CN1686156A - Clamycin structurization emulsion composition - Google Patents
Clamycin structurization emulsion composition Download PDFInfo
- Publication number
- CN1686156A CN1686156A CN 200510069552 CN200510069552A CN1686156A CN 1686156 A CN1686156 A CN 1686156A CN 200510069552 CN200510069552 CN 200510069552 CN 200510069552 A CN200510069552 A CN 200510069552A CN 1686156 A CN1686156 A CN 1686156A
- Authority
- CN
- China
- Prior art keywords
- clarithromycin
- water
- phospholipid
- cosolvent
- surfactant
- 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.)
- Pending
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- 239000000839 emulsion Substances 0.000 title claims description 39
- 239000000203 mixture Substances 0.000 title claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000006184 cosolvent Substances 0.000 claims abstract description 24
- -1 oily carrier Substances 0.000 claims abstract description 13
- 239000004094 surface-active agent Substances 0.000 claims abstract description 9
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims description 69
- 229960002626 clarithromycin Drugs 0.000 claims description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 21
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 13
- 150000003904 phospholipids Chemical class 0.000 claims description 13
- 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 claims description 12
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 235000012000 cholesterol Nutrition 0.000 claims description 6
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 6
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 6
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- 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 claims description 3
- 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 claims description 3
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- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 3
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- WCLNGBQPTVENHV-MKQVXYPISA-N cholesteryl nonanoate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCCC)C1 WCLNGBQPTVENHV-MKQVXYPISA-N 0.000 claims description 2
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
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- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 claims 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims 1
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- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims 1
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- 239000002076 α-tocopherol Substances 0.000 claims 1
- 235000004835 α-tocopherol Nutrition 0.000 claims 1
- 239000002131 composite material Substances 0.000 abstract 1
- 239000007764 o/w emulsion Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 239000008215 water for injection Substances 0.000 description 10
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
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- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 7
- 239000005642 Oleic acid Substances 0.000 description 7
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 7
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 7
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- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 6
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- FMMOOAYVCKXGMF-MURFETPASA-N ethyl linoleate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OCC FMMOOAYVCKXGMF-MURFETPASA-N 0.000 description 4
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A structuralized composite oil-in-water emulsion is prepared from clamycin, cosolvent, oily carrier, water and surfactant.
Description
Technical field
A kind of compositions that contains the stable oil-in-water structured emulsion of clarithromycin is characterized in that said composition contains: clarithromycin, clarithromycin cosolvent, oiliness carrier, water and surfactant; Described clarithromycin is to be dissolved in the clarithromycin cosolvent and to be gone into disastrously in the oiliness carrier, and clarithromycin and oiliness carrier form stable decentralized photo in water, the mean diameter≤0.5um of decentralized photo.
Background technology
Clarithromycin has another name called clarithromycin, is the derivant of erythromycin, and succeeded in developing by the big positive company of Japan the beginning of the nineties in last century, and register with trade name Clarith.Thereafter, big positive company at first produces to U.S. Abbott its technology transfer; Nineteen ninety is in Irish, Italy's listing, obtain the FDA approval in October, 1991 and be decided to be the listing of IB kind new medicine, trade name Biaxin, went on the market in the Hong-Kong with Klacid in 1993, celestial by name carat of the commodity in Europe and Asia, more than 50 country's listings in the whole world at present, market consumption steady-state growth, and in clinical, brought into play important function.Clarithromycin and tablet thereof, capsule have recorded into Chinese Pharmacopoeia version in 2000, and the dosage form of producing also has granule, dispersible tablet, slow releasing tablet, injection and dry suspension at present.
Clinical proof activity in vivo is 6～10 times of erythromycin, is 14～35 times of josamycin.And be feature to improve bioavailability, fabulous, long half time distributes in tissue and the cell, its adverse reaction rate is 3% only, is to be used for the treatment of upper respiratory tract and lower respiratory tract and skin, soft tissue infection, has become the macrolide antibiotics kind that replaces erythromycin.In addition, the U.S. FDA approved share clarithromycin and losec, the therapeutic scheme of the gastric and duodenal ulcers that causes as helicobacter pylori; This medicine also is the choice drug that the treatment HIV sufferers infects; Therefore, scholarly forecast, this medicine will be one of following 20 years world's antibacterials salable.Little liquid drugs injection and powder pin are abroad arranged, the import once of powder pin, because of zest is bigger, inreal at home listing retrieves Kelamycin injection and preparation method (publication number CN1452977) simultaneously, and the PVP that has adopted national forbidding is as cosolvent, and zest is bigger; A kind of clarithromycin injectable emulsion (publication number CN1452977), be the clarithromycin water soluble salt, be water soluble ingredient, envelop rate is very low after making Emulsion, because in existence of a large amount of medicines and the aqueous solution, and not wrapped into oil phase, irritating problem is not resolved, and does not also see this kind listing; Clarithromycin injectable emulsion and preparation method thereof (publication number CN1593447A), according to the embodiment that provides in the patent, even clarithromycin is heated to 95 degree, also be dissolved in soybean oil hardly, even if be dispersed in reluctantly make Emulsion in the oil phase after, placement a period of time just has the clarithromycin precipitation to separate out, even if minimum clarithromycin of limiting the quantity of is dissolved in the cosolvents such as ethanol in will inventing, after adding in the oil, fling to organic solvent, the Emulsion placement a period of time that makes still has the clarithromycin precipitation to separate out, and can not be wrapped up fully; The minimum amount of emulsifying agent has reached 5% of system in this patent, and experimental result shows that solution is thickness extremely, does not meet the requirement of Emulsion, because the phospholipid price of selecting for use is very high, certainly will increase the manufacturing cost of product, is unfavorable for market sale.
This shows, above patent does not all have to solve the problem of clarithromycin zest and stability at all, the present invention is according to discovering, clarithromycin wants to make stable oil-in-water system, a certain amount of oil phase cosolvent must be arranged, could guarantee that it forms stable dispersion in oil phase, the O/W Emulsion of making just can be stablized.Through screening, the spy has invented prescription of clamycin structurization emulsion and preparation method thereof.
With the structured emulsion that method of the present invention makes, not only highly stable (stored under refrigeration 1 year also not stratified), and also the phospholipid consumption is seldom, has reduced production cost, is beneficial to marketing.
Summary of the invention
Clamycin structurization emulsion of the present invention comprises nanometer microemulsion type and sub-nanometer emulsion type.Emulsion of the present invention is made up of medicine clarithromycin, clarithromycin cosolvent, oiliness carrier, water and surfactant.
Wherein the clarithromycin cosolvent is meant clarithromycin is dissolved in one or more mixture in ethanol, benzoic acid Bian ester, essence of Niobe, the ethyl benzoate.Oiliness carrier is meant one or more in triglyceride, fatty glyceride, fatty acid/alcohol, fatty-acid ethyl ester, sterol and derivant thereof, the polyoxyethylene fatty acid ester; Surfactant is meant one or more in phospholipid, tween, span, poloxamer (poloxamer), Polyethylene Glycol and the derivant thereof; Triglyceride wherein comprises in the triglyceride of soybean oil, Oleum Camelliae, Semen Maydis oil, safflower oil, Radix Oenotherae erythrosepalae oil, olive oil, C5-C14 one or more; Phospholipid comprises animal phospholipid such as Ovum Gallus domesticus Flavus lecithin, plant phospholipid such as in soybean phospholipid, synthetic phospholipid such as Polyethylene Glycol-DSPE (PEG2000-DSPE) and modified phospholipid such as the hydroxylation phospholipid one or more; Fatty acid/alcohol, fatty glyceride, fatty-acid ethyl ester, the carbochain that it is characterized in that fatty acid is C5-C24, such as in oleic acid, linoleic acid, glycerol monostearate, ethyl oleate, the Ethyl linoleate one or more; Polyethylene Glycol and derivant series thereof is characterized in that comprising as in Macrogol 200,400,600,1000,1500,2000,4000,6000, solutolHS15 and the polyethanediol succinate one or more; In sterol and the derivant thereof, it is characterized in that comprising in cholesterol, cholesterol acid ester, Cholesteryl pelargonate, the cholesterol benzoate one or more.
Wherein said clarithromycin with pharmaceutical dosage by solubilization in described oiliness carrier, clarithromycin and oiliness carrier form stable decentralized photo in water; Mean diameter≤the 500nm of decentralized photo wherein; On pharmaceutics, be called sodium rice breast and inferior sodium rice breast.
The inferior nano-emulsion preparation of clarithromycin injection of the present invention, its preparation method is as follows:
A) clarithromycin is dissolved in one or more cosolvent in ethanol, benzoic acid Bian ester, essence of Niobe, the ethyl benzoate, add fatty glyceride and triglyceride, make oil phase in 50～90 ℃ of high-speed stirred, remove volatile solvent, all the other components are dissolved in the suitable quantity of water, make water in 50～90 ℃ of high-speed stirred, profit is biphase to be mixed in 50～90 ℃ of high-speed stirred and to make primary emulsion, regulates pH value 4.0～6.0.
B) get primary emulsion in above-mentioned (a), water for injection is settled to recipe quantity, is transferred in the high pressure dispersing emulsification machine emulsifying repeatedly.To emulsion droplet mean diameter≤0.5 micron.
C) after the Emulsion of getting above-mentioned (b) filtered, inflated with nitrogen fill, sterilization were both.
Clarithromycin injection nano-emulsion preparation of the present invention, its preparation method is as follows:
A) clarithromycin is used an amount of dissolve with ethanol, add in one or more the compositions of an amount of Tween 80, propylene glycol, solutolHS15, polyoxyethylene castor oil, triglyceride, fully stir, add the water of recipe quantity again in 20～60 ℃, fully stir, regulate pH value 4.0～6.0.
B) microemulsion formulation of getting above-mentioned (a) is removed pyrogen with charcoal treatment, and after the aseptic filtration, the inflated with nitrogen fill both be sterilized must again.
Can also contain aromatic and antiseptic in the Orally taken emulsion, wherein aromatic comprises one or more in Fructus Citri tangerinae essence, flavoring banana essence, strawberry essence, the cream flavour, and antiseptic comprises one or more in parabens, the benzoic acids.
Specific embodiment
Embodiment one (sub-nanometer emulsion type)
Prescription 1: the mixture 5%～30% of clarithromycin 0.01%～1.0%, clarithromycin cosolvent 0.01%～5.0%, phosphatidase 11 .0%～6.0%, triglyceride and ethyl oleate, glycerol 1.0%～6.0%, oleic acid 1.0%～6.0%, water for injection adds to 100ml.
Taking by weighing clarithromycin 100-500mg is dissolved among clarithromycin cosolvent (0-5ml dehydrated alcohol and the 0-5ml benzoic acid Bian ester) 0.1-5.0ml, dissolve in the mixture and 0.1-5g oleic acid of 15g triglyceride and ethyl oleate, make mix homogeneously in 50 ℃～80 ℃ high-speed stirred, make oil phase; Ethanol is removed in evaporation; Take by weighing Ovum Gallus domesticus Flavus lecithin 2.0g, glycerol 3g, the water that adds recipe quantity makes abundant dispersion in 50 ℃～80 ℃ high-speed stirred, makes water.The biphase mixing of profit is made primary emulsion in 50 ℃～80 ℃ high-speed stirred.Get primary emulsion, water for injection is settled to recipe quantity, and regulating pH value is 5.0～7.0, is transferred in the high pressure dispersing emulsification machine, emulsifying is to emulsion droplet mean diameter≤0.5 micron repeatedly, and aseptic filtration, inflated with nitrogen fill, sterilization are both.Prescription 2: the mixture 5%～30% of clarithromycin 0.01%～1.0%, clarithromycin cosolvent 0.01%～5.0%, cholesterol acid ester 0.01%～1.0%, solutolHS150.1%～1.0%, phosphatidase 10 .5%～4.0%, glycerol 1.0%～6.0%, triglyceride and ethyl oleate, oleic acid 1.0%～6.0%, tocopherol 0.01%～1.0%, water for injection adds to 100ml.
Taking by weighing clarithromycin 100-500mg is dissolved among clarithromycin cosolvent (0-5ml dehydrated alcohol and the 0-5ml benzoic acid Bian ester) 0.1-5.0ml, dissolve in the mixture of 20g triglyceride and ethyl oleate, add oleic acid 0.1-0.5g, cholesterol acid ester 0.1-1.0g, make mix homogeneously in 50 ℃～80 ℃ high-speed stirred, make oil phase, ethanol is removed in evaporation; Take by weighing soybean phospholipid 1.5g, solutolHS15 0.5g, glycerol 3g, tocopherol 50mg, the water that adds recipe quantity makes abundant dispersion in 50 ℃～80 ℃ high-speed stirred, makes water.The biphase mixing of profit is made primary emulsion in 50 ℃～80 ℃ high-speed stirred.Get primary emulsion, water for injection is settled to recipe quantity, and regulating pH value is 5.0～7.0, is transferred in the high pressure dispersing emulsification machine, emulsifying is to emulsion droplet mean diameter≤0.5 micron repeatedly, and the fill of aseptic filtration inflated with nitrogen, sterilization are both.
Prescription 3: clarithromycin 0.01%～1.0%, clarithromycin cosolvent 0.01%～5.0%, cholesterol ester stearic acid 0.01%～1.0%, phosphatidase 10 .5%～4.0%, poloxamer 188 0.5%～3.0%, glycerol 1.0%～6.0%, triglyceride 5%～20%, Ethyl linoleate 2%～10%, oleic acid 1.0%～6.0%, tocopherol 0.01%～1.0%, water for injection adds to 100ml.
Taking by weighing clarithromycin 100-500mg is dissolved among clarithromycin cosolvent (0-5ml dehydrated alcohol and the 0-5ml benzoic acid Bian ester) 0.1-5.0ml, dissolve among the mixture of 20g triglyceride and ethyl oleate and 0.5g oleic acid, cholesterol ester stearic acid 0.1-1.0g, the Ethyl linoleate 2-10g, make mix homogeneously make oil phase in 50 ℃～80 ℃ high-speed stirred; The water that takes by weighing egg yolk lecithin 1.8g, solutolHS150.5g, glycerol 3g, tocopherol 50mg adding recipe quantity makes abundant dispersion in 50 ℃～80 ℃ high-speed stirred, makes water.The biphase mixing of profit is made primary emulsion in 50 ℃～80 ℃ high-speed stirred.Get primary emulsion, water for injection is settled to recipe quantity, and regulating pH value is 5.0～7.0, is transferred in the high pressure dispersing emulsification machine, emulsifying is to emulsion droplet mean diameter≤0.5 micron repeatedly, and the fill of aseptic filtration inflated with nitrogen, sterilization are both.
Embodiment two (nanometer microemulsion type)
Prescription 1: clarithromycin 0.01%～2.0%, clarithromycin cosolvent 0.01%～5.0%, ethyl oleate 0.01%～2.0%, solutolHS15 0.2%～5.0%, water for injection add to 100ml.
Taking by weighing clarithromycin 100-500mg is dissolved among clarithromycin cosolvent (0-5ml dehydrated alcohol and the 0-5ml benzoic acid Bian ester) 0.1-5.0ml, add ethyl oleate 0.1-1.0g, solutolHS15 1.5g and suitable quantity of water and make mix homogeneously in 20 ℃ of-80 ℃ of stirrings, add the injection water and be settled to 100ml, make microemulsion in 20 ℃ of-80 ℃ of stirrings.Be transferred in the high pressure dispersing emulsification machine, emulsifying is to emulsion droplet mean diameter≤0.5 micron repeatedly, regulating pH value is 5.0～7.0, and the fill of aseptic filtration inflated with nitrogen, sterilization are both.
Prescription 2: clarithromycin 0.01%～2.0%, clarithromycin cosolvent 0.01%～5.0%, poloxamer 188 0.2%～5.0%, Ethyl linoleate 0.01%～8%, Tween 80 0.01%～2.0%, water for injection adds to 100ml.
Taking by weighing clarithromycin 100-500mg is dissolved among clarithromycin cosolvent (0-5ml dehydrated alcohol and the 0-5ml benzoic acid Bian ester) 0.1-5.0ml, add in Tween 80 0.01-0.5g, ethyl oleate 0.5g, poloxamer 188 0.5g and the suitable quantity of water, make mix homogeneously in 20 ℃ of-80 ℃ of stirrings, add an amount of injection water capacity to 100ml, regulating pH value is 5.0～7.0, makes microemulsion in 20 ℃ of-80 ℃ of stirrings.Be transferred in the high pressure dispersing emulsification machine, emulsifying is to emulsion droplet mean diameter≤0.5 micron repeatedly, and the fill of aseptic filtration inflated with nitrogen, sterilization are both.
Prescription 3: clarithromycin 0.01%～2.0%, clarithromycin cosolvent 0.01%～5.0%, polyoxyethylene fatty acid ester 0.01%～5.0%, poloxamer 188 0.2%～10.0%, hydroxypropyl beta～cyclodextrin 0.1%～10.0%, water for injection add to 100ml.
Taking by weighing clarithromycin 100-500mg is dissolved among clarithromycin cosolvent (0-5ml dehydrated alcohol and the 0-5ml benzoic acid Bian ester) 0.1-5.0ml, add in polyoxyethylene castor oil, poloxamer 188 0.5-1.2g and the suitable quantity of water, make mix homogeneously in 20 ℃ of-80 ℃ of stirrings; Hydroxypropyl beta～cyclodextrin 0.1-0.5g is dissolved in the suitable quantity of water, and both are settled to 100ml at mixing, and regulating pH value is 5.0～7.0, makes microemulsion in 20 ℃ of-80 ℃ of high-speed stirred.The fill of aseptic filtration inflated with nitrogen, sterilization both got.
Embodiment three (blood vessel irritation test)
Trial drug: clarithromycin emulsion, the Beijing Jinfanghua Pharmaceutical Technology Co., Ltd provides.Clarithromycin powder pin, self-control is mixed with 5% solution with 0.9% sodium chloride injection during test.
Experimental animal: healthy rabbits, body weight 2.3～2.4kg.
Test method: get 10 of healthy rabbits, male and female half and half.Be divided into 2 every group of 0.9% sodium chloride injection matched group, clarithromycin powder pin group and clarithromycin emulsion Emulsion groups by body weight and sex, ear ear edge is pressed clinical administration concentration intravenous drip 10ml/kg, drip velocity 1ml/ branch, every day 1 time, continuous 7 days in a rabbit left side.Matched group is with method intravenous drip 0.9% sodium chloride injection.Observe the administration topical manifestations during except that each administration and after the administration, after the last intravenous drip, cut the medicine exterior feature of picking up the ears, conventional fixing after, go into pin proximal part 1cm place in the distance intravenous drip, cut the wide specimen of 0.5cm every 1cm, get 3 specimen altogether.Pathological observation under the mirror is carried out in section statining, the results are shown in following table:
The test of clarithromycin blood vessel irritation
| Project | The wide vasodilation of the rabbit ear | Red and swollen | Have or not cell infiltration |
| 0.9% sodium chloride injection matched group | ??- | ??- | ??- |
| Clarithromycin powder pin | ??++ | ??++ | ??+ |
| Clarithromycin sub-nanometer emulsion (prescription 1) | ??- | ??- | ??- |
| Clarithromycin sub-nanometer emulsion (prescription 2) | ??- | ??- | ??- |
| Clarithromycin sub-nanometer emulsion (prescription 3) | ??- | ??- | ??- |
Remarks: " ++ " is serious, "+" a little, "-" do not have.
Claims (10)
1, a kind of compositions that contains the stable oil-in-water structured emulsion of clarithromycin is characterized in that said composition contains: clarithromycin, clarithromycin cosolvent, oiliness carrier, water and surfactant; Described clarithromycin is to be dissolved in the clarithromycin cosolvent and to be gone into disastrously in the oiliness carrier, and described clarithromycin and oiliness carrier form stable decentralized photo in water, the mean diameter≤1um of decentralized photo.
2, be meant in triglyceride, fatty glyceride, fatty acid/alcohol, fatty-acid ethyl ester, sterol and derivant thereof, the polyoxyethylene fatty acid ester one or more according to the oiliness carrier in the claim 1; Wherein sterol and derivant thereof comprise in cholesterol, cholesterol acid ester, cholesterol ester stearic acid, Cholesteryl pelargonate and the cholesterol benzoate one or more.
3,, it is characterized in that taking from phospholipid, tween, span, poloxamer (poloxamer), solutolHS15, Polyethylene Glycol and the derivant thereof one or more according to the surfactant in the claim 1; Phospholipid is wherein taken from a kind of in Ovum Gallus domesticus Flavus lecithin, soybean phospholipid, synthetic phospholipid and the modified phospholipid.
4,, it is characterized in that further comprising antioxidant, as in alpha-tocopherol, ascorbyl palmitate, Butylated hydroxyanisole (BHA), the dibenzylatiooluene (BHT) one or more according to the surfactant in the claim 1.
5,, it is characterized in that further comprising in glycerol, propylene glycol, ethanol, the hydroxypropyl beta～cyclodextrin one or more according to the surfactant in the claim 1.
6, according to the compositions in the claim 1, wherein the consumption of clarithromycin is 0.01%-1% by weight.
7, according to the compositions in the claim 1, wherein the consumption of oiliness carrier is 0.1%-30% by weight.
8, according to the compositions in the claim 1, wherein the consumption of surfactant is 0.1%-10% by weight.
9,, it is characterized in that being selected from methanol, ethanol, ethyl acetate, benzoic acid Bian ester, essence of Niobe, the ethyl benzoate one or more according to the cosolvent in the claim 1.
10, according to the compositions in the claim 1, it is characterized in that to comprise aromatic and antiseptic, wherein aromatic comprises one or more in Fructus Citri tangerinae essence, flavoring banana essence, strawberry essence, the cream flavour, and antiseptic comprises one or more in parabens, the benzoic acids.
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| CN 200510069552 CN1686156A (en) | 2005-05-16 | 2005-05-16 | Clamycin structurization emulsion composition |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101045063B (en) * | 2006-03-28 | 2011-01-26 | 广州朗圣药业有限公司 | Clarithromycin water soluble preparation for injection use |
| CN105294791A (en) * | 2014-06-10 | 2016-02-03 | 无锡康福特药物科技有限公司 | Ultrafine powder of macrolide drug and preparation method for ultrafine powder |
| US20200368263A1 (en) * | 2019-05-24 | 2020-11-26 | Piedmont Animal Health Inc. | Long-acting injectable formulations and use thereof |
-
2005
- 2005-05-16 CN CN 200510069552 patent/CN1686156A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101045063B (en) * | 2006-03-28 | 2011-01-26 | 广州朗圣药业有限公司 | Clarithromycin water soluble preparation for injection use |
| CN105294791A (en) * | 2014-06-10 | 2016-02-03 | 无锡康福特药物科技有限公司 | Ultrafine powder of macrolide drug and preparation method for ultrafine powder |
| US20200368263A1 (en) * | 2019-05-24 | 2020-11-26 | Piedmont Animal Health Inc. | Long-acting injectable formulations and use thereof |
| JP2022533749A (en) * | 2019-05-24 | 2022-07-25 | ピードモント アニマル ヘルス インコーポレイテッド | Long-acting injectable formulations and their use |
| US12350281B2 (en) * | 2019-05-24 | 2025-07-08 | Dechra Veterinary Products, Llc | Long-acting injectable formulations and use thereof |
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