step and a lipid serving as a liposome membrane material are mixed to produce a liposome encapsulating the solution. The steps are performed in this order.
ここで、流動性物質における主成分としては、カルシウム、マグネシウム、亜鉛、鉄分などの鉱物系の元素が挙げられる。そして、難溶性物質としては、その金属自体又は金属塩を用いることができる。例えば、流動性物質における主成分がカルシウムの場合、難溶性物質として炭酸カルシウムを用いることができる。流動性物質における主成分がマグネシウムの場合、難溶性物質として水酸化マグネシウムを用いることができる。流動性物質における主成分が亜鉛の場合、難溶性物質として亜鉛そのものを用いることができる。流動性物質における主成分が鉄分の場合、難溶性物質として水酸化鉄を用いることができる。また、流動性物質における主成分としてはカルシウムなどの鉱物系の成分以外に、ヒアルロン酸、コンドロイチンなどを採用することもできる。 Here, examples of the main component in the fluid material include mineral elements such as calcium, magnesium, zinc, and iron. The metal itself or a metal salt can be used as the poorly soluble substance. For example, when the main component of the fluid substance is calcium, calcium carbonate can be used as the poorly soluble substance. When the main component of the fluid substance is magnesium, magnesium hydroxide can be used as the poorly soluble substance. When the main component of the fluid substance is zinc, zinc itself can be used as the sparingly soluble substance. When the main component of the fluid substance is iron, iron hydroxide can be used as the poorly soluble substance. In addition to mineral-based components such as calcium, hyaluronic acid, chondroitin, or the like can be used as the main component of the fluid substance.
まず酸性の溶液に難溶性物質を溶解させる場合の溶解工程及びｐＨ調節工程について説明を行う。溶解工程は、塩酸、酢酸、クエン酸、又はリンゴ酸などの酸性溶液（有機酸又は無機酸の溶液）中において難溶性物質を溶解させる工程である。難溶性物質の溶解を促進させるために加熱をしてもよい。また、酸性溶液は、例えば濃度が濃いもの（例えば、ｐＨ＝０以上４以下の溶液）を用いる。なお、リポソームを飲食品に用いる場合、酸性溶液としてはクエン酸の溶液を好適に用いることができる。 First, a dissolving step and a pH adjusting step in the case of dissolving a hardly soluble substance in an acidic solution will be described. The dissolving step is a step of dissolving a hardly soluble substance in an acidic solution (a solution of an organic acid or an inorganic acid) such as hydrochloric acid, acetic acid, citric acid or malic acid. Heating may be performed to accelerate the dissolution of the hardly soluble substance. Further, as the acidic solution, for example, one having a high concentration (for example, a solution having a pH of 0 or more and 4 or less) is used. When the liposome is used for food and drink, a citric acid solution can be preferably used as the acidic solution.
例えば、流動性物質の主成分がカルシウムで難溶性物質として炭酸カルシウムを用いる場合、溶解工程では、式１に示すように、例えば塩酸溶液に炭酸カルシウムを入れて炭酸カルシウムを溶解させる。溶解工程後の溶液（水溶液）は、塩化カルシウムが水に溶けた状態となり、また未反応の塩酸により酸性となる。
式１：ＣａＣＯ３＋２ＨＣｌ→ＣａＣｌ２＋Ｈ２Ｏ＋ＣＯ２
For example, when the main component of the fluid substance is calcium and calcium carbonate is used as a poorly soluble substance, in the dissolving step, for example, calcium carbonate is added to a hydrochloric acid solution to dissolve the calcium carbonate, as shown in Formula 1. The solution (aqueous solution) after the dissolving step becomes a state in which calcium chloride is dissolved in water, and becomes acidic due to unreacted hydrochloric acid.
Formula 1: CaCO 3 + 2HCl → CaCl 2 + H 2 O + CO 2
ｐＨ調節工程は、溶解工程後の溶液に対しｐＨ調整剤（中和剤）を混ぜることにより、溶液を所定のｐＨに調整する工程である。所定のｐＨは、６．５以上８以下の範囲である。ｐＨ調整剤としては、塩基性の物質を入れる。ｐＨ調整剤として、水酸化カルシウム、水酸化ナトリウム、アンモニアム又は炭酸水素ナトリウム（重曹）などを用いることができる。上述した例（溶解工程において塩酸溶液中でカルシウムを溶解させる例）の場合も、これらの物質を用いることができる。なお、リポソームを飲食品に用いる場合、ｐＨ調整剤としては炭酸水素ナトリウムを好適に用いることができる。 The pH adjusting step is a step of adjusting the solution to a predetermined pH by mixing a pH adjusting agent (neutralizing agent) with the solution after the dissolving step. The predetermined pH is in the range of 6.5 or more and 8 or less. A basic substance is added as a pH adjuster. As the pH adjuster, calcium hydroxide, sodium hydroxide, ammonia, sodium hydrogen carbonate (baking soda) or the like can be used. These substances can also be used in the case of the above-described example (example of dissolving calcium in a hydrochloric acid solution in the dissolving step). When the liposome is used for food and drink, sodium hydrogen carbonate can be preferably used as the pH adjuster.
次に、アルカリ性の溶液に難溶性物質を溶解させる場合の溶解工程及びｐＨ調節工程について説明を行う。溶解工程は、水酸化カルシウム、水酸化ナトリウム、アンモニアム又は炭酸水素ナトリウムなどのアルカリ性溶液中において難溶性物質を溶解させる工程である。難溶性物質の溶解を促進させるために加熱をしてもよい。また、アルカリ性溶液は、例えば濃度が濃いもの（例えば、ｐＨ＝１０以上１４以下の溶液）を用いる。なお、リポソームを食品に用いる場合、アルカリ性溶液としては炭酸水素ナトリウム溶液を好適に用いることができる。 Next, the dissolving step and the pH adjusting step when the hardly soluble substance is dissolved in an alkaline solution will be described. The dissolving step is a step of dissolving a hardly soluble substance in an alkaline solution such as calcium hydroxide, sodium hydroxide, ammonia or sodium hydrogencarbonate. Heating may be performed to accelerate the dissolution of the hardly soluble substance. As the alkaline solution, for example, a solution having a high concentration (for example, a solution having a pH of 10 or more and 14 or less) is used. When the liposome is used for food, a sodium hydrogen carbonate solution can be preferably used as the alkaline solution.
例えば、流動性物質の主成分として亜鉛を用いる場合、溶解工程では、式２に示すように、例えば水酸化ナトリウム溶液に亜鉛（難溶性物質）を入れて亜鉛を溶解させる。溶解工程後の溶液（水溶液）は、亜鉛イオンが水に溶けた状態となり、また未反応の水酸化ナトリウムによりアルカリ性となる。
式２：Ｚｎ＋２ＮａＯＨ＋２Ｈ２Ｏ→Ｎａ２［Ｚｎ（ＯＨ）４］＋Ｈ２
For example, when zinc is used as the main component of the fluid substance, in the dissolving step, for example, zinc (a sparingly soluble substance) is added to a sodium hydroxide solution to dissolve the zinc, as shown in Formula 2. The solution (aqueous solution) after the dissolution step becomes a state in which zinc ions are dissolved in water, and becomes alkaline due to unreacted sodium hydroxide.
Formula 2: Zn + 2NaOH + 2H 2 O → Na 2 [Zn (OH) 4 ] + H 2
ｐＨ調節工程は、溶解工程後の溶液に対しｐＨ調整剤（中和剤）を混ぜることにより、溶液を所定のｐＨに調整する工程である。所定のｐＨは、６．５以上８以下の範囲である。ｐＨ調整剤としては、酸性の物質を入れる。ｐＨ調整剤として、塩酸、酢酸、クエン酸、又はリンゴ酸などを用いることができる。上述した例（溶解工程において亜鉛を水酸化ナトリウムに溶解させる例）の場合も、これらを用いることができる。リポソームを食品に用いる場合、ｐＨ調整剤としてはクエン酸を好適に用いることができる。 The pH adjusting step is a step of adjusting the solution to a predetermined pH by mixing a pH adjusting agent (neutralizing agent) with the solution after the dissolving step. The predetermined pH is in the range of 6.5 or more and 8 or less. An acidic substance is added as a pH adjuster. As the pH adjusting agent, hydrochloric acid, acetic acid, citric acid, malic acid, or the like can be used. These can also be used in the case of the above-described example (example of dissolving zinc in sodium hydroxide in the dissolving step). When liposomes are used in foods, citric acid can be preferably used as a pH adjusting agent.
なお、酸性の溶液に難溶性物質を溶解させる場合であっても、アルカリ性の溶液に難溶性物質を溶解させる場合であっても、ｐＨ調整剤としては、ｐＨ調整剤を入れた溶液において、難溶性物質の溶解に用いた溶液との中和反応により生成される生成塩が溶解するものを選択してもよいし、生成塩が溶解しないもの選択してもよい。生成塩が溶解しないｐＨ調整剤を用いる場合は、ｐＨ調節工程後に、生成塩を濾過する工程を行う。 Even when the hardly soluble substance is dissolved in an acidic solution or when the hardly soluble substance is dissolved in an alkaline solution, the pH adjusting agent is difficult to dissolve in the solution containing the pH adjusting agent. It is possible to select one in which the produced salt produced by the neutralization reaction with the solution used to dissolve the soluble substance is dissolved, or one in which the produced salt is insoluble. When a pH adjusting agent that does not dissolve the produced salt is used, a step of filtering the produced salt is performed after the pH adjusting step.
次に、リポソーム化工程は、ｐＨ調節工程後の溶液（以下、「被内包液」という。）を内包するリポソームを製造する工程である。リポソーム化工程では、被内包液とリポソームの膜材料となる脂質（リン脂質、糖脂質など）とを混ぜ合せ、被内包液を内包するリポソームを形成する。リポソーム化工程におけるリポソームの製造には、バンガム法、逆相蒸発法、クロスフロー注入法、エクストルージョン法、フレンチプレス法、ホモジナイゼーション法、エタノール注入法、脱水−再水和法等の方法を用いることができる。 Next, the liposome formation step is a step of producing liposomes encapsulating the solution (hereinafter referred to as “encapsulated liquid”) after the pH adjustment step. In the liposome formation step, the encapsulated liquid is mixed with a lipid (phospholipid, glycolipid, etc.) that is a membrane material of the liposome to form a liposome encapsulating the encapsulated liquid. For the production of liposomes in the liposome formation step, methods such as the bangham method, the reverse phase evaporation method, the cross flow injection method, the extrusion method, the French press method, the homogenization method, the ethanol injection method, and the dehydration-rehydration method are used. Can be used.
例えばバンガム法を用いる場合、有機溶媒（クロロホルム、メタノールなど）に脂質を溶解させた後に、減圧下で有機溶媒を留去し脂質薄膜を得る。そして、ここに被内包液を加え、超音波乳化機などを用いて機械力で水和分散をさせることで、リポソームが製造される。なお、有機溶媒を用いずに、被内包液に脂質を分散させた脂質分散液を超音波乳化機により撹拌することによりリポソームを製造する方法を選択してもよい。 For example, when the bangham method is used, the lipid is dissolved in an organic solvent (chloroform, methanol, etc.), and then the organic solvent is distilled off under reduced pressure to obtain a lipid thin film. Then, the encapsulated liquid is added thereto, and the hydrate is dispersed by mechanical force using an ultrasonic emulsifier or the like to produce liposomes. In addition, you may select the method of manufacturing a liposome by stirring the lipid dispersion liquid which disperse | distributed the lipid in the encapsulated liquid with an ultrasonic emulsifier, without using an organic solvent.
また逆相蒸発法を用いる場合、有機溶媒（クロロホルムなど）に脂質を溶解させ、さらに被内包液を加えてエマルションとする。そして、減圧下において、エマルション中の有機溶媒を除去し、さらに水を添加することで、リポソームが製造される。 When the reverse phase evaporation method is used, the lipid is dissolved in an organic solvent (chloroform, etc.) and the liquid to be encapsulated is added to form an emulsion. Then, under reduced pressure, the organic solvent in the emulsion is removed, and water is further added to produce the liposome.
なお、リポソームの膜材料としてリン脂質を用いる場合、例えば大豆レシチン、ホスファチジルセリン等を用いることができる。リポソームの膜材料として糖脂質を用いる場合、ガラクトシルセラミド、ジガラクトシルグリセリド等を用いることができる。また、リポソームの膜材料として脂質以外に、コレステロール等の脂質膜安定化剤などを用いてもよい。 When phospholipid is used as the membrane material of the liposome, soybean lecithin, phosphatidylserine or the like can be used. When a glycolipid is used as the membrane material of the liposome, galactosylceramide, digalactosylglyceride or the like can be used. In addition to lipids, lipid membrane stabilizers such as cholesterol may be used as the membrane material of the liposome.
このように本実施形態によれば、酸性又はアルカリ性の溶液を用いた溶解工程と、溶解工程により難溶性物質が溶解した溶液を中性側に調整するｐＨ調節工程とを行うため、リポソームに内包させる流動性物質の主成分の原料として、難溶性物質を用いることができる。 As described above, according to the present embodiment, since the dissolving step using an acidic or alkaline solution and the pH adjusting step of adjusting the solution in which the hardly soluble substance is dissolved to the neutral side by the dissolving step are performed, the liposome is included. A poorly soluble substance can be used as a raw material of the main component of the fluid substance.
ここで、少なくともリポソーム化工程は、リポソーム製造装置で行われる。リポソーム化工程において製造された多数のリポソームについて、健康食品や化粧品、医薬品などに利用する場合、タンクなどの移動用容器に入れた状態でリポソーム製造装置から移動させる。この時、多数のリポソームは、移動用容器中において液体に浸漬させたリポソーム含有液の状態で移動させる。 Here, at least the liposome formation step is performed by a liposome manufacturing apparatus. When a large number of liposomes produced in the liposome formation step are used for health foods, cosmetics, pharmaceuticals, etc., they are moved from the liposome production apparatus while being placed in a transfer container such as a tank. At this time, a large number of liposomes are moved in the state of a liposome-containing liquid immersed in a liquid in a transfer container.
多数のリポソームを浸漬させる液体（リポソーム含有液の液成分）としては、リポソーム化工程においてリポソームを形成した溶液（以下、「リポソーム形成液」と言う。）をそのまま用いることもできるし、別の溶液を用いることもできる。別の溶液を用いる場合は、リポソーム形成液から多数のリポソームを単離して添加する。本実施形態では、何れの場合においても、リポソーム化工程後に、移動用容器の液体中において多数のリポソームを分散状態に維持するための増粘安定剤を添加する調整工程を行う。調整工程では、増粘安定剤の添加後のリポソーム含有液を攪拌する。なお、増粘安定剤の添加は、リポソーム含有液を移動用容器に入れる前に行ってもよいし、リポソーム含有液を入れた移動用容器において行ってもよい。 As a liquid for immersing a large number of liposomes (a liquid component of a liposome-containing liquid), a solution in which liposomes have been formed in the liposome formation step (hereinafter referred to as "liposome-forming liquid") can be used as it is, or another solution. Can also be used. When another solution is used, a large number of liposomes are isolated from the liposome forming solution and added. In this embodiment, in any case, after the liposome formation step, an adjustment step of adding a thickening stabilizer for maintaining a large number of liposomes in a dispersed state in the liquid in the transfer container is performed. In the adjusting step, the liposome-containing liquid after addition of the thickening stabilizer is stirred. The thickening stabilizer may be added before the liposome-containing liquid is placed in the transfer container, or may be added in the transfer container containing the liposome-containing liquid.
調整工程で添加する増粘安定剤としては、グリセリン、ペクチン、アラビアガム、グアーガム、キサンタンガム、タマリンドガム、カラギーナン、プロピレングリコール、カルボシキメチルセルロースなどを用いることができる。また、リポソーム含有液には増粘安定剤以外の添加剤（例えば、防腐剤、界面活性剤など）を加えてもよい。 As the thickening stabilizer added in the adjusting step, glycerin, pectin, gum arabic, guar gum, xanthan gum, tamarind gum, carrageenan, propylene glycol, carboxymethyl cellulose and the like can be used. Further, additives other than the thickening stabilizer (eg, preservatives, surfactants, etc.) may be added to the liposome-containing liquid.
ここで、移動用容器内のリポソーム含有液では、増粘安定剤がなければ、長時間が経過すると、沈殿によりリポソームが高密度の部分と低密度の部分が形成される。そのため、例えば、リポソーム含有液から、リポソーム含有液を入れたカプセル剤を製造する場合、カプセル間においてリポソーム数に偏りが生じる。 Here, in the liposome-containing liquid in the transfer container, if a thickening stabilizer is not present, a high density portion and a low density portion of the liposome are formed by precipitation over a long time. Therefore, for example, when a capsule containing the liposome-containing liquid is produced from the liposome-containing liquid, the number of liposomes is unevenly distributed among the capsules.
それに対し、本実施形態では、増粘安定剤を加える調整工程を行う。調整工程では、増粘安定剤を加えた後の容液を撹拌してリポソームを分散させる。そのため、長時間が経過しても、移動用容器内においてリポソームの密度がある程度均一に保たれる。従って、リポソーム含有液からカプセル剤を製造する場合、カプセル間におけるリポソーム数の偏りを抑制することができる。カプセル剤は、増粘安定剤を含むリポソーム含有液が封じ込められたものとなる。
［実施形態の変形例］
On the other hand, in the present embodiment, the adjusting step of adding the thickening stabilizer is performed. In the adjusting step, the liposome is dispersed by stirring the solution after adding the thickening stabilizer. Therefore, even after a long time has elapsed, the density of the liposomes can be kept uniform to some extent in the transfer container. Therefore, when a capsule is manufactured from a liposome-containing liquid, it is possible to suppress the deviation of the number of liposomes among capsules. The capsule contains a liposome-containing liquid containing a thickening stabilizer.
[Modification of Embodiment]
本実施形態における調整工程は、リポソームに内包させる流動性物質の主成分（例えば、Ｑ１０、クルクミン、ビタミン類等）の原料として、水に溶ける水溶性物質又は有機溶媒に溶ける脂溶性物質を用いる場合にも適用することができる。この場合、リポソームの製造方法は、原料（例えばＬ−アスコルビン酸）を液体（例えばＲＯ水）に溶解させてリポソームに内包させる被内包液を準備する溶解工程と、被内包液とリポソームの膜材料となる脂質とを混ぜ合わせて被内包液を内包するリポソームを製造するリポソーム化工程と、リポソーム化工程により製造された多数のリポソームと、多数のリポソームを浸漬させる液体と、その液体中において多数のリポソームを分散状態に維持するための増粘安定剤とを含むリポソーム含有液を製造する調整工程と、この順番で行う。 In the adjusting step in the present embodiment, when a water-soluble water-soluble substance or a fat-soluble substance soluble in an organic solvent is used as a raw material of the main component (eg, Q10, curcumin, vitamins, etc.) of the fluid substance to be encapsulated in the liposome. Can also be applied to. In this case, the method for producing liposomes includes a dissolution step of preparing an encapsulated liquid in which a raw material (eg, L-ascorbic acid) is dissolved in a liquid (eg, RO water) to be encapsulated in the liposome, and a membrane material for the encapsulated liquid and the liposome. A liposome forming step of producing a liposome encapsulating a liquid to be encapsulated by mixing with a lipid to be encapsulated, a large number of liposomes produced by the liposome forming step, a liquid in which a large number of liposomes are immersed, and a large number of liquids in the liquid. The adjustment step of producing a liposome-containing liquid containing a thickening stabilizer for maintaining the liposome in a dispersed state is performed in this order.
本発明は、リポソーム又はリポソーム含有液の製造方法等に適用可能である。 INDUSTRIAL APPLICABILITY The present invention is applicable to a method for producing a liposome or a liposome-containing liquid, and the like.
Claims (3)
酸性又はアルカリ性の溶液に、リポソームに内包させる流動性物質における主成分の原料として難溶性物質を溶解させる溶解工程と、
前記溶解工程により前記難溶性物質が溶解した溶液に、その溶液を中性側に調整するためのｐＨ調節剤を加えるｐＨ調節工程と、
前記ｐＨ調節工程後の溶液とリポソームの膜材料となる脂質とを混ぜ合せ、前記溶液を内包するリポソームを製造するリポソーム化工程とを含む、リポソームの製造方法。 A method for producing liposomes, comprising:
In an acidic or alkaline solution, a dissolution step of dissolving a poorly soluble substance as a raw material of the main component of the fluid substance to be encapsulated in liposomes,
A pH adjusting step of adding a pH adjusting agent for adjusting the solution to a neutral side, in a solution in which the hardly soluble substance is dissolved by the dissolving step,
A method for producing liposomes, comprising a step of producing a liposome encapsulating the solution by mixing the solution after the pH adjusting step with a lipid serving as a liposome membrane material.
リポソームに内包させる溶液とリポソームの膜材料となる脂質とを混ぜ合わせ、前記溶液を内包するリポソームを製造するリポソーム化工程と、
前記リポソーム化工程により製造された多数のリポソームと、前記多数のリポソームを浸漬させる液体と、前記液体中において前記多数のリポソームを分散状態に維持するための増粘安定剤とを含むリポソーム含有液を製造する調整工程とを含む、リポソーム含有液の製造方法。 A method for producing a liposome-containing liquid, comprising:
A liposome formation step of producing a liposome encapsulating the solution by mixing a solution to be encapsulated in the liposome with a lipid serving as a liposome membrane material,
A liposome-containing liquid containing a large number of liposomes produced by the liposome formation step, a liquid in which the large number of liposomes is immersed, and a thickening stabilizer for maintaining the large number of liposomes in a dispersed state in the liquid. A method for producing a liposome-containing liquid, which comprises a production step for producing.
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