CN102652833B - Gastric targeted drug carrier and preparation method thereof - Google Patents
Gastric targeted drug carrier and preparation method thereof Download PDFInfo
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- CN102652833B CN102652833B CN 201110050436 CN201110050436A CN102652833B CN 102652833 B CN102652833 B CN 102652833B CN 201110050436 CN201110050436 CN 201110050436 CN 201110050436 A CN201110050436 A CN 201110050436A CN 102652833 B CN102652833 B CN 102652833B
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Abstract
The invention relates to the field of drug carrier preparation, in particular to a gastric targeted drug carrier and a preparation method thereof. The gastric targeted drug carrier is prepared from the following raw materials: drug-containing emulsion and a crosslinking agent, wherein the drug-containing emulsion contains chitosan, chitosan quaternary ammonium salt and sodium glycerophosphate; and the crosslinking agent is used for crosslinking the emulsion into microspheres. The preparation method comprises the following steps: 1) preparing the drug-containing emulsion: with a aqueous solution of chitosan, chitosan quaternary ammonium salt and sodium glycerophosphate as an aqueous phase W, preparing the drug-containing emulsion with the aqueous phase, drugs and an oil phase containing an emulsifying agent; and 2) heating and stirring the drug-containing emulsion prepared in the step 1), crosslinking the chitosan quaternary ammonium salt and sodium glycerophosphate contained in the drug-containing emulsion to obtain gel microsphere suspension, heating the suspension and adding the crosslinking agent to carry out secondary crosslinking to solidify the gel microspheres. The drug carrier has the advantages of uniform and controllable grain size, high embedding rate and good dispersibility and simultaneously meets the requirements of the gastric targeted drug delivery carrier.
Description
Technical field
The present invention relates to the pharmaceutical carrier preparation field, particularly, the present invention relates to a kind of stomach target medicine carrier and preparation method thereof.
Background technology
The polysaccharide that chitosan is made up of glycosamine and N-acetyl glucosamine copolymer is the product of chitin deacetylase base, and chitosan can be dissolved in dilute acid soln owing to have free amine group on the strand, therefore has purposes more widely than chitin.Chitosan is as a kind of cationic biopolymer, has bioadhesive, biocompatibility and biological degradability, and its catabolite is nontoxic, non-immunogenicity, non-carcinogenesis, these uniquenesses of chitosan make it become the biological medicine carrier that has a extensive future, at document Chitosan-cellulose compositemembrane for affinity purification of biopolymers and immunoadsorption, Journal ofMembrane Science, 2002,197:185-197.L.Yang, W.W.Hsiao, P.Chen.; Preparation ofchitosan ethylcellulose complex microcapsule and its application in controlled release ofVitamin D
2, Biomaterials, 2002,23:4469-4473, Xin-Yuan Shi, Tian-Wei Tan; Evaluationof the biological properties of soluble chitosan and chitosan microspheres, InternationalJournal of Pharmaceutics, 1997,148:231-240.
Ruth Duncan, in report is all arranged.With chitosan and chitosan derivatives is that material is modified the chitosan quaternary ammonium salt of transforming preparation, is a kind of positively charged natural polysaccharide, is easy to adhere to the surface of cell as pharmaceutical carrier.Compare with chitosan, chitosan quaternary ammonium salt not only has good hydrophilicity and water solublity, and the introducing of quaternary ammonium group has increased short mucosa osmotic absorption ([4] Kotze A F of chitosan quaternary ammonium salt greatly, De Leeuw B J, Lueben H L, DeBoer A G, Verhoef J C, Junginger HE.Chitosans for enhanced delivery of therapeuticpeptides across intestinal epithelia:In vitro evaluation in Caco-2 cell monolayers.Int.J.Pharm, 1997,159:243-263).Murata etc. are used for the genophore experiment in nineteen ninety-five with chitosan quaternary ammonium salt, transfection HepG 2 cell (Murata JI effectively, Ohya Y, Ouchi T.Design of quaternary chitosanconjugate having antennary galactose residues as a gene delivery tool.Carbohydr.Polym, 1997,32 (2): 105-109).As a kind of novel gene vector, Kean studies the cytotoxicity and the transfection efficiency of chitosan quaternary ammonium salt carrier in addition.The result shows, compares with cation carrier polylysine commonly used, and in all concentration ranges of being tested, all tested chitosan quaternary ammonium salts all do not show significant cytotoxicity.Therefore, the microsphere of chitosan and chitosan quaternary ammonium salt composite material is a kind of gelation microsphere that has positive charge, have good pH sensitivity, adhesiveness, and these characteristics are features that the stomach targeting vector is possessed, so this type of microsphere is expected to become a kind of stomach targeted drug transport vehicle that has a extensive future.
Chitosan microball has good biocompatibility, bioadhesive and medicine controlled releasing performance.Chitosan microball is owing to contain more amino, character with polycation, so it can interact with the electronegative group of cell surface, with cell generation non-specific adsorption, thereby help cell in the sticking of chitosan microball material surface, have the good cell compatibility; In addition, chitosan has higher hydrophilic, studies show that (Sarah Nsereko, Mansoor Amiji, Loacallized delivery of paglitaxel in solid tumors from biodegradablechitin microparticle formulations, Biomaterials, 23 (2002) 2733-2731.), in dilute serum, water wetted material more can promote cell in the absorption of material surface with sprawl than hydrophobic material, its cytoskeleton of cell on the water wetted material also more in a organized way, and chitosan material has good water absorption character, suction promptly reaches behind the 20min saturated, and the hydroexpansivity of this hydrophilic gel of chitosan is very similar to cellular matrix with porous, has the favorable tissue compatibility.The positive charge of chitosan and electronegative mucomembranous surface form intermolecular attraction by electrostatic interaction makes it have adhesion characteristics.Another key property of chitosan is to can be used as pharmaceutical carrier, drug release is played slow releasing function, reduce drug toxicity, prolong drug curative effect (Radi Hejazi, Mansoor Amiji, Chitosan-basedgastrointestinal delivery systems, Journal of Controlled Release, 89 (2003) 151-165.).As adopt chitosan that insulin is carried out embedding, but when chitosan after cross-linking agent reacts, owing to its surperficial group and aldehyde radical react, just lose the non-specific adsorption between this and the cell.The delay of polypeptide drugs in the cationic polymer three-dimensional network mainly is to finish by the ionization between simple aquation and diffusion process or polymer and the medicine ion.Though the chitin quarternary ammonium salt aquagel microsphere has bioadhesive preferably, but it is as the disintegrate rapidly in the stomach sour environment of stomach drug administration carrier, in acid release medium (pH=5.0), because the dissolving of dissociating of chitosan quaternary ammonium salt microsphere, wherein the medicine of institute's embedding also is released into surrounding medium rapidly, the medicine of institute's embedding is all discharged in the 1h, do not have the excellent drug sustained release performance, though and chitosan has good pH sensitivity, but after reacting, itself and cross-linking agent lose targeting, the requirement that therefore independent use chitosan and chitosan quaternary ammonium salt can't satisfy stomach target administration carrier.
Summary of the invention
The object of the present invention is to provide a kind of stomach target medicine carrier.
A further object of the present invention is to provide a kind of method for preparing the stomach target medicine carrier.
According to stomach target medicine carrier of the present invention, described pharmaceutical carrier raw material comprises the pastille emulsion that contains chitosan, chitosan quaternary ammonium salt, sodium glycerophosphate; And the cross-linking agent that above-mentioned emulsion is cross-linked into microsphere.
According to stomach target medicine carrier of the present invention, the mass ratio of described chitosan and chitosan quaternary ammonium salt is 1: 0.1～10, the gross mass of chitosan and chitosan quaternary ammonium salt and the mass ratio of sodium glycerophosphate are 1: 1～10, be preferably 1: 0.5～2, wherein the quaternized substitution value of chitosan quaternary ammonium salt is 10%～80%.
According to stomach target medicine carrier of the present invention, described cross-linking agent is glutaraldehyde, genipin or epoxy chlorine, and wherein the mol ratio of cross-linking agent and chitosan and chitosan quaternary ammonium salt amino is 1: 1～10.
The present invention also provides a kind of method for preparing the stomach target medicine carrier, said method comprising the steps of:
1) preparation of pastille emulsion:
The aqueous acetic acid that water soluble drug is dissolved in chitosan quaternary ammonium salt, chitosan and sodium glycerophosphate is as water W, be dissolved with emulsifying agent oily matter as oil phase O, obtain w/o type pastille emulsion through emulsifying;
Perhaps
Fat-soluble medicine is dissolved in organic solvent as interior oil phase O
1, as water W, O is made in emulsifying with the aqueous acetic acid that is dissolved with chitosan quaternary ammonium salt, chitosan and sodium glycerophosphate
1/ W type colostric fluid, again with the oily matter that is dissolved with emulsifying agent as outer oil phase O
2, with outer oil phase O
2And O
1The emulsifying of/W type colostric fluid obtains O
1/ W/O
2Type pastille emulsion;
2) with w/o type in the step 1) or O
1/ W/O
2Type pastille emulsion heats up, and it is tentatively crosslinked that its chitosan quaternary ammonium salt that contains and sodium glycerophosphate are taken place, and obtains the gel micro-ball suspension, continue to heat up and add cross-linking agent, generation is for the second time crosslinked, and gel micro-ball is solidified, and the washing drying obtains the stomach target medicine carrier.
The method of stomach target medicine carrier produced according to the present invention is characterized in that, the mass ratio of chitosan, chitosan quaternary ammonium salt is 1: 0.1～10 in the described step 1), be preferably 1: 0.5～and 2; The gross mass of described chitosan and chitosan quaternary ammonium salt and the mass ratio of sodium glycerophosphate are 1: 1～10; Wherein the quaternized substitution value of chitosan quaternary ammonium salt is 10%～80%.
According to one embodiment of the invention, the concrete method for preparing the stomach target medicine carrier may further comprise the steps:
1) prepares the pastille emulsion earlier: when this medicine is hydrophilic medicament, with the aqueous acetic acid that is dissolved with hydrophilic medicament, chitosan quaternary ammonium salt, chitosan and sodium glycerophosphate as water (W), with be dissolved with emulsifying agent oily matter as oil phase O, prepare w/o type pastille emulsion through emulsifying; When this medicine is lipophilic drugs, earlier with the organic solvent that is dissolved with lipophilic drugs as interior oil phase (O
1), as water (W),, make O with the aqueous acetic acid that is dissolved with chitosan quaternary ammonium salt, chitosan and sodium glycerophosphate through emulsifying
1/ W type colostric fluid is again with this O
1/ W type colostric fluid is added to the oily matter that is dissolved with emulsifying agent, prepares O through emulsifying
1/ W/O
2Type pastille emulsion;
2) this pastille emulsion is made pharmaceutical carrier through the step curing method: earlier this emulsion is tentatively heated up, make its chitosan quaternary ammonium salt that contains and sodium glycerophosphate crosslinked, make the gel micro-ball suspension, heat up once more, and in this gel micro-ball suspension, add cross-linking agent, through cross-linking reaction, this microsphere is thoroughly solidified;
3) with the washing of above-mentioned microsphere process, collection and dry, make pharmaceutical carrier.
The method of stomach target medicine carrier produced according to the present invention, when the first step was solidified, sodium glycerophosphate (GP) was as cross-linking agent, and the amount ranges of this cross-linking agent is that the gross mass of chitosan and chitosan quaternary ammonium salt and the mass ratio of sodium glycerophosphate are 1: 1～10; Crosslinking time is 0.5～2h, and crosslinked temperature is 18～40 ℃, and preferably 30 ℃～40 ℃ most preferably is 36 ℃～38 ℃, and the oil phase revolution is 150～700rpm when crosslinked.The second step cross-linking agent and consumption are as follows: cross-linking agent can be glutaraldehyde, genipin, epoxychloropropane etc., the preferred glutaraldehyde that uses, can be the aqueous solution that contains the saturated toluene solution (GST) of glutaraldehyde or contain glutaraldehyde, the amount ranges of cross-linking agent be that the mol ratio of the amino of aldehyde radical or epoxy radicals and chitosan is 1: 1～10; Crosslinking time is 0.5～5h, and crosslinked temperature is 18～60 ℃, and preferred crosslinking temperature is 45 ℃～60 ℃, most preferably is 48 ℃～50 ℃, adopts temperature programming, and heating rate is 2 ℃/min, and the oil phase revolution is 150～700rpm when crosslinked.
The method of stomach target medicine carrier produced according to the present invention, oily matter and water are immiscible, wherein oil phase is selected the mixture of Oleum Ricini, olive oil, soybean oil or liquid paraffin and petroleum ether for use, the mixture of liquid paraffin and petroleum ether preferably, and both volume ratios are preferably 1: 2.Oil emulsifier must be dissolved in employed oily matter, can use polymer (as PO-500, PO-310), polyoxyethylene hydrogenated Oleum Ricini, sorbitan trioleate (class of department 85), sorbitan monooleate (class of department 80), anhydrous sorbitol tristearate (class of department 65), the oleophylic-hydrophilic block copolymers of sorbitan sesquioleate (Arlacel83), glycerin ether etc.The concentration of emulsifying agent is 0.5～10wt% in the oil phase.
The method of stomach target medicine carrier produced according to the present invention, the preparation method of above-mentioned w/o type emulsion is, prepare the w/o type pre-emulsion earlier, then this pre-emulsion was pressed down microporous membrane in elevated pressures, with the w/o type emulsion of preparation uniform particle diameter, the preferably hydrophobic SPG film of this microporous membrane is under optimal conditions, the diameter of micro ball breadth coefficient is controlled in 20%, and diameter can freely be controlled in 0.1～10 micron.
The method of stomach target medicine carrier produced according to the present invention, described lipophilic drugs can be selected safe stomach U.S., ranitidine, rapamycin etc., the present invention when the preparation lipophilic drugs, oil phase O in it
1Be the organic solvent of this medicine of solubilized, Qi Heshui does not dissolve each other, and preferably DMSO or chloroform are preparing O
1/ W type colostric fluid can add emulsifying agent in the oil phase in this, to improve embedding rate.Hydrophilic medicament can be cimetidine, proglumide, amoxicillin or gentamycin sulfate, rapamycin is when the whole body administration, find that in a large amount of clinical trials its side effect has symptoms such as nephrotoxicity, liver toxicity, cholesterol, hyperlipidemia, thrombocytopenia, pharmaceutical carrier by the present invention's preparation, but the stomach target administration reduces side effect.
The method of stomach target medicine carrier produced according to the present invention in the above-mentioned preparation, after pharmaceutical carrier thoroughly solidifies, is used it washings such as petroleum ether, methanol, distilled water successively, and with after its supercritical extraction drying, cryopreservation; Or directly will receive microsphere and under room temperature or low temperature, be stored in distilled water or the cell culture fluid.
The method of stomach target medicine carrier produced according to the present invention, because the mixing of chitosan, chitosan quaternary ammonium salt and sodium glycerophosphate, make existing chitosan microball of complex microsphere and chitosan quaternary ammonium salt microsphere advantage separately, the temperature sensitive property and the gelation that have such as the existence owing to sodium glycerophosphate of quaternary ammonium salt microsphere, the character of the spontaneous stable fluorescence of chitosan microball etc. give complex microsphere new feature again.Be in particular in: (1) chitosan quaternary ammonium salt microsphere is separately as pharmaceutical carrier the time, because it has porous, and the aperture of microsphere surface is bigger, make that small-molecule drug is easy to flow out from the aperture when embedding, greatly reduce the embedding rate of medicine, if and add chitosan, add the glutaraldehyde cross-linking agent at a certain temperature again, the not quaternised amino aldol reaction that takes place on the aldehyde radical of glutaraldehyde and amino on the chitosan and the chitosan quaternary ammonium salt, formerly the surface of the gel micro-ball of Xing Chenging forms certain network structure, make the aperture of gel micro-ball dwindle greatly, improved the embedding rate of medicine.(2) simultaneously, because the not quaternised amino aldol reaction that takes place on the aldehyde radical of glutaraldehyde and amino on the chitosan and the chitosan quaternary ammonium salt has formed big conjugated double bond and (C=N-C=C-), can show stronger, stable autofluorescence; Simultaneously, utilize the microsphere of receiving of Preparation of Chitosan not only to have good bio-compatibility, and there is rich functions group (hydroxyl and amino) on the surface, can be used for finishing and modification; Therefore, utilize the character and the chitosan special advantages of this stable fluorescence of chitosan nano-microspheres, can carry out the biological experiment of cellular level and animal level, and be easy to accurately quantitatively, solved in the past fluorescent material unstable because of labelling or that be difficult to labelling or embedding and leaked easily and can't carry out accurate quantitative problem.
According to stomach target medicine carrier of the present invention and preparation method thereof, by mixing with chitosan and chitosan quaternary ammonium salt material, and the strict control ratio between the two and the quaternary ammonium degree of selected chitosan quaternary ammonium salt, realized being prepared into the microsphere that complex microsphere is a kind of positively charged, the chitosan and the chitosan quaternary ammonium salt complex microsphere of preparation are dispersed among the PBS (pH=7.4), determining its Zeta electric potential is 20～28mV, therefore it can interact with the electronegative group of cell surface, with cell generation non-specific adsorption, thereby help pharmaceutical carrier sticking at cell surface, because the adhesion of pharmaceutical carrier, prolonged the time of staying of medicine at the gastric mucosa tissue, and then prolonged the soak time of medicine, thereby improve medicine bioavailability in vivo greatly.Simultaneously because the mixing of chitosan and chitosan quaternary ammonium salt material, add cross-linking agent such as glutaraldehyde at a certain temperature again, and by controlling the time and the temperature of cross-linking reaction, realized the crosslinked of suitable degree, make the surface of the gel micro-ball of formation form certain network structure, make the aperture of gel micro-ball dwindle greatly, improved the embedding rate of medicine, thereby make complex microsphere under (pH=1.2) extremely sour stomach physiological environment, good sensitivity is arranged, complex microsphere can keep 24h and the (see figure 7) that is not degraded at stomach, the pH sensitivity of complex microsphere is used its target administration carrier that can be used as acid sites, such as the target administration carrier as the stomach medicine.The pharmaceutical carrier of method for preparing has pH sensitivity, stomach adhesiveness, medicament slow release characteristic.In pH=1～3 environment, can keep good shapes, and do not degraded by sour environment.At stomach good adhesiveness is arranged, carrier accounts for 40%～90% of oral carrier total amount in the adherent amount of stomach, can realize the slow release effect of medicine at stomach behind the medicine carrying, slow releasing pharmaceutical in 24 hours, and medicine is 0.06mg/h～0.12mg/h in the rate of release of stomach.
The present invention also solved the chitosan of existing stirring and emulsifying method preparation and chitosan quaternary ammonium salt pharmaceutical carrier particle diameter heterogeneity and uncontrollable, embedding rate is low, bad dispersibility, simultaneously, prepared gel micro-ball satisfies the requirement of stomach targeted drug transport vehicle, i.e. adhesiveness, certain pH sensitivity and medicament slow release function.Be expected to utilize the characteristics such as homogeneity, pH sensitivity, adhesiveness of particle diameter, reach stable stomach targeting and discharge medicine, improve medicine in stomach local action concentration with avoid key issue such as systemic side effects.
Description of drawings
Fig. 1 prepares the schematic flow sheet of the pharmaceutical carrier of chitosan and chitosan quaternary ammonium salt composite material for mechanical mixing method;
Fig. 2 prepares the schematic flow sheet of the pharmaceutical carrier of chitosan and chitosan quaternary ammonium salt composite material for the quick film emulsion process of the present invention;
Fig. 3 is the optical microscopy map of the pharmaceutical carrier of embodiment 1 preparation chitosan and chitosan quaternary ammonium salt composite material;
Fig. 4 is that the electronics of the pharmaceutical carrier of embodiment 1 preparation chitosan and chitosan quaternary ammonium salt composite material shows mirror figure;
Fig. 5 is the optical microscopy map of the pharmaceutical carrier of embodiment 2 preparation chitosans and chitosan quaternary ammonium salt composite material;
Fig. 6 is the electron microscope picture of the pharmaceutical carrier of embodiment 2 preparation chitosans and chitosan quaternary ammonium salt composite material;
Fig. 7 is the electron microscope picture of the pharmaceutical carrier of embodiment 3 preparation chitosans and chitosan quaternary ammonium salt composite material;
Fig. 8 is the electron microscope picture of the pharmaceutical carrier of embodiment 4 preparation chitosans and chitosan quaternary ammonium salt composite material;
Fig. 9 is the particle size distribution of the pharmaceutical carrier of embodiment 4 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 10 is the release in vitro curve of rapamycin in the pharmaceutical carrier of the chitosan of embodiment 4 film emulsification methods preparations and chitosan quaternary ammonium salt composite material;
Figure 11 is the electron microscope picture of the pharmaceutical carrier of embodiment 5 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 12 is the electron microscope picture of the pharmaceutical carrier of embodiment 6 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 13 is the electron microscope picture of the pharmaceutical carrier of embodiment 7 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 14 is the electron microscope picture of the pharmaceutical carrier of embodiment 8 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 15 is the electron microscope picture of the pharmaceutical carrier of embodiment 9 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 16 is the electron microscope picture of the pharmaceutical carrier of embodiment 10 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 17 is the electron microscope picture of the pharmaceutical carrier of embodiment 11 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 18 is the electron microscope picture of the pharmaceutical carrier of embodiment 12 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 19 is the electron microscope picture of the pharmaceutical carrier of embodiment 13 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 20 is the electron microscope picture of the pharmaceutical carrier of embodiment 14 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 21 is the electron microscope picture of the pharmaceutical carrier of embodiment 15 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 22 is the electron microscope picture of the pharmaceutical carrier of embodiment 16 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 23 is the electron microscope picture of the pharmaceutical carrier of embodiment 17 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 24 is the electron microscope picture of the pharmaceutical carrier of embodiment 18 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 25 is the electron microscope picture of the pharmaceutical carrier of embodiment 19 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 26 is the electron microscope picture of the pharmaceutical carrier of embodiment 20 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 27 is the adhesion rate of the inherent stomach of pharmaceutical carrier different time of embodiment 4 preparation chitosans and chitosan quaternary ammonium salt composite material;
Figure 28 is the adhesion time scattergram of the pharmaceutical carrier of embodiment 4 preparation chitosans and chitosan quaternary ammonium salt composite material at stomach.
The specific embodiment
Embodiment 1
Accurately take by weighing chitosan (molecular weight 50,000), chitosan quaternary ammonium salt (quaternary ammonium-substituted degree 50%, molecular weight 50,000), sodium glycerophosphate is dissolved in 1% aqueous acetic acid, it is fully dissolved obtain chitosan, chitosan quaternary ammonium salt, the aqueous acetic acid of sodium glycerophosphate, its total concentration is 2.5wt%, chitosan wherein, the concentration of chitosan quaternary ammonium salt is respectively 0.5wt%, the concentration of sodium glycerophosphate is 1.5wt%, wherein the mass ratio of chitosan and chitosan quaternary ammonium salt is 1: 1, and the mass ratio of chitosan and chitosan quaternary ammonium salt gross mass and sodium glycerophosphate 2: 3.With this solution centrifugal insoluble impurities of removing under 8000rpm, it is standby as water to keep supernatant.Get 400 μ L10mg/mL rapamycin solution O
1(rapamycin is dissolved in the chloroform, and emulsifying agent PO-500 concentration is 1wt%) adds aqueous phase, and room temperature mechanical stirs, stirring condition 1000rpm, and 10min forms O
1/ W colostrum; Then colostrum slowly is added dropwise to the outer oil phase O of mixing of liquid paraffin and petroleum ether
2In (volume ratio is 1: 2, and emulsifying agent PO-500 concentration is 4wt%).Stir fast with mechanical agitator, stirring condition 1000rpm, 10min promptly gets O
1/ W/O
2Emulsion, 37 ℃ solidified 1 hour down; Later in emulsion, added the saturated toluene solution of a certain amount of glutaraldehyde in 1 hour, wherein the consumption of glutaraldehyde calculates according to following ratio, be that mol ratio amino on aldehyde radical on the glutaraldehyde and the chitosan is 1: 1, temperature programming, programming rate is about 2 ℃/min, to 50 ℃ of cross-linking reactions 5 hours, the stir speed (S.S.) of cross-linking reaction was 700rpm.After cross-linking reaction finished, centrifugal under 5000rpm, the supernatant of inclining was received microsphere with chitosan and chitosan quaternary ammonium salt and is separated from oil phase, uses petroleum ether, methanol, distilled water wash successively, and it is kept in the distilled water.Embedding rate through microplate reader detection of drugs carrier is 80%, discharges in the 24h fully in simulated gastric fluid, and rate of release is about 0.11mg/h, and the surface potential of microsphere is+24.18mV, and showing microsphere supportedly has good adhesiveness at stomach.The mean diameter of carrier microballoons and particle size distribution adopt Zeta potential and Particle Size Analyzer ZetaPlus to measure, and the average diameter of microsphere is 1000.0 nanometers in water, and the C.V. value is 38.07%, microscope figure as shown in Figure 3, Electronic Speculum figure is as shown in Figure 4.
Embodiment 2
Accurately take by weighing chitosan (molecular weight 50,000), chitosan quaternary ammonium salt (quaternary ammonium-substituted degree 50%, molecular weight 50,000), sodium glycerophosphate is dissolved in 1% aqueous acetic acid, it is fully dissolved obtain chitosan, chitosan quaternary ammonium salt, the aqueous acetic acid of sodium glycerophosphate, its total concentration is 2.5wt%, chitosan wherein, the concentration of chitosan quaternary ammonium salt is respectively 0.5wt%, the concentration of sodium glycerophosphate is 1.5wt%, wherein the mass ratio of chitosan and chitosan quaternary ammonium salt is 1: 1, and the mass ratio of chitosan and chitosan quaternary ammonium salt gross mass and sodium glycerophosphate 2: 3.With this solution centrifugal insoluble impurities of removing under 8000rpm, add the gentamycin sulfate (stomach medicine) of the 20wt% of chitosan and chitosan quaternary ammonium salt gross dry weight then and fully dissolve standby.Oil soluble emulsifying agent PO-500 is joined in the liquid paraffin of 60mL and the mixing oil phase of petroleum ether (volume ratio is 1: 2), and its concentration is 4wt%, is stirred to dissolve fully as oil phase; The water of getting 6.0g mixes with oil phase, mechanical agitation 1000rpm, and 30min obtains the w/o type emulsion; 37 ℃ solidified 1 hour down, later in emulsion, added the saturated toluene solution of a certain amount of glutaraldehyde in 1 hour, wherein the consumption of glutaraldehyde calculates according to following ratio, be that mol ratio amino on aldehyde radical on the glutaraldehyde and the chitosan is 1: 1, temperature programming to 50 ℃ cross-linking reaction 5 hours, the stir speed (S.S.) of cross-linking reaction are 700rpm.After cross-linking reaction finished, centrifugal under 5000rpm, the supernatant of inclining was received microsphere with chitosan and chitosan quaternary ammonium salt and is separated from oil phase, uses petroleum ether, methanol, distilled water wash successively, and it is kept in the distilled water.Embedding rate through microplate reader detection of drugs carrier is 83%, discharges fully in the 28h in simulated gastric fluid, and rate of release is about 0.09mg/h, and the surface potential of microsphere is 23.29, and the stomach targeting is respond well.The mean diameter of microsphere and particle size distribution adopt Zeta potential and Particle Size Analyzer ZetaPlus to measure, and the average diameter of microsphere is 1300.0 nanometers in water, and the C.V. value is 35.12%.Microscope figure as shown in Figure 5, Electronic Speculum figure is as shown in Figure 6.
Embodiment 3
Accurately take by weighing chitosan (molecular weight 50,000), chitosan quaternary ammonium salt (quaternary ammonium-substituted degree 70%, molecular weight 100,000), sodium glycerophosphate is dissolved in 1% aqueous acetic acid, it is fully dissolved obtain chitosan, chitosan quaternary ammonium salt, the aqueous acetic acid of sodium glycerophosphate, its total concentration is 2.5wt%, chitosan wherein, the concentration of chitosan quaternary ammonium salt is respectively 0.5wt%, the concentration of sodium glycerophosphate is 1.5wt%, wherein the mass ratio of chitosan and chitosan quaternary ammonium salt is 1: 1, and the mass ratio of chitosan and chitosan quaternary ammonium salt gross mass and sodium glycerophosphate 2: 3.With this solution centrifugal insoluble impurities of removing under 8000rpm, it is standby as water to keep supernatant.Get 400 μ L10mg/mL rapamycin solution O
1(rapamycin is dissolved in the chloroform, and emulsifying agent PO-500 concentration is 1wt%) adds aqueous phase, and room temperature mechanical stirs, stirring condition 1000rpm, and 10min forms the O1/W colostrum.Oil soluble emulsifying agent PO-500 is joined in the liquid paraffin of 60mL and the mixing oil phase of petroleum ether (volume ratio is 1: 2), and its concentration is 4wt%, is stirred to dissolving fully as outer oil phase O
2, then colostrum slowly is added dropwise in the outer oil phase of mixing of liquid paraffin and petroleum ether.Emulsifying 60s, 3 retainings (14000rpm/min) promptly get O
1/ W/O
2Emulsion, 37 ℃ solidified 1 hour down.Later in emulsion, added the saturated toluene solution of a certain amount of glutaraldehyde in 1 hour, wherein the consumption of glutaraldehyde calculates according to following ratio, be that mol ratio amino on aldehyde radical on the glutaraldehyde and the chitosan is 1: 1, temperature programming, programming rate is about 2 ℃/min, to 50 ℃ of cross-linking reactions 5 hours, the stir speed (S.S.) of cross-linking reaction was 700rpm.After cross-linking reaction finished, centrifugal under 5000rpm, the supernatant of inclining was received microsphere with chitosan and chitosan quaternary ammonium salt and is separated from oil phase, uses petroleum ether, methanol, distilled water wash successively, and it is kept in the distilled water.Embedding rate through microplate reader detection of drugs carrier is 85%, discharges in the 24h fully in simulated gastric fluid, and rate of release is about 0.11mg/h, and the surface potential of microsphere is+30mV, and the result among the respond well and embodiment 1 of stomach targeting matches.The mean diameter of microsphere and particle size distribution adopt Zeta potential and Particle Size Analyzer ZetaPlus to measure, and the average diameter of microsphere is 1500.0 nanometers in water, and the C.V. value is 34.28%, and stereoscan photograph as shown in Figure 7.
Embodiment 4
With the aperture be 2.8 microns hydrophilic SPG glass-film place liquid paraffin and petroleum ether mix oil phase (volume ratio 1: 2), soaked overnight or ultrasonic half an hour are fully soaked into fenestra by oil phase.Accurately take by weighing chitosan (molecular weight 50,000), chitosan quaternary ammonium salt (quaternary ammonium-substituted degree 70%, molecular weight 50,000), sodium glycerophosphate, be dissolved in 1% aqueous acetic acid, it is fully dissolved obtain chitosan, chitosan quaternary ammonium salt, the aqueous acetic acid of sodium glycerophosphate, as interior water, its total concentration is 2.5wt%, chitosan wherein, the concentration of chitosan quaternary ammonium salt is respectively 0.5wt%, the concentration of sodium glycerophosphate is 1.5wt%, wherein the mass ratio of chitosan and chitosan quaternary ammonium salt is 1: 1, and the mass ratio of chitosan and chitosan quaternary ammonium salt gross mass and sodium glycerophosphate 2: 3 is this solution centrifugal insoluble impurities of removing under 8000rpm, and it is standby as water to keep supernatant.Get 400 μ L 10mg/mL rapamycin solution O
1(rapamycin is dissolved in the chloroform, and emulsifying agent PO-500 concentration is 1wt%) adds aqueous phase with emulsifying device emulsifying 1min under third gear (6000rpm), forms O
1/ W type colostrum.Oil soluble emulsifying agent PO-500 is joined in the liquid paraffin of 60mL and the mixing oil phase of petroleum ether (volume ratio is 1: 2), and its concentration is 4wt%, is stirred to dissolving fully as outer oil phase O
2, then with gained O
1/ W type colostrum mixes with outer oil phase, with emulsifying device emulsifying 1min under third gear (6000rpm), forms O
1/ W/O
2Pre-emulsion is poured into rapidly in the film emulsifier unit, and under the nitrogen pressure of 0.4MPa, the SPG microporous membrane with its fast ram compression via hole footpath homogeneous obtains the O of size ratio than homogeneous
1/ W/O
2The type emulsion was pressed microporous membrane with the gained emulsion once more as pre-emulsion under the nitrogen pressure of 0.4MPa, emulsifying is five times repeatedly, finally obtained the O of uniform particle diameter
1/ W/O
2The type emulsion; Emulsifying finishes, and 37 ℃ solidified 1 hour down; Later in emulsion, added the saturated toluene solution of a certain amount of glutaraldehyde in 1 hour, wherein the consumption of glutaraldehyde calculates according to following ratio, be that mol ratio amino on aldehyde radical on the glutaraldehyde and the chitosan is 1: 1, temperature programming, temperature programming, programming rate is about 2 ℃/min, and to 50 ℃ of cross-linking reactions 5 hours, the stir speed (S.S.) of cross-linking reaction was 700rpm.After cross-linking reaction finished, centrifugal under 5000rpm, the supernatant that inclines was received microsphere with chitosan and chitosan quaternary ammonium salt and is separated from oil phase, uses petroleum ether, methanol, distilled water wash successively, and it is kept in the distilled water.The mean diameter of microsphere and particle size distribution adopt Zeta potential and Particle Size Analyzer ZetaPlus to measure, the average diameter of microsphere is 1500.0 nanometers in water, C.V. value is 13.8%, stereoscan photograph as shown in Figure 8, particle size distribution result as shown in Figure 9 shows that prepared chitosan and chitosan quaternary ammonium salt receive the microspherulite diameter homogeneous.
Wherein the embedding of rapamycin medicine reaches more than 90%, being released in the 24h of medicine near 100%, releasing effect as shown in figure 10, the substitution value of the chitosan quaternary ammonium salt in the reduction system can increase microsphere in the adhesion on gastric mucosa, obtain the more microsphere of positive charge, hole in the microsphere tails off, diminishes simultaneously, and the chitosan quaternary ammonium salt of therefore certain substitution value helps to improve the embedding rate of medicine, reduces release rate of drugs simultaneously.
Preparation method is with 4, and just the mass ratio of chitosan and chitosan quaternary ammonium salt is 1: 0.1, and its Zeta potential is+9.2mV that its electromicroscopic photograph as shown in figure 11.
Embodiment 6
Preparation method is with 4, and just the mass ratio of chitosan and chitosan quaternary ammonium salt is 1: 10, and its Zeta potential is+26.17mV that its electromicroscopic photograph as shown in figure 12.
Embodiment 7
Preparation method is with 4, and just the mass ratio of chitosan and chitosan quaternary ammonium salt gross mass and sodium glycerophosphate is 1: 1, and its Zeta potential is+21.32mV that its electromicroscopic photograph as shown in figure 13.
Preparation method is with 4, and just the mass ratio of chitosan and chitosan quaternary ammonium salt gross mass and sodium glycerophosphate is 1: 10, and its Zeta potential is+19.18mV that its electromicroscopic photograph as shown in figure 14.
Embodiment 9
Preparation method is with 4, and just the quaternary ammonium-substituted degree of chitosan quaternary ammonium salt is 10%, and the Zeta potential of microspheres prepared is+9.23mV that its electromicroscopic photograph as shown in figure 15.
Preparation method is with 4, and just the quaternary ammonium-substituted degree of chitosan quaternary ammonium salt is 80%, and the Zeta potential of microspheres prepared is+28.24mV that its electromicroscopic photograph as shown in figure 16.
Embodiment 11
Preparation method is with 4, and just the amino mol ratio of cross-linking agent and chitosan and chitosan quaternary ammonium salt is 1: 10, and its Zeta potential is+24.32mV that its electromicroscopic photograph as shown in figure 17.
Embodiment 12
Preparation method is with 4, and just first step crosslinking temperature is 18 ℃, and crosslinking time is 0.5h, and the Zeta potential of microspheres prepared is+23.21mV that its electromicroscopic photograph as shown in figure 18.
Embodiment 13
Preparation method is with 4, and just first step crosslinking temperature is 30 ℃, and crosslinking time is 0.5h, and the Zeta potential of microspheres prepared is+24.33mV that its electromicroscopic photograph as shown in figure 19.
Embodiment 14
Preparation method is with 4, and just first step crosslinking temperature is 36 ℃, and crosslinking time is 0.5h, and the Zeta potential of microspheres prepared is+26.22mV that its electromicroscopic photograph as shown in figure 20.
Preparation method is with 4, and just the mass ratio of chitosan and chitosan quaternary ammonium salt is 1: 0.5, and first step crosslinking temperature is 40 ℃, and crosslinking time is 0.5h, and the Zeta potential of microspheres prepared is+20.34mV that its electromicroscopic photograph as shown in figure 21.
Embodiment 16
Preparation method is with 9, and just the mass ratio of chitosan and chitosan quaternary ammonium salt is 1: 2, and crosslinking temperature was 38 ℃ during the first step was crosslinked, and first step crosslinking time is 2h, and the Zeta potential of microspheres prepared is+20.10mV that its electromicroscopic photograph as shown in figure 22.
Embodiment 17
Preparation method is with 4, and just the second step crosslinking temperature is 18 ℃, and the second step crosslinking time is 0.5h, and the Zeta potential of microspheres prepared is+18.31mV that its electromicroscopic photograph as shown in figure 23.
Embodiment 18
Preparation method is with 4, and just the second step crosslinking temperature is 45 ℃, and the second step crosslinking time is 0.5h, and the Zeta potential of microspheres prepared is+24.13mV that its electromicroscopic photograph as shown in figure 24.
Embodiment 19
Preparation method is with 4, and just the second step crosslinking temperature is 48 ℃, and the second step crosslinking time is 0.5h, and the Zeta potential of microspheres prepared is+26.64mV that its electromicroscopic photograph as shown in figure 25.
Preparation method is with 4, and just the second step crosslinking temperature is 60 ℃, and the second step crosslinking time is 0.5h, and the Zeta potential of microspheres prepared is+24.53mV that its electromicroscopic photograph as shown in figure 26.
Effect embodiment 1
With the pharmaceutical carrier of preparation among the preparation embodiment 4, carry out the mouse stomach experiment and further investigate the adhesion characteristics of carrier at stomach.Mice is divided into 8 groups before the experiment, every group of 8 mices, and water is can't help in fasting in advance 12 hours.Every mouse stomach amount is 400 μ L (3.6mg/mL), respectively at time period 0h, 1h, 3h, 4h, 6h, 8h, 12h, 24h takes out the stomach of every group of mice, rinse well with PBS=7.4 (0.1mol/mL), and the gastric tissue that 2 mices are arranged in every group is through solidifying, make tissue slice after the steps such as desaccharide, pharmaceutical carrier is carried out qualitative observation in the adhesiveness of stomach, to its adhesion situation of observing carrier directly perceived at stomach, find that by fluoroscopic examination carrier can have fine adhesiving effect at the gastric mucosa place, at the gastric mucosa place a tangible adherent zone is arranged, this will help the release of stomach targeted drug.The gastric tissue of every group of remaining 6 mice, rinse well, after corresponding enzymic digestion, 3000rpm is centrifugal, with microplate reader the stomach adhesiveness of carrier is carried out qualitative detection after PBS=7.4 (0.1mol/mL) suspends again, the result can keep certain adhesion rate as shown in figure 28 in 20 hours after carrier is entering stomach after the mouse stomach experiment, the result illustrates that the microspheres prepared carrier can realize the effect of the target slow-release and the controlled release of stomach medicine for a long time as shown in figure 27.
All the other the 19 groups microsphere supported stomach adhesiving effects that carry out equally that prepare the embodiment gained are tested, found that its adhesiving effect is similar to embodiment 4 gained results in the rate of release of stomach with medicine, can both realize the effect of the target slow-release and the controlled release of stomach medicine for a long time, it is feasible that explanation prepares microsphere supported method by this patent, and the slow release effect of the adhesion characteristics of microsphere and medicine repeatability is good.
Claims (10)
1. a stomach target medicine carrier is characterized in that, described pharmaceutical carrier raw material comprises:
The pastille emulsion that contains chitosan, chitosan quaternary ammonium salt, sodium glycerophosphate; And
Above-mentioned emulsion is cross-linked into the cross-linking agent of microsphere;
Wherein, the mass ratio of described chitosan and chitosan quaternary ammonium salt is 1:0.1～10, and the gross mass of chitosan and chitosan quaternary ammonium salt and the mass ratio of sodium glycerophosphate are 1: 1～10;
Wherein, the mol ratio of the amino of the aldehyde radical of described cross-linking agent or epoxy radicals and chitosan and chitosan quaternary ammonium salt is 1:1～10;
Wherein, the method for preparing described stomach target medicine carrier may further comprise the steps:
1) preparation of pastille emulsion: as water W, make the pastille emulsion with medicine and the oil phase that contains emulsifying agent with the aqueous solution of chitosan, chitosan quaternary ammonium salt and sodium glycerophosphate;
2) pastille emulsion in the step 1) is heated up, stir, it is tentatively crosslinked that its chitosan quaternary ammonium salt that contains and sodium glycerophosphate are taken place, obtain the gel micro-ball suspension, heat up and the adding cross-linking agent, take place for the second time crosslinked, gel micro-ball is solidified, and the washing drying obtains the stomach target medicine carrier.
2. stomach target medicine carrier according to claim 1 is characterized in that, the quaternized substitution value of described chitosan quaternary ammonium salt is 10%～80%.
3. stomach target medicine carrier according to claim 1 and 2 is characterized in that, the mass ratio of described chitosan and chitosan quaternary ammonium salt is 1:0.5～2.
4. stomach target medicine carrier according to claim 1 is characterized in that, described cross-linking agent is glutaraldehyde, genipin or epoxychloropropane.
5. a method for preparing the stomach target medicine carrier is characterized in that, said method comprising the steps of:
1) preparation of pastille emulsion: as water W, make the pastille emulsion with medicine and the oil phase that contains emulsifying agent with the aqueous solution of chitosan, chitosan quaternary ammonium salt and sodium glycerophosphate;
2) pastille emulsion in the step 1) is heated up, stir, it is tentatively crosslinked that its chitosan quaternary ammonium salt that contains and sodium glycerophosphate are taken place, obtain the gel micro-ball suspension, heat up and the adding cross-linking agent, take place for the second time crosslinked, gel micro-ball is solidified, and the washing drying obtains the stomach target medicine carrier;
Wherein, the mass ratio of chitosan, chitosan quaternary ammonium salt is 1:0.1～10 in the described step 1); The gross mass of described chitosan and chitosan quaternary ammonium salt and the mass ratio of sodium glycerophosphate are 1: 1～10; Described step 2) mol ratio of the amino of the aldehyde radical of cross-linking agent or epoxy radicals and chitosan and chitosan quaternary ammonium salt is 1:1～10 in.
6. according to the described method for preparing the stomach target medicine carrier of claim 5, it is characterized in that the quaternized substitution value of chitosan quaternary ammonium salt is 10%～80% in the described step 1).
7. according to the described method for preparing the stomach target medicine carrier of claim 5, it is characterized in that, described step 2) preliminary crosslinked crosslinking temperature is that 18～60 ℃, crosslinking time are 0.5～5h in, the back crosslinked cross-linking agent second time that heats up is glutaraldehyde, genipin or epoxychloropropane, crosslinked temperature is 18～60 ℃, crosslinking time is 0.5～5h, and the stir speed (S.S.) number is 150～700rpm when crosslinked.
8. according to the described method for preparing the stomach target medicine carrier of claim 7, it is characterized in that described step 2) preliminary crosslinked crosslinking temperature is 30 ℃～40 ℃, crosslinking temperature is 45 ℃～60 ℃ for the second time.
9. the described according to Claim 8 method for preparing the stomach target medicine carrier is characterized in that described step 2) preliminary crosslinked crosslinking temperature is 36 ℃～38 ℃, crosslinking temperature is 48 ℃～50 ℃ for the second time.
10. according to the described method for preparing the stomach target medicine carrier of claim 5, it is characterized in that, emulsifying agent is selected from polymer, polyoxyethylene hydrogenated Oleum Ricini, sorbitan trioleate, sorbitan monooleate, anhydrous sorbitol tristearate or the oleophylic-hydrophilic block copolymers of sorbitan sesquioleate, glycerin ether in the described step 1), and the concentration of emulsifying agent is 0.5～10wt% in the oil phase.
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