CN1281275C - Re-emulsifying carrier for homogeneous and stable hydrophilic medicine and its prepn process - Google Patents
Re-emulsifying carrier for homogeneous and stable hydrophilic medicine and its prepn process Download PDFInfo
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- CN1281275C CN1281275C CNB031308333A CN03130833A CN1281275C CN 1281275 C CN1281275 C CN 1281275C CN B031308333 A CNB031308333 A CN B031308333A CN 03130833 A CN03130833 A CN 03130833A CN 1281275 C CN1281275 C CN 1281275C
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Abstract
The present invention provides a multiple emulsion carrier of hydrophilic drugs with a uniform dimension and stable storage and a preparation method thereof, which is characterized in that the multiple emulsion carrier of hydrophilic drugs with a uniform dimension is prepared by mixing a water solution containing hydrophilic drugs (mitomycin, doxorubicin, protein drugs, etc.) with oily substances; preparing the mixture into an oil-in-water emulsion by using a homogeneous phase emulsifier; then pressing the oil-in-water emulsion in an external water phase containing a water soluble suspension stabilizer and /or an emulsifier through microporous membranes by pressure. Under optimum conditions, the diameter distribution coefficient of the multiple emulsion carrier is controlled within 10%, the diameter can be freely controlled from 1 to 100 micrometer, and the embedding rate of the drugs can reach as high as 98.6%; the storage of the multiple emulsion carrier is stable that the multiple emulsion carrier can be stored for more than two months at a temperature of 4 DEG C without drug leakage, and the drugs can be released at a certain speed at a temperature of 37 DEG C, thereby achieving the double goals of stable storage and transportation, and slow release of the drugs during treatment. The multiple emulsion carrier and the preparation method solve the problems of non-uniform grain diameters, low embedding rate and poor storage stability of the multiple emulsion carriers of the hydrophilic drugs prepared with the stirring emulsification method, and have the prospects of realizing the transportation process of the drugs to each hospital after being prepared in preparation factories, solving the problem that doctors have to prepare the drugs on site before operation, reducing the side effects of highly toxic drugs, and enhancing the treatment effects.
Description
Technical field
The invention belongs to the field of pharmaceutical preparations of pharmaceutical engineering.
Background technology
Biologically active drugs such as many cancer therapy drugs, protein all belong to hydrophilic medicament, for example, it is the hydrophilic cancer therapy drug of using always that mitomycin, amycin, cisplatin, tumor necrosis factor etc. are, if these medicines directly drop into human body, can be distributed in the various piece of human body randomly, normal cell is produced serious lethal effect, cause the immunity of human body to reduce.These low-molecule drugs can be got rid of external rapidly by glomerular filtration simultaneously.Drug level in the blood is remained valid more than the treatment concentration, and frequently medication causes very big side effect to human body.Therefore, the embedding of the hypertoxic medicine that, half-life big to side effect is short improves its half-life in vivo, reduces its side effect and be always the problem greatly paid close attention to of being subjected to.
With W/O/W type emulsion embedding hydrophilic medicament is a kind of method for preparing controlled release preparation of using always, is applied to various treatments.For example, comprise that Asia of China and African geographic liver cancer patient account for very big ratio in the world, and hepatic artery embolism is the first-selected therapy of unsuitable excision hepatocarcinoma
[1]Its principle be with embedding the emulsion or the microsphere drug carrier of anticarcinogen, import the nutrient artery of hepatoma carcinoma cell, it is rested in this nutrient artery, cut off on the one hand to cancerous cell supply nutrition, reduce the speed of growth of cancerous cell, make pharmaceutical carrier discharge medicine, kill cancer cell with certain speed on the other hand to cancerous cell.As oil phase, is interior water with the aqueous solution of mitomycin or amycin with super liquefaction iodized oil, and the emulsion carrier of preparing is the arterial thrombosis pharmaceutical carrier of using always.This is that metabolism is slow, can be trapped in affected part for a long time, plays targeting and controlled-release function because iodized oil and cancerous cell have special affinity interaction
[2]
But, the emulsion pharmaceutical carrier that existing preparation method (mechanical mixing method) prepares, the particle diameter heterogeneity, embedding rate is low, storge quality is unstable.For example, when the emulsion carrier of anticarcinogen is used for the artery embolization for treatment of hepatocarcinoma because the particle diameter heterogeneity, the emulsion pharmaceutical carrier injected Hepatic artery after, little drop can enter vein along with blood flow, thereby is distributed in other health tissues, causes serious adverse.In addition, because the emulsion instability, water and oil phase meeting sharp separation can not store for a long time, must oneself be prepared before treatment by the doctor, thereby cause the treatment poor repeatability; Even use immediately after the preparation, oil phase also can produce in Hepatic artery with water and separate, though iodized oil stays in cancerous tissue, medicine is along with blood flow flows to other health tissues rapidly, and causes serious adverse
[3]So, also do not have a kind of iodized oil emulsion preparation listing of anticarcinogen now.Therefore, the stability that improves the emulsion pharmaceutical carrier not only can reduce hypertoxic side effects of pharmaceutical drugs, can also realize being made in advance by the manufacturer, transports the flow process that each hospital uses to, to reach the treatment good reproducibility.And be expected to reduce hypertoxic side effects of pharmaceutical drugs, improve therapeutic effect.There is the scholar to pass through to add the method for glucose, delayed the time of medicine, but medicine can can't be preserved still for a long time gradually to external leakage to external leakage at interior aqueous phase.Nakano etc.
[4]By add the material of light specific gravity at oil phase,, reduce and divide interval velocity, but effect is still undesirable so that iodized oil proportion is close with water proportion.Therefore, the emulsion carrier of preparation size homogeneous, stable hydrophilic medicament is extremely important.
Analyzing the unsettled reason of emulsion, is because the particle diameter heterogeneity.During the particle diameter heterogeneity, the surface tension of droplet is big, is annexed by big drop easily, finally causes the profit layering.Therefore, the emulsion pharmaceutical carrier of preparation size homogeneous is the key of the stable emulsion pharmaceutical carrier of preparation.
Summary of the invention
This research provides the emulsion pharmaceutical carrier of size homogeneous, stable storing at hydrophilic medicament, with Transarterial Chemoembolization of being used for cancer etc.It is characterized in that the aqueous solution that contains hydrophilic medicament mixes with oily matter, be prepared into emulsion oil-in-water with the homogeneous phase emulsator after, this emulsion is pressed into outer water with pressure by microporous membrane, obtain the emulsion pharmaceutical carrier of size homogeneous.Under optimal conditions, the diameter Distribution coefficient of carrier is controlled in 10%, and diameter can freely be controlled in the 1-100 micron; Stable storing stores more than two months at 4 ℃, and drug leakage does not take place.And under 37 ℃ of conditions, can discharge with certain speed.Can solve when storing and transporting and stablize, reach the dual purpose that drug slow discharges during treatment.
Particle diameter heterogeneity, the embedding rate of hydrophilic medicament emulsion carrier that this technology has solved the preparation of stirring and emulsifying method is low, the problem of poor storage stability.Be expected to realize to transport the flow process of each hospital to, overcome the problem of in situ preparation before must performing the operation by the doctor by after manufacturer's prepared beforehand.Simultaneously, be expected to reduce the toxic and side effects of hydrophilic medicaments such as anticarcinogen, improve therapeutic effect.
This emulsion pharmaceutical carrier, preparation method and optimization formula thereof can also bring down column effect:
(1) the emulsion pharmaceutical carrier that provides of this patent also can be used for pulmonary carcinoma except that the artery embolization for treatment of hepatocarcinoma
[5], gastric cancer
[6]The embolotherapy of tremulous pulse.The particle diameter of regulation and control emulsion pharmaceutical carrier also can be used it for intravenous injection, subcutaneous injection, lumbar injection etc.
(2) the emulsion pharmaceutical carrier that provides of this patent is because uniform particle diameter and controlled uses this emulsion pharmaceutical carrier can carry out the research of particle diameter and therapeutic effect relation.This is because particle diameter and its distributing position and time in cancerous tissue of emulsion have bigger relation.If the size heterogeneity of pharmaceutical carrier then can't be carried out the research of this respect.
(3) the employed preparation method of this patent can be used for the embedding of all hydrophilic medicaments, as biologically active drugs such as protein, nucleic acid, hormone etc.Especially Wen He emulsification condition is expected to keep the activity of biologically active drug.
Description of drawings
The emulsion preparation of drug carriers flow process of Fig. 1 hydrophilic medicament.
The optical microscope photograph of the mitomycin emulsion pharmaceutical carrier of Fig. 2 embodiment 1 preparation.
Particle size distribution figure (the determining instrument: laser particle analyzer COULTER LS230) of the mitomycin emulsion pharmaceutical carrier of Fig. 3 embodiment 1 and comparative example 1 preparation.
The storage stability and the release curve of the mitomycin emulsion pharmaceutical carrier of Fig. 4 embodiment 1 and comparative example 1 preparation.
The vary in diameter (4 ℃) of the mitomycin emulsion pharmaceutical carrier of Fig. 5 embodiment 1 preparation.
The optical microscope photograph of the mitomycin emulsion pharmaceutical carrier of Fig. 6 comparative example 1 preparation.
Specific embodiments
The present invention includes the emulsion carrier and preparation method thereof of the hydrophilic medicament of size homogeneous, stable storing.The preparation of the emulsion carrier of hydrophilic medicament is by step preparation shown in Figure 1, and concrete grammar and step are described as follows:
1) preparation of w/o type colostrum
Hydrophilic medicament and other additive are dissolved in water, as interior water; More than one oil soluble emulsifying agent is dissolved in oil-based liquid, as oil phase.Interior water is mixed with oil phase, be prepared into the w/o type colostrum with the homogeneous phase emulsator.
Interior water additive can comprise harmless water-soluble substanceses such as glucose, sodium chloride, many alcohol; Hydrophilic medicament comprises cancer therapy drug, polypeptide, pharmaceutical grade protein, nucleic acid, vaccine, hormone, antibiotics etc., can be dissolved in interior water together or separately according to the treatment needs.Oil phase is to be liquid under the room temperature, with the immiscible oily matter of water.The dissolubility of lipophilicity substance in water preferably less than 0.2wt%, can use iodized oil, olive oil, cotton seed oil, Oleum Glycines, alkanes carbon compound etc. under 25 ℃ of conditions.Oil emulsifier must be dissolved in employed oily matter, can use polyoxyethylene hydrogenated Oleum Ricini, anhydrosorbitol trioleate (class of department 85), sorbitan oleate (class of department 80), anhydrosorbitol tristearate (class of department 65), oleophylic-hydrophilic block copolymers.Oil phase emulsifier concentration in the oil phase is 1-10wt%.Use lipophilic medicament together as needs, this lipophilic medicament can be dissolved in this oily matter.
The volume ratio of interior water and oil phase is 1: 1-1: 10.Oil phase is 1 with the volume ratio of outer water: 1-1: 100.2) preparation of W/O/W emulsion
With more than one the water solublity suspension stabilizer and/or emulsifiers dissolve in water, as outer water.With above-mentioned steps 1) resulting colostrum is pressed into outer water by perforated membrane.
The water solublity suspension stabilizer of above-mentioned outer aqueous phase can use polyvinyl alcohol, polypyrrole alkane ketone, Polyethylene Glycol, polyoxyethylene hydrogenated castor oil, polyglyceryl fatty acid ester, Tween-81 (Tween 80), polyoxyethylene sorbitol acid anhydride laurate (polysorbas20), lipophile-hydrophilic inlay and break copolymer etc.The scope of application of water soluble emulsifier is 0.1-20wt%.
The water soluble emulsifier of above-mentioned outer aqueous phase can use nonionic surfactant such as cationic surface active agents such as anionic surfactanies such as sodium lauryl sulphate, dodecylbenzene sodium sulfonate, alkylammonium salt, alkyl benzyl ammonium salt, polyoxyethylene nonylplenyl ether, polyglycol distearate, polyoxyethylene sorbitan stearate.The scope of application of surfactant is the 0.01-10wt% of outer water.
Embodiment 1
With the aperture is that the microporous membrane of 7 μ m places hydrophilic material to soak into, and makes pore membrane fully moistening.The D/W 2.5ml of preparation mitomycin, concentration of glucose is 5.8wt%, the addition of mitomycin is a 2.4mg/ml water.This aqueous solution is mixed with the super liquefaction iodized oil (being dissolved with oil soluble emulsifying agent) of 5.0ml, and the profit phase volume ratio is 2: 1.With homogeneous phase emulsator emulsifying 3min, obtain the w/o type colostrum.Water solublity suspension stabilizer and emulsifying agent are added in the 100ml water, be stirred to dissolving fully as outer water.W/o type colostrum 0.085Kgf/cm with 8.0g
2Constant pressure, the hydrophilic porous film by the aperture homogeneous is pressed into outer water, obtains the mitomycin iodized oil emulsion carrier of W/O/W type.With the diameter of laser particle analyzer (COULTER LS230) test emulsion pharmaceutical carrier, average diameter is 45.12 μ m, and the CV value is 8.92%.Optical microscope photograph as shown in Figure 2, particle size distribution as shown in Figure 3, particle size distribution is homogeneous very.
The mitomycin iodized oil emulsion pharmaceutical carrier of the getting 20g bag filter of packing into places the water of 4 ℃ and 37 ℃ to do dialysis test, and with the velocity fluctuation of 100rpm/min.Every the regular hour, take a sample the water outside bag filter, after the concentration of 365nm place mensuration mitomycin, calculate the concentration of the mitomycin of outer aqueous phase with ultraviolet spectrometry.With the concentration conversion of the mitomycin of the outer aqueous phase of (4 ℃) after 3 hours is embedding rate.The result as shown in Figure 4, it is good that embedding rate reaches under 94.0%, 4 ℃ of condition storage stability, through storing more than 60 days, mitomycin does not almost have outside water to discharge.And under 37 ℃ of conditions, mitomycin can outwards discharge with certain speed.The carrier change of size of the mitomycin under 4 ℃ of conditions of storage stores 30 days as shown in Figure 5, and particle diameter changes hardly.
Comparative example 1 (mechanical mixing method)
Adopt the prescription identical with example 1, prepare the D/W 2.5ml of mitomycin, concentration of glucose is 5.8wt%, and the addition of mitomycin is a 2.4mg/ml water.This aqueous solution is mixed with the super liquefaction iodized oil (being dissolved with oil soluble emulsifying agent) of 5.0ml, and the profit phase volume ratio is 2: 1.With homogeneous phase emulsator emulsifying 3min, obtain the w/o type colostrum.The emulsifying agent of water solublity suspending agent is added in the 100ml water, be stirred to dissolving fully as outer water.Outer water is mixed mutually with colostrum, magnetic agitation 1000rpm, 30min obtains the iodized oil anticarcinogen pharmaceutical carrier of W/O/W type.With the diameter of laser particle analyzer (COULTER LS230) test emulsion pharmaceutical carrier, particle size range is between 0.4-200 μ m, and the CV value is up to 86.0%.Optical microscope photograph as shown in Figure 6, particle size distribution as shown in Figure 3, the non-constant width of particle size distribution.Emulsion will take place and merge and oil-water stratification phenomenon poor stability in carrier after after the preparation several hours.
The mitomycin iodized oil emulsion pharmaceutical carrier of the getting 20g bag filter of packing into places 4 ℃ water to do dialysis test, and with the velocity fluctuation of 100rpm/min.Every the regular hour, take a sample the water outside bag filter, after the concentration of 365nm place mensuration mitomycin, calculate the concentration of the mitomycin of outer aqueous phase with ultraviolet spectrometry.With the concentration conversion of the mitomycin of the outer aqueous phase of (4 ℃) after 3 hours is embedding rate.The result as shown in Figure 4, embedding rate is a poor storage stability under 77.1%, 4 ℃ of condition, drug release rate reaches more than 50% in two days, stores after 16 days, mitomycin almost all has been released into outer water.
Embodiment 2
With the aperture is that the microporous membrane of 7 μ m places hydrophilic material to soak into, and makes pore membrane fully moistening.The D/W of preparation mitomycin, concentration of glucose is 5.8wt%, the addition of mitomycin is a 1.2mg/ml water.This aqueous solution is mixed with the super liquefaction iodized oil (being dissolved with oil soluble emulsifying agent) of 5ml, and the profit phase volume ratio is 3: 1.With homogeneous phase emulsator emulsifying 3min, obtain the w/o type colostrum.Water solublity suspension stabilizer and emulsifying agent are added in the 100ml water, be stirred to dissolving fully as outer water.W/o type colostrum 0.085Kgf/cm with 8.0g
2Constant pressure, the hydrophilic porous film by the aperture homogeneous is pressed into outer water, obtains the mitomycin iodized oil emulsion carrier of W/O/W type.With the diameter of laser particle analyzer (COULTER LS230) test emulsion pharmaceutical carrier, average diameter is 40.78 μ m, and the CV value is 11.0%.
The mitomycin iodized oil emulsion pharmaceutical carrier of the getting 10g bag filter of packing into places 4 ℃ water to do dialysis test, and with the velocity fluctuation of 120rpm/min.Every the regular hour, take a sample the water outside bag filter, with the concentration of ultraviolet spectrometry, calculate the concentration of the mitomycin of outer aqueous phase at 365nm place mensuration mitomycin.With the concentration conversion of the mitomycin of the outer aqueous phase of (4 ℃) after 3 hours is embedding rate.To reach 92.0%, 4 ℃ of following storage stability good for embedding rate as a result, and through storing 25 days, mitomycin does not almost have outside water to discharge.
Embodiment 3
With the aperture is that the microporous membrane of 7 μ m places hydrophilic material to soak into, and makes pore membrane fully moistening.The D/W of preparation amycin, concentration of glucose is 5.8wt%, the addition of amycin is a 10.0mg/ml water.This aqueous solution is mixed with the super liquefaction iodized oil (being dissolved with oil soluble emulsifying agent) of 5ml, and the profit phase volume ratio is 2: 1.With homogeneous phase emulsator emulsifying 3min, obtain the w/o type colostrum.Water solublity suspension stabilizer and emulsifying agent are added in the 100ml water, be stirred to dissolving fully as outer water.W/o type colostrum 0.085Kgf/cm with 8.0g
2Constant pressure, the hydrophilic porous film by the aperture homogeneous is pressed into outer water, obtains the amycin iodized oil emulsion carrier of W/O/W type.With the diameter of laser particle analyzer (COULTER LS230) test emulsion pharmaceutical carrier, average diameter is 43.40 μ m, and the CV value is 10.8%.
The amycin iodized oil emulsion pharmaceutical carrier of the getting 10g bag filter of packing into places 4 ℃ water to do dialysis test, and with the velocity fluctuation of 120rpm/min.Every the regular hour, take a sample the water outside bag filter, with the concentration of ultraviolet spectrometry, calculate the concentration of the amycin of outer aqueous phase at 486nm place mensuration amycin.With the concentration conversion of the amycin of the outer aqueous phase of (4 ℃) after 3 hours is embedding rate.To reach 98.6%, 4 ℃ of following storage stability good for embedding rate as a result.
Embodiment 4 (albuminous interpolation in the interior water)
With the aperture is that the microporous membrane of 7 μ m places hydrophilic material to soak into, and makes pore membrane fully moistening.The D/W of preparation amycin, concentration of glucose is 5.8wt%, and albuminous interpolation concentration is 0.2wt%, and the addition of amycin is a 12.0mg/ml water.This aqueous solution is mixed with the super liquefaction iodized oil (being dissolved with oil soluble emulsifying agent) of 5ml, and the profit phase volume ratio is 3: 1.With homogeneous phase emulsator emulsifying 3min, obtain the w/o type colostrum.Water solublity suspension stabilizer and the emulsifying agent of 1.0g are added in the 100ml water, be stirred to dissolving fully as outer water.W/o type colostrum 0.085Kgf/cm with 8.0g
2Constant pressure, the hydrophilic porous film by the aperture homogeneous is pressed into outer water, obtains the amycin iodized oil emulsion carrier of W/O/W type.With the diameter of laser particle analyzer (COULTER LS230) test emulsion pharmaceutical carrier, average diameter is 41.78 μ m, and the CV value is 11.2%.
The amycin iodized oil emulsion pharmaceutical carrier of the getting 10g bag filter of packing into places 4 ℃ water to do dialysis test, and with the velocity fluctuation of 120rpm/min.Every the regular hour, take a sample the water outside bag filter, with the concentration of ultraviolet spectrometry, calculate the concentration of the amycin of outer aqueous phase at 486nm place mensuration amycin.With the concentration conversion of the amycin of the outer aqueous phase of (4 ℃) after 3 hours is embedding rate.To reach 95.9%, 4 ℃ of following storage stability good for embedding rate as a result.
Embodiment 5 (change of fenestra)
With the aperture is that the microporous membrane of 5.2 μ m places hydrophilic material to soak into, and makes pore membrane fully moistening.The D/W of preparation amycin, concentration of glucose is 5.8wt%, the addition of amycin is a 12.0mg/ml water.This aqueous solution is mixed with the super liquefaction iodized oil (being dissolved with oil soluble emulsifying agent) of 5ml, and the profit phase volume ratio is 3: 1.With homogeneous phase emulsator emulsifying 3min, obtain the w/o type colostrum.Water solublity suspension stabilizer and emulsifying agent are added in the 100ml water, be stirred to dissolving fully as outer water.W/o type colostrum 0.125Kgf/cm with 8.0g
2Constant pressure, the hydrophilic porous film by the aperture homogeneous is pressed into outer water, obtains the amycin iodized oil emulsion carrier of W/O/W type.With the diameter of laser particle analyzer (COULTER LS230) test emulsion pharmaceutical carrier, average diameter is 26.40 μ m, and the CV value is 13.6%.
The amycin iodized oil emulsion pharmaceutical carrier of the getting 20g bag filter of packing into places 4 ℃ water to do dialysis test, and with the velocity fluctuation of 120rpm/min.Every the regular hour, take a sample the water outside bag filter, with the concentration of ultraviolet spectrometry, calculate the concentration of the amycin of outer aqueous phase at 486nm place mensuration amycin.With the concentration conversion of the amycin of the outer aqueous phase of (4 ℃) after 3 hours is embedding rate.To reach 95.9%, 4 ℃ of following storage stability good for embedding rate as a result.
Embodiment 6 (change of fenestra)
With the aperture is that the microporous membrane of 9.3 μ m places hydrophilic material to soak into, and makes pore membrane fully moistening.The D/W of preparation amycin, concentration of glucose is 5.8wt%, the addition of amycin is a 12.0mg/ml water.This aqueous solution is mixed with the super liquefaction iodized oil (being dissolved with oil soluble emulsifying agent) of 5ml, and the profit phase volume ratio is 3: 1.With homogeneous phase emulsator emulsifying 3min, obtain the w/o type colostrum.Water solublity suspension stabilizer and emulsifying agent are added in the 100ml water, be stirred to dissolving fully as outer water.With the w/o type colostrum of the 8.0g constant pressure with 0.055Kgf/cm, the hydrophilic porous film by the aperture homogeneous is pressed into outer water, obtains the amycin iodized oil emulsion carrier of W/O/W type.With the diameter of laser particle analyzer (COULTER LS230) test emulsion pharmaceutical carrier, average diameter is 52.62 μ m, and the CV value is 12.6%.
The amycin iodized oil emulsion pharmaceutical carrier of the getting 20g bag filter of packing into places 4 ℃ water to do dialysis test, and with the velocity fluctuation of 120rpm/min.Every the regular hour, take a sample the water outside bag filter, with the concentration of ultraviolet spectrometry, calculate the concentration of the amycin of outer aqueous phase at 486nm place mensuration amycin.With the concentration conversion of the amycin of the outer aqueous phase of (4 ℃) after 3 hours is embedding rate.To reach 98.6%, 4 ℃ of following storage stability good for embedding rate as a result.
List of references
1) Guo Weijian, Song Mingzhi, Yu Erxin easily becomes, Xu Yiyu etc., hepatic arterial chemoembolization is in conjunction with the research of outer radiotherapy hepatocarcinoma, Chinese tumor magazine, 1999,21 (1).
2) Chen Minshan, Li Jinqing, Zhang Yaqi, Lu Lixia, Zhang Weizhang, first cloud flies, Guo Rongping, Lin Xiaojun etc., heavy dose of iodized oil transcatheter hepatic arterial chemoembolization massive hepatocarcinoma, Chinese tumor magazine, 2001,23 (2), 165-167.
3)T.Hino?and?Y.Kawashima，S.Shimabayashi.Basic?study?for?stabilization?of?w/o/wemulsion?and?its?application?to?transcatheter?arterial?embolization?therapy.AdvancedDrug?Delivery?Reviews.2000，45，27-45.
4)H.Okochi?and?M.Nakano.Basic?studies?on?formulation，method?of?preparation?andcharacterization?of?water-in-water?type?multiple?emulsions?containing?vancomycin.Chem.Pharm.Bull.1996，44，180-186.
5) Hu Guodong, the interventional therapy progress of pulmonary carcinoma, clinical department of internal medicine magazine, 2002,19 (5), 326-327.
6) Gao Guobo, Wang Chengxia, intra arterial chemotherapy embolotherapy late gastric cancer, 2001,16 (6), 388-389.
Claims (5)
1, a kind of emulsion carrier of hydrophilic medicament, interior water by will containing hydrophilic medicament with contain oil soluble emulsifying agent and the dissolubility in water oil phase and be mixed with the oil-in-water type colostric fluid less than the oily matter of 0.2wt%, again this colostric fluid is joined the emulsifying and preparing once more of outer aqueous phase, the particle size range of emulsion carrier is the 1-100 micron, and the diameter Distribution coefficient is in 14%.
2, emulsion carrier as claimed in claim 1 is characterized in that, described outer water also contains the water solublity suspension stabilizer.
3, emulsion carrier as claimed in claim 1 is characterized in that, the volume ratio between described interior water and the described oil phase is 1: 1-1: 10; Volume ratio is 1 between described oil phase and the described outer water: 1-1: 100.
4, emulsion carrier as claimed in claim 1 is characterized in that, the medicine that described emulsion carrier comprises is stable storing under 4 ℃ of conditions, and the internal leakage rate was lower than 20% in 2 months, and under 37 ℃ of conditions, can slowly discharge.
5, the preparation method of the emulsion carrier of hydrophilic medicament as claimed in claim 1, it is characterized in that, the described interior water of claim 1 is mixed with described oil phase, after being prepared into the oil-in-water type colostrum with the emulsifying device, this colostrum is pressed into outer water with pressure by microporous membrane, obtains size homogeneous, stable W/O/W type emulsion pharmaceutical carrier.
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