CN101889985A - Medicament-carrying nano microspheres and preparation method thereof - Google Patents
Medicament-carrying nano microspheres and preparation method thereof Download PDFInfo
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Abstract
The invention relates to medicament-carrying nano microspheres. Each medicament-carrying nano microsphere comprises a core and a surface layer, wherein the core is made of a biologically degradable polymer material and a hydrophobic medicament; the surface layer is made of chitosan or derivative of the chitosan; in the core, the biologically degradable polymer material accounts for 50 to 95 weight percent and the hydrophobic medicament accounts for 5 to 50 weight percent; based on the weight of the core, the surface layer is 2 to 10 percent; and the particle size of the medicament-carrying nano microsphere ranges from 50 to 500 nanometers. The preparation method of the medicament-carrying nano microspheres of the invention comprises: slowing injecting organic solvent solution which contains a carrier material and the hydrophobic medicament in a large amount of water and adding aqueous solution of the chitosan or the derivative of the chitosan; or slowly injecting the organic solvent solution which contains a carrier material and the hydrophobic medicament in a large amount of the aqueous solution of the chitosan or the derivative of the chitosan to prepare the medicament-carrying nano microspheres. In the invention, the problem of preparing the medicament-carrying nano microspheres with stable hydrophilic surface layers by using the biologically degradable polymer or random copolymer is solved, and the drawbacks of use of an amphiphilic block (or graft) copolymer which is difficult to synthesize and easily falling of the hydrophilic surface layers of the prior art are overcome.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of medicament-carrying nano-microsphere and preparation method thereof, particularly relate to a kind of inside and outside double-deck medicament-carrying nano-microsphere and preparation method thereof.
Background technology
For improving the bioavailability and the curative effect of medicine, reduce the toxic and side effects of medicine, require medicine can not only discharge with predetermined speed in vivo, and can be in the lesions position enrichment.Novel medicine-carried system--drug-carried nanometer (ball) is expected to reach preferably above-mentioned target.Drug-carried nanometer refers generally to the solid-state or colloidal particle of particle diameter between 10nm-1000nm.Medicine or bioactive substance are distributed in particle inside or surperficial by physics or chemical action.Nanoparticle has many advantages aspect drug conveying:
(1) utilizes dimensional effect, can realize that nanoparticle selectivity in vivo distributes.As, particle diameter is removed from blood in the very fast phagocyte by reticuloendothelial system (RES) of the microsphere of 100nm-1000nm, arrive in the abundant liver of reticuloendothelium, the spleen tissue, and particle diameter can arrive during bone marrow etc. organizes less than the nanoparticle of 100nm.The size of control nanoparticle can make nanoparticle arrive specific tissue, plays the effect of passive target.In addition, the drug-carried nanometer surface is modified, can be prolonged the time of staying of nanoparticle in blood, thereby reduce administration number of times and dosage, improve the utilization rate of medicine.
(2) medicine is scattered in the inside or the surface of nanoparticle by the effect of chemistry or physics.Medicine can discharge by diffusion, also can by substrate itself gradually corrosion degraded be released.Thereby the nanoparticle drug delivery system can delay the release of medicine, the action time of prolong drug.
(3) as pharmaceutical pack being overlying on the inside of nanoparticle, the nanoparticle drug delivery system can also improve stability of drug, avoids medicine to degrade before arriving lesions position.
Because above plurality of advantages, the drug-carried nanometer drug delivery system has caused people's extensive studies interest.Polycaprolactone (PCL), polyglycolic acid (PGA), polylactic acid (PLA), poly butyric (PHB), polylactic acid-polyglycolic acid copolymer (PGLA), poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer (PHBV) with good biocompatibility and biodegradable performance all are ideal carriers of dewatering medicament.Can adopt emulsion-solvent evaporation method to prepare drug-carried nanometer.Be about to carrier material and medicine dissolution in organic solvent, then it joined in the water or pure water that contains emulsifying agent, stir or ultrasonic emulsification after, the decompression volatilization or to water dialysis remove organic solvent, can obtain being loaded with the nanoparticle of hydrophobic drug.The above-mentioned biodegradable polymers or the copolymer microsphere of the medicine carrying that the employing emulsion-solvent evaporation method prepares, size is bigger, usually at micron order, thereby can't directly arrive target tissue to drug conveying by mucosa or through the body circulation; Owing to its hydrophobic surface, microsphere is also very easily by protein adsorption with by identification of reticuloendothelial system ground macrophage and seizure simultaneously.For overcoming this defective, existing document or patent adopt the method for introducing hydrophilic block or grafted chain, prepare amphipathic block or graft copolymer, then with it as carrier material, by with medicine comicellization in selective solvent, prepare nuclear by hydrophobic block or grafted chain and dewatering medicament is formed, shell is made up of hydrophilic block or grafted chain medicament-carrying nano-microsphere.Adopt in the aqueous solution of organic solvent adding polyvinyl alcohol that contains polycaprolactone-polyethylene glycol copolymer and paclitaxel or gelatin as patent CN1561987A, ultrasonic emulsification, the volatilization organic solvent that reduces pressure then, having obtained particle diameter is the medicine carrying microballoons of 300-800nm.But the preparation of block or graft copolymer is difficulty relatively, and also can use some that the deleterious reagent of organism (as aromatic isocyanate, CN1425706A), is influenced the practical application of nanoparticle in its preparation process.The method that Chinese patent CN1903365A has then adopted the two dodecyl dimethyl ammoniums of bromination, poly-l-lysine or protamine sulfate to modify microparticle surfaces.It at first is emulsifying agent with PVA, adopt the solvent emulsion volatility process to prepare polycaprolactone, polylactic acid or the polylactic acid-polyglycolic acid copolymer particle of medicine carrying, then, adopt repeatedly high speed centrifugation-process for dispersing washing to remove emulsion breaker and lyophilization, at last, the drug-carried nanometer adding is contained in the water of dressing agent, after ultrasonic or high-speed stirred is disperseed, lyophilization.But these dressing agents are the surfaces that are present in microgranule with the form that simple physics coats, and in actual applications, microgranule enters in the body fluid by modes such as oral, injection, percutaneous or mucosa deliveries, because the dissolved dilution effect, its finishing thing is easy to come off.
Summary of the invention
The purpose of this invention is to provide a kind of medicament-carrying nano-microsphere and preparation method thereof, a kind of inside and outside double-deck medicament-carrying nano-microsphere and preparation method thereof just is provided.The invention solves the problem for preparing medicament-carrying nano-microsphere by biodegradable polymers or random copolymer, remedied prior art and must use amphipathic block (or grafting) copolymer of synthetic difficulty or the deficiency that hydrophilic surface layer comes off easily with stable hydrophilic top layer.
A kind of medicament-carrying nano-microsphere of the present invention comprises kernel and top layer, and its kernel is made up of biodegradable polymer and dewatering medicament, and its top layer is made up of the chitosan or derivatives thereof; In the kernel, the percentage by weight of biodegradable polymer is 50-95%, and the percentage by weight of dewatering medicament is 5-50%; The top layer is 2-10% with respect to the percentage by weight of kernel; The particle size range of described medicament-carrying nano-microsphere is 50nm-500nm;
Wherein, described biodegradable polymer is polycaprolactone, polyglycolic acid, polylactic acid, poly butyric, polylactic acid-polyglycolic acid copolymer or poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer.
As optimized technical scheme:
Aforesaid a kind of medicament-carrying nano-microsphere, wherein, the relative molecular mass of described biodegradable polymer is 3000-200000; Described biodegradable polymer is polycaprolactone, polyglycolic acid, polylactic acid, poly butyric, polylactic acid-polyglycolic acid copolymer or poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer of not process termination process; Described relative molecular weight of chitosan is 1500-100000, and deacetylation is greater than 90%; Described chitosan derivatives is a carboxymethyl chitosan; Described dewatering medicament is the outgrowth Docetaxel of inhibition blood vessel endothelium, paclitaxel or rapamycin, or the azithromycin of antiinflammatory or ibuprofen.
The preparation method of a kind of medicament-carrying nano-microsphere of the present invention comprises the following steps:
(1) dewatering medicament is dissolved in the organic solvent first, biodegradable polymer is dissolved in the organic solvent second, and then with both mix homogeneously, preparation contains the organic solvent solution of dewatering medicament and biodegradable polymer; In the described organic solvent solution, the concentration of its biodegradable polymer is 1-30mg/mL, and the weight ratio of described dewatering medicament and described biodegradable polymer is 1: 1～19; Described biodegradable polymer is polycaprolactone, polyglycolic acid, polylactic acid, poly butyric, polylactic acid-polyglycolic acid copolymer or poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer;
(2) under stirring condition, the organic solvent solution of step (1) preparation is slowly injected water, the volume ratio of described organic solvent solution and water is 1: 2-20, injection length is that (under the small lot condition, injection rate is 0.5-10mL/h to 1-6h, if container is amplified, injection rate will accelerate, but injection length remains unchanged), after injection finishes, continue to stir 0.5-4h; Then,, remove the organic solvent in the dispersion liquid, obtain the aqueous dispersions of drug-carried nanometer by the method that reduces pressure rotary evaporation or water is dialysed;
(3) the chitosan or derivatives thereof is dissolved in the acetic acid aqueous solution of 0.1-3vol.%, the preparation chitosan solution, in the described chitosan solution, the concentration of chitosan or derivatives thereof is 0.5-5mg/mL; Then, under stirring condition, chitosan solution is added in the aqueous dispersions of drug-carried nanometer of step (2) preparation, the volume ratio of the aqueous dispersions of described chitosan solution and described drug-carried nanometer is 1: 10-60, after continuing to stir 0.5-4h, lyophilization obtains having the medicament-carrying nano-microsphere powder on chitosan or derivatives thereof top layer.
The preparation method of aforesaid a kind of medicament-carrying nano-microsphere, wherein, the relative molecular mass of described biodegradable polymer is 3000-200000; Described biodegradable polymer is polycaprolactone, polyglycolic acid, polylactic acid, poly butyric, polylactic acid-polyglycolic acid copolymer or poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer of not process termination process; Described relative molecular weight of chitosan is 1500-100000, and deacetylation is greater than 90%; Described chitosan derivatives is a carboxymethyl chitosan; Described dewatering medicament is the outgrowth Docetaxel of inhibition blood vessel endothelium, paclitaxel or rapamycin, or the azithromycin of antiinflammatory or ibuprofen.
The preparation method of aforesaid a kind of medicament-carrying nano-microsphere, wherein, described organic solvent first or organic solvent second be can be miscible with water organic solvent methanol, ethanol, acetone, acetonitrile, oxolane, dioxy six alkane, dimethyl formamide, dimethyl acetylamide or dimethyl sulfoxide.
The present invention also provides the preparation method of another kind of medicament-carrying nano-microsphere, comprises the following steps:
(1) dewatering medicament is dissolved in the organic solvent first, biodegradable polymer is dissolved in the organic solvent second, and then with both mix homogeneously, preparation contains the organic solvent solution of dewatering medicament and biodegradable polymer; In the described organic solvent solution, the concentration of its biodegradable polymer is 1-30mg/mL, and the weight ratio of described dewatering medicament and described biodegradable polymer is 1: 1～19; Described biodegradable polymer is polycaprolactone, polyglycolic acid, polylactic acid, poly butyric, polylactic acid-polyglycolic acid copolymer or poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer;
(2) the chitosan or derivatives thereof is dissolved in the acetic acid aqueous solution of 0.1-3vol.% the preparation chitosan solution; In the described chitosan solution, the concentration of chitosan or derivatives thereof is 0.05-1mg/mL;
(3) under stirring condition, in the chitosan solution that the slow implantation step of organic solvent solution (2) that step (1) is prepared prepares, the volume ratio of described organic solvent solution and described chitosan solution is 1: 2-20; Injection length is 1-6h, after injection finishes, continues to stir 0.5-4h again; Then,, remove the organic solvent in the dispersion liquid by the method that reduces pressure rotary evaporation or water is dialysed, lyophilization then, obtaining the top layer is that chitosan or derivatives thereof, kernel are the powder of the medicament-carrying nano-microsphere of biodegradable polymer and medicine.
The preparation method of aforesaid a kind of medicament-carrying nano-microsphere, wherein, the relative molecular mass of described biodegradable polymer is 3000-200000; Described biodegradable polymer is polycaprolactone, polyglycolic acid, polylactic acid, poly butyric, polylactic acid-polyglycolic acid copolymer or poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer of not process termination process; Described relative molecular weight of chitosan is 1500-100000, and deacetylation is greater than 90%; Described chitosan derivatives is a carboxymethyl chitosan; Described dewatering medicament is the outgrowth Docetaxel of inhibition blood vessel endothelium, paclitaxel or rapamycin, or the azithromycin of antiinflammatory or ibuprofen.
The preparation method of aforesaid a kind of medicament-carrying nano-microsphere, wherein, described organic solvent first or organic solvent second be can be miscible with water organic solvent methanol, ethanol, acetone, acetonitrile, oxolane, dioxy six alkane, dimethyl formamide, dimethyl acetylamide or dimethyl sulfoxide.
The present invention provides a kind of using method of medicament-carrying nano-microsphere as claimed in claim 1 again, it is characterized in that: the powder of described medicament-carrying nano-microsphere by ultra-sonic dispersion in water, forming concentration is the aqueous dispersions of the medicament-carrying nano-microsphere of 0.1-50mg/mL, by the foley's tube mode administration of oral, injection, percutaneous, mucosa or interventional therapy.
Principle of the present invention:
Because the existence of water-wet side carboxyl and terminal hydroxy group in polycaprolactone (PCL), polyglycolic acid (PGA), polylactic acid (PLA), poly butyric (PHB), polylactic acid-polyglycolic acid copolymer (PGLA), poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer (PHBV) carrier material, the similar of this carrier material is in the micromolecule surfactant, and just the hydrophobic segment of carrier material is longer.When the organic solvent solution of carrier material and dewatering medicament was slowly injected a large amount of water, the microfacies counter-rotating had taken place.Concerning the hydrophobic segment and dewatering medicament of carrier material, medium changes poor solvent into by original good solvent, hydrophobic segment and dewatering medicament can be assembled the collapse into ball, and injection rate makes the carrier material macromole have time enough to adjust its conformation slowly, thus make its hydrophilic end group optionally enrichment be distributed in the surface of microgranule.Because the electrical charge rejection effect of ionized end carboxyl and the hydrophilic interaction of unionized end carboxyl and terminal hydroxy group, microgranule energy stable dispersion is in medium.
The drug-carried nanometer surface with negative charge, can with the chitosan or derivatives thereof molecule generation positive and negative charge effect of positively charged, simultaneously, the drug-carried nanometer surface with hydrophilic hydroxyl groups and carboxyl, can with chitosan or derivatives thereof molecule with hydroxyl, carboxyl and the amino hydrogen bond action that takes place, thereby, by follow-up simple adsorption treatment, just can form one deck chitosan or derivatives thereof on the drug-carried nanometer surface, obtaining the top layer is that chitosan or derivatives thereof, kernel are the medicament-carrying nano-microsphere of drug-carried nanometer.
When the slow injection of the organic solvent solution of carrier material and dewatering medicament is contained the water of chitosan or derivatives thereof in a large number, the hydrophobic segment of carrier material and dewatering medicament can be assembled the collapse into ball, by with the positive and negative charge effect and the hydrogen bond action of its surface hydrophilic end group, the chitosan or derivatives thereof can be adsorbed on aggregation that carrier material and dewatering medicament form around, make its stable existence in medium.Thus, also can obtain the top layer is that chitosan or derivatives thereof, kernel are the medicament-carrying nano-microsphere of carrier material and dewatering medicament.
Because chitosan or derivatives thereof top layer is to combine with hydrophobic medicine carrying kernel by hydrogen bond action and positive and negative charge effect, rather than simple physics coats, thereby, the chitosan or derivatives thereof top layer of prepared medicament-carrying nano-microsphere has stability preferably, can not come off in application.
The invention has the beneficial effects as follows:
(1) method of the present invention is simple, need not to use amphipathic block or the graft copolymer and the emulsifying agent of synthetic difficulty, just can prepare medicament-carrying nano-microsphere;
(2) existence on chitosan or derivatives thereof top layer, on the one hand, make microsphere surface positively charged, can be by electronegative glycosaminoglycan effect contained in positive and negative charge effect and the vascular wall tissue, promote the absorption of medicament-carrying nano-microsphere in blood vessel wall and resident, thereby can improve the curative effect of medicament-carrying nano-microsphere in the treatment of vascular restenosis; On the other hand, can also eliminate the polyesters carrier material local inflammation problem that the acid product that produces causes of in human body, degrading.
The specific embodiment
Below in conjunction with the specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Among each embodiment, the mean diameter of medicament-carrying nano-microsphere is to obtain by the dynamic light scattering test.With the aqueous dispersions lyophilization of medicament-carrying nano-microsphere, behind the medicine in the selective solvent extraction medicament-carrying nano-microsphere lyophilized powder of medicine,, thereby calculate drug loading and envelop rate by the concentration of high effective liquid chromatography for measuring extract Chinese medicine.
A kind of medicament-carrying nano-microsphere of the present invention comprises kernel and top layer, and its kernel is made up of biodegradable polymer and dewatering medicament, and its top layer is made up of the chitosan or derivatives thereof; In the kernel, the percentage by weight of biodegradable polymer is 50-95%, and the percentage by weight of dewatering medicament is 5-50%; The top layer is 2-10% with respect to the percentage by weight of kernel; The particle size range of described medicament-carrying nano-microsphere is 50nm-500nm; Wherein, described biodegradable polymer is polycaprolactone, polyglycolic acid, polylactic acid, poly butyric, polylactic acid-polyglycolic acid copolymer or poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer.
A kind of using method of medicament-carrying nano-microsphere, the powder of medicament-carrying nano-microsphere by ultra-sonic dispersion in water, forming concentration is the aqueous dispersions of the medicament-carrying nano-microsphere of 0.1-50mg/mL, by the foley's tube mode administration of oral, injection, percutaneous, mucosa or interventional therapy.
Embodiment 1
Take by weighing 50mg polycaprolactone (PCL) and be dissolved in the 4mL dimethyl sulfoxide, take by weighing the 20mg azithromycin and be dissolved in the 1mL dimethyl sulfoxide, then, with both mix homogeneously, preparation contains the organic solvent solution of PCL and azithromycin.Under stirring condition, organic solvent solution is injected 50mL water with the speed of 1.5mL/h, after injection finishes, continue to stir 0.5h.Then,, remove organic solvent, obtain aqueous dispersions with blue opalescent drug-carried nanometer with in its bag filter of packing into big water gaging being dialysed.The mean diameter of drug-carried nanometer is 163nm, and polydispersity coefficient is 0.12.Drug loading is 39%, and envelop rate is 97.5%.Chitosan is dissolved in the aqueous acetic acid of 1vol%, compound concentration is the chitosan solution of 1mg/mL.Under stirring condition, the 3mL chitosan solution is added in the aqueous dispersions of above-mentioned drug-carried nanometer, continue to stir 0.5h, obtaining the top layer is that chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PCL and azithromycin, after its lyophilization, obtain the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 192nm, and polydispersity coefficient is 0.15.
Embodiment 2
Take by weighing 8.6mg polycaprolactone (PCL) and be dissolved in the 8.6mL acetone, take by weighing the 8.6mg azithromycin and be dissolved in the 0.4mL methanol, then, with both mix homogeneously, preparation contains the organic solvent solution of PCL and azithromycin.Under stirring condition, organic solvent solution is injected 18mL water with the speed of 1.5mL/h, after injection finishes, continue to stir 4h.Then, rotary evaporation under 60 ℃ and vacuum below the 200mbar is removed organic solvent, obtains the aqueous dispersions with blue opalescent drug-carried nanometer.The mean diameter of drug-carried nanometer is 168nm, and polydispersity coefficient is 0.10.Drug loading is 93%, and envelop rate is 93%.Chitosan is dissolved in the aqueous acetic acid of 0.1vol%, compound concentration is the chitosan solution of 0.96mg/mL.Under stirring condition, the 1.8mL chitosan solution is added in the aqueous dispersions of above-mentioned drug-carried nanometer, continue to stir 4h, obtaining the top layer is that chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PCL and azithromycin, after its lyophilization, obtain the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 224nm, and polydispersity coefficient is 0.16.
Embodiment 3
Take by weighing 150mg polylactic acid (PLA) and be dissolved in the 4.5mL dimethyl formamide, take by weighing the 7.9mg paclitaxel and be dissolved in the 0.5mL ethanol, then, with both mix homogeneously, preparation contains the organic solvent solution of PLA and paclitaxel.Under stirring condition, organic solvent solution is injected 100mL water with the speed of 1.5mL/h, after injection finishes, continue to stir 2h.Then,, remove organic solvent, obtain aqueous dispersions with blue opalescent drug-carried nanometer with in its bag filter of packing into big water gaging being dialysed.The mean diameter of drug-carried nanometer is 417nm, and polydispersity coefficient is 0.18.Drug loading is 5.24%, and envelop rate is 99.5%.Chitosan is dissolved in the aqueous acetic acid of 1vol%, compound concentration is the chitosan solution of 1.9mg/mL.Under stirring condition, the 1.66mL chitosan solution is added in the aqueous dispersions of above-mentioned drug-carried nanometer, continue to stir 0.5h, obtaining the top layer is that chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PLA and paclitaxel, after its lyophilization, obtain the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 453nm, and polydispersity coefficient is 0.18.
Embodiment 4
Take by weighing 100mg polyglycolic acid (PGA) and be dissolved in the 4.5mL dimethyl formamide, take by weighing the 12mg Docetaxel and be dissolved in the 0.5mL acetonitrile, then, with both mix homogeneously, preparation contains the organic solvent solution of PGA and Docetaxel.Under stirring condition, organic solvent solution is injected 50mL water with the speed of 1.5mL/h, after injection finishes, continue to stir 2h.Then,, remove organic solvent, obtain aqueous dispersions with blue opalescent drug-carried nanometer with in its bag filter of packing into big water gaging being dialysed.The mean diameter of drug-carried nanometer is 282nm, and polydispersity coefficient is 0.16.Drug loading is 11.8%, and envelop rate is 98.3%.Chitosan is dissolved in the aqueous acetic acid of 3vol%, compound concentration is the chitosan solution of 5mg/mL.Under stirring condition, the 1.2mL chitosan solution is added in the aqueous dispersions of above-mentioned drug-carried nanometer, continue to stir 0.5h, obtaining the top layer is that chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PGA and Docetaxel, after its lyophilization, obtain the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 327nm, and polydispersity coefficient is 0.18.
Embodiment 5
Take by weighing 50mg poly butyric (PHB) and be dissolved in the 4.8mL dimethyl formamide, take by weighing the 20mg rapamycin and be dissolved in the 0.2mL methanol, then, with both mix homogeneously, preparation contains the organic solvent solution of PHB and rapamycin.Under stirring condition, organic solvent solution is injected 50mL water with the speed of 5mL/h, after injection finishes, continue to stir 2h.Then,, remove organic solvent, obtain aqueous dispersions with blue opalescent drug-carried nanometer with in its bag filter of packing into big water gaging being dialysed.The mean diameter of drug-carried nanometer is 182nm, and polydispersity coefficient is 0.12.Drug loading is 38.9%, and envelop rate is 97.3%.Chitosan is dissolved in the aqueous acetic acid of 1vol%, compound concentration is the chitosan solution of 0.5mg/mL.Under stirring condition, the 3mL chitosan solution is added in the aqueous dispersions of above-mentioned drug-carried nanometer, continue to stir 0.5h, obtaining the top layer is that chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PHB and rapamycin, after its lyophilization, obtain the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 202nm, and polydispersity coefficient is 0.12.
Embodiment 6
Take by weighing 50mg polylactic acid-polyglycolic acid copolymer (PGLA) and be dissolved in the 4.8mL dimethyl formamide, take by weighing the 20mg ibuprofen and be dissolved in the 0.2mL acetone, then, with both mix homogeneously, preparation contains the organic solvent solution of PGLA and ibuprofen.Under stirring condition, organic solvent solution is injected 50mL water with the speed of 1.5mL/h, after injection finishes, continue to stir 2h.Then,, remove organic solvent, obtain aqueous dispersions with blue opalescent drug-carried nanometer with in its bag filter of packing into big water gaging being dialysed.The mean diameter of drug-carried nanometer is 122nm, and polydispersity coefficient is 0.12.Drug loading is 35.2%, and envelop rate is 88%.Chitosan is dissolved in the aqueous acetic acid of 1vol%, compound concentration is the chitosan solution of 1mg/mL.Under stirring condition, the 3mL chitosan solution is added in the aqueous dispersions of above-mentioned drug-carried nanometer, continue to stir 0.5h, obtaining the top layer is that chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PGLA and ibuprofen, after its lyophilization, obtain the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 148nm, and polydispersity coefficient is 0.12.
Embodiment 7
Taking by weighing 50mg poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer (PHBV) is dissolved in the 4.8mL dimethyl acetylamide, taking by weighing the 20mg azithromycin is dissolved in the 0.2mL dimethyl acetylamide, then, with both mix homogeneously, preparation contains the organic solvent solution of PHBV and azithromycin.Under stirring condition, organic solvent solution is injected 50mL water with the speed of 2.5mL/h, after injection finishes, continue to stir 2h.Then,, remove organic solvent, obtain aqueous dispersions with blue opalescent drug-carried nanometer with in its bag filter of packing into big water gaging being dialysed.The mean diameter of drug-carried nanometer is 152nm, and polydispersity coefficient is 0.12.Drug loading is 39.2%, and envelop rate is 98%.Chitosan is dissolved in the aqueous acetic acid of 1vol%, compound concentration is the chitosan solution of 1mg/mL.Under stirring condition, the 3mL chitosan solution is added in the aqueous dispersions of above-mentioned drug-carried nanometer, continue to stir 0.5h, obtaining the top layer is that chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PHBV and azithromycin, after its lyophilization, obtain the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 174nm, and polydispersity coefficient is 0.12.
Embodiment 8
Take by weighing 50mg polycaprolactone (PCL) and be dissolved in the 4mL oxolane, take by weighing the 20mg azithromycin and be dissolved in the 1mL methanol, then, with both mix homogeneously, preparation contains the organic solvent solution of PCL and azithromycin.Under stirring condition, organic solvent solution is injected 50mL water with the speed of 1.5mL/h, after injection finishes, continue to stir 0.5h.Then, rotary evaporation under 60 ℃ and vacuum below the 200mbar remove organic solvent, and the concentrated solution volume obtains the aqueous dispersions with light blue opalescent drug-carried nanometer to 20mL.The mean diameter of drug-carried nanometer is 177nm, and polydispersity coefficient is 0.12.Drug loading is 39.6%, and envelop rate is 99%.Chitosan is dissolved in the aqueous acetic acid of 2vol%, compound concentration is the chitosan solution of 3mg/mL.Under stirring condition, the 1mL chitosan solution is added in the aqueous dispersions of above-mentioned drug-carried nanometer, continue to stir 0.5h, obtaining the top layer is that chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PCL and azithromycin, after its lyophilization, obtain the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 213nm, and polydispersity coefficient is 0.18.
Embodiment 9
Take by weighing 50mg polycaprolactone (PCL) and be dissolved in 4mL dioxy six alkane, take by weighing the 20mg azithromycin and be dissolved in the 1mL ethanol, then, with both mix homogeneously, preparation contains the organic solvent solution of PCL and azithromycin.Under stirring condition, organic solvent solution is injected 50mL water with the speed of 1.5mL/h, after injection finishes, continue to stir 0.5h.Then,, remove organic solvent, obtain aqueous dispersions with blue opalescent drug-carried nanometer with in its bag filter of packing into big water gaging being dialysed.The mean diameter of drug-carried nanometer is 157nm, and polydispersity coefficient is 0.12.Drug loading is 39.2%, and envelop rate is 98%.Chitosan is dissolved in the aqueous acetic acid of 2vol%, compound concentration is the chitosan solution of 3mg/mL.Under stirring condition, the 1mL chitosan solution is added in the aqueous dispersions of above-mentioned drug-carried nanometer, continue to stir 0.5h, obtaining the top layer is that chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PCL and azithromycin, after its lyophilization, obtain the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 183nm, and polydispersity coefficient is 0.15.
Embodiment 10
Take by weighing 50mg polycaprolactone (PCL) and be dissolved in the 4mL acetone, take by weighing the 20mg azithromycin and be dissolved in the 1mL acetone, then, with both mix homogeneously, preparation contains the organic solvent solution of PCL and azithromycin.Under stirring condition, organic solvent solution is injected 50mL water with the speed of 1.5mL/h, after injection finishes, continue to stir 0.5h.Then, 60.℃ and the following vacuum of 200mbar under rotary evaporation, remove organic solvent, and the concentrated solution volume obtains the aqueous dispersions with light blue opalescent drug-carried nanometer to 20mL.The mean diameter of drug-carried nanometer is 214nm, and polydispersity coefficient is 0.13.Drug loading is 39%, and envelop rate is 97.5%.Carboxymethyl chitosan is dissolved in the aqueous acetic acid of 0.1vol%, compound concentration is the carboxymethyl chitosan sugar juice of 1mg/mL.Under stirring condition, 3mL carboxymethyl chitosan sugar juice is added in the aqueous dispersions of above-mentioned drug-carried nanometer, continue to stir 0.5h, obtaining the top layer is that carboxymethyl chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PCL and azithromycin, after its lyophilization, obtain the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 239nm, and polydispersity coefficient is 0.15.
Embodiment 11
Take by weighing 50mgPCL and be dissolved in the 4mL acetone, take by weighing the 20mg azithromycin and be dissolved in the 1mL acetone, then, with both mix homogeneously, preparation contains the organic solvent solution of PCL and azithromycin.Chitosan is dissolved in the aqueous acetic acid of 0.1vol%, compound concentration is the chitosan solution of 0.05mg/mL.Under stirring condition,, after injection finishes, continue to stir 0.5h with the chitosan solution of organic solvent solution with the speed injection 50mL of 1.5mL/h.Then, rotary evaporation under 60 ℃ and vacuum below the 200mbar is removed organic solvent, and obtaining the top layer is that chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PCL and azithromycin, after its lyophilization, obtains the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 303nm, and polydispersity coefficient is 0.18.
Embodiment 12
Take by weighing 100mg PHBV and be dissolved in the 4mL dimethyl acetylamide, take by weighing the 40mg azithromycin and be dissolved in the 1mL dimethyl acetylamide, then, with both mix homogeneously, preparation contains the organic solvent solution of PHBV and azithromycin.Chitosan is dissolved in the aqueous acetic acid of 3vol%, compound concentration is the chitosan solution of 1mg/mL.Under stirring condition,, after injection finishes, continue to stir 4h with the chitosan solution of organic solvent solution with the speed injection 14mL of 0.9mL/h.Then, with in its bag filter of packing into big water gaging being dialysed, remove organic solvent, obtaining the top layer is that chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PHBV and azithromycin, after its lyophilization, obtains the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 423nm, and polydispersity coefficient is 0.26.
Embodiment 13
Take by weighing 100mg PLA and be dissolved in the 4mL dimethyl sulfoxide, take by weighing the 40mg rapamycin and be dissolved in the 1mL dimethyl sulfoxide, then, with both mix homogeneously, preparation contains the organic solvent solution of PLA and rapamycin.Chitosan is dissolved in the aqueous acetic acid of 0.5vol%, compound concentration is the chitosan solution of 0.1mg/mL.Under stirring condition,, after injection finishes, continue to stir 2h with the chitosan solution of organic solvent solution with the speed injection 100mL of 5mL/h.Then, with in its bag filter of packing into big water gaging being dialysed, remove organic solvent, obtaining the top layer is that chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PLA and rapamycin, after its lyophilization, obtains the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 286nm, and polydispersity coefficient is 0.20.
Embodiment 14
Take by weighing 50mg PLA and be dissolved in the 4.5mL dimethyl formamide, take by weighing 10mg paclitaxel element and be dissolved in the 0.5mL ethanol, then, with both mix homogeneously, preparation contains the organic solvent solution of PLA and paclitaxel.Carboxymethyl chitosan is dissolved in the aqueous acetic acid of 0.1vol%, compound concentration is the carboxymethyl chitosan sugar juice of 0.05mg/mL.Under stirring condition,, after injection finishes, continue to stir 0.5h with the carboxymethyl chitosan sugar juice of organic solvent solution with the speed injection 50mL of 1.5mL/h.Then,, remove organic solvent with in its bag filter of packing into big water gaging being dialysed,, obtaining the top layer is that carboxymethyl chitosan, kernel are the aqueous dispersions of the medicament-carrying nano-microsphere of PLA and paclitaxel, after its lyophilization, obtains the medicament-carrying nano-microsphere powder.The mean diameter of medicament-carrying nano-microsphere is 316nm, and polydispersity coefficient is 0.18.
Claims (9)
1. medicament-carrying nano-microsphere, it is characterized in that: comprise kernel and top layer, its kernel is made up of biodegradable polymer and dewatering medicament, and its top layer is made up of the chitosan or derivatives thereof; In the kernel, the percentage by weight of biodegradable polymer is 50-95%, and the percentage by weight of dewatering medicament is 5-50%; The top layer is 2-10% with respect to the percentage by weight of kernel; The particle size range of described medicament-carrying nano-microsphere is 50nm-500nm;
Wherein, described biodegradable polymer is polycaprolactone, polyglycolic acid, polylactic acid, poly butyric, polylactic acid-polyglycolic acid copolymer or poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer.
2. a kind of medicament-carrying nano-microsphere as claimed in claim 1 is characterized in that, the relative molecular mass of described biodegradable polymer is 3000-200000; Described biodegradable polymer is polycaprolactone, polyglycolic acid, polylactic acid, poly butyric, polylactic acid-polyglycolic acid copolymer or poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer of not process termination process; Described relative molecular weight of chitosan is 1500-100000, and deacetylation is greater than 90%; Described chitosan derivatives is a carboxymethyl chitosan; Described dewatering medicament is the outgrowth Docetaxel of inhibition blood vessel endothelium, paclitaxel or rapamycin, or the azithromycin of antiinflammatory or ibuprofen.
3. the preparation method of a medicament-carrying nano-microsphere is characterized in that comprising the following steps:
(1) dewatering medicament is dissolved in the organic solvent first, biodegradable polymer is dissolved in the organic solvent second, and then with both mix homogeneously, preparation contains the organic solvent solution of dewatering medicament and biodegradable polymer; In the described organic solvent solution, the concentration of its biodegradable polymer is 1-30mg/mL, and the weight ratio of described dewatering medicament and described biodegradable polymer is 1: 1～19; Described biodegradable polymer is polycaprolactone, polyglycolic acid, polylactic acid, poly butyric, polylactic acid-polyglycolic acid copolymer or poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer;
(2) under stirring condition, the organic solvent solution that step (1) is prepared slowly injects water, and the volume ratio of described organic solvent solution and water is 1: 2-20, and injection length is 1-6h, after injection finishes, continues to stir 0.5-4h; Then,, remove the organic solvent in the dispersion liquid, obtain the aqueous dispersions of drug-carried nanometer by the method that reduces pressure rotary evaporation or water is dialysed;
(3) the chitosan or derivatives thereof is dissolved in the acetic acid aqueous solution of 0.1-3vol.%, the preparation chitosan solution, in the described chitosan solution, the concentration of chitosan or derivatives thereof is 0.5-5mg/mL; Then, under stirring condition, chitosan solution is added in the aqueous dispersions of drug-carried nanometer of step (2) preparation, the volume ratio of the aqueous dispersions of described chitosan solution and described drug-carried nanometer is 1: 10-60, after continuing to stir 0.5-4h, lyophilization obtains having the medicament-carrying nano-microsphere powder on chitosan or derivatives thereof top layer.
4. the preparation method of a kind of medicament-carrying nano-microsphere as claimed in claim 3 is characterized in that, the relative molecular mass of described biodegradable polymer is 3000-200000; Described biodegradable polymer is polycaprolactone, polyglycolic acid, polylactic acid, poly butyric, polylactic acid-polyglycolic acid copolymer or poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer of not process termination process; Described relative molecular weight of chitosan is 1500-100000, and deacetylation is greater than 90%; Described chitosan derivatives is a carboxymethyl chitosan; Described dewatering medicament is the outgrowth Docetaxel of inhibition blood vessel endothelium, paclitaxel or rapamycin, or the azithromycin of antiinflammatory or ibuprofen.
5. the preparation method of a kind of medicament-carrying nano-microsphere as claimed in claim 3, it is characterized in that, described organic solvent first or organic solvent second be can be miscible with water organic solvent methanol, ethanol, acetone, acetonitrile, oxolane, dioxy six alkane, dimethyl formamide, dimethyl acetylamide or dimethyl sulfoxide.
6. the preparation method of a medicament-carrying nano-microsphere is characterized in that comprising the following steps:
(1) dewatering medicament is dissolved in the organic solvent first, biodegradable polymer is dissolved in the organic solvent second, and then with both mix homogeneously, preparation contains the organic solvent solution of dewatering medicament and biodegradable polymer; In the described organic solvent solution, the concentration of its biodegradable polymer is 1-30mg/mL, and the weight ratio of described dewatering medicament and described biodegradable polymer is 1: 1～19; Described biodegradable polymer is polycaprolactone, polyglycolic acid, polylactic acid, poly butyric, polylactic acid-polyglycolic acid copolymer or poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer;
(2) the chitosan or derivatives thereof is dissolved in the acetic acid aqueous solution of 0.1-3vol.% the preparation chitosan solution; In the described chitosan solution, the concentration of chitosan or derivatives thereof is 0.05-1mg/mL;
(3) under stirring condition, in the chitosan solution that the slow implantation step of organic solvent solution (2) that step (1) is prepared prepares, the volume ratio of described organic solvent solution and described chitosan solution is 1: 2-20; Injection length is 1-6h, after injection finishes, continues to stir 0.5-4h again; Then,, remove the organic solvent in the dispersion liquid by the method that reduces pressure rotary evaporation or water is dialysed, lyophilization then, obtaining the top layer is that chitosan or derivatives thereof, kernel are the powder of the medicament-carrying nano-microsphere of biodegradable polymer and medicine.
7. the preparation method of a kind of medicament-carrying nano-microsphere as claimed in claim 6 is characterized in that, the relative molecular mass of described biodegradable polymer is 3000-200000; Described biodegradable polymer is polycaprolactone, polyglycolic acid, polylactic acid, poly butyric, polylactic acid-polyglycolic acid copolymer or poly-(3-hydroxybutyric acid)-poly-(3-hydroxypentanoic acid) copolymer of not process termination process; Described relative molecular weight of chitosan is 1500-100000, and deacetylation is greater than 90%; Described chitosan derivatives is a carboxymethyl chitosan; Described dewatering medicament is the outgrowth Docetaxel of inhibition blood vessel endothelium, paclitaxel or rapamycin, or the azithromycin of antiinflammatory or ibuprofen.
8. the preparation method of a kind of medicament-carrying nano-microsphere as claimed in claim 6, it is characterized in that, described organic solvent first or organic solvent second be can be miscible with water organic solvent methanol, ethanol, acetone, acetonitrile, oxolane, dioxy six alkane, dimethyl formamide, dimethyl acetylamide or dimethyl sulfoxide.
9. the using method of a medicament-carrying nano-microsphere as claimed in claim 1, it is characterized in that: the powder of described medicament-carrying nano-microsphere by ultra-sonic dispersion in water, forming concentration is the aqueous dispersions of the medicament-carrying nano-microsphere of 0.1-50mg/mL, by the foley's tube mode administration of oral, injection, percutaneous, mucosa or interventional therapy.
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