CN104784698A - Hierarchical porous polylactic acid drug carrier and preparation method thereof - Google Patents
Hierarchical porous polylactic acid drug carrier and preparation method thereof Download PDFInfo
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Abstract
The invention provides an hierarchical porous polylactic acid drug carrier and a preparation method thereof. Aminated mesoporous silica nanoparticles and polylactic acid particles are subjected to chemical bonding to prepare the drug carrier for electrostatic adsorption of adriamycin and cancer treatment, and drug denaturation, drug decomposition and other disadvantages cannot be produced. At the same time, the porous structure can effectively improve the specific surface area and adsorption capacity, and the unique carboxylation effect enables better application of the porous polylactic acid drug carrier to electrostatic adsorption of adriamycin and pH-responsive long-term sustained drug release systems.
Description
Technical field
The invention belongs to medicine functional material preparation field, especially multi-stage porous polylactic acid pharmaceutical carrier and preparation method thereof.
Background technology
Long-term agents slow-released system based on biomaterial is intended to the comfortableness improving patient, reduces the fluctuation of blood level, reduces the side effect of clinical efficacy required dosage, and improves existing pharmacotherapy.Recently, research shows, with traditional medicament carrier system as self-assembling technique, emulsion method, solvent casting method, compares with micro electro mechanical system (MEMS) technology etc., particulate delivery system has the biology and/or dysbolismus that reduce medicine, improves drug conveying efficiency, reduces the advantage of dosage and reduction side effect.But, use microgranule to be used for the particular problem that faces of drug-supplying system and comprise initial burst behavior, drug pack (homogenizing, ultrasound wave etc.) etc. under extreme condition, seriously limit its application medically.Therefore, for realizing the long-term agents slow-released system of patient satisfaction, the exploitation based on the new drug carrier of microgranule is very urgent.
Polylactic acid (PLA) and derivant thereof have excellent biocompatibility, bioavailability and biodegradability, being used for the clinical practice of the mankind by food and drug administration (FDA) approval, is the candidate material of long-term delivery system.But being similar to most microparticular drug carrier system, also there is burst drug release behavior in PLA microsphere.In addition, carry out encapsulation parcel under the extreme conditions such as hydrophilic medicament needs by such as homogeneity usually, ultrasonic, this may bring certain infringement to the drug molecule of parcel, reduces its pharmaceutically active.Meanwhile, the drug delivery technologies of adsorbing as a kind of Noninvasive is widely used in nano-medicament carrier system, as mesoporous silicon oxide, and meso-porous carbon material etc.PLA microsphere is due to its intrinsic hydrophobicity and lack enough functional groups, and Drug absorbability efficiency is very low.Therefore, medium hole nano particles mix the advantage that intact mesoporous nano-grain and micrograde polymer substrate can be provided collaborative for it.
Article Hierarchical Structure of Electrospun Composite Fibers for Long-Term Controlled DrugRelease Carriers (application of nanometer hierarchical pore composite fibre in long-term control drug release), Adv.Healthcare Mater, 2012, 1:809 – 814, with Pomegranate ?Structured Electrosprayed Microspheres for Long ?TermControlled Drug Release.Particle & Particle Systems Characterization (Shi Liu ?the application of structuring EFI microsphere in long-term control drug release), Part.Part.Syst.Charact.2014, point out that mesoporous silica nano-particle and polylactic acid can realize the long-term sustained release of medicine by physical bond.But it by polylactic acid and mesoporous silica particles physical bond, there will be the drawbacks such as the medicine degeneration that causes of high-energy input that electrostatic high-pressure electricity produces and medicament decomposes by electrostatic spinning.
Summary of the invention
For Shortcomings in prior art, the invention provides a kind of multi-stage porous polylactic acid pharmaceutical carrier and preparation method thereof, chemical bonding is carried out with polylactic acid microgranule by amination mesoporous silicon dioxide nano particle, preparing can for the pharmaceutical carrier of Electrostatic Absorption amycin for treatment of cancer, the drawbacks such as medicine degeneration and medicament decomposes can not be produced, simultaneously, its loose structure had can effectively increasing specific surface area and adsorption capacity, and the carboxylation of its uniqueness makes this hole polylactic acid pharmaceutical carrier can be applied to Electrostatic Absorption load and the pH response long-term agents slow-released system of amycin better.
The present invention realizes above-mentioned technical purpose by following technological means.
A kind of multi-stage porous polylactic acid pharmaceutical carrier, by amination mesoporous silicon oxide (MSNs-NH
2) nanoparticle and polylactic acid microgranule prepared by chemical bonding.
The present invention also comprises the preparation method of multi-stage porous polylactic acid pharmaceutical carrier, comprises the steps:
S1, preparation MSNs-NH
2nanoparticle;
The preparation of S2, macropore bowl-shape polylactic acid microgranule: using the deionized water solution of polyvinyl alcohol as interior phase, polylactic acid, class 80 of department, dichloromethane, as mesophase spherule, describedly interiorly form oil-in-water type (W with mesophase spherule homogenize
1/ O) colostrum; The deionized water solution of cetyl ammonium bromide (CTAB) is as foreign minister, and described foreign minister and described colostrum homogenize form water-in-oil-in water (W
1/ O/W
2) two emulsion, by after dichloromethane volatilization in described pair of emulsion bowl-shape polylactic acid microgranule, described polylactic acid microgranule is hydrolyzed in the deionized water solution of inorganic base final the bowl-shape polylactic acid microgranule of macropore;
The preparation of S3, multi-stage porous polylactic acid pharmaceutical carrier: MSNs-NH
2, macropore bowl-shape polylactic acid microgranule, excessive 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) and N-hydroxy-succinamide (NHS) react to obtain polymer in the buffer solution of pH=7.0 in S2, by centrifugal for described polymer, washing, dry after carboxylated, washing, dry product.
In S2, PVA and CTAB not only can reduce interface energy as surfactant, and its aqueous solution is respectively elecrtonegativity and electropositive, under a large amount of positive electricity existent condition of foreign minister, inside mutually electronegative water droplet is induced out, and then forms unique bowl-shape polylactic acid microgranule.By changing the bowl-shape pH value of polylactic acid microgranule hydrolysising condition and the addition of NaOH, quantity and the pore size of the pore of bowl-shape polylactic acid microparticle surfaces can effectively regulate.
React in the buffer solution of pH=7.0 in S3, be conducive to preventing amino and carboxyl from aqueous electrolytic ionization occurring, thus ensure MSNs-NH
2chemical bonding can be carried out smoothly under EDC and NHS existence condition with polylactic acid microgranule.
Further, MSNs-NH described in S1
2the preparation method of nanoparticle is: be incorporated in 70 ~ 90 DEG C stir mixed to CTAB and ammonium fluoride, add tetraethyl orthosilicate, stir centrifugal nano SiO 2 particle after 3 ~ 5h, described nano SiO 2 particle being scattered in volume fraction is also reflux to remove CTAB in the ethanol solution hydrochloride of 37.5%, product is centrifugal, washing after MSNs, then MSNs and 3-aminopropyl triethoxysilane is refluxed, products therefrom carried out centrifugal, washing, dry obtain final MSNs-NH2 nanoparticle.
In such scheme, in the deionized water solution of polyvinyl alcohol described in S2, polyvinyl alcohol concentration is 0.099 ~ 1.01g/mL;
In the deionized water solution of CTAB described in S2, the concentration of CTAB is 0.050 ~ 0.054g/mL.
The amount ratio of polylactic acid described in S2, class 80 of department, dichloromethane is (99 ~ 101) mg/ (39 ~ 41) mg/ (0.99 ~ 1.01) mL.
In such scheme, interior described in S2 is 1:20 with mesophase spherule volume ratio; The volume ratio of described colostrum and described foreign minister is 1:4.
In such scheme, the amount ratio of the deionized water solution of product described in S2 and described inorganic base is (99 ~ 101) mg/ (4.9 ~ 5.1) mL.
In such scheme, inorganic alkali solution described in S2 is the deionized water solution of sodium hydroxide, and the concentration of described sodium hydroxide is 4.85 ~ 5.15mg/mL.
In such scheme, buffer solution described in S3 is phosphate buffer.
In such scheme, MSNs-NH described in S3
2, the mass ratio of polylactic acid microgranule is (4.9 ~ 5.1)/(9.9 ~ 10.1) in S2;
The alcoholic solution of the carboxylated use succinic anhydrides of polymer described in S3, in the alcoholic solution of described succinic anhydrides, the concentration of succinic anhydrides is 9.9 ~ 20.2mg/mL.
In such scheme, the alcoholic solution amount ratio of described polymer and described succinic anhydrides is (9.9 ~ 10.1) mg/ (9.9 ~ 10.1) mL.
Beneficial effect of the present invention:
(1) multi-stage porous polylactic acid pharmaceutical carrier of the present invention has hierarchical porous structure, can effectively increase specific surface area and adsorption capacity;
(2) amination mesoporous silicon dioxide nano particle of chemical bonding is conducive to further carboxylated modification and is applied to amycin Electrostatic Absorption;
(3) multi-stage porous polylactic acid pharmaceutical carrier of the present invention has good pH response property, can realize quick adsorption amycin, simultaneously its Heat stability is good, biodegradable, and biocompatibility is good, has the characteristic of significant long-term release medicine.
Accompanying drawing explanation
Fig. 1 is MSNs-NH described in the embodiment of the present invention 1
2transmission electron microscope picture.
In Fig. 2 A for the emulsion figure of colostrum described in the embodiment of the present invention 1, B be the emulsion figure of two emulsion described in the embodiment of the present invention 1.
Fig. 3 is the scanning electron microscope (SEM) photograph before polylactic acid microgranule hydrolysis described in the embodiment of the present invention 1.
In Fig. 4, A, B, C, D, E, F are hydrolyzed the optical microscope figure of 10min, 20min, 30min, 40min, 50min, 60min for polylactic acid microgranule described in the embodiment of the present invention 1 in NaOH solution.
In Fig. 5, A, B, C, D, E, F are the scanning electron microscope (SEM) photograph of the macropore product that in Fig. 4, polylactic acid microgranule different time in NaOH solution obtains, and a, b, c, d, e, f are respectively the enlarged drawing of A, B, C, D, E, F.
In Fig. 6 A, B be respectively described in the embodiment of the present invention 1 carboxylated before multi-stage porous polylactic acid pharmaceutical carrier and surface amplify after scanning electron microscope (SEM) photograph, C, D be respectively carboxylated described in the embodiment of the present invention 1 after multi-stage porous polylactic acid pharmaceutical carrier and surface amplify after scanning electron microscope (SEM) photograph.
Fig. 7 is the curve of the multi-stage porous polylactic acid pharmaceutical carrier slow release amycin under condition of different pH after carboxylated described in the embodiment of the present invention 1.
Fig. 8 is the release graphics in the multi-stage porous polylactic acid pharmaceutical carrier after carboxylated described in the embodiment of the present invention 1 90 days.
Detailed description of the invention
Below in conjunction with accompanying drawing and specific embodiment, the present invention is further illustrated, but protection scope of the present invention is not limited to this.
Amycin absorption carriage described in technique scheme and long-term sustained release performance testing method are specially:
(1) absorption carriage
20 milligrams carboxylated after bowl-shape multi-stage porous polylactic acid pharmaceutical carrier add 5 milliliters of 1 milligram of every milliliter of Doxorubicin solution in PBS solution, carry out absorption carriage (pH=6.5), stir 24 hours under 30 DEG C of constant temperature.Bowl-shape multi-stage porous polylactic acid pharmaceutical carrier after carboxylated after load amycin is by collected by centrifugation, and the DOX then washing the physical absorption on solution removal surface several times with PBS remains.Finally, adopt ultraviolet-uisible spectrophotometer at 480nm detection of drugs content.According to result, calculate carboxylated after the packaging efficiency (EE) of bowl-shape multi-stage porous polylactic acid pharmaceutical carrier and bearing capacity (LC):
(2) long-term sustained release amycin behavioral study:
The release dynamics (10mg) of the bowl-shape multi-stage porous polylactic acid pharmaceutical carrier release amycin after carboxylated measures (pH=1 in the buffer solution of the different pH value of 25mL, 3,5,7.4), water bath with thermostatic control mild or moderate shake (100 revs/min) at 37 DEG C.In predetermined time interval, collect the buffer solution of 0.1 milliliter and add 0.1 milliliter of fresh buffer release liquid.Measured the burst size of medicine by ultraviolet visible spectrophotometry, the standard correction figure of the amycin within the scope of 0 ~ 0.05 milligram of every ml concn determines the DOX concentration discharged.According to result, calculate accumulation amycin burst size:
Wherein M
tbe the burst size that amycin is at time t, M is the total burst size of amycin.
Embodiment 1
1, the preparation of multi-stage porous polylactic acid pharmaceutical carrier:
(1) amination mesoporous silicon oxide (MSNs-NH is prepared
2) nanoparticle:
Preparation 0.91g cetyl ammonium bromide and 1.4g ammonium fluoride mixed solution, mechanical agitation at 80 DEG C, 4.5mL TEOS slowly adds; After stirring 3h, centrifugalize MSNs nano-particle, obtained nano-particle redispersion, refluxes 24 hours at 90 DEG C to 199mL containing in the ethanol solution hydrochloride of 4mL 37.5% mass ratio, and this process repeats to guarantee for twice to remove surfactant completely.The product obtained carries out centrifugal, uses deionized water rinsing.MSNs nano-particle 0.99g after dehydration and the APTES 1.4g product obtained for 16 hours that refluxes at 120 DEG C obtains MSNs-NH
2carry out centrifugalize, with ether and dichloromethane mixture washing (1/1, V/V) and 60 DEG C dry 24 hours in atmosphere.
(2) preparation of the bowl-shape polylactic acid microgranule of macropore:
Phase polyethylene alcohol-water solution in 0.19mL 0.89g/mL and 3.9mL oil phase homogenize are formed stable colostrum (W
1/ O), the polylactic acid of oil phase to be amount ratio be 99mg:39mg:0.99mL, class 80 of department, dichloromethane.Then foreign minister's aqueous solution homogenizing of 1.0mL colostrum and 4mL 0.05g/mL CTAB is formed two emulsion (W
1/ O/W
2), at 50 DEG C, solvent volatilization 30min forms bowl-shape polylactic acid microgranule.Finally obtained bowl-shape polylactic acid microgranule 99mg is hydrolyzed 1h in 4.9mL 4.85mg/mL NaOH solution and obtains the bowl-shape polylactic acid microgranule of macropore.
(3) preparation of multi-stage porous polylactic acid pharmaceutical carrier:
First, hydrophilic MSNs-NH
2nanoparticle 4.99mg to add in pH=7.0PBS buffer solution ultrasonic 20 ~ 30 minutes.
Then, macropore bowl-shape polylactic acid microgranule 9.9mg adds in above-mentioned solution, and after even with the bowl-shape polylactic acid microparticulate of macropore, excessive EDC/NHS reacts 12h at adding 30 DEG C; The centrifugal rear water of polymer obtained and ethanol purge 3 times, drying, obtains product.
Finally, the 9.9mg product obtained is cleaned with excessive water after acidify 12h in the alcoholic solution of 9.9mL 9.9mg/mL succinic anhydrides, dry, obtain multi-stage porous polylactic acid pharmaceutical carrier.
Fig. 1 is MSNs-NH of the present invention
2transmission electron microscope picture, as seen from the figure, the MSNs-NH of preparation
2the mean diameter of nanoparticle is at about 110nm.
In Fig. 2, the emulsion figure of A to be the emulsion figure of colostrum of the present invention, B be of the present invention pair of emulsion, has as can be seen from the figure successfully prepared colostrum and two emulsion.
Fig. 3 is the scanning electron microscope (SEM) photograph before polylactic acid microgranule of the present invention hydrolysis, and as seen from the figure, the average diameter before the hydrolysis of polylactic acid microgranule is 10 μm, and its smooth surface atresia.
Fig. 4 is the optical microscope figure that polylactic acid microgranule of the present invention is hydrolyzed in NaOH solution, the optical microscope figure of hydrolysis 10min (A), 20min (B), 30min (C), 40min (D), 50min (E) and 60min (F) is respectively in figure, as can be seen from the figure, the intensification of polylactic acid microgranule along with hydrolysis degree and the prolongation of hydrolysis time, quantity tails off gradually, and surface is coarse gradually.
Fig. 5 is the scanning electron microscope (SEM) photograph that in Fig. 4, polylactic acid microgranule is hydrolyzed the macropore product obtained in various degree in NaOH solution, as can be seen from the figure, the average diameter of the macropore product obtained is 10 μm, and in its surperficial different loci drilling after hydrolysis, and along with the continuous intensification of hydrolysis degree, the hole on its surface constantly increases.
In Fig. 6 A, B be respectively of the present invention carboxylated before multi-stage porous polylactic acid pharmaceutical carrier and surface amplify after scanning electron microscope (SEM) photograph, C, D be respectively of the present invention carboxylated after multi-stage porous polylactic acid pharmaceutical carrier and surface amplify after scanning electron microscope (SEM) photograph, as can be seen from the figure, MSNs-NH
2nanoparticle success key and in polylactic acid microparticle surfaces and inside, to be uniformly dispersed and engagement amount is large, obtain carboxylated after multi-stage porous polylactic acid pharmaceutical carrier maintain the pattern of multi-stage porous polylactic acid pharmaceutical carrier originally, and nanometer Granular composite on it is even.
2, absorption and release performance research
(1) get 20mg multi-stage porous polylactic acid pharmaceutical carrier to add 5 milliliters of 1mg/mL Doxorubicin solution in PBS solution, carry out absorption carriage (pH=6.5), stir 24 hours under 30 DEG C of constant temperature.Multi-stage porous polylactic acid pharmaceutical carrier after carboxylated after load amycin is by collected by centrifugation, and the DOX then washing the physical absorption on solution removal surface several times with PBS remains.Finally, adopt ultraviolet-uisible spectrophotometer at 480nm detection of drugs content.According to result, calculate carboxylated after the packaging efficiency (EE) of multi-stage porous polylactic acid pharmaceutical carrier and bearing capacity (LC).
Result shows: the bowl-shape multi-stage porous polylactic acid pharmaceutical carrier after carboxylated adsorbs the very capable of amycin, packaging efficiency reaches 90.14%, bearing capacity reaches 45.07%, and compared with original non-carboxylated bowl-shape multi-stage porous polylactic acid pharmaceutical carrier, its absorbability greatly improves 2-3 doubly.
(2) release dynamics (10 milligrams) of the multi-stage porous polylactic acid pharmaceutical carrier release amycin after carboxylated measures (pH=1 in the buffer solution of 25 milliliters of different pH value, 3,5,7.4), water bath with thermostatic control mild or moderate shake (100 revs/min) at 37 DEG C.In predetermined time interval, collect the buffer solution of 0.1 milliliter and add 0.1 milliliter of fresh buffer release liquid.Measured the burst size of medicine by ultraviolet visible spectrophotometry, the standard correction figure of the amycin in 0-0.05mg/mL concentration range determines the DOX concentration discharged.According to result, calculate accumulation amycin burst size.
Result shows: the release in the bowl-shape multi-stage porous polylactic acid pharmaceutical carrier of amycin after carboxylated increases with the reduction of pH, and presents excellent long-term releasability.In the buffer solution of pH=5.0, the bowl-shape multi-stage porous polylactic acid pharmaceutical carrier after carboxylated only discharges 9.2% amycin in first three sky, and reaches slow release balance after 60 days.
Fig. 7 be of the present invention carboxylated after the curve of multi-stage porous polylactic acid pharmaceutical carrier slow release amycin under condition of different pH, embodiment 1 obtain carboxylated after multi-stage porous polylactic acid pharmaceutical carrier embody slow-release capability with pH and time correlation, good slow release behavior is presented under pH=5.0 condition, may be due to part carboxyl deprotonation under this condition, reduce electrostatic capacity, thus cause the release of amycin.
Fig. 8 be of the present invention carboxylated after multi-stage porous polylactic acid pharmaceutical carrier 90 days in release graphics, as can be seen from the figure, embodiment 1 obtain carboxylated after bowl-shape multi-stage porous polylactic acid pharmaceutical carrier embody good long-term sustained release ability, have good potential applicability in clinical practice.
Embodiment 2
1, the preparation of multi-stage porous polylactic acid pharmaceutical carrier:
(1) amination mesoporous silicon oxide (MSNs-NH is prepared
2) nanoparticle:
Preparation 1.00g cetyl ammonium bromide and 1.5g ammonium fluoride mixed solution, mechanical agitation at 80 DEG C, 4.5mL TEOS slowly adds; After stirring 3h, centrifugalize MSNs nano-particle, obtained nano-particle redispersion, refluxes 24 hours at 90 DEG C to 200mL containing in the ethanol solution hydrochloride of 4.5mL37.5% mass ratio, and this process repeats to guarantee for twice to remove surfactant completely.The product obtained carries out centrifugal, uses deionized water rinsing.MSNs nano-particle 1.00g after dehydration and the APTES 1.5g product obtained for 16 hours that refluxes at 120 DEG C obtains MSNs-NH
2carry out centrifugalize, with ether and dichloromethane mixture washing (1/1, V/V) and 60 DEG C dry 24 hours in atmosphere.
(2) preparation of the bowl-shape polylactic acid microgranule of macropore:
Phase polyethylene alcohol-water solution in 0.2mL 0.95g/mL and 4.0mL oil phase homogenize are formed stable colostrum (W
1/ O), the polylactic acid of oil phase to be amount ratio be 101mg:41mg:1.01mL, class 80 of department, dichloromethane.Then foreign minister's aqueous solution homogenizing of 1.0mL colostrum and 4mL 0.05g/mL CTAB is formed two emulsion (W
1/ O/W
2), at 50 DEG C, solvent volatilization 30min forms bowl-shape polylactic acid microgranule.Finally obtained bowl-shape polylactic acid microgranule 100mg is hydrolyzed 1h in 5.0mL 5.0mg/mL NaOH solution and obtains the bowl-shape polylactic acid microgranule of macropore.
(3) preparation of multi-stage porous polylactic acid pharmaceutical carrier:
First, hydrophilic MSNs-NH
2nanoparticle 5.0mg to add in pH=7.0PBS buffer solution ultrasonic 20 ~ 30 minutes.
Then, macropore bowl-shape polylactic acid microgranule 10.0mg adds in above-mentioned solution, and after even with the bowl-shape polylactic acid microparticulate of macropore, excessive EDC/NHS reacts 12h at adding 30 DEG C; The centrifugal rear water of polymer obtained and ethanol purge 3 times, drying, obtains product.
Finally, the 10.0mg product obtained is cleaned with excessive water after acidify 12h in the alcoholic solution of 10.0mL 15.0mg/mL succinic anhydrides, dry, obtain multi-stage porous polylactic acid pharmaceutical carrier.
2, absorption and release performance research
(1) get 20mg carboxylated after bowl-shape multi-stage porous polylactic acid pharmaceutical carrier add 5mL 1mg/mL Doxorubicin solution in PBS solution, carry out absorption carriage (pH=6.5), stir 24 hours under 30 DEG C of constant temperature.Bowl-shape multi-stage porous polylactic acid pharmaceutical carrier after carboxylated after load amycin is by collected by centrifugation, and the DOX then washing the physical absorption on solution removal surface several times with PBS remains.Finally, adopt ultraviolet-uisible spectrophotometer at 480nm detection of drugs content.According to result, calculate carboxylated after the packaging efficiency (EE) of bowl-shape multi-stage porous polylactic acid pharmaceutical carrier and bearing capacity (LC).
Result shows: the bowl-shape multi-stage porous polylactic acid pharmaceutical carrier after carboxylated adsorbs the very capable of amycin, packaging efficiency reaches 90.14%, bearing capacity reaches 45.07%, and absorbability greatly improves 2-3 doubly compared with original non-carboxylated bowl-shape multi-stage porous polylactic acid pharmaceutical carrier.
(2) release dynamics (10mg) of the bowl-shape multi-stage porous polylactic acid pharmaceutical carrier release amycin after carboxylated measures (pH=1 in the buffer solution of the different pH value of 25mL, 3,5,7.4), water bath with thermostatic control mild or moderate shake (100 revs/min) at 37 DEG C.In predetermined time interval, collect the buffer solution of 0.1 milliliter and add the fresh buffer release liquid of 0.1mL.Measured the burst size of medicine by ultraviolet visible spectrophotometry, the standard correction figure of the amycin in 0-0.05mg/mL concentration range determines the DOX concentration discharged.According to result, calculate accumulation amycin burst size.
Result shows: the release in the bowl-shape multi-stage porous polylactic acid pharmaceutical carrier of amycin after carboxylated increases with the reduction of pH, and presents excellent long-term releasability.In the buffer solution of pH=5.0, the bowl-shape multi-stage porous polylactic acid pharmaceutical carrier after carboxylated only discharges 9.2% amycin in first three sky, and reaches slow release balance after 60 days.
Embodiment 3
1, the preparation of multi-stage porous polylactic acid pharmaceutical carrier:
(1) amination mesoporous silicon oxide (MSNs-NH is prepared
2) nanoparticle:
Preparation 1.10g cetyl ammonium bromide and 1.6g ammonium fluoride mixed solution, mechanical agitation at 80 DEG C, 4.5mL TEOS slowly adds; After stirring 3h, centrifugalize MSNs nano-particle, obtained nano-particle redispersion, refluxes 24 hours at 90 DEG C to 200mL containing in the ethanol solution hydrochloride of 5mL37.5% mass ratio, and this process repeats to guarantee for twice to remove surfactant completely.The product obtained carries out centrifugal, uses deionized water rinsing.MSNs nano-particle 1.01g after dehydration and the APTES 1.6g product obtained for 16 hours that refluxes at 120 DEG C obtains MSNs-NH
2carry out centrifugalize, with ether and dichloromethane mixture washing (1/1, V/V) and 60 DEG C dry 24 hours in atmosphere.
(2) preparation of the bowl-shape polylactic acid microgranule of macropore:
Phase polyethylene alcohol-water solution in 0.2mL 1.01g/mL and 4mL oil phase homogenize are formed stable colostrum (W
1/ O), the polylactic acid of oil phase to be amount ratio be 101mg:41mg:1.01mL, class 80 of department, dichloromethane.Then foreign minister's aqueous solution homogenizing of 1.0mL colostrum and 4mL 0.054g/mL CTAB is formed two emulsion (W
1/ O/W
2), at 50 DEG C, solvent volatilization 30min forms bowl-shape polylactic acid microgranule.Finally obtained bowl-shape polylactic acid microgranule 101mg is hydrolyzed 1h in 5.1mL 5.15mg/mL NaOH solution and obtains the bowl-shape polylactic acid microgranule of macropore.
(3) preparation of multi-stage porous polylactic acid pharmaceutical carrier:
First, hydrophilic MSNs-NH
2nanoparticle 5.1mg to add in pH=7.0PBS buffer solution ultrasonic 20 ~ 30 minutes.
Then, macropore bowl-shape polylactic acid microgranule 10.1mg adds in above-mentioned solution, and after even with the bowl-shape polylactic acid microparticulate of macropore, excessive EDC/NHS reacts 12h at adding 30 DEG C; The centrifugal rear water of polymer obtained and ethanol purge 3 times, drying, obtains product.
Finally, the 10.1mg product obtained is cleaned with excessive water after acidify 12h in the alcoholic solution of 10.1mL 20.2mg/mL succinic anhydrides, dry, obtain multi-stage porous polylactic acid pharmaceutical carrier.
2, absorption and release performance research
(1) get 20mg carboxylated after bowl-shape multi-stage porous polylactic acid pharmaceutical carrier add 5mL 1mg/mL Doxorubicin solution in PBS solution, carry out absorption carriage (pH=6.5), stir 24 hours under 30 DEG C of constant temperature.Bowl-shape multi-stage porous polylactic acid pharmaceutical carrier after carboxylated after load amycin is by collected by centrifugation, and the DOX then washing the physical absorption on solution removal surface several times with PBS remains.Finally, adopt ultraviolet-uisible spectrophotometer at 480nm detection of drugs content.According to result, calculate carboxylated after the packaging efficiency (EE) of bowl-shape multi-stage porous polylactic acid pharmaceutical carrier and bearing capacity (LC).
Result shows: the bowl-shape multi-stage porous polylactic acid pharmaceutical carrier after carboxylated adsorbs the very capable of amycin, packaging efficiency reaches 90.14%, bearing capacity reaches 45.07%, and absorbability greatly improves 2-3 doubly compared with original non-carboxylated bowl-shape multi-stage porous polylactic acid pharmaceutical carrier.
(2) release dynamics (10mg) of the bowl-shape multi-stage porous polylactic acid pharmaceutical carrier release amycin after carboxylated measures (pH=1 in the buffer solution of the different pH value of 25mL, 3,5,7.4), water bath with thermostatic control mild or moderate shake (100 revs/min) at 37 DEG C.In predetermined time interval, collect the buffer solution of 0.1 milliliter and add the fresh buffer release liquid of 0.1mL.Measured the burst size of medicine by ultraviolet visible spectrophotometry, the standard correction figure of the amycin in 0-0.05mg/mL concentration range determines the DOX concentration discharged.According to result, calculate accumulation amycin burst size.
Result shows: the release in the bowl-shape multi-stage porous polylactic acid pharmaceutical carrier of amycin after carboxylated increases with the reduction of pH, and presents excellent long-term releasability.In the buffer solution of pH=5.0, the bowl-shape multi-stage porous polylactic acid pharmaceutical carrier after carboxylated only discharges 9.2% amycin in first three sky, and reaches slow release balance after 60 days.
Described embodiment is preferred embodiment of the present invention; but the present invention is not limited to above-mentioned embodiment; when not deviating from flesh and blood of the present invention, any apparent improvement that those skilled in the art can make, replacement or modification all belong to protection scope of the present invention.
Claims (10)
1. a multi-stage porous polylactic acid pharmaceutical carrier, is characterized in that, described pharmaceutical carrier is by amination mesoporous silicon oxide (MSNs-NH
2) nanoparticle and polylactic acid microgranule prepared by chemical bonding.
2. prepare a method for multi-stage porous polylactic acid pharmaceutical carrier described in claim 1, it is characterized in that, comprise the steps:
S1, preparation MSNs-NH
2nanoparticle;
The preparation of S2, macropore bowl-shape polylactic acid microgranule: using the deionized water solution of polyvinyl alcohol as interior phase, polylactic acid, class 80 of department, dichloromethane, as mesophase spherule, describedly interiorly form oil-in-water type (W with mesophase spherule homogenize
1/ O) colostrum; The deionized water solution of cetyl ammonium bromide (CTAB) is as foreign minister, and described foreign minister and described colostrum homogenize form water-in-oil-in water (W
1/ O/W
2) two emulsion, obtain bowl-shape polylactic acid microgranule by described pair of emulsion after dichloromethane volatilization, described polylactic acid microgranule is hydrolyzed in the deionized water solution of inorganic base to obtain the bowl-shape polylactic acid microgranule of macropore;
The preparation of S3, multi-stage porous polylactic acid pharmaceutical carrier: MSNs-NH
2, macropore bowl-shape polylactic acid microgranule, excessive 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) and N-hydroxy-succinamide (NHS) react to obtain polymer in the buffer solution of pH=7.0 in S2, by centrifugal for described polymer, washing, dry after carboxylated, washing, dry product.
3. the preparation method of multi-stage porous polylactic acid pharmaceutical carrier as claimed in claim 2, is characterized in that, MSNs-NH described in S1
2the preparation method of nanoparticle is: CTAB, ammonium fluoride are mixed and be incorporated in 70 ~ 90 DEG C of stirrings, add tetraethyl orthosilicate, stir centrifugal nano SiO 2 particle after 3 ~ 5h, described nano SiO 2 particle being scattered in volume fraction is also reflux to remove CTAB in the ethanol solution hydrochloride of 37.5%, reflux with 3-aminopropyl triethoxysilane after product is centrifugal, washing, products therefrom is carried out centrifugal, washing, the final MSNs-NH2 nanoparticle of drying acquisition.
4. the preparation method of multi-stage porous polylactic acid pharmaceutical carrier as claimed in claim 2, it is characterized in that, in the deionized water solution of polyvinyl alcohol described in S2, polyvinyl alcohol concentration is 0.89 ~ 1.01g/mL;
In the deionized water solution of CTAB described in S2, the concentration of CTAB is 0.050 ~ 0.054g/mL.
The amount ratio of polylactic acid described in S2, class 80 of department, dichloromethane is (99 ~ 101) mg/ (39 ~ 41) mg/ (0.99 ~ 1.01) mL.
5. the preparation method of multi-stage porous polylactic acid pharmaceutical carrier as claimed in claim 2, is characterized in that, interior described in S2 is 1:20 with mesophase spherule volume ratio; The volume ratio of described colostrum and described foreign minister is 1:4.
6. the preparation method of multi-stage porous polylactic acid pharmaceutical carrier as claimed in claim 2, it is characterized in that, the amount ratio of the deionized water solution of product described in S2 and described inorganic base is (99 ~ 101) mg/ (4.9 ~ 5.1) mL.
7. the preparation method of multi-stage porous polylactic acid pharmaceutical carrier as claimed in claim 2, it is characterized in that, inorganic alkali solution described in S2 is the deionized water solution of sodium hydroxide, and the concentration of described sodium hydroxide is 4.85 ~ 5.15mg/mL.
8. the preparation method of multi-stage porous polylactic acid pharmaceutical carrier as claimed in claim 2, it is characterized in that, buffer solution described in S3 is phosphate buffer.
9. the preparation method of multi-stage porous polylactic acid pharmaceutical carrier as claimed in claim 2, is characterized in that, MSNs-NH described in S3
2, the mass ratio of polylactic acid microgranule is (4.9 ~ 5.1)/(9.9 ~ 10.1) in S2;
The alcoholic solution of the carboxylated use succinic anhydrides of polymer described in S3, in the alcoholic solution of described succinic anhydrides, the concentration of succinic anhydrides is 9.9 ~ 20.2mg/mL.
10. the preparation method of multi-stage porous polylactic acid pharmaceutical carrier as claimed in claim 8, it is characterized in that, the alcoholic solution amount ratio of described polymer and described succinic anhydrides is (9.9 ~ 10.1) mg/ (9.9 ~ 10.1) mL.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105664242A (en) * | 2016-02-03 | 2016-06-15 | 重庆科技学院 | Method for preparing PLGA microspheres with porous surfaces |
| CN107595804A (en) * | 2017-11-03 | 2018-01-19 | 西南大学 | A kind of preparation method and applications of the new bowl-shape particle of load medicine |
| CN110124089A (en) * | 2019-04-17 | 2019-08-16 | 江苏大学 | A kind of porous antibacterial biological foam dressing of peelable type and preparation method thereof |
| CN112294974A (en) * | 2020-11-18 | 2021-02-02 | 西安组织工程与再生医学研究所 | Drug-loaded microparticle with multistage sustained and controlled release effects and preparation method thereof |
| CN113913096A (en) * | 2021-09-24 | 2022-01-11 | 四川汇园宝新材料科技有限公司 | Antiviral coating and preparation method thereof |
| CN115920074A (en) * | 2022-12-02 | 2023-04-07 | 黄冈师范学院 | Mesoporous silicon nano delivery carrier, drug-loaded compound, preparation method and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102068706A (en) * | 2010-12-30 | 2011-05-25 | 上海师范大学 | Preparation method of silicon dioxide (SiO2) ultrasonic imaging radiography material |
| CN103800292A (en) * | 2014-02-28 | 2014-05-21 | 东华大学 | Preparation method of organic/inorganic hybrid nano fiber drug carrying microsphere |
-
2015
- 2015-03-09 CN CN201510102768.4A patent/CN104784698A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102068706A (en) * | 2010-12-30 | 2011-05-25 | 上海师范大学 | Preparation method of silicon dioxide (SiO2) ultrasonic imaging radiography material |
| CN103800292A (en) * | 2014-02-28 | 2014-05-21 | 东华大学 | Preparation method of organic/inorganic hybrid nano fiber drug carrying microsphere |
Non-Patent Citations (1)
| Title |
|---|
| JIANMING PAN, ET AL.: "A hierarchical porous bowl-like PLA@ MSNs-COOH composite for pH-dominated long-term controlled release of doxorubicin and integrated nanoparticle for potential second treatment", 《BIOMACROMOLECULES》 * |
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| CN105664242A (en) * | 2016-02-03 | 2016-06-15 | 重庆科技学院 | Method for preparing PLGA microspheres with porous surfaces |
| CN107595804A (en) * | 2017-11-03 | 2018-01-19 | 西南大学 | A kind of preparation method and applications of the new bowl-shape particle of load medicine |
| CN110124089A (en) * | 2019-04-17 | 2019-08-16 | 江苏大学 | A kind of porous antibacterial biological foam dressing of peelable type and preparation method thereof |
| CN112294974A (en) * | 2020-11-18 | 2021-02-02 | 西安组织工程与再生医学研究所 | Drug-loaded microparticle with multistage sustained and controlled release effects and preparation method thereof |
| WO2022105039A1 (en) * | 2020-11-18 | 2022-05-27 | 西安组织工程与再生医学研究所 | Drug-loaded particles with multi-stage sustained and controlled release effect, and preparation method therefor |
| CN113913096A (en) * | 2021-09-24 | 2022-01-11 | 四川汇园宝新材料科技有限公司 | Antiviral coating and preparation method thereof |
| CN113913096B (en) * | 2021-09-24 | 2022-05-06 | 四川汇园宝新材料科技有限公司 | Antiviral coating and preparation method thereof |
| CN115920074A (en) * | 2022-12-02 | 2023-04-07 | 黄冈师范学院 | Mesoporous silicon nano delivery carrier, drug-loaded compound, preparation method and application |
| CN115920074B (en) * | 2022-12-02 | 2023-08-25 | 黄冈师范学院 | Mesoporous silicon nano delivery carrier, medicine-carrying compound, preparation method and application |
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