JPH0737381B2 - Vitamin E aqueous preparation - Google Patents
Vitamin E aqueous preparationInfo
- Publication number
- JPH0737381B2 JPH0737381B2 JP62119932A JP11993287A JPH0737381B2 JP H0737381 B2 JPH0737381 B2 JP H0737381B2 JP 62119932 A JP62119932 A JP 62119932A JP 11993287 A JP11993287 A JP 11993287A JP H0737381 B2 JPH0737381 B2 JP H0737381B2
- Authority
- JP
- Japan
- Prior art keywords
- vitamin
- hemisuccinate
- alkali metal
- water
- aqueous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 title claims description 64
- 229930003427 Vitamin E Natural products 0.000 title claims description 31
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 title claims description 31
- 239000011709 vitamin E Substances 0.000 title claims description 31
- 229940046009 vitamin E Drugs 0.000 title claims description 31
- 235000019165 vitamin E Nutrition 0.000 title claims description 31
- 238000002360 preparation method Methods 0.000 title claims description 17
- -1 alkali metal salt Chemical class 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 229910052783 alkali metal Inorganic materials 0.000 claims description 13
- 239000000839 emulsion Substances 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- 230000001804 emulsifying effect Effects 0.000 claims description 6
- 239000003889 eye drop Substances 0.000 claims description 5
- 238000009210 therapy by ultrasound Methods 0.000 claims description 5
- 238000004945 emulsification Methods 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims 1
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 159000000000 sodium salts Chemical class 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000003995 emulsifying agent Substances 0.000 description 5
- 230000003381 solubilizing effect Effects 0.000 description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 239000000787 lecithin Substances 0.000 description 4
- 235000010445 lecithin Nutrition 0.000 description 4
- 229940067606 lecithin Drugs 0.000 description 4
- 239000002736 nonionic surfactant Substances 0.000 description 4
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 4
- 229930182490 saponin Natural products 0.000 description 4
- 150000007949 saponins Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960000984 tocofersolan Drugs 0.000 description 4
- 229940088594 vitamin Drugs 0.000 description 4
- 229930003231 vitamin Natural products 0.000 description 4
- 235000013343 vitamin Nutrition 0.000 description 4
- 239000011782 vitamin Substances 0.000 description 4
- 150000003722 vitamin derivatives Chemical class 0.000 description 4
- 239000002076 α-tocopherol Substances 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229940087168 alpha tocopherol Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002168 ethanoic acid esters Chemical class 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 150000003900 succinic acid esters Chemical class 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 2
- 235000004835 α-tocopherol Nutrition 0.000 description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960003260 chlorhexidine Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 「産業上の利用分野」 本発明は、ビタミンＥヘミコハク酸エステルのアルカリ
金属塩の医薬として有用な水性製剤を提供するものであ
る。DETAILED DESCRIPTION OF THE INVENTION "Industrial field of application" The present invention provides an aqueous preparation useful as a medicine of an alkali metal salt of vitamin E hemisuccinate.
「従来技術」 ビタミンＥは天然の抗酸化剤として一般に知られ医薬、
化粧品、食品分野で広く用いられている。ビタミンＥに
は天然型ビタミンＥ（ｄ−α−トコフェロール）と非天
然型ビタミンＥ（d1−α−トコフェロール）があり、ま
たその脂肪酸エステルとしては酢酸エステル、コハク酸
エステル、ニコチン酸エステル等がある。しかし、これ
らのものは水にほとんど溶解しないため、高濃度のビタ
ミンＥ類を点眼剤、注射剤あるいはドリンク剤等の水性
製剤とするのは非常に困難とされていた。この問題に対
し、従来技術として非イオン性界面活性剤を用いて可溶
化または乳化する方法、天然の界面活性剤であるレシチ
ンあるいはサポニンを用いて可溶化または乳化する方
法、ポリグリセリン脂肪酸エステルまたはアルコール類
を用いて可溶化または乳化する方法等が考えられてい
る。"Prior Art" Vitamin E is a drug commonly known as a natural antioxidant,
Widely used in cosmetics and food fields. Vitamin E includes natural vitamin E (d-α-tocopherol) and non-natural vitamin E (d1-α-tocopherol), and fatty acid esters thereof include acetic acid ester, succinic acid ester, and nicotinic acid ester. . However, since these substances are hardly dissolved in water, it has been considered very difficult to make high-concentration vitamin Es into aqueous preparations such as eye drops, injections and drinks. To solve this problem, as a conventional technique, a method of solubilizing or emulsifying using a nonionic surfactant, a method of solubilizing or emulsifying using lecithin or saponin which is a natural surfactant, polyglycerin fatty acid ester or alcohol A method of solubilizing or emulsifying using a class is considered.
「発明が解決しようとする問題点」 しかしながら、高濃度のビタミンＥ水性製剤において
は、レシチンはその化学的安定性に難点があり、非イオ
ン性界面活性剤やサポニンを使用する場合はその添加量
が非常に多いこと、アルコール類はその刺激性のため好
ましくない等の問題がある。"Problems to be Solved by the Invention" However, in a high-concentration vitamin E aqueous preparation, lecithin has a difficulty in its chemical stability, and when a nonionic surfactant or saponin is used, the addition amount thereof is small. However, alcohols are not preferable because they are irritating.
「問題を解決する為の手段および作用」 本発明者等はビタミンＥ類を水性製剤とする際の問題を
解決すべく鋭意研究した結果、ビタミンＥのヘミコハク
酸エステルのアルカリ金属塩を用いることにより溶解補
助剤および乳化剤をまったく含まないビタミンＥの高濃
度の水性乳化組成物を得る事に成功した。"Means and Actions for Solving Problems" The inventors of the present invention have conducted diligent research to solve the problem of forming vitamin Es into an aqueous preparation, and as a result, by using an alkali metal salt of hemisuccinate of vitamin E, We have succeeded in obtaining a high-concentration aqueous emulsion composition of vitamin E that does not contain any solubilizer or emulsifier.
「発明の開示」 ビタミンＥは天然の抗酸化剤として一般に知られ医薬、
化粧品、食品分野で広く用いられている。ビタミンＥに
は天然型ビタミンＥ（（ｄ−α−トコフェロール）と非
天然型ビタミンＥ（d1−α−トコフェロール）があり、
またその脂肪酸エステルとしては酢酸エステル、コハク
酸エステル、ニコチン酸エステル等がある（以下ビタミ
ンＥと俗称する）。しかし、これらのものは水にほとん
ど溶解しないため、高濃度のビタミンＥ類を点眼剤、注
射剤あるいはドリンク剤等の水性製剤とするのは非常に
困難とされていた。ビタミンＥ類を水性製剤とする為に
非イオン性界面活性剤、天然の界面活性剤であるレシチ
ン又はサポニンを用いた可溶化あるいは乳化する方法、
さらにはポリグリセリン脂肪酸エステル又はアルコール
類を用いた可溶化あるいは乳化する方法が検討されてい
た。しかしながら、ビタミンＥを高濃度に配合する場
合、レシチンはその化学的安定性に難点があり、非イオ
ン性界面活性剤やサポニンを使用する場合はその添加量
が非常に多いこと、アルコール類はその刺激性のため好
ましくない等の問題があり、満足できる水性製剤を提供
できなかった。本発明者らは医薬として満足し得るビタ
ミンＥの水性製剤を種々検討した結果、ヘミコハク酸エ
ステルのアルカリ金属塩を用いると驚くべきことに溶解
補助剤や乳化剤を用いなくても医薬として満足し得る水
性製剤が得られる事を見い出した。本発明の水性製剤は
均一でかつ安定性の高い乳化製剤であって、ビタミンＥ
のヘミコハク酸エステルのアルカリ金属塩を使用する事
によって、均一でかつ安定性の高い乳化製剤が得られる
ものである。アルカリ金属の代表例としてはナトリウ
ム、カリウムがあげられ、適宜選択することができる。DISCLOSURE OF THE INVENTION Vitamin E is a drug commonly known as a natural antioxidant,
Widely used in cosmetics and food fields. Vitamin E includes natural vitamin E ((d-α-tocopherol) and non-natural vitamin E (d1-α-tocopherol),
Examples of the fatty acid ester include acetic acid ester, succinic acid ester, nicotinic acid ester and the like (hereinafter commonly referred to as vitamin E). However, since these substances are hardly dissolved in water, it has been considered very difficult to make high-concentration vitamin Es into aqueous preparations such as eye drops, injections and drinks. A method for solubilizing or emulsifying vitamin Es using a nonionic surfactant, lecithin or saponin which is a natural surfactant to prepare an aqueous preparation,
Further, a method of solubilizing or emulsifying using polyglycerin fatty acid ester or alcohol has been studied. However, when vitamin E is blended in a high concentration, lecithin has a difficulty in its chemical stability, and when a nonionic surfactant or saponin is used, the addition amount is very large, and alcohols are There is a problem that it is not preferable because of its irritation, and a satisfactory aqueous preparation cannot be provided. As a result of various studies on an aqueous preparation of vitamin E which is satisfactory as a medicine, the present inventors surprisingly can be satisfied as a medicine without using a solubilizer or an emulsifier, when an alkali metal salt of hemisuccinate is used. It has been found that an aqueous formulation is obtained. The aqueous preparation of the present invention is a uniform and highly stable emulsified preparation, which contains vitamin E.
By using the alkali metal salt of the hemisuccinate ester, the uniform and highly stable emulsion preparation can be obtained. Representative examples of the alkali metal include sodium and potassium, which can be appropriately selected.
ここで用いるビタミンＥのヘミコハク酸エステルのアル
カリ金属塩は水に分散させる前に予め調製してもよい
し、ビタミンＥのヘミコハク酸エステルを水に懸濁させ
たのち所定量のアルカリ金属を加えることにより調製し
てもよい。The alkali metal salt of hemi-succinic acid ester of vitamin E used here may be prepared in advance before being dispersed in water, or the hemi-succinic acid ester of vitamin E may be suspended in water and then a predetermined amount of alkali metal is added. You may prepare by.
ビタミンＥのヘミコハク酸エステルのアルカリ金属塩を
水に加え攪拌するだけで均一な水性乳化組性物を得るこ
とができるが、より均一で安定な水性乳化組成物を得る
ため超音波処理、高圧噴射乳化処理あるいは濾過処理す
ることにより乳化液滴の粒子径をさらに細かくし乳化系
の安定化を図ることが好ましい。A uniform aqueous emulsion composition can be obtained simply by adding an alkali metal salt of a hemi-succinate ester of vitamin E to water and stirring it. However, in order to obtain a more uniform and stable aqueous emulsion composition, ultrasonic treatment and high-pressure injection are performed. It is preferable to further reduce the particle size of the emulsified droplets by performing an emulsification treatment or a filtration treatment to stabilize the emulsification system.
本発明の水性製剤は点眼剤、注射剤等に使用することが
できる。The aqueous preparation of the present invention can be used in eye drops, injections and the like.
このビタミンＥヘミコハク酸エステルの乳化組成物には
必要に応じて等張化剤として塩化ナトリウム等の無機塩
類、ホウ酸、マンニトール等の糖類、グリセリン等の通
常点眼剤や注射剤に用いられる等張化剤、緩衝剤として
酢酸ナトリウム、クエン酸、リン酸ナトリウム、ホウ酸
一ホウ砂、イプシロンアミノカプロン酸等の緩衝剤およ
び防腐剤としてパラオキシ安息香酸エステル類、塩化ベ
ンザルコニウム、グルクロン酸クロルヘキシジン、フェ
ネチルアルコール、ソルビン酸等、また必要に応じてED
TA、アスコルビン酸、亜硫酸水素ナトリウム等の安定化
剤を加えることができる。In this emulsion composition of vitamin E hemisuccinate, an isotonic agent such as an inorganic salt such as sodium chloride as a tonicity agent, a saccharide such as boric acid or mannitol, a normal eye drop such as glycerin or an injection is used as an isotonic agent, if necessary. Agents and buffers such as sodium acetate, citric acid, sodium phosphate, monoborax borate, epsilon aminocaproic acid, etc. as buffering agents and preservatives, paraoxybenzoic acid esters, benzalkonium chloride, chlorhexidine glucuronic acid, phenethyl alcohol , Sorbic acid, etc., and if necessary ED
Stabilizers such as TA, ascorbic acid and sodium bisulfite can be added.
本発明のビタミンＥのヘミコハク酸エステルの水性製剤
の代表的製造方法について説明すると、ビタミンＥヘミ
コハク酸エステルをアルコールに溶解しこれに等モルの
アルカリ金属水酸化物を加え凍結乾燥してビタミンＥヘ
ミコハク酸エステルのアルカリ金属塩を得たのち、水に
分散させ超音波処理、高圧噴射乳化処理、濾過処理のう
ち１つあるいはそれらを組み合せた処理方法により乳化
液滴の微細化を行い均一で安定な乳化組成物を得る。な
お、ビタミンＥヘミコハク酸エステルのアルカリ金属塩
の調製方法および乳化液滴の微細化はその他の公知の方
法であってもよくこれにより限定されるものではない。A typical method for producing an aqueous preparation of a vitamin E hemisuccinate of the present invention will be described. Vitamin E hemisuccinate is dissolved in alcohol, an equimolar amount of an alkali metal hydroxide is added thereto, and the mixture is freeze-dried to obtain a vitamin E hemisuccinate. After obtaining the alkali metal salt of the acid ester, it is dispersed in water and one of ultrasonic treatment, high-pressure jet emulsification treatment, filtration treatment or a combination thereof is used to atomize the emulsified droplets to make it uniform and stable. An emulsified composition is obtained. The method for preparing the alkali metal salt of vitamin E hemisuccinate and the atomization of the emulsified droplets may be other known methods, and are not limited thereto.
「実施例」 参考例１ ビタミンＥのヘミコハク酸エステル2gをエタノール10ml
に溶解し、1N水酸化ナトリウム3.76mlを加え、さらに水
100mlを加えた後、凍結乾燥してビタミンＥのヘミコハ
ク酸エステルのナトリウム塩を得た。"Example" Reference Example 1 2 g of hemi-succinate ester of vitamin E and 10 ml of ethanol
Dissolved in water, added 3.76 ml of 1N sodium hydroxide, and added water.
After adding 100 ml, it was freeze-dried to obtain a sodium salt of a hemisuccinate ester of vitamin E.
実施例１ 参考例１で得たビタミンＥのヘミコハク酸エステルのナ
トリウム塩1gに生理食塩液10mlを加え攪拌したのち10％
（W/V）のビタミンＥヘミコハク酸エステルのナトリウ
ム塩の均一な乳化液を得た。Example 1 10 g of physiological saline was added to 1 g of the sodium salt of hemisuccinate of vitamin E obtained in Reference Example 1 and stirred, and then 10%.
A uniform emulsion of the sodium salt of Vitamin E hemisuccinate (W / V) was obtained.
実施例２ 参考例１で得たビタミンＥのヘミコハク酸エステルのナ
トリウム塩0.1gに2.5％グリセリン水溶液10mlを加え５
分間超音波処理を行い均一な１％（W/V）のビタミンＥ
ヘミコハク酸エステルのナトリウム塩の乳化液を得た。Example 2 To 0.1 g of the sodium hemisuccinate ester of vitamin E obtained in Reference Example 1 was added 10 ml of a 2.5% glycerin aqueous solution, and then 5
1 minute (W / V) Vitamin E with ultrasonic treatment for 1 minute
An emulsion of the sodium salt of hemisuccinate was obtained.
参考例２ ビタミンＥのヘミコハク酸エステル2gをエタノール20ml
に溶解し、1N水酸化カリウム3.76mlを加え、さらに水10
0mlを加えた後凍結乾燥してビタミンＥのヘミコハク酸
エステルのカリウム塩を得た。Reference example 2 Vitamin E hemisuccinate 2 g ethanol 20 ml
Dissolved in water, added 3.76 ml of 1N potassium hydroxide, and added water 10
After adding 0 ml, it was freeze-dried to obtain a potassium salt of a hemisuccinate ester of vitamin E.
実施例３ 参考例２の方法に従って調製したビタミンＥのヘミコハ
ク酸エステルのカリウム塩20gに生理食塩液100mlおよび
0.005％の塩化ベンザルコニウムを加え、高圧噴射型乳
化機（マントンゴーリンホモミキサー）を用いて500kg/
cm2の圧力で10回処理し、20％（W/V）のビタミンＥヘミ
コハク酸エステルのカリウム塩の均一で安定な乳化液を
得た。Example 3 20 g of potassium hemisuccinate of vitamin E prepared according to the method of Reference Example 2 was added to 100 g of physiological saline.
Add 0.005% benzalkonium chloride and use a high-pressure injection type emulsifier (Manton-Gaulin homomixer) to obtain 500 kg /
Treatment with a pressure of cm 2 was repeated 10 times to obtain a uniform and stable emulsion of 20% (W / V) potassium salt of vitamin E hemisuccinate.
実施例４ 参考例１で得たビタミンＥのヘミコハク酸エステルのナ
トリウム塩1gにpH6のリン酸緩衝液10ml、塩化ベンザル
コニウム0.005％およびEDTA0.05％を加え0.1μｍの孔径
のポリカーボネートフィルターを用いて濾過し、10％
（W/V）のビタミンＥヘミコハク酸エステルのナトリウ
ム塩の均一で安定な乳化液を得た。Example 4 To 1 g of the sodium salt of hemisuccinate ester of vitamin E obtained in Reference Example 1 was added 10 ml of a pH 6 phosphate buffer solution, 0.005% of benzalkonium chloride and 0.05% of EDTA, and a polycarbonate filter having a pore size of 0.1 μm was used. Filtered and 10%
A homogeneous and stable emulsion of the sodium salt of the vitamin E hemisuccinate (W / V) was obtained.
実施例５ ビタミンＥのヘミコハク酸エステル1gに水50mlを加え攪
拌しながら0.1N水酸化ナトリウム18.8mlを加え充分攪拌
したのちさらに水を加え全量100mlとする。この液を10
分間超音波処理したのち高圧噴射型乳化機を用いて500k
g/cm2の圧力で10回処理し、１％（W/V）のビタミンＥヘ
ミコハク酸エステルのナトリウム塩を含む均一で安定な
乳化剤を得た。Example 5 To 1 g of hemi-succinic acid ester of vitamin E, 50 ml of water was added, and 18.8 ml of 0.1N sodium hydroxide was added with stirring, and after sufficient stirring, water was further added to make 100 ml in total. This liquid 10
After ultrasonic treatment for 5 minutes, use a high-pressure jet type emulsifier for 500k
The mixture was treated 10 times at a pressure of g / cm 2 to obtain a uniform and stable emulsifier containing 1% (W / V) of sodium salt of vitamin E hemisuccinate.
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 昭57−163313（ＪＰ，Ａ) 特開 昭59−210024（ＪＰ，Ａ) 特公 昭42−17822（ＪＰ，Ｂ１) ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-57-163313 (JP, A) JP-A-59-210024 (JP, A) JP-B-42-17822 (JP, B1)
Claims (3)
カリ金属塩を水に乳化してなる水性乳化製剤。1. An aqueous emulsified preparation obtained by emulsifying an alkali metal salt of a hemisuccinate of vitamin E in water.
記載の水性乳化製剤。2. The aqueous emulsion preparation according to claim 1, wherein the dosage form is an eye drop.
カリ金属塩を水に加え、超音波処理、高圧噴射乳化処理
およびまたは濾過処理することを特徴とするビタミンＥ
のヘミコハク酸エステルアルカリ金属塩の水性乳化製剤
の製造法。3. Vitamin E characterized by adding an alkali metal salt of hemisuccinate ester of vitamin E to water and subjecting to ultrasonic treatment, high-pressure injection emulsification treatment and / or filtration treatment.
A method for producing an aqueous emulsion preparation of an alkali metal hemisuccinate ester of.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62119932A JPH0737381B2 (en) | 1987-05-15 | 1987-05-15 | Vitamin E aqueous preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62119932A JPH0737381B2 (en) | 1987-05-15 | 1987-05-15 | Vitamin E aqueous preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6470413A JPS6470413A (en) | 1989-03-15 |
| JPH0737381B2 true JPH0737381B2 (en) | 1995-04-26 |
Family
ID=14773736
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62119932A Expired - Fee Related JPH0737381B2 (en) | 1987-05-15 | 1987-05-15 | Vitamin E aqueous preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0737381B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2811036B2 (en) * | 1992-05-26 | 1998-10-15 | 参天製薬株式会社 | Vitamin E eye drops |
| EP0798305B1 (en) * | 1995-10-17 | 2007-10-03 | Showa Denko Kabushiki Kaisha | High-purity tocopherol phosphates, process for the preparation thereof, method for analysis thereof, and cosmetics |
| US6379688B2 (en) * | 1997-02-28 | 2002-04-30 | Senju Pharmaceutical Co., Ltd. | Preservative for emulsion and emulsion containing same |
| TWI787221B (en) * | 2016-12-19 | 2022-12-21 | 日商獅子股份有限公司 | Ophthalmic composition and its production method |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57163313A (en) * | 1981-03-31 | 1982-10-07 | Nippon Shinyaku Co Ltd | Vitamin e pharmaceutical and its preparation |
| JPS59210024A (en) * | 1983-05-13 | 1984-11-28 | Taiyo Kagaku Kk | Emulsified tocopherol |
-
1987
- 1987-05-15 JP JP62119932A patent/JPH0737381B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6470413A (en) | 1989-03-15 |
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