CN102935235B - Preparation method of modified casein drug-carrying controlled-release thin film - Google Patents
Preparation method of modified casein drug-carrying controlled-release thin film Download PDFInfo
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- CN102935235B CN102935235B CN201210476118.2A CN201210476118A CN102935235B CN 102935235 B CN102935235 B CN 102935235B CN 201210476118 A CN201210476118 A CN 201210476118A CN 102935235 B CN102935235 B CN 102935235B
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Abstract
The invention relates to a preparation method of a modified casein drug-carrying controlled-release thin film. In the prior art that a drug-carrying material is made from the natural high molecular material, a drug-carrying medium is usually made from chitosan, starch and cellulose, while the research that the drug-carrying thin film is prepared by taking natural protein casein as the medium is hard to see in public reports. The preparation method takes casein as the drug-carrying medium, and comprises the following steps of: firstly, introducing nano-silica particles by the in-situ hydrolysis of ethyl orthosilicate, and introducing a silane coupling agent capable of stabilizing a system and improving the crosslinking degree of the thin film to prepare casein-base composite emulsion; and filming by drying the emulsion, and immersing the film into ibuprofen solution dissolved in organic solvent to form into the drug-carrying thin film by means of freeze drying after the adsorption reaches the balance. Therefore, a stronger acting force is formed between the active group of the composite emulsion and the active group of the drug to obtain the drug-carrying thin film of which the loading efficiency is greater than 60%, wherein the drug-carrying thin film is better in controlled-release performance, and has the potential application value.
Description
Technical field
The present invention relates to the preparation method of the composite drug-loaded thin film of a kind of natural polymer subbase, particularly a kind of preparation method of modified Casein carried medicine sustained-release thin film.
Background technology
In recent years, due to it, preferably biocompatibility and the parent that is day by day subject to biological medicine and pharmaceutical field researcher look at biodegradable polymer.Wherein, natural product based high molecular is due to wide material sources and avirulence, and be widely used in research (the Y. Lu of drug carrier material aspect, S.C. Chen, Micro and nano-fabrication of biodegradable polymers for drug delivery[J]. Advanced Drug Delivery Reviews. 2004,56: 1621 – 1633).
Casein is as a kind of protein of natural fully biodegradable, (the Y.D. Livney that receives much concern in medicine-carried system owing to having compared with strong ionic adsorption, surface activity, emulsibility, self assembly and stability, Milk proteins as vehicles for bioactives[J] .Curr. Opin. Journal of Colloid and Interface Science. 2010,15: 73-83).According to bibliographical information, it can be prepared to different shape as (Ahmed O. Elzoghby such as hydrogel, micro-/ nano particle, composites as pharmaceutical carrier, Wael S. Abo El-Fotoh, Nazik A. Elgindy. Casein-based formulations as promising controlled release drug delivery systems[J]. Journal of Controlled Release. 2011,153: 206 – 216).But, for the also rarely seen open report of research of casein base load medicine thin film.Through the retrieval of prior art document is found, only having the employing caseins such as Abu Diak et al is matrix, prepare by introducing the plasticizers such as oleic acid the material that can be used for medication coat, but the prepared medication coat drug loading rate of this method is not high, and slow-releasing (the O. Abu Diak that can not meet the demands, A. Bani-Jaber, B. Amro, D. Jones, G.P. Andrews, The manufacture and characterization of casein films as novel tablet coatings, Trans. IChemE, C, Food Bioproducts Process. 2007, : 85:284 – 290.).
Nanoparticle is if silicon dioxide is due to its special small-size effect, specific surface area effect and with the strong combination of polymeric matrix and the parent who is day by day subject to researcher look at, be introduced into performance that polymer can give matrix uniqueness as thermostability, mechanical strength, surface tension and drug adsorption (W. Sto ¨ ber, A. Fink, E. Bohn, Controlled growth of monodisperse silica spheres in the micron size range. Journal of Colloid and Interface Science. 1968, 26:62-69.).But, so far, nano silicon is introduced to casein and prepare the research of drug carrier material and yet there are no open report.
Summary of the invention
The object of the invention is to overcome the shortcoming of above-mentioned prior art, a kind of preparation method of modified Casein carried medicine sustained-release thin film is provided, according to said method the medicine-carried system of preparation has improved medicine carrying efficiency, and has controlled the prominent phenomenon of releasing of medicine.
For achieving the above object, the technical solution used in the present invention is:
Getting mass fraction is that the casein of 2.1～8.4 parts, 0.525～2.1 part of triethanolamine and 33～83 parts of deionized waters add in there-necked flask, controlling temperature is 65～70 DEG C, keep stirring 120～150 minutes, get mass fraction and be the caprolactam of 0.9～3.6 part, add in the deionized water of 3.6～12.4 parts, it is 25% caprolactam water solution that uniform stirring obtains mass percent; Regulate temperature to reach 75 DEG C～80 DEG C, drip the silane coupler of caprolactam water solution and 0.6 part～1.8 parts simultaneously, wait to dropwise, continue insulation reaction 30～60 minutes, get mass fraction and be the ethyl orthosilicate of 0.4 part～1.6 parts, the water soluble starter aqueous solution that is 10%～20% concentration with mass percent is added dropwise to system simultaneously, after dropwising, and insulation reaction 120～180 minutes; Be down to room temperature, add appropriate mass percent be 30% ammonia regulation system pH value be 7.5 ±, obtain casein base silicon dioxide composite emulsion; Casting film-forming in the plastic culture dish that is 90mm at diameter by emulsion, after drying at room temperature 12h, puts to 50 DEG C of vacuum drying ovens and is dried 4h.Obtain casein base silicon dioxide laminated film.Get the ibuprofen of 0.05 part～0.10 part, be dissolved in the oxolane of 100 parts～200 parts, after medicine dissolves completely, get 5.0 parts～6.0 parts casein base silicon dioxide laminated films that pack in bag filter, and immerse in medicine dispersion liquid medicine is adsorbed, monitor during this time the concentration of solution Chinese medicine every 2h, in the time that concentration no longer changes, be considered as medicine and reach adsorption equilibrium, boil off organic solvent, lyophilization, obtains the composite drug-loaded thin film of casein base silicon dioxide.
Product in the present invention is native protein casein based nano composite material, therefore, it has the excellent specific property of protein-based filmogen and the nano effect of inorganic silicon dioxide particle concurrently, has the features such as high temperature resistant, resistance to water is strong, mechanical property is excellent, drug adsorption is strong.Measure by experiment, the drug loading efficiency of such material reaches more than 60%, and sustained release rate is slower, and 15h medicine accumulative total rate of release is 100%.Therefore the modified Casein that, adopts the method to prepare is the drug carrier material that a class is good.
brief description of the drawings:
Fig. 1 is the surface (a, c) and section (b, d) SEM figure of (c, d) after casein based coextruded film carrying medicament (a, b) and drug release;
Fig. 2 is the influence curves of different dioxide-containing silicas to medicine carrying laminated film medicament slow release performance.
detailed description of the invention:
The present invention taking at casein as base material, introduce nano silicon medicine to absorption property by the mode of in-situ hydrolysis, on the one hand, the discontinuity of the film forming of casein own causes become thin film to have micropore, on the other hand, silicon dioxide has huge specific surface area and can produce stronger interface interaction with polymeric matrix, therefore, the active group of complex emulsions can and pharmaceutically active group between form stronger active force, thereby can obtain the medicine carrying casein based coextruded film that load efficiency is higher.Be intended to develop bio-compatible, medicine carrying is efficient, rate of release is slow drug delivery system.
embodiment 1:
Getting mass fraction is that the casein of 2.1 parts, 0.525 part of triethanolamine and 33 parts of deionized waters add in there-necked flask, control 65 DEG C of temperature, keep stirring 120 minutes, get mass fraction and be the caprolactam of 0.9 part, add in the deionized water of 3.6 parts, it is 25% caprolactam water solution that uniform stirring obtains mass percent; Regulate temperature to reach 75 DEG C, drip the silane coupler of caprolactam water solution and 0.6 part simultaneously, wait to dropwise, continue insulation reaction 30 minutes, get mass fraction and be the ethyl orthosilicate of 0.4 part, the water soluble starter aqueous solution that is 10% concentration with mass percent is added dropwise to system simultaneously, after dropwising, and insulation reaction 120 minutes; Be down to room temperature, add appropriate mass percent be 30% ammonia regulation system pH value be 7.5 ±, obtain casein base silicon dioxide composite emulsion.Casting film-forming in the plastic culture dish that is 90mm at diameter by emulsion, after drying at room temperature 12h, puts to 50 DEG C of vacuum drying ovens and is dried 4h, obtains casein base silicon dioxide laminated film; Get the ibuprofen of 0.05 part, be dissolved in the oxolane of 100 parts, after medicine dissolves completely, get 5.0 parts of casein base silicon dioxide laminated films that pack in bag filter, and immerse in medicine dispersion liquid medicine is adsorbed, every the concentration of 2h monitoring solution Chinese medicine, in the time that concentration no longer changes, be considered as medicine and reach adsorption equilibrium during this time; Boil off organic solvent, lyophilization, obtains the composite drug-loaded thin film of casein base silicon dioxide.
embodiment 2:
Getting mass fraction is that the casein of 4.2 parts, 1.05 parts of triethanolamine and 50 parts of deionized waters add in there-necked flask, control 67 DEG C of temperature, keep stirring 130 minutes, get mass fraction and be the caprolactam of 1.8 parts, add in the deionized water of 6.6 parts, it is 25% caprolactam water solution that uniform stirring obtains mass percent; Regulate temperature to reach 77 DEG C, drip the silane coupler of caprolactam water solution and 1.0 parts simultaneously, wait to dropwise, continue insulation reaction 40 minutes, get mass fraction and be the ethyl orthosilicate of 0.8 part, the water soluble starter aqueous solution that is 13% concentration with mass percent is added dropwise to system simultaneously, after dropwising, and insulation reaction 140 minutes; Be down to room temperature, add appropriate mass percent be 30% ammonia regulation system pH value be 7.5 ±, obtain casein base silicon dioxide composite emulsion; Casting film-forming in the plastic culture dish that is 90mm at diameter by emulsion, after drying at room temperature 12h, puts to 50 DEG C of vacuum drying ovens and is dried 4h, obtains casein base silicon dioxide laminated film.Get the ibuprofen of 0.075 part, be dissolved in the oxolane of 130 parts, after medicine dissolves completely, get 5.3 parts of casein base silicon dioxide laminated films that pack in bag filter, and immerse in medicine dispersion liquid medicine is adsorbed, every the concentration of 2h monitoring solution Chinese medicine, in the time that concentration no longer changes, be considered as medicine and reach adsorption equilibrium during this time.Boil off organic solvent, lyophilization, obtains the composite drug-loaded thin film of casein base silicon dioxide.
embodiment 3:
Getting mass fraction is that the casein of 6.3 parts, 1.575 parts of triethanolamine and 66 parts of deionized waters add in there-necked flask, control 69 DEG C of temperature, keep stirring 140 minutes, get mass fraction and be the caprolactam of 2.7 parts, add in the deionized water of 9.4 parts, it is 25% caprolactam water solution that uniform stirring obtains mass percent; Regulate temperature to reach 78 DEG C, drip the silane coupler of caprolactam water solution and 1.4 parts simultaneously, wait to dropwise, continue insulation reaction 50 minutes, get mass fraction and be the ethyl orthosilicate of 1.2 parts, the water soluble starter aqueous solution that is 15% concentration with mass percent is added dropwise to system simultaneously, after dropwising, and insulation reaction 160 minutes.Be down to room temperature, add appropriate mass percent be 30% ammonia regulation system pH value be 7.5 ±, obtain casein base silicon dioxide composite emulsion; Casting film-forming in the plastic culture dish that is 90mm at diameter by emulsion, after drying at room temperature 12h, puts to 50 DEG C of vacuum drying ovens and is dried 4h, obtains casein base silicon dioxide laminated film.Get the ibuprofen of 0.087 part, be dissolved in the oxolane of 170 parts, after medicine dissolves completely, get 5.7 parts of casein base silicon dioxide laminated films that pack in bag filter, and immerse in medicine dispersion liquid medicine is adsorbed, every the concentration of 2h monitoring solution Chinese medicine, in the time that concentration no longer changes, be considered as medicine and reach adsorption equilibrium during this time; Boil off organic solvent, lyophilization, obtains the composite drug-loaded thin film of casein base silicon dioxide.
embodiment 4:
Getting mass fraction is that the casein of 8.4 parts, 2.1 parts of triethanolamine and 83 parts of deionized waters add in there-necked flask, control temperature 70 C, keep stirring 150 minutes, get mass fraction and be the caprolactam of 3.6 parts, add in the deionized water of 12.4 parts, it is 25% caprolactam water solution that uniform stirring obtains mass percent; Regulate temperature to reach 80 DEG C, drip the silane coupler of caprolactam water solution and 1.8 parts simultaneously, wait to dropwise, continue insulation reaction 60 minutes, get mass fraction and be the ethyl orthosilicate of 1.6 parts, the water soluble starter aqueous solution that is 20% concentration with mass percent is added dropwise to system simultaneously, after dropwising, and insulation reaction 180 minutes; Be down to room temperature, add appropriate mass percent be 30% ammonia regulation system pH value be 7.5 ±, obtain casein base silicon dioxide composite emulsion; Casting film-forming in the plastic culture dish that is 90mm at diameter by emulsion, after drying at room temperature 12h, puts to 50 DEG C of vacuum drying ovens and is dried 4h, obtains casein base silicon dioxide laminated film.Get the ibuprofen of 0.10 part, be dissolved in the oxolane of 200 parts, after medicine dissolves completely, get 6.0 parts of casein base silicon dioxide laminated films that pack in bag filter, and immerse in medicine dispersion liquid medicine is adsorbed, every the concentration of 2h monitoring solution Chinese medicine, in the time that concentration no longer changes, be considered as medicine and reach adsorption equilibrium during this time.Boil off organic solvent, lyophilization, obtains the composite drug-loaded thin film of casein base silicon dioxide.
Be the surface (a, c) and section (b, d) SEM figure of (c, d) after casein based coextruded film carrying medicament (a, b) and drug release from Fig. 1; Fig. 2 is the influence curves of different dioxide-containing silicas to medicine carrying laminated film medicament slow release performance.Can find out with reference to Fig. 1: crystallization does not all appear in surface and section at medicine carrying thin film, medicine load being distributed in thin film is equably described.Can obtain with reference to Fig. 2: thin film reaches 100% to medicine accumulative total release rate at 15h rear, illustrates that it has stronger slow releasing function.
Claims (3)
1. a preparation method for modified Casein carried medicine sustained-release thin film, is characterized in that, comprises the steps:
(1) preparation of modified Casein emulsion
Getting mass fraction is that the casein of 2.1～8.4 parts, 0.525～2.1 part of triethanolamine and 33～83 parts of deionized waters add in there-necked flask, control 65～70 DEG C of temperature, keep stirring 120～150 minutes, get mass fraction and be the caprolactam of 0.9～3.6 part, add in the deionized water of 3.6～12.4 parts, it is 25% caprolactam water solution that uniform stirring obtains mass percent; Regulate temperature to reach 75 DEG C～80 DEG C, drip the silane coupler of caprolactam water solution and 0.6 part～1.8 parts simultaneously, wait to dropwise, continue insulation reaction 30～60 minutes, get mass fraction and be the ethyl orthosilicate of 0.4 part～1.6 parts, the water soluble starter aqueous solution that is 10%～20% concentration with mass percent is added dropwise to system simultaneously, after dropwising, and insulation reaction 120～180 minutes; Be down to room temperature, adding appropriate mass percent is that 30% ammonia regulation system pH value is 7.5, obtains modified Casein emulsion;
Wherein water soluble starter is water solublity persulfate, is selected from potassium peroxydisulfate or Ammonium persulfate.; Silane coupler is the alkoxy silane that contains two keys, is selected from vinyltrimethoxy silane, VTES or γ-methacryloxypropyl trimethoxy silane;
(2) preparation of modified Casein thin film
Casting film-forming in the plastic culture dish that is 90mm at diameter by modified Casein emulsion, after drying at room temperature 12h, puts to 50 DEG C of vacuum drying ovens and is dried 4h, obtains modified Casein thin film;
(3) preparation of modified Casein carried medicine sustained-release thin film
Get mass fraction and be the ibuprofen of 0.05 part～0.10 part, be dissolved in the oxolane of 100 parts～200 parts, after medicine dissolves completely, get 5.0 parts～6.0 parts modified Casein thin film that pack in bag filter, and immerse in medicine dispersion liquid medicine is adsorbed, every the concentration of 2h monitoring solution Chinese medicine, in the time that concentration no longer changes, be considered as medicine and reach adsorption equilibrium during this time; Boil off organic solvent, lyophilization, obtains modified Casein carried medicine sustained-release thin film.
2. the preparation method of a kind of modified Casein carried medicine sustained-release thin film according to claim 1, it is characterized in that: this carried medicine sustained-release thin film is taking casein as carrier, taking nano silicon as adsorbent, utilize the discontinuity of the film forming of casein own and the adsorptivity of silicon dioxide, the medicine carrying thin film that absorption ibuprofen forms; The raising of its sustained release performance also mainly relies on shell silicon dioxide to drug release rate inhibition.
3. the preparation method of a kind of modified Casein carried medicine sustained-release thin film according to claim 1, it is characterized in that: the method for monitor drug concentration is adopted to the absorbance of ultraviolet-visible spectrophotometer at 264nm wavelength place detection of drugs solution, treat that absorbance remains unchanged, think that thin film adsorbs medicine reaches capacity.
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