CN1073412C - Method for prepn. of macromolecule microcapsule - Google Patents
Method for prepn. of macromolecule microcapsule Download PDFInfo
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- CN1073412C CN1073412C CN98101117A CN98101117A CN1073412C CN 1073412 C CN1073412 C CN 1073412C CN 98101117 A CN98101117 A CN 98101117A CN 98101117 A CN98101117 A CN 98101117A CN 1073412 C CN1073412 C CN 1073412C
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- microcyst
- macromolecule
- alkali
- amide derivatives
- random polypropylene
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Abstract
本发明的微粒体制备用的高分子乳化—稳定剂其主链为亲水性高分子长链结构、其支链为疏水性碳氢长链。具体结构是一类含盐基碳氢长支链的聚丙烯酸胺衍生物，由于其特定的结构，因此具有稳定乳液及成球的作用，用该物质作为微包囊的稳定剂，尤其适于在水体系对药物固体粉末的微包囊化。The polymer emulsifying-stabilizer prepared for use in microsomes of the present invention has a main chain of a hydrophilic polymer long chain structure, and its branch chains are hydrophobic hydrocarbon long chains. The specific structure is a kind of polyacrylic acid amine derivatives containing salt-based long-chain branched hydrocarbons. Due to its specific structure, it has the effect of stabilizing emulsions and forming balls. Using this substance as a stabilizer for microencapsulation is especially suitable for Microencapsulation of pharmaceutical solid powders in aqueous systems.
Description
The present invention relates to a kind of macromolecule microcyst and preparation method thereof.
Micro-encapsulation technology begins to grow up from the fifties.After manufacturing pressure sensitive no carbon required is applied, just develop into every field from micro-encapsulation technology in 1954 gradually, wherein at first on food, agricultural, cosmetics, cultural goods and household products, obtained application.In recent years, micro-encapsulation technology has obtained using widely at medical domain again.The function that not only has target function and control drug release as the macromolecule microcyst and the pharmaceutical preparation of nanoscale encapsulation of coating material with macromolecule, and can play and prevent that protein and polypeptide drug are in vivo by enzymolysis with keep bioactive effect, thereby be expected to make these medicines to realize oralization, thereby cause attention widely.
Functional polymer journal 1997, advantage such as V10 (3) 429-435 has reported the method for preparing microcyst, and wherein solvent extraction and solvent evaporated method be because easy and simple to handle, and technical process is simple, and equipment requirements is low, thereby be widely used.The report for preparing microcyst with the method for solvent extraction and solvent evaporation starts from the sixties the earliest.Preparation method is mainly finished by two steps, at first be the formation of emulsion droplet, and then remove solvent in the drop: promptly make the emulsion system of Water-In-Oil (W/O) or oil-in-water (O/W) earlier under the Stabilization of the emulsification of emulsifying agent and stabilizing agent according to the character of lapping, extraction by solvent and evaporation remove to desolvate and obtain microcyst then.Use this method, select suitable preparation parameter, can reach the purpose of preparation different-grain diameter scope microcyst.Normally used emulsifying agent is a class surfactant, mainly is that some have the micromolecular compound of surface active function, and it act as the emulsion droplet particle diameter is diminished, and particle size distribution narrows down.The selection of emulsifying agent needs to decide according to its HLB (hydrophile-lipophile balance) value.Because the size of emulsion droplet has directly determined the size of final microcyst, so the selection of emulsifying agent and consumption thereof is quite important, the synergism that also adopts two or more emulsifying agents sometimes is to reach better emulsifying effectiveness.Stabilizing agent mainly is synthetic or natural polymer substance; for example polyvinyl alcohol (PVA), Polyethylene Glycol (PEG), gelatin etc.; they form protecting film by the surface at emulsion droplet; reach the Stabilization of emulsion to reduce the phase inter coagulation between drop, so stabilizing agent is also very important to the formation of drop.Thus, obtain that particle diameter is controlled, the encapsulation microsome of even particle size distribution, it is proper that key is how to reach the compatibility of stabilizing agent and emulsifying agent, makes by the synergism between them to reach satisfied emulsifying effectiveness.Yet in practical operation, because the different stabilizing agents and the nature difference of emulsifying agent will realize that the suitable compatibility of stabilizing agent and emulsifying agent has ideal particle diameter with preparation, and the stable emulsion of even particle size distribution are very difficult.Particularly at the microcyst that carries out hydroaropic substance or when carrying out the microcyst of pressed powder, encapsulation ratio is low, content of dispersion is low, the parcel effect is poorer.
The present invention has overcome the method that adopts emulsifying agent and stabilizing agent to prepare the macromolecule microcyst in the prior art respectively, and the emulsifying-stabilizing agent that provides a kind of employing to have emulsifying-stability concurrently prepares the method for macromolecule microcyst.
For solving the compatibility problems of emulsifying agent and stabilizing agent, the present invention proposes the emulsification that has concurrently that a class is used to prepare microcyst and have the novel emulsion-stabilizing agent of Stabilization again, this emulsifying-stabilizing agent is a macromolecular compound, its main chain is the hydrophilic macromolecule long-chain, and side chain is the hydrophobicity long-chain hydrocarbon.Concrete structure is the random polypropylene amide derivatives that a class contains the hydrocarbon long-chain branch of alkali, and its chemical structural formula is as follows:
The molar content of the hydrocarbon long-chain branch of alkali
Be 0.1-30%, hydrocarbon long-chain branch R (C
nH
2n+1) be the hydrocarbon chain of 5-18 carbon atom, the acid ion-A of alkali
-Can be sulfonate radical-SO
3 -, carboxylate radical-COO-, cation M
+Can be sodium (Na
+), potassium (K
+), lithium (Li
+), ammonia (NH
4 +) or hydrogen (H
+) ion.
The molecular weight of the polyacrylamide derivative of the hydrocarbon long-chain branch of alkali is 10000-200000.
The present invention adopts and has the random polypropylene amide derivatives that contains the hydrocarbon long-chain branch of alkali of emulsifying-Stabilization concurrently as emulsifying-stabilizing agent, because being form with valence bond to each other, they fix, thereby it is more stable, reliable and effective and consumption reduces, in addition, this stabilizing agent that contains branched structure is compared with the stabilizing agent of the complete straight chain type structure of routine use, more helps to strengthen internal friction power, increases the effect between stabilizing agent and emulsion droplet, thereby reduce the generation of cohesion.Therefore consumption also can reduce widely.
This type of new macromolecule emulsion-stabilizing agent is applicable to the microcyst that carries out drug solution, also is applicable to the microcyst of solid drugs powder, and its microcyst preparation method follows these steps to carry out:
(1) to the microcyst of drug solution:
(1) with the encapsulation biodegradable polymer, (molecular weight is 2000-200000 as poly-Acetic acid, hydroxy-, bimol. cyclic ester, polylactide, polycaprolactone, lactide-glycolide copolymer, caprolactone-lactide copolymer, polycaprolactone-copolyether, polylactide-copolyether, polylactide-polycaprolactone-polyethers terpolymer etc., with 5000-80000 for better) with oiliness organic solvent dissolutions such as dichloromethane, chloroform, dichloroethanes, make the solution that concentration is the 5-300 mg/ml;
(2), make the solution of 1-50 mg/ml with medicine dissolved in distilled water such as insulin, bovine serum albumin or streptomycins;
(3) be 40 by volume with above-mentioned two kinds of solution: 1-2: 1, ultrasonic emulsification 30-120 second in the presence of micromolecule surfactants such as emulsifying agent department class 80, class of department 60, polysorbate60, Tween 80, make water-in-oil emulsion;
(4) be 1 by volume with above-mentioned water-in-oil emulsion: 5-1: 50, stir in the aqueous solution of random polypropylene amide derivatives that contains the hydrocarbon long-chain branch of alkali of the present invention that adds concentration and be 0.5-10% as emulsifying-stabilizing agent, mixing speed is 5000-20000 rev/min, mixing time is 0.5-5 minute, makes water-in-oil-in-water compositions;
(5) water-in-oil-in-water compositions is continued to stir 1-5 hour, mixing speed is 500-2000 rev/min, adopt centrifugal separation method to isolate the encapsulation microsome then, the reuse distilled water washs, washing times is 1-5 time, the microsome that obtains is carried out lyophilization, obtain high-polymer encapsulated drug microparticles body.
(2) for the micro-encapsulation of solid drugs powder:
(1) with the encapsulation biodegradable polymer, (molecular weight is 2000-200000 as poly-Acetic acid, hydroxy-, bimol. cyclic ester, polylactide, polycaprolactone, lactide-glycolide copolymer, caprolactone-lactide copolymer, polycaprolactone-copolyether, polylactide-copolyether, polylactide-polycaprolactone-polyethers terpolymer etc., with 5000-80000 for better) with oiliness organic solvent dissolutions such as dichloromethane, chloroform, dichloroethanes, make the solution that concentration is the 5-300 mg/ml;
(2) medical solid powder such as 5-50 milligram insulin, 5-fluorouracil or streptomycin are dispersed in encapsulation with in the high molecular solution;
(3) be 1 by volume with this dispersion liquid: 5-1: 100, the present invention who adds concentration and be 0.5-10% contains in the aqueous solution of polyacrylamide derivative as emulsifying-stabilizing agent of the hydrocarbon long-chain branch of alkali and stirs, mixing speed is 3000-10000 rev/min, mixing time is 15-120 minute, adopt centrifugal separation method to isolate the encapsulation microsome again, the reuse distilled water washs, washing times is 1-5 time, the microsome that obtains is carried out lyophilization, finally obtain the product-high-polymer encapsulated drug microparticles body of purpose.
By the prepared microsome of the present invention, for the micro-encapsulation of drug solution, particle diameter can be regulated between the 1-50 micron, and for the micro-encapsulation of medical solid powder, particle diameter changes with the variation of medical solid powder medicaments.
Embodiment 1,
The dichloromethane solution of 5mg insulin solution and 200mg polylactide (molecular weight is 200000) ultrasonic emulsification 1 minute in the presence of department class 80, the formation water-in-oil emulsion.The molar content of the present invention that adds 100ml 10% under 10000 rev/mins of mixing speeds is 30%, contains the aqueous solution of random polypropylene amide derivatives of the hydrocarbon long-chain branch sodium sulfonate of 5 carbon atoms, emulsifying 1 minute.The gained water-in-oil-in-water compositions stirred the microcyst centrifugalize that obtains 2 hours at 2000 rev/mins.Clean four times with distilled water, be dispersed at last in the water, lyophilization obtains the polylactide encapsulated insulin microsome.
Embodiment 2,
10mg 5-fluorouracil powder is homodisperse in the dichloromethane solution of 300mg polylactide-co-glycolide (molecular weight is 30000), this dispersion liquid is under 3000 rev/mins of mixing speeds, the molar content of the present invention of injecting 100ml0.25% is 0.1%, contain the aqueous solution of random polypropylene amide derivatives of the hydrocarbon long-chain branch carboxylic acid sodium of 18 carbon atoms, stirred 30 minutes.The microcyst centrifugalize that obtains.Clean three times with distilled water, be dispersed at last in the water, lyophilization obtains polylactide-co-glycolide encapsulation 5-fluorouracil microsome.
Embodiment 3,
30mg streptomycin pressed powder is dispersed in the chloroform soln of 300mg polycaprolactone (molecular weight is 120000), the molar content of the present invention of injecting 100ml 12% under 10000 rev/mins the mixing speed is 30%, the aqueous solution of random polypropylene amide derivatives that contains the hydrocarbon long-chain branch ichthyodin of 5 carbon atoms, stirred the microcyst centrifugalize that obtains 60 minutes.Clean three times with distilled water, be dispersed at last in the water, lyophilization obtains polycaprolactone encapsulation streptomycin microsome.Embodiment 4,
The dichloroethane solution of 20mg Bovine Serum Albumin in Aqueous Solution and 200mg polylactide (molecular weight is 5000) ultrasonic emulsification 1 minute in the presence of department class 80, form water-in-oil emulsion, under 15000 rev/mins of mixing speeds, the molar content of the present invention of injecting 100ml 10% is 10%, the aqueous solution of random polypropylene amide derivatives that contains the hydrocarbon long-chain branch carboxylic acid ammonium of 18 carbon atoms, emulsifying 1 minute.The gained water-in-oil-in-water compositions stirred the microcyst centrifugalize that obtains 2 hours at 2000 rev/mins.Clean four times with distilled water, be dispersed at last in the water, lyophilization obtains polylactide encapsulation bovine serum albumin microsome.
Embodiment 5,
The dichloromethane solution of 10mg insulin solution and 200mg polycaprolactone-copolyether (molecular weight is 80000) ultrasonic emulsification 45 seconds in the presence of department class 80, the molar content of the present invention of injecting 100ml 10% is 30%, the aqueous solution of random polypropylene amide derivatives that contains the hydrocarbon long-chain branch carboxylic acid potassium of 18 carbon atoms, emulsifying 5 minutes.The gained water-in-oil-in-water compositions stirred the microcyst centrifugalize that obtains 3 hours at 1000 rev/mins.Clean four times with distilled water, be dispersed at last in the water, lyophilization obtains polycaprolactone-copolyether encapsulated insulin microsome.
Embodiment 6,
Observe by the SEM of the streptomycin microcyst of embodiment 3 methods preparations and to show, the microcyst smooth surface that obtains, particle size distribution is even.The polarizing microscope photo of microcyst has shown the distinctive black cross extinction pattern of streptomycin spherocrystal.
Claims (6)
1, a kind of preparation method of macromolecule microcyst is characterized in that the microcyst for drug solution, and step is carried out in the following order:
(1) biological degradability polylactone macromolecule is made the solution that concentration is the 5-300 mg/ml with dichloromethane, chloroform or dichloroethanes dissolving,
(2) with insulin, bovine serum albumin or streptomycin water soluble drug dissolved in distilled water, make the solution that concentration is the 1-50 mg/ml;
(3) be 40 by volume with above-mentioned two kinds of solution: 1-2: 1 in the presence of emulsifying agent ultrasonic emulsification 30-120 second, make water-in-oil emulsion;
(4) be 1 by volume with this water-in-oil emulsion: 5-1: 50, add concentration and be in the aqueous solution of the random polypropylene amide derivatives that contains the hydrocarbon long-chain branch of alkali of 0.5-10% and stir;
(5) adopt centrifugal method to isolate the encapsulation microsome, the reuse distilled water washs, lyophilization,
The described structural formula that contains the random polypropylene amide derivatives of the hydrocarbon long-chain branch of alkali is:
In the formula
M
+Cation is sodium, potassium, lithium, ammonia or chloride ion, A
-For sulfonate radical or carboxylate radical R are the hydrocarbon chain of 5-18 carbon atom.
2, the preparation method of a kind of macromolecule microcyst according to claim 1 is characterized in that the described molecular weight that contains the random polypropylene amide derivatives of the hydrocarbon long-chain branch of alkali is 10000-200000;
3, the preparation method of a kind of macromolecule microcyst according to claim 1 is characterized in that the described concentration that contains the random polypropylene amide derivatives aqueous solution of the hydrocarbon long-chain branch of alkali is 0.25-10%;
4, the preparation method of a kind of macromolecule microcyst according to claim 1 is characterized in that the microcyst for the medical solid powder, and step is carried out in the following order:
(1) biodegradation polylactone macromolecule is dissolved with dichloromethane, chloroform or dichloroethanes, make the solution that concentration is the 5-300 mg/ml;
(2) 5-50 milligram insulin, 5-fluorouracil or streptomycin medicament pressed powder are dispersed in the high molecular solution;
(3) be 1 by volume with this dispersion liquid: 5-1: 100, add concentration and be in the aqueous solution of the random polypropylene amide derivatives that contains the hydrocarbon long-chain branch of alkali of 0.5-10% and stir, mixing time is 15-120 minute, adopt centrifugal separation method to isolate the encapsulation microsome, the reuse distilled water washs, lyophilization.
The described structural formula that contains the random polypropylene amide derivatives of the hydrocarbon long-chain branch of alkali is:
In the formula
M
+Cation is sodium, potassium, lithium, ammonia or chloride ion, A
-For sulfonate radical or carboxylate radical R are the hydrocarbon chain of 5-18 carbon atom;
5, the preparation method of a kind of macromolecule microcyst according to claim 4 is characterized in that the described molecular weight that contains the random polypropylene amide derivatives of the hydrocarbon long-chain branch of alkali is 10000-200000;
6, the preparation method of a kind of macromolecule microcyst according to claim 4 is characterized in that the described concentration that contains the random polypropylene amide derivatives aqueous solution of the hydrocarbon long-chain branch of alkali is 0.25-10%.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN98101117A CN1073412C (en) | 1998-03-19 | 1998-03-19 | Method for prepn. of macromolecule microcapsule |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN98101117A CN1073412C (en) | 1998-03-19 | 1998-03-19 | Method for prepn. of macromolecule microcapsule |
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| Publication Number | Publication Date |
|---|---|
| CN1229646A CN1229646A (en) | 1999-09-29 |
| CN1073412C true CN1073412C (en) | 2001-10-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98101117A Expired - Fee Related CN1073412C (en) | 1998-03-19 | 1998-03-19 | Method for prepn. of macromolecule microcapsule |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1302807C (en) * | 2004-03-19 | 2007-03-07 | 中国科学院长春应用化学研究所 | Biological degradable macromolecule microspheres of carrying insulin and preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7923034B2 (en) * | 2003-06-03 | 2011-04-12 | Santen Pharmaceutical Co., Ltd. | Process for producing microparticles |
| CA2817964C (en) | 2010-11-17 | 2018-06-12 | Chugai Seiyaku Kabushiki Kaisha | Multi-specific antigen-binding molecule having alternative function to function of blood coagulation factor viii |
| CN103211281B (en) * | 2013-04-10 | 2015-01-28 | 陕西科技大学 | Preparation method of anti-oxidation water-in-oil microemulsion |
| TWI700300B (en) | 2014-09-26 | 2020-08-01 | 日商中外製藥股份有限公司 | Antibodies that neutralize substances with the function of FVIII coagulation factor (FVIII) |
| TWI701435B (en) | 2014-09-26 | 2020-08-11 | 日商中外製藥股份有限公司 | Method to determine the reactivity of FVIII |
| TWI538958B (en) * | 2015-05-18 | 2016-06-21 | Nanya Plastics Corp | A preparation method of polyphenylene ether microspore dispersions |
| MX2018012648A (en) | 2016-04-28 | 2019-01-30 | Chugai Pharmaceutical Co Ltd | Antibody-containing preparation. |
| MX2020003472A (en) | 2017-11-01 | 2020-08-03 | Chugai Pharmaceutical Co Ltd | VARIANT AND ISOFORM OF ANTIBODIES WITH REDUCED BIOLOGICAL ACTIVITY. |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997026869A1 (en) * | 1996-01-24 | 1997-07-31 | United States Government Represented By The Secretary Of The Army | Novel 'burst-free' sustained release poly-(lactide/glycolide) microspheres |
-
1998
- 1998-03-19 CN CN98101117A patent/CN1073412C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997026869A1 (en) * | 1996-01-24 | 1997-07-31 | United States Government Represented By The Secretary Of The Army | Novel 'burst-free' sustained release poly-(lactide/glycolide) microspheres |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1302807C (en) * | 2004-03-19 | 2007-03-07 | 中国科学院长春应用化学研究所 | Biological degradable macromolecule microspheres of carrying insulin and preparation method |
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|---|---|
| CN1229646A (en) | 1999-09-29 |
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