CN103417975A - Preparing method of corrosion type silicon dioxide xerogel drug sustained-release material - Google Patents
Preparing method of corrosion type silicon dioxide xerogel drug sustained-release material Download PDFInfo
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Abstract
The invention discloses a preparing method of a corrosion type silicon dioxide xerogel drug sustained-release material. The preparing method comprises the following steps: mixing and stirring 50-99 percent by weight of organo-siloxanes of which silicon atoms are all connected with alkoxy, 1-50 percent by weight of organo-siloxanes of which alkoxy is partly replaced with alkyl branches difficult to hydrolyze, a certain amount of solvent, and acid catalysts for 10-120 minutes at the temperature of 20-60 DEG C, performing the cohydrolysis and the copolycondensation, adding drug of which the weight is 0.1-50% of the total weight of the two kinds of organo-siloxanes after the sufficient reaction, adding the base catalysts to enable hydrolysates be to quickly crosslinked after the complete dissolution, stirring for 1-30 minutes, and drying to obtain the drug sustained-release material after the product is solidified. The preparing method can calculate and control the drug load accurately, and the shape and the size of the drug sustained-release material can be adjusted flexibly according to the drug releasing requirement. The preparing method is simple in process, good in biocompatibility, and non-toxic to the human body, and has a wide application prospect in controllable release and clinical trials of drug suitable for sustained-release application.
Description
Technical field
The present invention relates to a kind of preparation method of erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine, belong to the preparing technical field of Thermosensitive Material Used for Controlled Releasing of Medicine.
Background technology
As a kind of widely used drug release carrier, silica xerogel prepared by the room temperature sol-gel process (abbreviation xerogel) has good biocompatibility, chemical stability and dimensional stability are good, avirulence, the reaction condition gentleness, the advantages such as technique simply is easy to control, and the matrix microstructure is flexible adjustable, be subject to scholar's extensive concern.Due to its gentle reaction condition, active substantially without impact on drug molecule in xerogel preparation and carrying medicament process, be applicable to very much the release that polypeptide, protein and DNA etc. have the inside and outside labile drugs.
Medicine is generally controlled by the regulation and control to its porous morphosis in the release of xerogel, but the xerogel aperture is generally less than 10 nm, and it is slower to degrade, to the release of the macromolecular drugs such as polypeptide, protein and DNA generally long (reach some months even several years) consuming time, be difficult to reach the requirement that need effectively discharge in short-term, limited greatly its application.Such as employing room temperature sol-gel processes such as Santos, the control of protein is discharged and is studied, due to adopt be protein directly be dissolved in colloidal sol and after gel process be carried on the xerogel matrix, the drug loading amount is accurately controlled.Yet this method is because the xerogel pore size is only 5 nm left and right, and protein release is slow, within 9 months, only discharges 30% medicine, and protein utilization is lower.
The current research modification to xerogel load macromolecular drug is generally and prepares the meso-porous titanium dioxide silica xerogel, increases the xerogel aperture and makes the macromole loads such as protein, DNA wherein and be easy to stripping.Such as employing cetyl trimethyl ammonium bromide (cetyltrimethylammonium bromide such as Trewyn, CTAB) for surfactant, regulate and control with ethyl orthosilicate (tetraethoxysilane, the morphosis of the xerogel TEOS) prepared for forerunner's agent, and dissolve or the mode of calcining is removed CTAB by acid, stay the load of regular microcellular structure for protein, within 30 days, burst size is 21%.But its drug loading is generally that earth silicon material is infiltrated on to protein compression solution, exist load time length easily to make protein inactivation, can not accurately control the problems such as initial load concentration of medicine.The people such as Huh adopt forerunner's agent copolymerization of two kinds of different functional groups side chains,, lipophilic group ratio regulation and control micellar conformation structure hydrophilic by regulating, the hollow nanoparticle of formation different shape, different microcellular structures after calcining.But this method preparation technology is loaded down with trivial details, protein load rate low (being only 20-40%) is serious to the pharmaceutical grade protein waste.
Summary of the invention
The deficiency existed for above-mentioned prior art, the objective of the invention is to propose a kind of copolycondensation of the organosiloxane that utilizes different structure and the way that alkalization Quick cross-linking forming step prepares erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine, this way has accurate Calculation drug loading amount, release time controlled, slow-release material form and size controlled, the characteristics that do not need second operation to take out after having discharged flexibly flexibly, drug release that slow-release material of its final preparation can suitable great majority has the slow release demand.
Ultimate principle of the present invention is, the organosiloxane that silicon atom all is connected with alkoxyl (be called for short siloxanes A), alkoxyl partly are substituted by the organosiloxane (being called for short siloxanes B), solvent and the acid catalyst that are difficult for the hydrolysis alkyl branches and fully stir and carry out cohydrolysis and copolycondensation, with the back loading macromolecular drug, be stirred to fully and dissolve.Add product, to the base catalyst of human body nonhazardous effect, added organosiloxane is carried out to Quick cross-linking, product solidifies rapidly and molding again, and its morphosis changes with the release demand is different; And in siloxanes B, the sterically hindered effect of alkyl branches can destroy the silica substrate ordered structure that siloxanes A forms, the silica xerogel matrix cross-linked structure generated is significantly reduced, matrix is more soluble in buffer, thereby make the medicine effectively stripping as required of load, obtain the erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine of required release behavior.
The present invention is based on above-mentioned principle, realize that the technical scheme that its goal of the invention adopts is: the present invention is by weight percentage, will account for organosiloxane that 50 ~ 99% silicon atom all is connected with alkoxyl, 1 ~ 50% alkoxyl partly be substituted by the organosiloxane of the alkyl branches of facile hydrolysis not and can in the subsequent drying process, remove and be not counted in above-mentioned solvent in adding gross weight and acid catalyst 20 ~ 60
oMix under C and stir 10 ~ 120 minutes, carry out cohydrolysis and the copolycondensation of added organosiloxane, the medicine that adds afterwards the made preparation process stable performance that accounts for above-mentioned two kinds of organosiloxane gross weights 0.1 ~ 50% and the application of suitable slow release, after dissolving fully, add again product to make the hydrolyzate Quick cross-linking to the base catalyst of human body nonhazardous effect, stir 1 ~ 30 minute drying after product solidifies, can obtain prepared erosion type silicon dioxide Thermosensitive Material Used for Controlled Releasing of Medicine.The actual negative carrying capacity of medicine can add the ratio of quality and silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine quality to obtain by medicine.
In such scheme, the organosiloxane that described silicon atom all is connected with alkoxyl is that the siliconoxygen bond hydrolytic cleavage can generate the silicon hydroxyl under catalyst action, further polycondensation, the dry organosiloxane that can form the network of silica structure, the organosiloxane that silicon atom all is connected with alkoxyl for this reason can be selected the organosiloxane mixture of one or more (containing two kinds) in methyl silicate, ethyl orthosilicate, dimethoxy diethoxy silane, six ethyoxyl disilane etc.The addition of the organosiloxane that silicon atom all is connected with alkoxyl is 50 ~ 99%(weight), but comprehensive matrix corrosion behavior and drug release behavior investigation, its preferential addition scope of selecting is 70 ~ 95%, also can suitably reduce according to the needs of drug release; But, in order not make matrix dissolve the too fast drug release that causes, obviously prominent releasing occurs, its content generally is not less than 50%.
In such scheme, it is that the alkoxyl hydrolytic cleavage can generate the silicon hydroxyl under catalyst action that described alkoxyl partly is substituted by the organosiloxane that is difficult for the hydrolysis alkyl branches, but the alkyl branches of contained not facile hydrolysis makes sterically hindered significantly increase, so more difficult formation of silicon dioxide cross-linked structure, alkoxyl partly is substituted by the organosiloxane that is difficult for the hydrolysis alkyl branches and can be selected dimethyldimethoxysil,ne for this reason, propyl-triethoxysilicane, the organosiloxane mixture of one or more in 3-aminopropyl triethoxysilane and 3-(triethoxysilicane) propyl group succinic anhydrides etc. (containing two kinds).The addition that alkoxyl partly is substituted by the organosiloxane that is difficult for the hydrolysis alkyl branches is 1 ~ 50%(weight), but comprehensive matrix corrosion behavior and drug release behavior are investigated, its preferential addition scope of selecting is 5 ~ 30%, also can suitably increase according to the needs of drug release.In order not make matrix dissolve the too fast drug release that causes, obviously prominent releasing occurs, its content generally is no more than 50%.
In technique scheme, described to make the molecular weight range of choice of the medicine of preparation process stable performance and suitable slow release application be 50 ~ 1000000.Wherein, the medicine of micromolecule amount (molecular weight is less than 2000) can be selected cefalexin, vancomycin and bupivacaine etc.; For ensuring good releasing effect, realize the controllable release of medicine, be generally or preferably choose the medicine that molecular weight is greater than 2000, as polypeptide, protein, gene, RNA and DNA etc.Macromolecular drug can be a kind of, can be also two or more medicinal mixture with aforementioned features.
In technique scheme, describedly can in the subsequent drying process, remove, be not counted in the organic or inorganic acid that molecular weight that the acid catalyst of two kinds of (i.e. two classes) organosiloxanes in adding gross weight is effumability is less than 200, example hydrochloric acid, nitric acid and acetic acid etc.Acid catalyst can be a kind of, can be also two or more acid catalyst mixture with These characteristics.
In technique scheme, described product is the organic or inorganic alkali that nontoxic or volatile molecular weight is less than 200 to the base catalyst of human body nonhazardous effect, as sodium hydroxide, potassium hydroxide and ammonia spirit etc.Base catalyst can be a kind of, can be also two or more base catalyst mixture with These characteristics.
In technique scheme, describedly can in the subsequent drying process, remove, be not counted in the micromolecular compound that the solvent of two kinds of (i.e. two classes) organosiloxanes in adding gross weight is less than 500 for the molecular weight that can dissolve the above-mentioned organosiloxane of mentioning and hydrolysate, medicine and catalyst, as water, methanol, ethanol, chloroform etc.Solvent can be a kind of, can be also two or more solvent mixture with These characteristics.
The organosiloxane that silicon atom all is connected with alkoxyl, alkoxyl partly are substituted by the organosiloxane, solvent and the acid catalyst mixing that are difficult for the hydrolysis alkyl branches and fully stir and make its hydrolysis, and preferential control of reaction temperature is 25-40
oC, also can according to circumstances suitably raise or reduce reaction temperature.Consider the drug inactivation that the too low hydrolysis easily caused of temperature is crossed slowly and excess Temperature causes, reaction temperature is generally 20-60
oC.Response time, preferential control was 10 ~ 60 minutes, also can require according to the hydrolysis of added organosiloxane the proper extension response time.Consider that the long response time can reduce the preparation efficiency of Thermosensitive Material Used for Controlled Releasing of Medicine and reduce substrate performance, the response time generally is no more than 120 minutes and (annotates: mixing time=response time).Add drug molecule after hydrolysis, continue stirring medicine is fully dissolved, the preferential control of dissolution time is 1 ~ 30 minute, also can adopt form or the proper extension dissolution time that add drug solution according to the medicine dissolution situation.Consider that long mixing time may make pharmaceutically active reduce, dissolution time generally is no more than 1 hour.Add afterwards base catalyst to make the rapid crosslinking curing of hydrolyzate, mixing time 1 ~ 30 minute, the degree of cross linking is adjustable flexibly.Subsequently product is carried out to drying and form the silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine, the preferential control of drying condition is 30 ~ 45
oVacuum drying under C, also can be according to the matrix drying regime baking temperature that suitably raises.The macromolecular drug such as protein, DNA of considering preferential employing is the responsive to temperature type medicine, and too high temperature can make the drug molecule inactivation, and baking temperature generally is no more than 60
oC.Xerogel, through grinding screening, obtains the slow releasing carrier of medication of required particle diameter, and the size adjustable extent is 10 ~ 500 μ m, can meet the demand of most drug releases.
The silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine of load macromolecular drug prepared with prior art by the present invention is compared, sum up have advantages of following outstanding:
(1) energy accurate Calculation and control drug loading amount, overcome because the inaccurate release amount of medicine caused of drug loading amount metering is difficult to an accurate difficult problem of controlling.
(2) can make the organosiloxane Quick cross-linking be hydrolyzed adding of base catalyst, can shorten greatly the xerogel preparation time on the one hand, save process costs, can regulate and control flexibly the chemical constitution of silica xerogel on the other hand, make the degree of cross linking of silica xerogel more controlled, xerogel also can show more various solubility behavior in buffer, thereby realizes effective controllable release of macromolecular drug.
(3) adding due to base catalyst, gained silica xerogel form and size are controlled flexibly, can adjust according to the release demand, and typing is convenient, can prepare the adjustable granule of size, spherical, lamellar and the various structures such as block, be suitable for the release of most of slow releasing pharmaceuticals.
(4) it is intermolecular sterically hindered that the alkyl branches structure that the alkoxyl added partly is substituted by the organosiloxane that is difficult for the hydrolysis alkyl branches can enlarge markedly organosiloxane, destroys the cross-linked structure of the silica xerogel generated.Can regulate and control flexibly the silica xerogel chemical constitution by alkyl branches length and size, its dissolving in buffer can be changed with the difference of the demand of release, thus the release behavior of accurate Effective Regulation medicine.
(5) the silica xerogel matrix dissolves with the release of carrying medicament gradually once entering human body, completes after drug release and does not need second operation to take out, and its rate of dissolution is controlled flexibly, easy to use, and subsequent processes is simple.
(6) erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine preparation method disclosed by the invention, can the residual reagent that human body is had to burden in material, and technique is simple, and biocompatibility is good, to human body nonhazardous effect.
(7) the erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine that adopts method of the present invention to prepare, be applicable to the release that great majority have the medicine of slow release demand, is particularly useful for the controllable release of the macromolecular drugs such as polypeptide, protein and DNA.The present invention provides a kind of new method for the controlled release materials for preparing macromolecular drug, and its slow-release material is with a wide range of applications clinically.
The specific embodiment
By the following examples the present invention is further described specifically.Be necessary to be pointed out that at this following examples are only for the present invention is described further; can not be interpreted as limiting the scope of the invention; this art skilled person makes some nonessential improvement and adjustment according to the invention described above content to the present invention, still belongs to protection scope of the present invention.
The organosiloxane that the silicon atom used in embodiment all is connected with alkoxyl is with methyl silicate, ethyl orthosilicate, dimethoxy diethoxy silane and six ethyoxyl disilane are example, and alkoxyl partly is substituted by is difficult for being hydrolyzed the organosiloxane of alkyl branches with dimethyldimethoxysil,ne, propyl-triethoxysilicane, 3-aminopropyl triethoxysilane and 3-(triethoxysilicane) propyl group succinic anhydrides is example, and macromolecular drug is with bovine serum albumin, trypsin ihhibitor and nerve growth factor are example, and acid catalyst is with hydrochloric acid, nitric acid and acetic acid are example, and base catalyst is with sodium hydroxide, potassium hydroxide and ammonia are example, and solvent is with water, methanol, ethanol and chloroform are example, but the present invention the organosiloxane that all is connected with alkoxyl of spendable silicon atom, alkoxyl partly is substituted by the organosiloxane that is difficult for the hydrolysis alkyl branches, macromolecular drug, acid catalyst and solvent are not limited to the organosiloxane that the silicon atom that used in embodiment all is connected with alkoxyl, alkoxyl partly is substituted by the organosiloxane that is difficult for the hydrolysis alkyl branches, macromolecular drug, acid base catalysator and solvent.
The good effect that the present invention produces can describe with embodiment.
Embodiment 1
By methyl silicate 1 g, 3-(triethoxysilicane) propyl group succinic anhydrides 0.4 g, hydrochloric acid 0.2 ml, deionized water 1 ml inserts in flat vial, in room temperature (approximately 25
oC) lower magnetic force stirs 30 minutes, carry out cohydrolysis and copolycondensation, form homogeneous colloidal sol, add bovine serum albumin 25 mg (annotate: the addition of bovine serum albumin be methyl silicate and 3-(triethoxysilicane) propyl group succinic anhydrides add gross weight 1.8%), after mix homogeneously, (after dissolving fully) dropwise splashes into 0.1ml 1N sodium hydroxide solution, stir and within 15 minutes, make mixed solution be cross-linked to form rapidly network structure, be placed in 40
oThe C vacuum drying oven is dried the silica xerogel that obtains the load bovine serum albumin to constant weight, i.e. erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.70 g, and now the drug loading amount accounts for 3.6% of xerogel quality total amount.
The above-mentioned silica xerogel prepared is ground, is sieved into to the granule of 40-70 μ m, accurately weighing 25 mg are placed in the TRIS buffer (tris buffer) of 10 ml pH=7.4, shift out the tris buffer and add 10 new ml Tris buffer every certain hour, adopt colloidal gold method to be tested protein concentration, concrete grammar is as follows:
Accurately measure the colloidal gold solution of 0.8 ml cold preservation in 1.5 ml centrifuge tubes, standing its temperature that makes is room temperature, accurately adds 10 μ l Tris buffer to be measured vigorous stirring, puts into 37
oStanding 50 min of C incubator react completely gold colloidal and bovine serum albumin, adopt the concentration of ordinary dissolution of ultraviolet-visible spectrophotometer test bovine serum albumin in the Tris buffer, and test wavelength is 595 nm.The standard curve concentration range of bovine serum albumin is 0.5-20 μ g/ml, and in this scope, TI concentration and absorbance demonstrate good linear relationship (Rc > 0.99).After tested, the silica xerogel of dry preparation dissolves fully in 96 hours in buffer, and medicine discharged slowly at 24 hours, and burst size is that 20%, 96 hour burst size is 89%.
Embodiment 2
Ethyl orthosilicate 1g, 3-(triethoxysilicane) propyl group succinic anhydrides 0.25g, hydrochloric acid 0.3ml, deionized water 1ml, at room temperature magnetic agitation is 1 hour, carry out cohydrolysis and copolycondensation, form homogeneous colloidal sol, add bovine serum albumin 25 mg (annotate: the addition of bovine serum albumin be ethyl orthosilicate and 3-(triethoxysilicane) propyl group succinic anhydrides add gross weight 2.0%), dropwise splash into 0.15ml 1N sodium hydroxide solution after mix homogeneously, stir and within 15 minutes, make the rapid cross-linked structure of colloidal sol, be placed in 40
oThe C vacuum drying oven is dried to constant weight, obtains erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.58 g, and now the drug loading amount accounts for 4.3% of xerogel quality total amount.
Add shape, the size of base catalyst afterproduct silica xerogel adjustable flexibly, the above-mentioned silica xerogel prepared can be ground, is sieved into the granule of 200-300 μ m, accurately weighing 25 mg are placed in the described tris buffer of 10 ml embodiment 1, and adopt the described drug level method of testing of embodiment 1 to drug release behavior tested.Medicine 24 hours discharges approximately 10%, and is good linearity and discharges, and within 11 days, discharges 83%.
Embodiment 3
Ethyl orthosilicate 1g, 3-(triethoxysilicane) propyl group succinic anhydrides 0.10g, hydrochloric acid 0.5ml, deionized water 1ml, room temperature magnetic agitation 30 minutes, carry out cohydrolysis and copolycondensation, form homogeneous colloidal sol, add bovine serum albumin 30 mg (annotate: the addition of bovine serum albumin be ethyl orthosilicate and 3-(triethoxysilicane) propyl group succinic anhydrides add gross weight 2.7%), dropwise splash into 0.15ml 1N potassium hydroxide solution after mix homogeneously, stir and within 10 minutes, make colloidal sol form rapidly cross-linked structure, be placed in 40
oThe C vacuum drying oven is dried to constant weight, obtains erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.49 g, and now the drug loading amount accounts for 6.1% of xerogel quality total amount.
The above-mentioned silica xerogel prepared is ground, is sieved into to the granule of 40-70 μ m, accurately weighing 25 mg are placed in the described tris buffer of 10 ml embodiment 1, and adopt the described drug level method of testing of embodiment 1 to drug release behavior tested.14 days burst sizes of medicine are 89%, and reach almostlinear release.
Embodiment 4
Six ethyoxyl disilane 1g, 3-(triethoxysilicane) propyl group succinic anhydrides 0.4g, hydrochloric acid 0.2ml, ethanol 1ml, room temperature magnetic agitation 1 hour, carry out cohydrolysis and copolycondensation, form homogeneous colloidal sol, add bovine serum albumin 30 mg (annotate: the addition of bovine serum albumin be six ethyoxyl disilane and 3-(triethoxysilicane) propyl group succinic anhydrides add gross weight 2.1%), dropwise splash into 0.1ml 1N potassium hydroxide solution after mix homogeneously, stir and within 15 minutes, make colloidal sol form rapidly cross-linked structure, be placed in 40
oThe C vacuum drying oven is dried to constant weight, obtains erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.62 g, and now the drug loading amount accounts for 4.8% of xerogel quality total amount.
The above-mentioned silica xerogel prepared is ground, is sieved into to the granule of 70-100 μ m, accurately weighing 25 mg are placed in the described tris buffer of 10 ml embodiment 1, and adopt the described drug level method of testing of embodiment 1 to drug release behavior tested.Ground, sieved, obtained the granule that particle diameter is.It is 92% that 24 hours burst sizes of medicine are about 24%, 3 day burst size.
Embodiment 5
Dimethoxy diethoxy silane 1g, dimethyldimethoxysil,ne 0.20g, hydrochloric acid 0.2ml, deionized water 1ml, room temperature magnetic agitation 0.5 hour, carry out cohydrolysis and copolycondensation, form homogeneous colloidal sol, add trypsin ihhibitor 30 mg (annotate: the addition of bovine serum albumin be dimethoxy diethoxy silane and dimethyldimethoxysil,ne add gross weight 2.5%), dropwise splash into 0.15ml 1N potassium hydroxide solution after mix homogeneously, stir and within 8 minutes, make colloidal sol form rapidly cross-linked structure, be placed in 40
oThe C vacuum drying oven is dried to constant weight, obtains erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.51 g, and now the drug loading amount accounts for 5.9% of xerogel quality total amount.
The above-mentioned silica xerogel prepared is ground, is sieved into to the granule of 100-200 μ m, accurately weighing 25 mg are placed in the described tris buffer of 10 ml embodiment 1, and adopt the described drug level method of testing of embodiment 1 to drug release behavior tested.Silica xerogel slowly dissolves in buffer, and medicine is that almostlinear discharges, and within 7 days, discharges approximately 75%.
Embodiment 6
Methyl silicate 1g, 3-aminopropyl triethoxysilane 0.20g, nitric acid 0.3ml, ethanol 1ml, deionized water 0.2ml, room temperature magnetic agitation 1 hour, carry out cohydrolysis and copolycondensation, form homogeneous colloidal sol, add trypsin ihhibitor 35 mg (annotate: the addition of trypsin ihhibitor be methyl silicate and 3-aminopropyl triethoxysilane add gross weight 2.9%), dropwise splash into 0.1ml 1N ammonia spirit after mix homogeneously, stir and within 20 minutes, make colloidal sol form rapidly gel, be placed in 40
oThe C vacuum drying oven is dried to constant weight, obtains erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.54 g, and now the drug loading amount accounts for 6.5% of xerogel quality total amount.
The above-mentioned silica xerogel prepared is ground, is sieved into to the granule of 100-200 μ m, accurately weighing 25 mg are placed in the described tris buffer of 10 ml embodiment 1, and adopt the described drug level method of testing of embodiment 1 to drug release behavior tested.Medicine is that in silica xerogel almostlinear discharges, and within 12 days, discharges approximately 77%.
Embodiment 7
Methyl silicate 1g, 3-aminopropyl triethoxysilane 0.10g, nitric acid 0.3ml, ethanol 0.5ml, methanol 0.5ml, deionized water 0.1ml, room temperature magnetic agitation 1 hour, carry out cohydrolysis and copolycondensation, form homogeneous colloidal sol, add trypsin ihhibitor 25 mg (annotate: the addition of trypsin ihhibitor be methyl silicate and 3-aminopropyl triethoxysilane add gross weight 2.3%), dropwise splash into 0.1ml 2N ammonia spirit after mix homogeneously, stir and within 10 minutes, make colloidal sol form rapidly cross-linked structure, be placed in 40
oThe C vacuum drying oven is dried to constant weight, obtains erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.51 g, and now the drug loading amount accounts for 4.9% of xerogel quality total amount.
The above-mentioned silica xerogel prepared is ground, is sieved into to the granule of 300-500 μ m, accurately weighing 25 mg are placed in the described tris buffer of 10 ml embodiment 1, and adopt the described drug level method of testing of embodiment 1 to drug release behavior tested.Medicine is divided into three phases at silica xerogel, within first 3 days, is that the slower linearity of rate of release discharges, and within 3 days, burst size is 21%, within 4-12 days afterwards, discharge very fast, within 12 days, burst size is 81%, within 5 days subsequently, for discharging slower almostlinear, discharges, and within 17 days, the drug release total amount is 91%.
Embodiment 8
Ethyl orthosilicate 1g, 3-(triethoxysilicane) propyl group succinic anhydrides 0.10g, acetic acid 0.4ml, chloroform 0.5ml, deionized water 0.5ml, room temperature magnetic agitation 0.5 hour, carry out cohydrolysis and copolycondensation, form homogeneous colloidal sol, add nerve growth factor 20 mg (annotate: the addition of nerve growth factor be ethyl orthosilicate and 3-(triethoxysilicane) propyl group succinic anhydrides add gross weight 1.8%), dropwise splash into 0.1ml 1N ammonia spirit after mix homogeneously, stir and within 20 minutes, make colloidal sol form rapidly cross-linked structure, be placed in 40
oThe C vacuum drying oven is dried to constant weight, obtains erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.49 g, and now the drug loading amount accounts for 4.1% of xerogel quality total amount.
The above-mentioned silica xerogel prepared is ground, is sieved into to the granule of 100-200 μ m, accurately weighing 25 mg are placed in the described tris buffer of 10 ml embodiment 1, and adopt the described drug level method of testing of embodiment 1 to drug release behavior tested.Medicine is that almostlinear discharges at silica xerogel, and within 14 days, burst size is 87%.
Embodiment 9
Dimethoxy diethoxy silane 1g, 3-(triethoxysilicane) propyl group succinic anhydrides 0.05g, acetic acid 0.2ml, deionized water 1ml, chloroform 0.3ml, room temperature magnetic agitation 1 hour, carry out cohydrolysis and copolycondensation, form homogeneous colloidal sol, add nerve growth factor 25mg (annotate: the addition of nerve growth factor be dimethoxy diethoxy silane and 3-(triethoxysilicane) propyl group succinic anhydrides add gross weight 2.4%), dropwise splash into 0.1ml 1N ammonia spirit after mix homogeneously, stir and within 20 minutes, make colloidal sol form rapidly cross-linked structure, be placed in 40
oThe C vacuum drying oven is dried to constant weight, obtains erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.41 g, and now the drug loading amount accounts for 6.1% of xerogel quality total amount.
The above-mentioned silica xerogel prepared is ground, is sieved into to the granule of 100-200 μ m, accurately weighing 25 mg are placed in the described tris buffer of 10 ml embodiment 1, and adopt the described drug level method of testing of embodiment 1 to drug release behavior tested.Medicine 24 hours discharges approximately 18%, reaches afterwards almostlinear and discharges, and within 14 days, burst size is 79%.
Embodiment 10
Methyl silicate 0.2g, six ethyoxyl disiloxane 0.8g, dimethyldimethoxysil,ne 0.25g, hydrochloric acid 0.5ml, chloroform 0.5ml, dehydrated alcohol 0.2ml, deionized water 0.2ml, the room temperature magnetic agitation forms in 0.5 hour, carry out cohydrolysis and copolycondensation, homogeneous colloidal sol, (annotate: the addition of bovine serum albumin is methyl silicate to add bovine serum albumin 25 mg, six ethyoxyl disilane and dimethyldimethoxysil,ne three add gross weight 2.0%), dropwise splash into 0.1ml 1N ammonia spirit after mix homogeneously, stir and within 20 minutes, make colloidal sol form rapidly cross-linked structure, be placed in 40
othe C vacuum drying oven is dried to constant weight, obtains erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.55 g, and now the drug loading amount accounts for 4.5% of xerogel quality total amount.
The above-mentioned silica xerogel prepared is ground, is sieved into to the granule of 200-300 μ m, accurately weighing 25 mg are placed in the described tris buffer of 10 ml embodiment 1, and adopt the described drug level method of testing of embodiment 1 to drug release behavior tested.24 hours burst sizes of medicine are about 15%, reach afterwards almostlinear and discharge, and within 15 days, total burst size is 91%.
Embodiment 11
Ethyl orthosilicate 1g, dimethoxy diethoxy silane 0.2g, 3-(triethoxysilicane) propyl group succinic anhydrides 0.2g, dimethyldimethoxysil,ne 0.2g, hydrochloric acid 0.5ml, deionized water 0.5ml, dehydrated alcohol 0.5ml, room temperature magnetic agitation colloidal sol, (annotate: the addition of bovine serum albumin is ethyl orthosilicate to add bovine serum albumin 30 mg, the dimethoxy diethoxy silane, 3-(triethoxysilicane) propyl group succinic anhydrides and dimethyldimethoxysil,ne add gross weight 1.9%), dropwise splash into 0.1ml 1N potassium hydroxide solution after mix homogeneously, stir and within 15 minutes, make colloidal sol form rapidly cross-linked structure, be placed in 40
othe C vacuum drying oven is dried to constant weight, obtains erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.57 g, and now the drug loading amount accounts for 5.3% of xerogel quality total amount.
The above-mentioned silica xerogel prepared is ground, is sieved into to the granule of 40-70 μ m, accurately weighing 25 mg are placed in the described tris buffer of 10 ml embodiment 1, and adopt the described drug level method of testing of embodiment 1 to drug release behavior tested.Silica xerogel dissolved fully at 3 days, and medicine was almostlinear and discharges in 7 days, and burst size is 95%.
Embodiment 12
Ethyl orthosilicate 1g, six ethyoxyl disilane 0.1g, 3-(triethoxysilicane) propyl group succinic anhydrides 0.15g, propyl-triethoxysilicane 0.1g, hydrochloric acid 0.1ml, acetic acid 0.2ml, deionized water 0.2ml, dehydrated alcohol 1.0 ml, room temperature magnetic agitation 0.5 hour, carry out cohydrolysis and copolycondensation, form homogeneous colloidal sol, (annotate: the addition of bovine serum albumin is ethyl orthosilicate to add bovine serum albumin 30 mg, six ethyoxyl disilane, 3-(triethoxysilicane) propyl group succinic anhydrides and propyl-triethoxysilicane add gross weight 2.2%), dropwise splash into 0.1ml 1N ammonia spirit after mix homogeneously, stir and within 20 minutes, make colloidal sol form rapidly cross-linked structure, be placed in 40
othe C vacuum drying oven is dried to constant weight, obtains erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.54 g, and now the drug loading amount accounts for 5.6% of xerogel quality total amount.
The above-mentioned silica xerogel prepared is ground, is sieved into to the granule of 20-40 μ m, accurately weighing 25 mg are placed in the described tris buffer of 10 ml embodiment 1, and adopt the described drug level method of testing of embodiment 1 to drug release behavior tested.Silica xerogel dissolves fully in 72 hours, and release amount of medicine reaches 94%.
Embodiment 13
Methyl silicate 0.9g, dimethoxy diethoxy silane 0.1g, propyl-triethoxysilicane 0.2g, acetic acid 0.5ml, deionized water 0.2ml, dehydrated alcohol 1.0 ml, room temperature magnetic agitation 1 hour, carry out cohydrolysis and copolycondensation, form homogeneous colloidal sol, (annotate: the addition of trypsin ihhibitor is methyl silicate to add trypsin ihhibitor 23 mg, dimethoxy diethoxy silane and propyl-triethoxysilicane three add gross weight 1.9%), dropwise splash into 0.1ml 1N potassium hydroxide solution after mix homogeneously, stir and within 15 minutes, make colloidal sol form rapidly cross-linked structure, be placed in 40
othe C vacuum drying oven is dried to constant weight, obtains erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.45 g, and now the drug loading amount accounts for 5.1% of xerogel quality total amount.
The above-mentioned silica xerogel prepared is ground, is sieved into to the granule of 20-40 μ m, accurately weighing 25 mg are placed in the described tris buffer of 10 ml embodiment 1, and adopt the described drug level method of testing of embodiment 1 to drug release behavior tested.14 days burst sizes of medicine reach 95%.
Embodiment 14
Ethyl orthosilicate 1g, 3-(triethoxysilicane) propyl group succinic anhydrides 0.25g, hydrochloric acid 0.3ml, deionized water 1ml, at room temperature magnetic agitation is 1 hour, carry out cohydrolysis and copolycondensation, form homogeneous colloidal sol, add cefalexin 25 mg (annotate: the addition of cefalexin be ethyl orthosilicate and 3-(triethoxysilicane) propyl group succinic anhydrides add gross weight 2.0%), dropwise splash into 0.15ml 1N sodium hydroxide solution after mix homogeneously, stir and within 15 minutes, make the rapid cross-linked structure of colloidal sol, be placed in 40
oThe C vacuum drying oven is dried to constant weight, obtains erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine 0.58 g, and now the drug loading amount accounts for 4.3% of xerogel quality total amount.
The above-mentioned silica xerogel prepared is ground to form to the granule of 40-70 μ m, accurately weighing 25 mg are placed in 10 ml phosphate buffers (PBS), shift out the PBS buffer and add 10 new ml PBS buffer every certain hour, and the stripping concentration of employing ultraviolet-visible spectrophotometer testing drug, the test wavelength of employing is 262 nm.Cefalexin discharges 37%, 48 hour burst size in 2 hours and reaches 81%, and dashing forward, it is comparatively obvious to release.
Claims (10)
1. the preparation method of an erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine, it is characterized in that by weight percentage, will account for 50 ~ 99%(weight) the organosiloxane that all is connected with alkoxyl of silicon atom, 1 ~ 50% alkoxyl partly be substituted by the organosiloxane of the alkyl branches of facile hydrolysis not and can in the subsequent drying process, remove and be not counted in above-mentioned solvent in adding gross weight and acid catalyst 20 ~ 60
oMix under C and stir 10 ~ 120 minutes, carry out cohydrolysis and copolycondensation, fully after the reaction, add the made preparation process stable performance that accounts for above-mentioned two kinds of organosiloxane gross weights 0.1 ~ 50% and the medicine of suitable slow release application, after dissolving fully, add again base catalyst to make the hydrolyzate Quick cross-linking, stir 1 ~ 30 minute drying after product solidifies, can obtain prepared erosion type silicon dioxide Thermosensitive Material Used for Controlled Releasing of Medicine.
2. according to the preparation method of erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine claimed in claim 1, it is characterized in that the organosiloxane that described silicon atom all is connected with alkoxyl is one or more in methyl silicate, ethyl orthosilicate, dimethoxy diethoxy silane and six ethyoxyl disilane.
3. according to the preparation method of erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine claimed in claim 1, it is characterized in that the organosiloxane that said alkoxyl partly is substituted by is difficult for the hydrolysis alkyl branches is one or more in dimethyldimethoxysil,ne, propyl-triethoxysilicane, 3-aminopropyl triethoxysilane and 3-(triethoxysilicane) propyl group succinic anhydrides.
4. according to the preparation method of erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine claimed in claim 1, it is characterized in that described to make the molecular weight range of choice of the medicine of preparation process stable performance and the application of suitable slow release be 50 ~ 1000000.
5. according to the preparation method of erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine claimed in claim 4, it is characterized in that the described molecular weight of the medicine of preparation process stable performance and the application of suitable slow release that makes is greater than 2000; This medicine is one or more in polypeptide, protein, gene, RNA, DNA.
6. according to the preparation method of erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine claimed in claim 1, it is characterized in that the organic or inorganic acid that molecular weight that the described acid catalyst that can remove is effumability is less than 200 in the subsequent drying process.
7. according to the preparation method of erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine claimed in claim 6, it is characterized in that the described acid catalyst that can remove is one or more in hydrochloric acid, nitric acid and acetic acid in the subsequent drying process.
8. according to the preparation method of erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine claimed in claim 1, it is characterized in that described base catalyst is the organic or inorganic alkali that nontoxic or volatile molecular weight is less than 200; This organic or inorganic alkali is one or more in sodium hydroxide, potassium hydroxide and ammonia spirit.
9. according to the preparation method of erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine claimed in claim 1, it is characterized in that the micromolecular compound that the described solvent that can remove is less than 500 for the volatile molecular weight that can dissolve the different organosiloxanes mentioned and hydrolysate, medicine and acid base catalysator in the subsequent drying process.
10. according to the preparation method of erosion type silica xerogel Thermosensitive Material Used for Controlled Releasing of Medicine claimed in claim 9, it is characterized in that the described solvent that can remove is one or more in water, methanol, ethanol and chloroform in the subsequent drying process.
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