CN1615828A - Allicin injection emulsion and preparation method thereof - Google Patents
Allicin injection emulsion and preparation method thereof Download PDFInfo
- Publication number
- CN1615828A CN1615828A CNA2004100608155A CN200410060815A CN1615828A CN 1615828 A CN1615828 A CN 1615828A CN A2004100608155 A CNA2004100608155 A CN A2004100608155A CN 200410060815 A CN200410060815 A CN 200410060815A CN 1615828 A CN1615828 A CN 1615828A
- Authority
- CN
- China
- Prior art keywords
- injection
- allicin
- garlicin
- emulsifier
- weight
- 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.)
- Granted
Links
- 238000002347 injection Methods 0.000 title claims abstract description 101
- 239000007924 injection Substances 0.000 title claims abstract description 101
- 239000000839 emulsion Substances 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- JDLKFOPOAOFWQN-VIFPVBQESA-N Allicin Natural products C=CCS[S@](=O)CC=C JDLKFOPOAOFWQN-VIFPVBQESA-N 0.000 title claims abstract description 18
- JDLKFOPOAOFWQN-UHFFFAOYSA-N allicin Chemical compound C=CCSS(=O)CC=C JDLKFOPOAOFWQN-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 235000010081 allicin Nutrition 0.000 title claims abstract description 18
- 238000004945 emulsification Methods 0.000 title description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000003921 oil Substances 0.000 claims abstract description 18
- 239000002245 particle Substances 0.000 claims abstract description 18
- 210000003022 colostrum Anatomy 0.000 claims abstract description 17
- 235000021277 colostrum Nutrition 0.000 claims abstract description 17
- 239000008215 water for injection Substances 0.000 claims abstract description 16
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 14
- 239000012982 microporous membrane Substances 0.000 claims abstract description 10
- 239000007957 coemulsifier Substances 0.000 claims abstract description 9
- 239000007951 isotonicity adjuster Substances 0.000 claims abstract description 8
- 239000006185 dispersion Substances 0.000 claims abstract description 4
- 239000002609 medium Substances 0.000 claims abstract description 3
- 239000002612 dispersion medium Substances 0.000 claims abstract 3
- 238000010298 pulverizing process Methods 0.000 claims abstract 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 41
- 235000011187 glycerol Nutrition 0.000 claims description 14
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 10
- 239000004094 surface-active agent Substances 0.000 claims description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 7
- 229920001993 poloxamer 188 Polymers 0.000 claims description 7
- 229940044519 poloxamer 188 Drugs 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 5
- -1 palmitic acid glycol ester Chemical class 0.000 claims description 5
- 150000003904 phospholipids Chemical group 0.000 claims description 5
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 4
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 4
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 4
- 239000004380 Cholic acid Substances 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 239000005642 Oleic acid Substances 0.000 claims description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 4
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 4
- 235000019416 cholic acid Nutrition 0.000 claims description 4
- 229960002471 cholic acid Drugs 0.000 claims description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 2
- 229960003964 deoxycholic acid Drugs 0.000 claims description 2
- 125000005456 glyceride group Chemical group 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 229960000502 poloxamer Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 239000002131 composite material Substances 0.000 claims 2
- 235000021314 Palmitic acid Nutrition 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 235000014113 dietary fatty acids Nutrition 0.000 claims 1
- 239000000194 fatty acid Substances 0.000 claims 1
- 229930195729 fatty acid Natural products 0.000 claims 1
- 235000001727 glucose Nutrition 0.000 claims 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N n-hexadecanoic acid Natural products CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 9
- 230000007794 irritation Effects 0.000 abstract description 5
- 238000010253 intravenous injection Methods 0.000 abstract description 4
- 230000002792 vascular Effects 0.000 abstract description 3
- 235000013336 milk Nutrition 0.000 abstract 1
- 239000008267 milk Substances 0.000 abstract 1
- 210000004080 milk Anatomy 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 21
- 239000012071 phase Substances 0.000 description 20
- 235000019198 oils Nutrition 0.000 description 16
- 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 14
- 239000008347 soybean phospholipid Substances 0.000 description 14
- 238000005303 weighing Methods 0.000 description 14
- 235000012424 soybean oil Nutrition 0.000 description 13
- 239000003549 soybean oil Substances 0.000 description 13
- 210000003462 vein Anatomy 0.000 description 12
- 239000002552 dosage form Substances 0.000 description 11
- 239000004530 micro-emulsion Substances 0.000 description 10
- 230000001954 sterilising effect Effects 0.000 description 9
- 238000004659 sterilization and disinfection Methods 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 210000004204 blood vessel Anatomy 0.000 description 8
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- 238000000034 method Methods 0.000 description 7
- 206010030113 Oedema Diseases 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
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- 239000003814 drug Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000001804 emulsifying effect Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 150000002168 ethanoic acid esters Chemical class 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 241000234282 Allium Species 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
- 206010020565 Hyperaemia Diseases 0.000 description 2
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- 239000002775 capsule Substances 0.000 description 2
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- 210000000582 semen Anatomy 0.000 description 2
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- 210000001519 tissue Anatomy 0.000 description 2
- 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 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 240000002234 Allium sativum Species 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 241001105098 Angelica keiskei Species 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
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- 241001646826 Isodon rubescens Species 0.000 description 1
- 241000234280 Liliaceae Species 0.000 description 1
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
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- 230000002146 bilateral effect Effects 0.000 description 1
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- 239000008280 blood Substances 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
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- 235000005822 corn Nutrition 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
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- NNYBQONXHNTVIJ-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=C1C(C=CC=C1CC)=C1N2 NNYBQONXHNTVIJ-UHFFFAOYSA-N 0.000 description 1
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- 239000011630 iodine Substances 0.000 description 1
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- 230000002147 killing effect Effects 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
本发明涉及大蒜素注射乳剂，该注射剂为一水性分散体，分散相平均粒径≤1μm，含有0.5～2.5份重量的大蒜素、0.2～7.5份重量的注射用乳化剂、0～3份的助乳化剂、5～20份重量的油相分散介质、0.5～3份重量的等渗剂，注射剂中大蒜素的含量为1～20mg/ml。其制备方法：将大蒜素、乳化剂、助乳化剂、油相介质、等渗剂混合，加注射用水；然后经超声波粉碎形成初乳，用高压乳匀机进一步乳化至形成的水性分散相的平均粒径≤1μm，调节pH值到5～7，经微孔滤膜过滤，灌封、灭菌即得大蒜素注射剂。本发明不仅解决了大蒜素水溶性差的问题，而且还减轻了大蒜素静脉注射时的血管刺激性并提高了大蒜素的稳定性。The invention relates to an allicin injection emulsion. The injection is an aqueous dispersion, the average particle diameter of the dispersed phase is less than or equal to 1 μm, and contains 0.5 to 2.5 parts by weight of allicin, 0.2 to 7.5 parts by weight of an emulsifier for injection, and 0 to 3 parts by weight of Co-emulsifier, 5-20 parts by weight of oil phase dispersion medium, 0.5-3 parts by weight of isotonic agent, and the content of allicin in the injection is 1-20 mg/ml. Its preparation method: mix allicin, emulsifier, co-emulsifier, oil phase medium, and isotonic agent, add water for injection; then form colostrum through ultrasonic pulverization, and further emulsify with a high-pressure milk homogenizer until the water-based dispersed phase formed The average particle size is ≤1 μm, the pH value is adjusted to 5-7, filtered through a microporous membrane, potted and sterilized to obtain the allicin injection. The invention not only solves the problem of poor water solubility of the allicin, but also reduces the vascular irritation of the allicin during intravenous injection and improves the stability of the allicin.
Description
Technical field
The present invention relates to garlicin injection Emulsion and preparation method thereof, belong to medical technical field.
Background technology
Garlicin is the main component of the Bulbus Allii volatile oil that obtains by steam distillation etc. after crushed of the underground bulb of Liliaceae allium Bulbus Allii Allium Satirum L., the English of garlicin is called Allitride, chemistry allicin by name, molecular formula is C
6H
10S
3, molecular weight is 178.33, molecular structural formula is as follows:
Garlicin is mainly used in sterilization, is described as natural natural " broad ectrum antibiotic ", and various bacteria and fungus are all had inhibition and killing action, can be used for treating dysentery and enteritis etc., and in recent years, garlicin also is used to tumor treatment clinically.In addition, garlicin also has effects such as human body immunity improving, blood pressure lowering, blood fat reducing, antioxidation.But garlicin is water-soluble hardly, to thermally labile, and when being applied to the human injection skin and mucosa is had zest, and these have all limited its application clinically.
Relate to the compound preparation that adopts garlicin and other biological active component or Chinese herbal medicine to form by document, for example to disclose by angelica keiskei koidzumi, chitosan, Semen Coicis, radix sophorae, Semen Cuscutae, garlicin, Rabdosia rubescens, Herba Hedyotidis Diffusae, Poria, Artemisia absinihium L and ascorbic acid be the preparation method of a kind of Chinese medicine medicine for preventing of making of raw material to Chinese patent CN02132474.3, and comprised in capsule, tablet, powder, the oral liquid etc. with dosage form and exterior-applied formulations such as unguentum, baste.
It is raw material and iodine or lodine chloride generation chemical reaction that Chinese patent CN95110445.4 discloses with the garlicin, generates Iodized modified garlic essence, adsorbs the powder of favorable dispersibility in the water of making odorless again through emulsifying, glucose.
Chinese patent CN03111531.4 discloses the clathrate of garlicin and Oleum Bulbus Allii and cyclodextrin derivative and has made dosage forms such as transfusion, aqueous injection, injectable powder, tablet, capsule, micropill.
03112233.7 number Chinese patent application discloses injection that the garlicin hydroxypropyl-beta-cyclodextrin inclusion makes and preparation method thereof, solved the water solublity problem when garlicin is made injection to a certain extent, but the inclusion rate of this kind clathrate is generally not satisfactory, and the zest of garlicin and special odor often improve not quite.
All ubiquity is big to the body zest in the involved preparation of above patent documentation, and the insufficient problem of garlicin stability brings adverse influence for the clinical practice and the storage of garlicin preparation.
Purpose of the present invention just be to provide a kind of when having better stability and intravenous injection to less irritating garlicin injection Emulsion of blood vessel and preparation method thereof.
The inventor is for achieving the above object, use micro-emulsion technology and prepare garlicin injection, not only solved the problem of garlicin poorly water-soluble, but also when having alleviated the garlicin intravenous injection to the zest of blood vessel and improved the stability of garlicin, thereby finished the present invention.
Summary of the invention
The technical solution adopted in the present invention is as follows: garlicin injection, this injection is an aqueous dispersion, particle diameter of dispersing phase≤1 μ m, contain the oil phase disperse medium of the injection emulsifying agent of the garlicin of 0.5～2.5 part of weight, 0.2～7.5 part of weight, 0～3 part co-emulsifier, 5～20 parts of weight, the isotonic agent of 0.5～3 part of weight, the content of garlicin is 1～20mg/ml in the injection.
Garlicin used in the present invention can be to extract or CO by vapor distillation, squeezing from Bulbus Allii
2The garlicin extract of garlicin content 〉=80% that methods such as supercritical extraction obtain, more preferably the garlicin synthetic product of garlicin content 〉=95%.
Emulsifying agent of the present invention is the compound emulsifying agent of one or more combination in any in phospholipid surfactant (as fabaceous lecithin, egg phosphatide), poloxamer (Poloxamer) class surfactant, Tween 80, polyglycereol Palmic acid diol ester, Drewmulse and the acetic acid esters of mono, the compound emulsifying agent that preferred phospholipid surfactant or itself and Poloxame 188 make up.
Co-emulsifier among the present invention is generally polar organic matter (the nonionic surfactant that the alcohols of medium chain and HLB value suitable of chain length than surfactant chain length, as mannitol, n-butyl alcohol, hexanol, ethylene glycol, propylene glycol etc.), it both can increase the compliance of film, help the formation of microemulsion emulsion droplet interfacial film, can increase the dissolubility of emulsifying agent again, further reduce surface tension.Help the stable of microemulsion.
Garlicin oil phase disperse medium among the present invention is vegetable oil (as soybean oil, Oleum Ricini, safranine caul-fat (safflower), corn wet goods), contain the medium chain triglyceride of the fatty glyceride of 6-12 carbon atom.
Isotonic agent among the present invention can be glycerol, sorbitol, xylitol, glucose.
Also some additives be can add among the present invention, as the hydrochloric acid of pH value or sodium hydroxide are used to regulate and as the dl-alpha-tocopherol of antioxidant.The interfacial film of Emulsion can change because of adding fat-soluble medicine in addition, so the present invention also can further add the stabilizing agent that can be positioned in the interfacial film. their molecule is normally partly hydrophilic, partly lipophilic, surface activity is not high, but because of increasing the electrostatic surface charges of molecular separating force and emulsion droplet, so can improve the stability of film.The preferred cholic acid of these stabilizing agents, deoxycholic acid and salt thereof, more preferably oleic acid or its sodium salt.The weight ratio of these additives and principal agent garlicin is 0～0.5: 0.5～2.5.
Employed adjuvant requires to meet national injection standard among the present invention, and the use of solvent must meet medicinal standard equally.
The vein emulsion type that the present invention can be made into is meant the intravenous injection emulsion of the mean diameter≤1 μ m of decentralized photo.Wherein the particle size range of decentralized photo 100-500nm be the submicron emulsion dosage form, particle diameter is the microemulsion dosage form below 100nm.And the breadth coefficient PI value of both particle diameters all answers≤and 0.5.
The invention provides the preparation method of above-mentioned vein emulsified injection, with garlicin, emulsifying agent, co-emulsifier, oil-phase medium, isotonic agent, additives with 0.5～2.5: 0.2～7.5: 0～3: 5～20: 0.5～3: 0～0.5 part by weight mixes, add the injection water, the content that makes garlicin in the injection that makes is 1～20mg/ml; Form colostrum through ultrasonic grinding then, with the mean diameter≤1 μ m of the further emulsifying of high pressure dispersing emulsification machine to the aqueous disperse phase that forms, regulate pH value to 5～7, through filtering with microporous membrane, embedding, sterilization promptly get garlicin injection.
Decentralized photo particle diameter and particle size distribution FACTOR P I value are measured by laser particle analyzer (Britain Malvern company, Nano S90 type) among the present invention.Garlicin assay employing HPLC (Agilent1000 type chromatograph of liquid, Hypersil ODS chromatographic column (4.6*250mm), ultraviolet detection wavelength X=253nm, mobile phase is methanol: water=60: 40) measure.The pH value of Emulsion injection is measured by accurate pH meter (the Shanghai thunder is precision instrument factory now, the PHS-3C type).
The present invention makes the dispersion system of garlicin by emulsifying technology, and garlicin is obviously increased in the dissolubility of aqueous phase, and the change of size of these systems show that this system has advantages of higher stability before and after 100 ℃ of heating 30min by measuring.Its experiment situation is as shown in table 1:
Table 1
After heating before the heating
Mean diameter d (nm) breadth coefficient PI mean diameter d (nm) breadth coefficient PI
Garlicin Emulsion 200.36 0.318 205.25 0.304
Blood vessel irritation experiment simultaneously shows, be used for intravenous drip after the prepared garlicin Emulsion dilution of the present invention, its blood vessel irritation and commercially available common garlicin injection relatively have greatly improved, experimental technique with reference to country about the chemicals zest, anaphylaxis and hemolytic investigative technique guideline, two kinds of preparations are set 0.15mg/ml and two dosage groups of 0.45mg/ml respectively, totally 4 experimental grouies, random packet, every group 3 the white rabbit of screech owl, dosage all is 4.0ml/kg, with each group rabbit left side auricular vein distal end injection, and the normal saline of injecting same volume simultaneously in contrast, regularly observes the variation of rabbit bilateral auricular vein after the administration, puts to death rabbit after 48 hours, and do the conventional organization section, the standards of grading of every index are as shown in table 2:
Table 2: blood vessel irritation observation index and standards of grading
| Perusal | Microscopic examination | ||
| Observation index | The standards of grading score | Observation index | The standards of grading score |
| Congestion of blood vessel tissue edema | Normal 0 mild hyperaemia, lines clear 1 is congested rubescent, the unclear 2 severe hyperemia of lines are aubergine 3 no edema 0 slight edema 1 obvious edema 2 serious edema 3 | The blood vessel surrounding tissue | Complete 0 endothelial injuries of endothelium and vascular wall 1 vascular thrombosis embolism 2 angiorrhoxises 3 normal 0 oedema, 1 hemorrhage 2 inflammatory cell infiltrations 3 |
Every score accumulated value of every group is got its meansigma methods divided by rabbit ear number, and the zest criterion is that meansigma methods≤0.5 is nonirritant; Meansigma methods 0.5～2.5 is slight zest; 2.5～4.5 is the moderate zest; Meansigma methods 〉=4.5 are the severe zest.Experimental result is as shown in table 3:
Table 3
The administration concentration preparation rabbit ear is counted the meansigma methods result and is judged
0.12mg/ml garlicin injection Emulsion 30 nonirritants
Commercially available garlicin normal injection agent 3 0.67 slight zests
0.24mg/ml garlicin injection Emulsion 3 0.33 nonirritants
Commercially available garlicin normal injection agent 3 3.0 moderate zests
Show that by above data the more commercially available common garlicin injection of the prepared garlicin injection of the present invention can reduce the blood vessel irritation of garlicin better.
The present invention has reduced the influence of outer bound pair garlicin by garlicin is wrapped in the nano level emulsion droplet, and the heat stability of garlicin is improved.2ml among the present invention: the commercially available garlicin normal injection agent of the garlicin injection Emulsion of 30mg specification and same specification places 40 ℃, 60 ℃, 80 ℃ thermostatic drying chamber 10d respectively, sampling and measuring garlicin content at regular intervals, and result such as table 4:
Table 4
Temperature/℃ heated time/d garlicin content/labelled amount (%)
The agent of garlicin injection Emulsion garlicin normal injection
40℃????????????2?????????????98????????????????103
6?????????????91????????????????85
10????????????81????????????????76
60℃????????????2?????????????95????????????????91
6?????????????87????????????????70
10????????????76????????????????69
80℃????????????2?????????????90????????????????81
6?????????????82????????????????70
10????????????73????????????????52
Can show by above experimental result, the prepared garlicin Emulsion of the present invention is tried under the temperature at 3, the trend that garlicin content reduces in time all is starkly lower than commercially available garlicin injection, and increase along with temperature, the content of prepared injection reduces amplitude and is significantly less than commercially available garlicin injection among the present invention, so can show that from above experiment the more commercially available garlicin injection of garlicin injection Emulsion of the present invention has higher heat stability.
The specific embodiment
Embodiment 1: the preparation of garlicin vein Submicroemulsion injection, and the prescription of this dosage form consists of:
Synthetic garlicin (content of garlicin is 97.0～103.0%) 2g
Injection soybean phospholipid 10g
Injection soybean oil 16g
Glycerol for injection 3g
Water for injection adds to 1000ml
Preparation method is:
1. the garlicin that takes by weighing recipe quantity adds abundant mix homogeneously in the injection soybean oil, makes into oil phase;
2. take by weighing the water for injection of injection soybean phospholipid, glycerol for injection and the 100ml of prescribed dose, stir to make and dissolve fully;
3. under agitation oil phase is added aqueous phase, put into the supersonic cell crusher after the stirring and pulverize and stir, make the formation colostrum;
4. colostrum being moved into and making mean diameter through homogenize in the high pressure dispersing emulsification machine is 206.25nm, and particle diameter≤500nm accounts for 98.2% of sum, and the PI value is 0.315 Emulsion;
5. emulsion is through 0.45 μ m filtering with microporous membrane;
6. regulate pH to 5.68, and carry out assay, recording its content is 101.2% of labelled amount
7. embedding, flowing steam sterilization promptly gets garlicin vein Submicroemulsion injection.
Embodiment 2: the preparation of garlicin Submicroemulsion injection, and the prescription of this dosage form consists of:
Synthetic garlicin (content of garlicin is 97.0～103.0%) 8g
Injection soybean phospholipid 21g
Poloxamer 188 3.5g
Injection propylene glycol 4g
Injection mannitol 14.5g
Injection soybean oil 100g
Water for injection adds to 1000ml
Preparation method is:
1. the garlicin that takes by weighing recipe quantity adds abundant mix homogeneously in the injection soybean oil, makes into oil phase;
2. take by weighing the water for injection of injection soybean phospholipid, poloxamer 188, injection propylene glycol, injection mannitol and the 250ml of prescribed dose, stir to make and dissolve fully, make into water;
3. under agitation oil phase is added aqueous phase, put into the supersonic cell crusher after the stirring and pulverize and stir, make the formation colostrum;
4. colostrum being moved into and making mean diameter through homogenize in the high pressure dispersing emulsification machine is 186.0nm, and particle diameter≤500nm accounts for 99.1% of sum, and the PI value is 0.295 Emulsion;
5. emulsion is through 0.45 μ m filtering with microporous membrane;
6. regulate pH to 6.02, and carry out assay, recording its content is 102.4% of labelled amount;
7. embedding, flowing steam sterilization promptly gets the garlicin Submicroemulsion injection.
Embodiment 3: the preparation of garlicin Submicroemulsion injection, and the prescription of this dosage form consists of:
Garlicin raw material medicine (content of garlicin is 81.0～87.0%) 12.5g
Injection soybean phospholipid 15g
Tween 80 4g
Glycerol for injection 7g
Oleum Ricini 100g
NaTDC 2.5g
Water for injection adds to 1000ml
Preparation method is:
1. the garlicin that takes by weighing recipe quantity adds abundant mix homogeneously in the injection Oleum Ricini, makes into oil phase;
2. take by weighing the water for injection of injection soybean phospholipid, Tween 80, glycerol for injection, NaTDC and the 500ml of prescribed dose, stir to make and dissolve fully, make into water;
3. under agitation oil phase is added aqueous phase, put into the supersonic cell crusher after the stirring and pulverize and stir, make the formation colostrum;
4. colostrum being moved into and making mean diameter through homogenize in the high pressure dispersing emulsification machine is 256.4nm, and particle diameter≤500nm accounts for 98.6% of sum, and the PI value is 0.320 Emulsion;
5. emulsion is through 0.45 μ m filtering with microporous membrane;
6. regulate pH to 6.81, and carry out assay, recording its content is 98.5% of labelled amount;
7. embedding, flowing steam sterilization promptly gets the garlicin Submicroemulsion injection.
Embodiment 4: the preparation of garlicin Submicroemulsion injection, and the prescription of this dosage form consists of:
Synthetic garlicin (content of garlicin is 97.0～103.0%) 20g
Injection soybean phospholipid 56g
Polyglycereol Palmic acid diol ester 3g
Drewmulse??????????????????????????????????????0.5g
Poloxamer 188 0.8g
Glycerol for injection 25g
Injection soybean oil 150g
Water for injection adds to 1000ml
Preparation method is:
1. the garlicin that takes by weighing recipe quantity adds abundant mix homogeneously in the injection soybean oil, makes into oil phase;
2. take by weighing the water for injection of injection soybean phospholipid, polyglycereol Palmic acid diol ester, Drewmulse, poloxamer 188, glycerol for injection and the 500ml of prescribed dose, stir to make and dissolve fully, make into water;
3. under agitation oil phase is added aqueous phase, put into the supersonic cell crusher after the stirring and pulverize and stir, make the formation colostrum;
4. colostrum being moved into and making mean diameter through homogenize in the high pressure dispersing emulsification machine is 268.0nm, and particle diameter≤500nm accounts for 96.7% of sum, and the PI value is 0.298 Emulsion;
5. emulsion is through 0.45 μ m filtering with microporous membrane;
6. regulate pH to 5.95, and carry out assay, recording its content is 101.0% of labelled amount;
7. embedding, flowing steam sterilization promptly gets the garlicin Submicroemulsion injection.
Embodiment 5: the preparation of garlicin vein micro-emulsion injecta, and the prescription of this dosage form consists of:
Synthetic garlicin (content of garlicin is 81.0～87.0%) 10g
Injection soybean phospholipid 15g
Injection soybean oil 100g
Glycerol for injection 25g
Oleic acid 3g
Water for injection adds to 1000ml
Preparation method is:
1. the garlicin that takes by weighing recipe quantity adds abundant mix homogeneously in the injection soybean oil, makes into oil phase;
2. take by weighing the water for injection of injection soybean phospholipid, glycerol for injection, oleic acid and the 250ml of prescribed dose, stir to make and dissolve fully;
3. under agitation oil phase is added aqueous phase, put into the supersonic cell crusher after the stirring and pulverize and stir, make the formation colostrum;
4. colostrum being moved in the high pressure dispersing emulsification machine and making mean diameter through homogenize repeatedly is 85.14nm, and 96.2% and the PI value that account for sum of particle diameter≤100nm is 0.259 Emulsion;
5. emulsion is through 0.22 μ m filtering with microporous membrane;
6. regulate pH to 6.94, and carry out assay, recording its content is 98.9% of labelled amount;
7. embedding, flowing steam sterilization promptly gets garlicin vein micro-emulsion injecta.
Embodiment 6: the preparation of garlicin vein micro-emulsion injecta, and the prescription of this dosage form consists of:
Synthetic garlicin (content of garlicin is 90.3～96.3%) 5g
Injection soybean phospholipid 12.5g
Poloxamer 188 1.5g
Injection soybean oil 60g
Glycerol for injection 18g
NaTDC 0.5g
Water for injection adds to 1000ml
Preparation method is:
1. the garlicin that takes by weighing recipe quantity adds abundant mix homogeneously in the injection soybean oil, makes into oil phase;
2. take by weighing the water for injection of injection soybean phospholipid, poloxamer 188, glycerol for injection, NaTDC and the 500ml of prescribed dose, stir to make and dissolve fully;
3. under agitation oil phase is added aqueous phase, put into the supersonic cell crusher after the stirring and pulverize and stir, make the formation colostrum;
4. colostrum being moved in the high pressure dispersing emulsification machine and making mean diameter through homogenize repeatedly is 75.85nm, and 98.4% and the PI value that account for sum of particle diameter≤100nm is 0.204 Emulsion;
5. emulsion is through 0.22 μ m filtering with microporous membrane;
6. regulate pH to 5.96, and carry out assay, recording its content is 102.4% of labelled amount;
7. embedding, flowing steam sterilization promptly gets garlicin vein micro-emulsion injecta.
Embodiment 7: the preparation of garlicin vein micro-emulsion injecta, and the prescription of this dosage form consists of:
Synthetic garlicin (content of garlicin is 81.0～87.0%) 18g
Injection soybean phospholipid 42g
Acetic acid esters of mono 0.5g
Injection soybean oil 150g
Glycerol for injection 25g
Cholic acid 2.5g
Water for injection adds to 1000ml
Preparation method is:
1. the garlicin that takes by weighing recipe quantity adds abundant mix homogeneously in the injection soybean oil, makes into oil phase;
2. take by weighing the water for injection of injection soybean phospholipid, acetic acid esters of mono, glycerol for injection, cholic acid and the 500ml of prescribed dose, stir to make and dissolve fully;
3. under agitation oil phase is added aqueous phase, put into the supersonic cell crusher after the stirring and pulverize and stir, make the formation colostrum;
4. colostrum being moved in the high pressure dispersing emulsification machine and making mean diameter through homogenize repeatedly is 92.1nm, and 98.5% and the PI value that account for sum of particle diameter≤100nm is 0.204 Emulsion;
5. emulsion is through 0.22 μ m filtering with microporous membrane;
6. regulate PH to 6.12, and carry out assay, recording its content is 100.3% of labelled amount;
7. embedding, flowing steam sterilization promptly gets garlicin vein micro-emulsion injecta.
Claims (10)
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