CN101112360B - Allicin fatty milk injection and preparation technics thereof - Google Patents
Allicin fatty milk injection and preparation technics thereof Download PDFInfo
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- CN101112360B CN101112360B CN2006100197706A CN200610019770A CN101112360B CN 101112360 B CN101112360 B CN 101112360B CN 2006100197706 A CN2006100197706 A CN 2006100197706A CN 200610019770 A CN200610019770 A CN 200610019770A CN 101112360 B CN101112360 B CN 101112360B
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- 239000007924 injection Substances 0.000 title claims abstract description 31
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- 239000008267 milk Substances 0.000 title claims description 4
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- JDLKFOPOAOFWQN-UHFFFAOYSA-N allicin Chemical compound C=CCSS(=O)CC=C JDLKFOPOAOFWQN-UHFFFAOYSA-N 0.000 title abstract description 5
- 235000010081 allicin Nutrition 0.000 title abstract description 5
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims abstract description 19
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims abstract description 18
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- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 abstract description 7
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
The invention discloses an allicin fat emulsion injection and a preparation process thereof; the invention is the drug which is made by the materials with the following mix ratios by weight, while the pH value of which is 6.5 to 7.5, the average particle size of the emulsion particles is 200nm, and the particle size thereof is 100 to 300nm and the Zeta potential is minus 50 to 80mv. The raw materials are: allicin, egg yolk lecithin, pluronic F68, oleic acid, and injection water and so on. The preparation process is that the egg yolk lecithin, oleic acid, vitamin E and soya bean oil are taken at first under the aseptic conditions for mixing, heating, agitating and dissolving, then the allicin is added to agitate till dissolution, and the filtrate can be obtained after the pressure filtration by a microporous membrane; the glycerol is taken at first and the injection water, disodium ethylene diamine tetraacetate and pluronic F68 are added for mixing and agitating till the dissolution, then the filtrate can be obtained after the pressure filtration by the microporous membrane; after the mixture of the two filtrates, a high speed agitator is used for agitating, the product is finally obtained through a high pressure homogenizer. The invention is characterized by no irritating effect and good stability, etc.
Description
Technical field:
The present invention relates to a kind of garlicin fat emulsion injection and preparation technology thereof.
Background technology:
Garlicin is a hydrophobic drug, and it has effect such as antiviral preferably, and is soluble in the medicine of oil phase solvent.Present clinical use garlicin injection has special odor and zest, and patient is difficult to accept.The water solublity of garlicin is very low, needs adding cosolvent and solubilizing agent to increase water solublity in the preparation process, and cosolvent and solubilizing agent are generally tween 80 class material, and this class material also can cause hemolytic reaction, and the patient is had big toxic and side effects.The less stable of garlicin aqueous solution is seen light, the easily decomposition of air chance heat in preservation, cause that content descends, and untoward reaction increases; The clinically intravenously administrables that adopt of garlicin injection need slowly splash into more, and with the sensation of blood vessel wall twinge and heating, make that patient's misery is difficult to stand, part patient can produce side effect such as phlebitis, influences the clinical drug use.Need deeper injection and local anaesthetics such as many and procaine to share during intramuscular injection and reduce zest, thereby many people discontinue medication for this reason.For overcoming above-mentioned shortcoming, must provide the garlicin injection novel form (being the garlicin fat emulsion injection) of a kind of nonirritant, good stability.
Summary of the invention:
The objective of the invention is to propose a kind of nonirritant, good stability, without the garlicin fat emulsion injection and the preparation method of tween 80 class material.
The technical solution adopted in the present invention is: it be by the following weight proportion raw material make that pH value is 6.5～7.5, breast grain mean diameter is 200nm, breast grain particle size range is 100～300nm, Zeta potential is the medicine of-50～80mv: each raw material weight proportioning: 0.080～0.150 part of garlicin, 6～15 parts of soybean oils, 0.4～2.4 part of Ovum Gallus domesticus Flavus lecithin, general youth Buddhist nun restrains F680.5～3 part, 0～0.75 part of oleic acid, 1.0～2.5 parts of glycerol, 0.005～0.01 part of disodiumedetate, 0.2～1 part of vitamin E, 85～100 parts of waters for injection.Character is the micro white emulsion drop, with sodium sulfide test solution reaction displaing yellow.Pluronic F68 Chinese translation described in the present patent application is that general youth Buddhist nun restrains F68, EDTA-Na
2Chinese disodiumedetate by name.Above-mentioned formula optimization injection soybean oil, the injection Ovum Gallus domesticus Flavus lecithin.
The preparation technology of garlicin fat emulsion injection of the present invention, comprise the steps: under aseptic condition, get Ovum Gallus domesticus Flavus lecithin, oleic acid, vitamin E, the soybean oil of recipe quantity, mix, heat to 60～70 ℃, and stirring and dissolving, the garlicin that adds recipe quantity is stirred to dissolving, is to filter to get filtrate under 1～15MPa through 0.22 μ m politef microporous filter membrane at moulding pressure; Get recipe quantity glycerol, add recipe quantity water for injection, the disodiumedetate, the general youth Buddhist nun that add recipe quantity restrain F68 and mix, and are stirred to dissolving, are to filter to get filtrate under 1～15MPa through 0.22 μ m politef microporous filter membrane at moulding pressure; After above-mentioned two filtrates are mixed, using rotating speed is the homogenizer stirring of 4000～8000rpm, then by the high pressure dispersing emulsification machine, pressure is controlled at 50000～80000psi, the mixing filtrate pH of Huo Deing is 6.5～7.5 at last, gets final product till pH of mixed is 6.5～7.5 until regulating if pH value can suitably not drip the 0.1M sodium hydroxide solution in this scope; The mixed liquor of above-mentioned acquisition is garlicin fat emulsion injection product, and the mean diameter of product is that 200nm, breast grain particle size range are that 100～300nm, Zeta potential are the medicine of-50～80mv.The gained medicine fills nitrogen, packing, obedient label.The rotating speed of homogenizer is preferably 8000rpm and stirs, and high pressure dispersing emulsification machine controlled pressure is preferably 50000psi.Can filter to get filtrate under moulding pressure is preferably 1～5MP through 0.22 μ m politef microporous filter membrane in the above-mentioned technology, 0.22 μ m is the aperture of politef microporous filter membrane.
Above-mentioned garlicin fat emulsion injection packing specification has 1ml:5mg; 1ml:10mg; 2ml:30mg; 2ml:60mg; 2ml:120mg, 5ml:30mg; 5ml:60mg.Intravenous drip, a 60～120mg, the child is cut down according to the circumstance, and is diluted in 5%～10% the glucose or Dextrose and Sodium Chloride Inj. of 500ml～1000ml, slowly instils 1 time on the one.Its purposes is the same with at present used garlicin.
1) adopts Ovum Gallus domesticus Flavus lecithin and Pluronic F68 to form blended emulsifier in the present invention's prescription, specifically the reasons are as follows: when the assessment lipomul, mainly will investigate its physical stability and chemical stability.The leading indicator commonly used of investigating its physical stability has: particle diameter (polydispersity coefficient), polydispersity coefficient, centrifugal stability.We find to adopt the blended emulsifier of Ovum Gallus domesticus Flavus lecithin and Pluronic F68 composition, compare with the lipomul that only uses phospholipid, can obviously reduce particle diameter, increase centrifugal stability (seeing Table 1).Perhaps, reducing particle diameter is not the most important in this scope, but represents that the parameter of size uniformity coefficient is that " polydispersity coefficient " this numerical value is the smaller the better.Compare with the lipomul that only uses phospholipid, the prescription that we provide has obtained very little polydispersity coefficient numerical value; Centrifugal stability parameter is to be illustrated under the 4000rpm centrifugal condition simultaneously, the state that solution top changes in the test tube, numerical value is more little, expression solution solution uniformity under external force changes size, just prepared lipomul physical stability is good, do not use Pluronic F68 only to use the lipomul of phospholipid under the similarity condition, centrifugal stable numerical value changes relatively large.So the present invention adopts the blended emulsifier of Pluronic F68 and Ovum Gallus domesticus Flavus lecithin.Our prescription is in the table 1: garlicin 100mg, Ovum Gallus domesticus Flavus lecithin 2 grams, oleic acid 0.50 gram, vitamin E 0.5 gram, soybean oil 10 grams, 100 milliliters of waters for injection, 50 milligrams of disodiumedetates, Pluronic F680.5 gram.No F68 prescription is in the table 1: garlicin 100mg, Ovum Gallus domesticus Flavus lecithin 2 grams, oleic acid 0.50 gram, vitamin E 0.5 gram, soybean oil 10 grams, 100 milliliters of waters for injection, 50 milligrams of disodiumedetates.No oleic acid prescription in the table 1: garlicin 100mg, Ovum Gallus domesticus Flavus lecithin 2 grams, vitamin E 0.5 gram, soybean oil 10 grams, 100 milliliters of waters for injection, 50 milligrams of disodiumedetates, Pluronic F680.5 gram.Glycerol prescription in the table 1: refer to add again in addition in prescription glycerol 1 gram, promptly prescription is garlicin 100mg, Ovum Gallus domesticus Flavus lecithin 2 grams, oleic acid 0.50 gram, vitamin E 0.5 gram, soybean oil 10 grams, 100 milliliters of waters for injection, 50 milligrams of disodiumedetates, Pluronic F680.5 gram, glycerol 1 gram.
Table 1
2) same the present invention adds oleic acid, vitamin E, EDTA=Na
2Back advantage, effect are as follows:
Find in the test that other prescription condition is the same, floating on the Emulsion when no oleic acid has oil droplet, the bad (see figure 1) of emulsifying.After adding oleic acid, the no oil droplet (see figure 2) in surface.
Simultaneously compare polydispersity coefficient and centrifugal stable two indexs with no oleic prescription having under the oleic acid prescription.Add vitamin E, the increase of EDTA-Na2 discovery chemical stability, see Table 1.Vitamin E is common antioxidant; EDTA-Na
2Can prevent the influence (catalytic action) of metal ion, simultaneously EDTA-Na to garlicin
2Also has bacteriostasis.
3) the present invention adopts the amount of bigger glycerol, and 1 gram glycerol has following advantage:
Amounts of glycerol is in 0～0.5% scope the time, and the osmotic pressure of lipomul is lower than the osmotic pressure of 0.9%NaCl.Thereby be not suitable for direct venous transfusion or use with the transfusion of a small amount of transfusion mixing posterior vein, must mix with a large amount of transfusions.Therefore we select 1.0～2.5 parts of glycerol, can mix with a small amount of transfusion when clinical use or directly use.
4) according to dlvo theory, the surface charge absolute value of disperse system (comprising lipomul) must be about 30.From this aspect, we are the Zeta potential indexs that obtain and determine to carry out lipomul quality research and control by experiment, and formerly patent application CN200410013573.4 does not provide and limit this quality index.Do not limit, the one, illustrate that those research work are coarse or not strict, the 2nd, can't guarantee prepared lipomul quality, control this index parameter simultaneously aborning.
5) adopt the high pressure dispersing emulsification machine in the processing step of the present invention, can be controlled at pressure 50000psi well, be guaranteed.
6) in the technology of the present invention, it is aseptic to adopt 0.22 μ m politef filtering with microporous membrane to guarantee earlier, with patent application CN200410013573.4 degerming method contrast formerly, has following advantage:
Filter method of the present invention can be guaranteed chemical stability, has other bibliographical information to say, autoclaving is to destroy garlicin.Carry out according to the sterile production condition at the very start and supplementary material is filtered from producing, just to filter, to have reasonability and necessity than one procedure in the end.We are also clear and definite filter membrane aperture, 0.22 μ m politef microporous filter membrane illustrates our professional and preciseness.Just filter at last in the production technology, have very big probability can't remove thermal source, if or autoclaved words, be to destroy garlicin.
The present invention has following advantage:
1) garlicin fat emulsion injection of the present invention, be a kind of oil-in-water emulsion, garlicin is soluble in the oil preparation, and with the extensive mixed of oil, divided dose is accurate, need not to add cosolvent, garlicin exists in the oil phase of Emulsion, slowly discharges in blood behind the intravasation, so alleviated zest greatly to blood vessel, can not make patient agonizing, side effect such as be difficult to stand with the sensation of blood vessel wall twinge and heating.
2) product of the present invention is because of being oil-in-water type garlicin fat emulsion injection, garlicin is wrapped in the oil phase of Emulsion, directly do not contact with light, air, medicine in the oil droplet can reduce hydrolysis, cover bad smell, alleviate zest and the permeability to organize of garlicin to mucosa, increase the stable absorbability that reaches medicine, make medicament slow release prolong drug effect, improve biological availability, reduced dosage, reduced the toxic and side effects of medicine, cost saving, product of the present invention have certain lymph affinity simultaneously.
3) primary raw material of this product preparation is a Bulbus Allii, its main component is garlicin (allicin .Ailitridin), in garlicin, add appropriate amount of auxiliary materials and cardiovascular disease, antitumor, raising immunity, antioxidant radical etc. are all had good effect through the garlicin fat emulsion injection that science is mixed with, be applicable to deep fungal and bacterial infection, be used for diseases such as anti-treating acute and chronic dysentery and enteritis, pertussis, pulmonary and gastral fungal infection, Candida albicans bacteremia, cryptococcal meningitis, pulmonary tuberculosis.
4) the preparation technology advanced person of this product, reliable, the oil phase particle size range is at 100～300nm in the medicament, drug loading is bigger, and the particle diameter of may command Emulsion and particle size distribution rheological properties, the electrochemical properties that can change the Emulsion surface to a certain extent adapts to clinical needs with the character of controlling Emulsion.
5) to have preparation technology simple for this product, carries out according to the sterile production condition at the very start and supplementary material is filtered from producing, and just filters than one procedure in the end, has reasonability and necessity.We are also clear and definite filter membrane aperture.Just filter at last in the production technology, have very big probability can't remove thermal source, if or autoclaved words, be to destroy garlicin.Adopt the high pressure dispersing emulsification machine in the processing step of the present invention, can be controlled at pressure 50000psi well, product quality is guaranteed.It is to prevent that product is oxidized that last product fills the nitrogen purpose.
Description of drawings:
Fig. 1 is the prescription condition: garlicin 100mg, Ovum Gallus domesticus Flavus lecithin 2 grams, vitamin E 0.5 gram, soybean oil 10 grams, 100 milliliters of waters for injection, 50 milligrams of disodiumedetates, Pluronic F680.5 gram are tested the photo that obtains product, do not have to float on the oleic acid Emulsion this moment oil droplet, and emulsifying is bad.
Fig. 2 is the prescription condition: garlicin 100mg, Ovum Gallus domesticus Flavus lecithin 2 grams, oleic acid 0.50 gram, vitamin E 0.5 gram, soybean oil 10 grams, 100 milliliters of waters for injection, 50 milligrams of disodiumedetates, Pluronic F680.5 gram are tested the photo that obtains the no oil droplet in surface behind the adding oleic acid.
The specific embodiment:
Describe the present invention below in conjunction with embodiment:
Embodiment
Get Ovum Gallus domesticus Flavus lecithin 2 grams, oleic acid 0.50 gram, vitamin E 0.5 gram, soybean oil 10 grams of recipe quantity, mix, heat to 70 ℃, and stirring and dissolving, add garlicin 100mg again and be stirred to dissolving, 5MPa filters through the pressurization of 0.22 μ m politef microporous filter membrane, gets filtrate; Get recipe quantity glycerol 1 gram, add under the room temperature and inject water 90 grams, 50 milligrams of disodiumedetates of adding, Pluronic F680.5 restrain mixing, are stirred to dissolving, and 5MPa filters through the pressurization of 0.22 μ m politef microporous filter membrane, gets filtrate; Two filtrate room temperature mix down, homogenizer, rotating speed 8000rpm stirs, and the high pressure dispersing emulsification machine is controlled at pressure 50000psi, and pH of mixed is 7.2, be garlicin fat milk product, the oil phase particle size range of product is 100～300nm, mean diameter 200nm, Zeta potential-30mv, character is the micro white emulsion drop, with sodium sulfide test solution reaction displaing yellow.Fill nitrogen, packing, obedient label.
Its packing specification has 1ml:5mg; 1ml:10mg; 2ml:30mg; 2ml:60mg; 5ml:30mg; 5ml:60mg.
Claims (4)
1. garlicin fat emulsion injection, it be by the following weight proportion raw material make that pH value is 6.5～7.5, breast grain mean diameter is 200nm, breast grain particle size range is 100～300nm, Zeta potential is the medicine of-50～80mv: each raw material weight proportioning: 0.080～0.150 part of garlicin, 6～15 parts of soybean oils, 0.4～2.4 part of Ovum Gallus domesticus Flavus lecithin, general youth Buddhist nun restrains 0.5～3 part of F68,0～0.75 part of oleic acid, 1.0～2.5 parts of glycerol, 0.005～0.01 part of disodiumedetate, 0.2～1 part of vitamin E, 85～100 parts of waters for injection.
2. the preparation technology of the described garlicin fat emulsion injection of claim 1, comprise the steps: under aseptic condition, get Ovum Gallus domesticus Flavus lecithin, oleic acid, vitamin E, the soybean oil of recipe quantity, mix, heat to 60～70 ℃, and stirring and dissolving, the garlicin that adds recipe quantity is stirred to dissolving, is to filter to get filtrate under 1～15MPa through 0.22 μ m politef microporous filter membrane at moulding pressure; Get recipe quantity glycerol, add recipe quantity water for injection, the disodiumedetate, the general youth Buddhist nun that add recipe quantity restrain F68 and mix, and are stirred to dissolving, are to filter to get filtrate under 1～15MPa through 0.22 μ m politef microporous filter membrane at moulding pressure; After above-mentioned two filtrates are mixed, using rotating speed is the homogenizer stirring of 4000～8000rpm, then by the high pressure dispersing emulsification machine, pressure is controlled at 50000～80000psi, the mixing filtrate pH of Huo Deing is 6.5～7.5 at last, be garlicin fat emulsion injection product, the mean diameter of product is that 200nm, breast grain particle size range are that 100～300nm, Zeta potential are the medicine of-50～80mv.
3. the preparation method of garlicin fat milk according to claim 2, the rotating speed that it is characterized in that homogenizer are that 8000rpm stirs, and high pressure dispersing emulsification machine controlled pressure is 50000psi.
4. the preparation method of garlicin fat milk according to claim 2 is characterized in that be to filter to get filtrate under 1～5MP through 0.22 μ m politef microporous filter membrane at moulding pressure.
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| CN2006100197706A CN101112360B (en) | 2006-07-28 | 2006-07-28 | Allicin fatty milk injection and preparation technics thereof |
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| CN2006100197706A CN101112360B (en) | 2006-07-28 | 2006-07-28 | Allicin fatty milk injection and preparation technics thereof |
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| CN101112360B true CN101112360B (en) | 2010-09-29 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1615828A (en) * | 2004-09-09 | 2005-05-18 | 华中科技大学 | Garlicin injection emulsion and its preparing method |
| CN1686090A (en) * | 2005-04-18 | 2005-10-26 | 四川科伦药业股份有限公司 | Garlicin injection agent medicine and its preparation method |
| CN1698753A (en) * | 2005-05-12 | 2005-11-23 | 沈阳药科大学 | Garlicin and garlic oil emulsion capable of filtering and eliminating bacteria and preparation process thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1615828A (en) * | 2004-09-09 | 2005-05-18 | 华中科技大学 | Garlicin injection emulsion and its preparing method |
| CN1686090A (en) * | 2005-04-18 | 2005-10-26 | 四川科伦药业股份有限公司 | Garlicin injection agent medicine and its preparation method |
| CN1698753A (en) * | 2005-05-12 | 2005-11-23 | 沈阳药科大学 | Garlicin and garlic oil emulsion capable of filtering and eliminating bacteria and preparation process thereof |
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| Title |
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| 储晓琴.大蒜油亚微乳的研究.沈阳药科大学硕士学位论文.2004,第三章 大蒜油亚微乳的制备. * |
| 郭涛等.静脉注射用大蒜油亚微乳的制备.中国药学杂志40 8.2005,40(8),602-605. |
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