CN101053810A - Method for preparing high molecular micro nanometer capsule - Google Patents
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Abstract
一种高分子功能材料领域的高分子微纳米囊的制备方法，首先配制水溶性药物溶液、油溶性药物溶液；然后将高分子材料溶解在油溶性药物溶液中，形成聚合物溶液；其后将水溶性药物溶液注入聚合物溶液中制成水－油乳液；而后再将该乳液注入稳定剂溶液中，制成水－油－水的双重乳液；接着将该双重乳液注入固化剂溶液中，得到固化微囊的悬浮液；再将该悬浮液离心分离出微囊，洗涤，冷冻干燥，得到的干燥粉末置于密闭容器中，经抽真空、瞬间充入气体至标准大气压、密闭保存后，得到高分子微纳米囊，该微纳米曩粒径为纳米至微米级，能应用于常规超声造影及分子成像，实现了油溶性药物与水溶性药物的配伍，并具有控制释放功效。A method for preparing polymer micro-nanocapsules in the field of polymer functional materials, first preparing a water-soluble drug solution and an oil-soluble drug solution; then dissolving the polymer material in the oil-soluble drug solution to form a polymer solution; The water-soluble drug solution is injected into the polymer solution to form a water-oil emulsion; then the emulsion is injected into the stabilizer solution to form a water-oil-water double emulsion; then the double emulsion is injected into the curing agent solution to obtain Solidify the suspension of microcapsules; then centrifuge the suspension to separate the microcapsules, wash, and freeze-dry. The obtained dry powder is placed in a closed container, vacuumized, filled with gas to standard atmospheric pressure for a moment, and sealed and stored to obtain Polymer micro-nanocapsules, the particle size of which is nanometer to micrometer, can be applied to conventional contrast-enhanced ultrasound and molecular imaging, realize the compatibility of oil-soluble drugs and water-soluble drugs, and have the effect of controlled release.
Description
Technical field
That the present invention relates to is a kind of preparation method of technical field of polymer materials, specifically is a kind of preparation method of high molecular micro nanometer capsule.
Background technology
The microencapsulation product of medicine is widely used as a kind of important formulation, and the main purpose of drug microcapsuleization comprises: bad smell and the taste of 1. covering medicine; 2. improve stability of drug; 3. prevent medicine inactivation or reduce stimulation in stomach to stomach; 4. make the liquid drug solid state so that use and store; 5. the compatibility that helps compound medicine; 6. make medicine have slowly-releasing or controlled release properties; 7. make medicine have target; 8. can be with living cells or bioactivator parcel.The microcapsules of medicine are from initial external application, develop into oral so that intravenous injection.The micro nanometer capsule acoustic contrast agent not only can strengthen ultrasonoscopy as a kind of novel medicament carrier, also has potential targeted therapy effect.Utilize the cavitation effect of micro nanometer capsule under ultrasonic mediation, can carry medicine and do the treatment of ultrasonic fixed point target tissue, have potential significant application value aspect carrying at other drugs such as thromboembolism treatment, antineoplastic treatments.The associated methods of present micro nanometer capsule and medicine has multiple, but their total problems are to be difficult to realize the compatibility of water soluble drug and oil-soluble medicine, are difficult to carry multiple different water soluble drug or oil-soluble medicine simultaneously.
Find through literature search prior art, Chinese patent publication number CN 1739806A, the name be called " acoustical contrast medium of polymer material and preparation method thereof " patent disclosure a kind of macromolecule microvesicle acoustic contrast, the average diameter of its microvesicle is at micron order, less than red blood cell, can be freely by pulmonary circulation, but not seeing through vascular wall, is a kind of blood pool imaging agent, and ultrasonic imaging only limits in the blood vessel.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, a kind of preparation method of high molecular micro nanometer capsule is provided, its average grain diameter with high molecular micro nanometer capsule is regulated and control at micron or nanoscale, satisfy conventional ultrasonic contrast demand and nanoscale microcapsular ultrasound contrast agent as of the requirement of novel medicament carrier, realize the ultrasonic contrast function of the compatibility and the micro nanometer capsule of water soluble drug and oil-soluble medicine simultaneously for particle size.
The present invention is achieved through the following technical solutions, the present invention includes following concrete steps:
A, measure water soluble drug, it is dispersed in the water, making concentration is the water soluble drug solution of 0.2～10mg/mL;
B, measure oil-soluble medicine, it is dispersed in the organic solvent, making concentration is the oil-soluble medicine solution of 0.2～10mg/mL;
C, get macromolecular material, it is dissolved in the above-mentioned oil-soluble medicine solution, forming concentration is 5～250mg/mL polymer solution;
D, get stabilizing agent, it is dissolved in the water, forming concentration is the stabiliser solution of 0.1～10wt.%;
E, be 1: 40～1: 2, in water or water soluble drug solution injection of polymer solution,, stir 0.5～5min, make water-fat liquor with the mixing speed of 6000～23000rpm by the volume ratio of water or water soluble drug solution and polymer solution;
F, be 1: 2～1: 40, above-mentioned water-fat liquor is injected stabiliser solution,, stir 1～10min, make the double emulsion of water-oil-water with the mixing speed of 300～20000rpm by the volume ratio of water-fat liquor and stabiliser solution;
G, be 1: 2～1: 200, curing agent is dissolved in the water, form curing agent solution by the volume ratio of curing agent and water;
The double emulsion of h, Jiang Shui-oil-water injects the curing agent solution of equal volume, with the mixing speed of 300～3000rpm, continues to stir 1～12h, obtains suspension of curing microcapsules;
I, above-mentioned suspension of curing microcapsules centrifugation is gone out micro-capsule, successively with distilled water washing 1～3 time, non-polar solven washing 1～3 time is carried out freeze drying to micro-capsule, dried powder;
J, above-mentioned dried powder is placed closed container, after vacuumizing, moment charges into gas to standard atmospheric pressure, and the airtight preservation of dried powder that will handle through said process, obtain high molecular micro nanometer capsule.
Described high molecular micro nanometer capsule, its average grain diameter between 100nm～10 μ m, wall thickness 20～2000nm, shell is made up of macromolecular material and oil-soluble medicine, and interior bag water soluble drug and be filled with gas has ultrasonic contrast, medicine controlled releasing, gene and carries function.
Can a load water soluble drug in the described high molecular micro nanometer capsule or load oil-soluble medicine only, also can be simultaneously in shell load water soluble drug in load oil-soluble medicine, the kernel.
Described water soluble drug is one or more the combination in acetazolamide, hydrochloric acid NA-872, amino acid, bleomycin and hydrochloride thereof, natrium citricum, the endoxan, but is not limited to above-mentioned several material.
Described oil-soluble medicine is ibuprofen, Ciprofloxacin, theophylline, papaverine hydrochloride, a kind of in the acetaminophenol, but is not limited to above-mentioned several material.
Described organic solvent be oiliness, low boiling, with the not miscible organic solvent of water, be one or more the combination in carrene, chloroform, the dichloroethanes, but be not limited to above-mentioned several material.
Described macromolecular material is lipophile macromolecule or the copolymer that contains the lipophile segment, be that molecular weight is 5,000～500,000 aliphatic polyester (as the binary between polylactide, polycaprolactone, lactone ternary is random or block copolymer, lactone and polyethers between binary or ternary is random or block copolymer), a kind of in the polybutylcyanoacrylate, poe, poly-epsilon-caprolactone, polyureas alkane, polyaminoacid, but be not limited to above-mentioned several material.
Described stabilizing agent is natural or synthetic polymer substance, be one or more the combination in anion surfactant, gelatin and the derivative thereof of D-sorbite type, polyvinyl alcohol, polyphenyl sulfonic acid, hydroxyethylcellulose, hydroxypropyl cellulose, glucan, the polyvinylpyrrolidone, but be not limited to above-mentioned several material.
Described curing agent is a hydrophilic solvent, is one or more the combination in methyl alcohol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, sec-butyl alcohol, the tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, the cyclopentanol, but is not limited to above-mentioned several material.
Described nonpolar washing agent is meant and can dissolves the oil-soluble medicine that does not wrap into, can not dissolve the solvent of micro-capsule wall, be one or more the combination in n-hexane, cyclohexane, dodecane, chlorinated dodecane, atoleine, tetrachloromethane, toluene, dimethylbenzene, parachlorotoluene, the styrene, but be not limited to above-mentioned several material.
Described gas is air, N for strengthening the biologically inert gas of micro-capsule ultrasonic echo dispersion effect
2, O
2, CO
2, SF
6, CF
4, C
2F
6, C
3F
6, C
3F
8, C
4F
8, C
4F
10, C
5F
10, C
5F
12In one or more combination, but be not limited to above-mentioned several material.
The present invention at first utilizes sonic oscillation and mechanical agitation to form the double emulsion of water-oil-water, wherein water soluble drug is dissolved in inner water, oil-soluble medicine is dissolved in middle oil phase, oil phase solvent evaporation in the middle of making by means such as mechanical agitation, spray-drying, freeze dryings then, the distillation of internal water phase solvent, obtain inner occluded water soluble drug at last, the hollow high molecular micro nanometer capsule of shell parcel oil-soluble medicine, under negative pressure state, biologically inert gas charged into this micro nanometer capsule inside, thereby make this micro nanometer capsule have both the ultrasonic contrast function.Regulate size, the wall thickness of high molecular micro nanometer capsule, kind and the molecular weight and the inflation type etc. of macromolecular material, can change the acoustic characteristic of micro nanometer capsule, to cooperate different clinical practice requirements; And the medicine carrying of micro nanometer capsule, Release Performance also can be adjusted by technological parameter.
The present invention utilizes the characteristics of high-molecular copolymer properties of materials and double emulsion-solvent evaporation process, prepare average grain diameter and cover nanometer to micron-sized biodegradation high molecular micro nanometer capsule, conventional ultrasonic contrast can not only be used for, of the requirement of target micro nanometer capsule acoustic contrast agent can also be satisfied particle size.Meanwhile, high molecular micro nanometer capsule inside is entered in the water soluble drug embedding, oil-soluble medicine wraps up in the shell of high molecular micro nanometer capsule, has realized water-soluble and oily soluble drug compatibility, and can carry multiple different water soluble drug or oil-soluble medicine.Biodegradable Polymers by regulating the degradation rate of macromolecular material, is controlled release to medicine as the wall material.Thisly have the high molecular micro nanometer capsule that ultrasonic contrast, medicine carried, controlled release function concurrently, can be applicable to fields such as molecular imaging, medicine and gene target treatment.
The specific embodiment
Below embodiments of the invention are elaborated: present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
Measure the 4mg ibuprofen, it is dispersed in the 20mL chloroform; Get the 0.1g molecular weight and be 210,000 PLLA, it is dissolved in the above-mentioned oil-soluble medicine solution, form polymer solution, the polyvinyl alcohol water solution of preparing 40mL0.1% (mass percent) simultaneously is standby;
The 0.5mL distilled water is injected above-mentioned polymer solution, and the mixing speed stirring 0.5min with 6000rpm makes water-fat liquor; Again above-mentioned water-fat liquor is injected the polyvinyl alcohol water solution of having prepared,, make the double emulsion of water-oil-water with the mixing speed stirring 1min of 300rpm;
The isopropanol water solution of preparation 60mL 0.5% (percent by volume), the double emulsion of above-mentioned water-oil-water is injected the isopropanol water solution of having prepared, mixing speed with 2000rpm continues to stir 8h, obtain suspension of curing microcapsules, this suspension centrifugation is gone out micro-capsule, distilled water washing 1 time, n-hexane washing 3 times are carried out freeze drying to micro-capsule then, get dried powder;
Above-mentioned dried powder is placed closed container, and after vacuumizing, moment charges into carbon dioxide to standard atmospheric pressure, and the encapsulation preservation, promptly obtains pulverous high molecular micro nanometer capsule with ultrasonic contrast function, parcel oil-soluble medicine.
Embodiment 2
Measure the 200mg Ciprofloxacin, it is dispersed in the 20mL chloroform; Get the 5g molecular weight and be 210,000 PLLA, it is dissolved in the above-mentioned oil-soluble medicine solution, forming polymer solution, to prepare the polyvinyl alcohol water solution of 40mL 0.1% (mass percent) simultaneously standby;
The 0.5mL distilled water is injected above-mentioned polymer solution, and the mixing speed stirring 0.5min with 6000rpm makes water-fat liquor; Again above-mentioned water-fat liquor is injected the polyvinyl alcohol water solution of having prepared,, make the double emulsion of water-oil-water with the mixing speed stirring 1min of 300rpm;
The isopropanol water solution of preparation 60mL 0.5% (percent by volume), the double emulsion of above-mentioned water-oil-water is injected the isopropanol water solution of having prepared, mixing speed with 2000rpm continues to stir 8h, obtain suspension of curing microcapsules, this suspension centrifugation is gone out micro-capsule, distilled water washing 3 times, n-hexane washing 1 time are carried out freeze drying to micro-capsule then, get dried powder;
Above-mentioned dried powder is placed closed container, and after vacuumizing, moment charges into carbon dioxide to standard atmospheric pressure, and the encapsulation preservation, promptly obtains pulverous high molecular micro nanometer capsule with ultrasonic contrast function, parcel oil-soluble medicine.
Embodiment 3
Measure the 4mg ibuprofen, it is dispersed in the 20mL carrene; Get the 0.1g molecular weight and be 50,000 poe, it is dissolved in the above-mentioned oil-soluble medicine solution, form polymer solution, the amino acid solution of hydroxyethyl cellulose aqueous solution, 1mL 0.2mg/mL of preparing 200mL1.0% (mass percent) simultaneously is standby;
The amino acid solution of 1mL 0.2mg/mL is injected above-mentioned polymer solution, and the mixing speed stirring 1min with 10000rpm makes water-fat liquor; Again above-mentioned water-fat liquor is injected the hydroxyethyl cellulose aqueous solution of having prepared,, make the double emulsion of water-oil-water with the mixing speed stirring 3min of 1000rpm;
The ethanol water of preparation 220mL 30% (percentage by volume), the double emulsion of above-mentioned water-oil-water is injected the ethanol water of having prepared, mixing speed with 500rpm continues to stir 2h, obtain suspension of curing microcapsules, this suspension centrifugation is gone out micro-capsule, distilled water washing 3 times, cyclohexane washing 2 times are carried out freeze drying to micro-capsule then, get dried powder;
Above-mentioned dried powder is placed closed container, and after vacuumizing, moment charges into C
3F
8Gas is to standard atmospheric pressure, and encapsulation preserves, and promptly obtains pulverously having the ultrasonic contrast function, wrapping up the high molecular micro nanometer capsule of oil-soluble medicine and water soluble drug simultaneously.
Embodiment 4
Measure the 100mg Ciprofloxacin, it is dispersed in the 20mL dichloroethanes; Get the 5g molecular weight and be 100,000 DL PLA, it is dissolved in the above-mentioned oil-soluble medicine solution, form polymer solution, the sodium citrate aqueous solution of hydroxypropyl cellulose aqueous solution, 1mL 10mg/mL of preparing 200mL 1.0% (mass percent) simultaneously is standby;
The sodium citrate aqueous solution of 1mL 10mg/mL is injected above-mentioned polymer solution, and the mixing speed stirring 1min with 10000rpm makes water-fat liquor; Again above-mentioned water-fat liquor is injected the hydroxypropyl cellulose aqueous solution of having prepared,, make the double emulsion of water-oil-water with the mixing speed stirring 3min of 1000rpm;
The methanol aqueous solution of preparation 220mL 30% (percentage by volume), the double emulsion of above-mentioned water-oil-water is injected the methanol aqueous solution of having prepared, mixing speed with 500rpm continues to stir 2h, obtain suspension of curing microcapsules, this suspension centrifugation is gone out micro-capsule, distilled water washing 3 times, n-hexane washing 3 times are carried out freeze drying to micro-capsule then, get dried powder;
Above-mentioned dried powder is placed closed container, and after vacuumizing, moment charges into SF
6Gas is to standard atmospheric pressure, and encapsulation preserves, and promptly obtains pulverously having the ultrasonic contrast function, wrapping up the high molecular micro nanometer capsule of oil-soluble medicine and water soluble drug simultaneously.
Embodiment 5
Get the 1g molecular weight and be 250,000 poly-third hand over glycolide, it is dissolved in the 20mL carrene, the amino acid solution of polyvinyl alcohol water solution, 2mL 0.2mg/mL of preparing 400mL 3.0% (mass percent) simultaneously is standby;
The amino acid solution of 2mL 0.2mg/mL is injected above-mentioned macromolecule material solution, and the mixing speed stirring 2min with 15000rpm makes water-fat liquor; Again above-mentioned water-fat liquor is injected the polyvinyl alcohol water solution of having prepared,, make the double emulsion of water-oil-water with the mixing speed stirring 5min of 10000rpm;
The n-butanol aqueous solution of preparation 420mL 5% (percentage by volume), the double emulsion of above-mentioned water-oil-water is injected the n-butanol aqueous solution of having prepared, mixing speed with 1000rpm continues to stir 1h, obtain suspension of curing microcapsules, this suspension centrifugation is gone out micro-capsule, distilled water washing 2 times, cyclohexane washing 1 time are carried out freeze drying to micro-capsule then, get dried powder;
Above-mentioned dried powder is placed closed container, and after vacuumizing, moment charges into C
2F
6Gas is to standard atmospheric pressure, and the encapsulation preservation, promptly obtains pulverous high molecular micro nanometer capsule with ultrasonic contrast function, coated water-soluble medicine.
Embodiment 6
Get the 1g molecular weight and be 50,000 polybutylcyanoacrylate, it is dissolved in the 20mL chloroform, the endoxan aqueous solution of aqueous gelatin solution, 2mL 10mg/mL of preparing 400mL 3.0% (mass percent) simultaneously is standby;
The endoxan aqueous solution of 2mL 10mg/mL is injected above-mentioned macromolecule material solution, and the mixing speed stirring 2min with 15000rpm makes water-fat liquor; Again above-mentioned water-fat liquor is injected the aqueous gelatin solution of having prepared,, make the double emulsion of water-oil-water with the mixing speed stirring 5min of 10000rpm;
The ethanol water of preparation 420mL 5% (percentage by volume), the double emulsion of above-mentioned water-oil-water is injected the ethanol water of having prepared, mixing speed with 1000rpm continues to stir 1h, obtain suspension of curing microcapsules, this suspension centrifugation is gone out micro-capsule, distilled water washing 2 times, n-hexane washing 2 times are carried out freeze drying to micro-capsule then, get dried powder;
Above-mentioned dried powder is placed closed container, and after vacuumizing, moment charges into carbon dioxide to standard atmospheric pressure, and the encapsulation preservation, promptly obtains pulverous high molecular micro nanometer capsule with ultrasonic contrast function, coated water-soluble medicine.
Embodiment 7
Measure the 100mg theophylline, it is dispersed in the 20mL dichloroethanes; Get the 3g molecular weight and be 150,000 PLLA, it is dissolved in the above-mentioned oil-soluble medicine solution, form polymer solution, the sodium citrate aqueous solution of aqueous gelatin solution, 5mL 1mg/mL of preparing 750mL5.0% (mass percent) simultaneously is standby;
The sodium citrate aqueous solution of 5mL 1mg/mL is injected above-mentioned polymer solution, and the mixing speed stirring 4min with 20000rpm makes water-fat liquor; Again above-mentioned water-fat liquor is injected the aqueous gelatin solution of having prepared,, make the double emulsion of water-oil-water with the mixing speed stirring 8min of 15000rpm;
The methanol aqueous solution of preparation 770mL 10% (percentage by volume), the double emulsion of above-mentioned water-oil-water is injected the methanol aqueous solution of having prepared, mixing speed with 3000rpm continues to stir 4h, obtain suspension of curing microcapsules, this suspension centrifugation is gone out micro-capsule, distilled water washing 2 times, cyclohexane washing 3 times are carried out freeze drying to micro-capsule then, get dried powder;
Above-mentioned dried powder is placed closed container, and after vacuumizing, moment charges into air to standard atmospheric pressure, and encapsulation preserves, and promptly obtains pulverously having the ultrasonic contrast function, wrapping up the high molecular micro nanometer capsule of oil-soluble medicine and water soluble drug simultaneously.
Embodiment 8
Measure the 20mg theophylline, it is dispersed in the 20mL carrene; Get the 2g molecular weight and be 300,000 DL PLA, it is dissolved in the above-mentioned oil-soluble medicine solution, form polymer solution, the endoxan aqueous solution of glucan aqueous solution, 5mL 2mg/mL of preparing 750mL5.0% (mass percent) simultaneously is standby;
The endoxan aqueous solution of 5mL 2mg/mL is injected above-mentioned polymer solution, and the mixing speed stirring 4min with 20000rpm makes water-fat liquor; Again above-mentioned water-fat liquor is injected the glucan aqueous solution of having prepared,, make the double emulsion of water-oil-water with the mixing speed stirring 8min of 15000rpm;
The isopropanol water solution of preparation 770mL 10% (percentage by volume), the double emulsion of above-mentioned water-oil-water is injected the isopropanol water solution of having prepared, mixing speed with 3000rpm continues to stir 4h, obtain suspension of curing microcapsules, this suspension centrifugation is gone out micro-capsule, distilled water washing 1 time, n-hexane washing 1 time are carried out freeze drying to micro-capsule then, get dried powder;
Above-mentioned dried powder is placed closed container, and after vacuumizing, moment charges into oxygen to standard atmospheric pressure, and encapsulation preserves, and promptly obtains pulverously having the ultrasonic contrast function, wrapping up the high molecular micro nanometer capsule of oil-soluble medicine and water soluble drug simultaneously.
Embodiment 9
Measure the 50mg brufen, it is dispersed in the 20mL dichloroethanes; Get the 5g molecular weight and be 50,000 polybutylcyanoacrylate, it is dissolved in the above-mentioned oil-soluble medicine solution, form polymer solution, the amino acid solution of aqueous gelatin solution, 10mL 1mg/mL of preparing 1200mL 10% (mass percent) simultaneously is standby;
The amino acid solution of 10mL 1mg/mL is injected above-mentioned polymer solution, and the mixing speed stirring 5min with 23000rpm makes water-fat liquor; Again above-mentioned water-fat liquor is injected the aqueous gelatin solution of having prepared,, make the double emulsion of water-oil-water with the mixing speed stirring 10min of 20000rpm;
The ethanol water of preparation 1230mL 20% (percentage by volume), the double emulsion of above-mentioned water-oil-water is injected the ethanol water of having prepared, mixing speed with 300rpm continues to stir 12h, obtain suspension of curing microcapsules, this suspension centrifugation is gone out micro-capsule, distilled water washing 1 time, cyclohexane washing 2 times are carried out freeze drying to micro-capsule then, get dried powder;
Above-mentioned dried powder is placed closed container, and after vacuumizing, moment charges into nitrogen to standard atmospheric pressure, and encapsulation preserves, and promptly obtains pulverously having the ultrasonic contrast function, wrapping up the high molecular micro nanometer capsule of oil-soluble medicine and water soluble drug simultaneously.
Embodiment 10
Measure the 200mg theophylline, it is dispersed in the 20mL carrene; Get the 0.1g molecular weight and be 300,000 poly-epsilon-caprolactone, it is dissolved in the above-mentioned oil-soluble medicine solution, form polymer solution, the sodium citrate aqueous solution of hydroxypropyl cellulose aqueous solution, 10mL 5mg/mL of preparing 1200mL 10% (mass percent) simultaneously is standby;
The sodium citrate aqueous solution of 10mL 5mg/mL is injected above-mentioned polymer solution, and the mixing speed stirring 5min with 23000rpm makes water-fat liquor; Again above-mentioned water-fat liquor is injected the hydroxypropyl cellulose aqueous solution of having prepared,, make the double emulsion of water-oil-water with the mixing speed stirring 10min of 20000rpm;
The n-butanol aqueous solution of preparation 1230mL 20% (percentage by volume), the double emulsion of above-mentioned water-oil-water is injected the n-butanol aqueous solution of having prepared, mixing speed with 300rpm continues to stir 12h, obtain suspension of curing microcapsules, this suspension centrifugation is gone out micro-capsule, distilled water washing 1 time, n-hexane washing 3 times are carried out freeze drying to micro-capsule then, get dried powder;
Above-mentioned dried powder is placed closed container, and after vacuumizing, moment charges into C
4F
8Gas is to standard atmospheric pressure, and encapsulation preserves, and promptly obtains pulverously having the ultrasonic contrast function, wrapping up the high molecular micro nanometer capsule of oil-soluble medicine and water soluble drug simultaneously.
Claims (10)
1, a kind of preparation method of high molecular micro nanometer capsule is characterized in that, specifically comprises the steps:
A, measure water soluble drug, it is dispersed in the water, make water soluble drug solution;
B, measure oil-soluble medicine, it is dispersed in the organic solvent, make oil-soluble medicine solution;
C, get macromolecular material, it is dissolved in the oil-soluble medicine solution, form polymer solution;
D, get stabilizing agent, it is dissolved in the water, form stabiliser solution;
E, be 1: 40～1: 2, in water or water soluble drug solution injection of polymer solution, stir, make water-fat liquor by the volume ratio of water or water soluble drug solution and polymer solution;
F, be 1: 2～1: 40, water-fat liquor is injected stabiliser solution, stir, make the double emulsion of water-oil-water by the volume ratio of water-fat liquor and stabiliser solution;
G, curing agent is dissolved in the water, forms curing agent solution;
The double emulsion of h, Jiang Shui-oil-water injects the curing agent solution of equal volume, stirs, and obtains suspension of curing microcapsules;
I, the suspension of curing microcapsules centrifugation is gone out micro-capsule, and, carry out freeze drying then, obtain dried powder its washing;
J, dried powder is placed closed container, after vacuumizing, moment charges into gas to standard atmospheric pressure, and the airtight preservation of dried powder that will handle through said process, obtain high molecular micro nanometer capsule.
2, the preparation method of high molecular micro nanometer capsule according to claim 1, it is characterized in that, described water soluble drug is one or more the combination in acetazolamide, hydrochloric acid NA-872, amino acid, bleomycin and hydrochloride, natrium citricum or the endoxan;
3, the preparation method of high molecular micro nanometer capsule according to claim 1 is characterized in that, described oil-soluble medicine is ibuprofen, Ciprofloxacin, theophylline, papaverine hydrochloride, to one or more the combination in the acetaminophenol.
4, the preparation method of high molecular micro nanometer capsule according to claim 1 is characterized in that, described organic solvent is one or more the combination in carrene, chloroform, the dichloroethanes.
5, the preparation method of high molecular micro nanometer capsule according to claim 1, it is characterized in that, described macromolecular material is that molecular weight is 5, the combination of one or more in 000～500,000 aliphatic polyester, polybutylcyanoacrylate, poe, poly-epsilon-caprolactone, polyureas alkane, the polyaminoacid.
6, the preparation method of high molecular micro nanometer capsule according to claim 1, it is characterized in that described stabilizing agent is anion surfactant, gelatin and derivative thereof, polyvinyl alcohol, polyphenyl sulfonic acid, hydroxyethylcellulose, hydroxypropyl cellulose, the glucan of D-sorbite type, one or more the combination in the polyvinylpyrrolidone.
7, the preparation method of high molecular micro nanometer capsule according to claim 1, it is characterized in that described curing agent is one or more the combination in methyl alcohol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, sec-butyl alcohol, the tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, the cyclopentanol.
8, the preparation method of high molecular micro nanometer capsule according to claim 1 is characterized in that, the washing described in the step I is with distilled water, non-polar solven washing 1～3 time.
9, the preparation method of high molecular micro nanometer capsule according to claim 8, it is characterized in that described nonpolar washing agent is one or more the combination in n-hexane, cyclohexane, dodecane, chlorinated dodecane, atoleine, tetrachloromethane, toluene, dimethylbenzene, parachlorotoluene, the styrene.
10, the preparation method of high molecular micro nanometer capsule according to claim 1 is characterized in that, described gas is air, N
2, O
2, CO
2, SF
6, CF
4, C
2F
6, C
3F
6, C
3F
8, C
4F
8, C
4F
10, C
5F
10, C
5F
12In one or more combination.
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| EP2549986A4 (en) * | 2010-03-24 | 2016-03-02 | Univ Northeastern | MULTICOMPARTIMENTAL ADMINISTRATION OF MACROPHAGES |
| CN105943498A (en) * | 2016-06-22 | 2016-09-21 | 中国海洋大学 | Controllable emulsifying preparation method of PLGA micro-nano carriers of different scales |
| CN104379248B (en) * | 2012-05-29 | 2016-11-23 | 卡普苏姆公司 | Targeted nano granule for biologic applications |
| CN108112238A (en) * | 2015-01-27 | 2018-06-01 | 卡里西亚公司 | encapsulating method |
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2007
- 2007-03-01 CN CNB2007100377347A patent/CN100467114C/en not_active Expired - Fee Related
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| EP2549986A4 (en) * | 2010-03-24 | 2016-03-02 | Univ Northeastern | MULTICOMPARTIMENTAL ADMINISTRATION OF MACROPHAGES |
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| CN102525935A (en) * | 2012-01-18 | 2012-07-04 | 上海交通大学医学院 | Brain delivery method for nano-medicament carrier |
| CN104379248B (en) * | 2012-05-29 | 2016-11-23 | 卡普苏姆公司 | Targeted nano granule for biologic applications |
| CN104739761A (en) * | 2013-12-26 | 2015-07-01 | 康普药业股份有限公司 | Preparation method of ambroxol hydrochloride nanoparticles |
| CN108112238A (en) * | 2015-01-27 | 2018-06-01 | 卡里西亚公司 | encapsulating method |
| CN108112238B (en) * | 2015-01-27 | 2021-06-04 | 卡里西亚公司 | Encapsulation method |
| US11517872B2 (en) | 2015-01-27 | 2022-12-06 | Calyxia | Encapsulation method |
| CN105943498A (en) * | 2016-06-22 | 2016-09-21 | 中国海洋大学 | Controllable emulsifying preparation method of PLGA micro-nano carriers of different scales |
| CN111773433A (en) * | 2020-07-21 | 2020-10-16 | 北京积水潭医院 | A kind of preparation method of drug-loaded nano-bubble bone cement |
| CN111773433B (en) * | 2020-07-21 | 2022-02-08 | 北京积水潭医院 | Preparation method of drug-loaded nano-bubble bone cement |
| CN112300767A (en) * | 2020-09-22 | 2021-02-02 | 山东大学 | Green targeted microcapsule, preparation system, preparation method and application |
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