CN101940554A - Multi-core adhesive microspheres for loading water soluble low molecular medicament and preparation method thereof - Google Patents
Multi-core adhesive microspheres for loading water soluble low molecular medicament and preparation method thereof Download PDFInfo
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Abstract
The invention discloses multi-core adhesive microspheres capable of loading a water soluble low molecular medicament. The microspheres are ionic cross-linked chitosan/gelatin microspheres, wherein acrylic resin microspheres for wrapping and controlling the releasing of the water soluble low molecular medicament are dispersed in the microspheres. A preparation method comprises the following steps of: dispersing or dissolving the medicament into solution of acrylic resin-containing organic solvent; preparing medicament-loading microsphere cores by an emulsification solvent volatilization method; dispersing the cores in the solution of chitosan and gelatin; preparing W/O type mixture from the mixture and oily ingredients; solidifying the gelatin at a low temperature and separating the microspheres from the oil phase; and finally performing cross linking with ionic cross-linking aqueous solution. The chitosan medicament-loading microspheres have the advantages of controllable particle size distribution, good release control effect of water soluble medicament, adjustable releasing rate, high biological adhesion, simple preparation method, and mild condition.
Description
Technical field
The present invention relates to a kind of multinuclear core that can be used for load soluble small molecular medicine and adhere to microsphere and preparation method thereof, belong to field of pharmaceutical preparations.
Background of invention
The Entogastric lingering preparation be a class can prolong drug at gastric transit time and improve the preparation of medicine at the local concentration of gastric mucosa.The Entogastric lingering preparation is for absorbing under one's belt or be a kind of good means of administration at the medicine that gastric plays local action, the antibacterials of using as ulcer that anti-helicobacter pylori is caused etc.The stomach adhesion preparation is considered to a kind of drug-supplying system of gastric retention preferably in recent years, is subjected to extensive studies.
Chitosan is a kind of copolymer that is obtained by de-acetyl chitin, has excellent biological compatibility.Chitosan is owing to have a large amount of amino in the molecular structure, and ionizing makes chitosan have positive electricity under acid resistance condition, can produce electrostatic interaction with electronegative rete malpighii and make chitosan and have good mucosa-adherent.Chitosan adhesion microsphere often is used to wrap up antibacterials in recent years and makes stomach adhesion drug-supplying system, reaches the purpose of targeted therapy helicobacter pylori.
Because chitosan dissolves in acid solution, so that the chitosan microball that is prepared from as host material bag medicine carrying thing with chitosan must carry out is crosslinked to keep its integrity in gastric acid, the cross-linking method of main use has ionic cross-linking and chemical crosslink technique.Simple and the mild condition of ionic cross-linking preparation, the microsphere adhesiveness of preparation is good.Since ionomer be reversible physical crosslinking and strength a little less than, amino Ionized effect in the sour environment can make the violent swelling of microsphere, the space of its gel can reach 5-100nm, is far longer than most small-molecule drug.Although this ionomer chitosan microball can have good controlled release properties for the medicine of biomacromolecule and some poorly water-solubles, but it is difficult to the release of control soluble small molecular medicine in sour environment, and many antibiotic commonly used exactly be water solublity preferably small-molecule drug (as the ampicillin, tetracyclines etc.), this has just limited the application of ionomer chitosan microball in the stomach adhesion preparation.RadiHejazi and Mansoor Amiji (Int.J.Pharm.2002.235,87-94) reported that a kind of bag for preparing with the method for ionomer carries the chitosan microball of tetracycline, its environment Chinese medicine in pH1.2 and 2.0 discharges fully at 5min, rate of release is too fast, may cause the gastric retention character of microsphere to lose meaning.Therefore, though the chitosan microball of this ionomer itself has good sticking property,, cause the drug level in the gastric mucosa to be difficult to keep because its bag medicine carrying thing discharges rapidly.
Chemical crosslinking is a kind of covalent cross-linking method, and cross-linking agent commonly used is the twain-aldehyde compound material, and the chitosan microball of its preparation has netted closely gel structure, for the soluble small molecular medicine good controlled-release function can be arranged.But there is toxic and side effects in vivo in the aldehyde radical cross-linking agent, and this has also just limited its application on biomedicine to a certain extent.
In addition, the degree of freedom of a large amount of strands that studies show that chitosan microball with and surface amino groups content how much be its adhering principal element of decision, because covalent cross-linking has limited the degree of freedom of chitosan molecule and greatly reduced the free ammonia base unit weight of chitosan microball, so covalent cross-linking can bring the problem of chitosan sugar microsphere adhesiveness reduction.Except that chemical crosslinking; the some other method that can improve chitosan microball to the release behavior of soluble small molecular medicine; comprise reacetylation and, also can its adhesiveness be descended because of reducing chitosan microball surface free amine group content at chitosan microball outer wrapping other materials.
Acrylic resin is a widely used macromolecular material in the pharmaceuticals industry, is meant the medicinal acrylic resin polymer of a big class.By selecting different resin structures, different prescription, production technology and solvent composition for use, can synthesize the acrylic resin of dissimilar, different performance and different purposes.Insoluble type of water and enteric solubility acrylic resin can be used as the release of slow-release material better controlled soluble small molecular medicine in sour environment, but because it does not have sticking property, these two kinds of materials only are often used as sustained-release matrix sheet material and enteric-coating material, and do not see the report of using it for the stomach retention sustained-release microsphere.
Summary of the invention
Chitosan adheres to the problems referred to above that microsphere exists in the prior art in order to solve, the inventor introduces chitosan microball by creationary discovering with acrylic resin, can not only improve the adhesion property of chitosan microball, and can also further control the soluble small molecular drug release, enlarged the application of chitosan microball in Gastroretentive formulations.
The purpose of this invention is to provide a kind of multinuclear core that is used for load soluble small molecular medicine and adhere to microsphere, its version is that the acrylic resin controlled release nuclear core that will be loaded with medicine is embedded among chitosan/gelatine microsphere, carry with releasing effect for the bag of soluble small molecular medicine so better, and the greatly reservation of degree of the adhesiveness of glycan substrate.
The multinuclear core that is used for load soluble small molecular medicine that the invention provides adheres to microsphere, it is characterized in that comprising the microsphere substrate of the chitosan/gelatin with ionomer, and is scattered in the acrylic resin nuclear core that is used for carrying medicament wherein.
Soluble small molecular medicine described in the present invention, dissolubility is greater than 0.01% (W/V) in the water when being meant 20 ℃, and relative molecular weight is less than 5000 daltonian medicines.
The multinuclear core that is used for load soluble small molecular medicine of the present invention adheres to microsphere, it is characterized in that comprising the microsphere substrate of chitosan/gelatin with ionomer, and the acrylic resin that is used for load soluble small molecular medicine that is scattered in is wherein examined core, wherein based on the weight portion meter, 1～12 part of soluble small molecular medicine, 1～3 part of acrylic resin, 2～50 parts of chitosans, 2～50 parts in gelatin; Further preferably, 1～8 part of soluble small molecular medicine, 1～2 part of acrylic resin, 9～24 parts of chitosans, 9～24 parts in gelatin.
As exemplarily, soluble small molecular medicine of the present invention is selected from:
(1) water solublity local action treatment gastric ulcer, gastritis medicine are as Ecabet Sodium, omeprazole, La Beila azoles, pantoprazole, misoprostol, grace prostatitis alcohol etc.;
(2) be easy to absorb under one's belt weak acidic drug, as ferulic acid, diclofenac sodium, indomethacin, aspirin, captopril, oxacillin sodium, furosemide, etacrynic acid, ticrynafen, Nateglinide, clavulanate potassium etc.;
(3) water soluble antibiotics and other antibacterials are as tetracycline, amoxicillin, ampicillin, metronidazole, tinidazole, levofloxacin, Gatifloxacin, furazolidone, gentamycin, rifamycin, tetracycline, erythromycin, clarithromycin, azithromycin, berberine hydrochloride etc.;
As just exemplary illustration, and unrestricted protection scope of the present invention, the present invention preferably prepares the multinuclear core with berberine hydrochloride and adheres to microsphere.
Microsphere substrate with chitosan/gelatin of ionomer of the present invention is by the mixture of chitosan and gelatin and the formed ionomer attitude of sodium tripolyphosphate structure.
The acrylic resin nuclear core that is used for carrying medicament of the present invention, preferably the medicine carrying nuclear core microsphere that is prepared from by enteric solubility or water-insoluble acrylic resin.Described enteric solubility or water-insoluble acrylic resin mainly comprise acrylic resin II number, III number,
Wait one or more mixture.
Preferably, the multinuclear core that is used for load soluble small molecular medicine of the present invention adheres to microsphere, weight ratio between the chitosan/gelatine microsphere host material of the acrylic resin of carrying medicament nuclear core and ionomer was generally 1: 2～1: 10, further preferably 1: 3～1: 6
Another object of the present invention has provided the method that a kind of preparation is used for the multinuclear core adhesion microsphere of load soluble small molecular medicine, may further comprise the steps:
(1) forms the acrylic resin microsphere that contains the water solublity small-molecule drug;
(2) acid solution with acrylic resin microsphere and chitosan/gelatin forms the water-in-oil emulsion system;
(3) the water-in-oil emulsion system that is obtained is under agitation lowered the temperature, and microsphere is solidified, and oil phase is separated with the microsphere that solidifies;
(4) microsphere that separation is obtained and sodium tripolyphosphate carry out ionomer, obtain being used for the multinuclear core adhesion microsphere of load water soluble drug.
The present invention further provides the method for preparing the multinuclear core adhesion microsphere that is used for load soluble small molecular medicine particularly, may further comprise the steps:
(1) soluble small molecular medicine and antiplastering aid adding are contained in the organic solvent solution of acrylic resin, gained solution is joined oiliness to be become in the oil phase be grouped into and fully stirs to form Emulsion, under agitation make the organic solvent volatilization in the inner phase complete then, the separation oil phase obtains acrylic acid nuclear core microsphere and washs with the volatile nonpolar organic solvent;
(2) the acrylic resin nuclear core microsphere that forms is scattered in 30～50 ℃ the acid solution of chitosan/gelatin, again this mixture solution is joined under 30～50 ℃ condition by in emulsifying agent and the oil phase that oiliness becomes to be grouped into and stir, form the water-in-oil emulsion system;
(3) the water-in-oil emulsion system that forms under agitation is cooled to below 10 ℃, preferred-10～4 ℃,, separates oil phase and the microsphere that solidifies so that microsphere solidifies;
(4) microsphere of gained is joined in the cold sodium tripolyphosphate crosslinker solution carry out ionomer, obtain the described multinuclear core that is used for the load water soluble drug and adhere to microsphere, microsphere is isolated after scouring, dehydration and dry from ionomer solution.
Acrylic resin in the step (1) is enteric solubility or water-insoluble acrylic resin, comprise acrylic resin II number, III number,
Deng and its one or more mixture.
According to the material difference of selected acrylic resin, organic solvent used in the step (1) can be selected ethanol, acetone, and perhaps the mixed solvent of the two is made into the organic solvent solution that contains acrylic resin 0.5-3% (w/v).If the dissolving water that adds 5～10% (v/v) in bad order is to increase dissolving.If select for use acetone as solvent, the oil phase of the continuous phase that is used as should be saturated with acetone in advance.
Antiplastering aid described in the step (1) selects generally that pharmaceutically the acceptable dissolubility is little, contact angle is big, and the pressed powder adjuvant that granule is trickle is as aluminium stearate, magnesium stearate, calcium hydroxide, zinc hydroxide etc., preferred aluminium stearate and magnesium stearate, solubility is 0.1-3% (w/v).
The oiliness composition that constitutes oil phase in the step (1) is general selects pharmaceutically acceptable alkanes Hydrocarbon, as one or more mixture of liquid paraffin, olive oil, sunflower seed wet goods.
Volatile nonpolar solvents described in the step (1) can be selected the miscible volatile nonpolar organic solvent of any and used oiliness composition in theory for use, comprise normal hexane, cyclohexane extraction, heptane, petroleum ether, ether, chloroform, carbon tetrachloride, toluene, dimethylbenzene etc., preferred cyclohexane extraction and petroleum ether.
The acid solution of chitosan/gelatin in the step (2) is as solvent and be dissolved with the chitosan of 0.5-10% (w/v) and the mixture solution of the gelatin of 0.5-10% (w/v) with acid solutions such as acetic acid or hydrochloric acid.
The oiliness composition that constitutes oil phase in the step (2) is general selects pharmaceutically acceptable alkanes Hydrocarbon, as one or more mixture of liquid paraffin, olive oil, sunflower seed wet goods; Described emulsifying agent can be selected the non-ionic surface active agent of HLB value at 4-7, particularly as Span series and Tween series and mutual mixture of arranging in pairs or groups thereof etc. such as Span60, Span65, Span80, Span85, Tween20, Tween40, Tween60, Tween80.
Described water-in-oil emulsion system, be that chitosan/gelatin acid solution of thinking the acrylic resin microsphere that is dispersed with 0.5-5% (w/v) is a decentralized photo, with oiliness become be grouped into and to contain HLB value be that the oil mixture of the non-ionic surface active agent of 4-7 is its continuous phase, the water-in-oil type mixture of composition.Described water-in-oil emulsion system, its decentralized photo be 1 to volume ratio continuously: 20-1: 5.
The preferred use cryosel of the cooling of step (3) is bathed cooling.
The temperature of the cold crosslinker solution in the step (4) is-10～10 ℃, preferred-5～4 ℃.
The preferably sodium tripolyphosphate solution of 0.5～2% (w/v) of the cold crosslinker solution in the step (4).
Preparation method of the present invention, further preferred embodiment is as follows:
(1) acrylic resin is dissolved in organic solvents such as acetone, ethanol, be made into the organic solvent solution that contains acrylic resin 0.5-3% (w/v), water soluble drug and antiplastering aid are dispersed in this solution, this mixture is joined fully stirring in the oil phase, form Emulsion, under agitation that the organic solvent volatile matter of introversion is complete then, separate oil phase and obtain acrylic acid microsphere nuclear core and use the volatile nonpolar organic solvent washing.
(2) under 30-40 ℃ temperature, chitosan and gelatin are dissolved in the viscosity solution that forms the gelatin of the chitosan and 0.5～10% (w/v) that contains 0.5～10% (w/v) in the acid solutions such as acetic acid or hydrochloric acid, the acrylic resin for preparing is dispersed in this viscosity solution, and this mixture joined in the oil phase that contains emulsifying agent under 30-40 ℃ condition stir, form the water-in-oil emulsion system.The weight ratio of acrylic resin nuclear core microsphere and chitosan/gelatin substrate material is 1: 3～1: 6.
(3) the water-in-oil type mixture of above-mentioned formation is under agitation bathed to reduce the temperature to below 4 ℃ by cryosel gelatin is solidified, oil phase is separated with the microsphere that solidifies.The microsphere that above-mentioned separation is obtained joins in-5～4 ℃ the sodium tripolyphosphate solution of 0.5～2% (w/v) and carries out ionomer, obtain the said multinuclear core that can be used for the load water soluble drug and adhere to microsphere, with wash successively with distilled water and normal hexane after the ionomer solution separating, dehydration is also dry.
Said sodium tripolyphosphate solution solubility is more excellent at 0.5-2wt% in the step (3), and crosslinking time is can reach effect preferably in 3 minutes, and prolongs crosslinking time and may reduce envelop rate because of the seepage that increases medicine.
Studies show that the particle diameter of the acrylic resin nuclear core in the multinuclear core adhesion microsphere of the present invention can influence the rate of release of small-molecule drug.Control by regulating rotating speed, the solubility of acrylic resin and the amount of antiplastering aid, under the prerequisite that guarantees nuclear core microsphere form, mixing speed generally can be controlled in 600-1200 rev/min, the concentration of acrylic resin can be regulated between 0.5-3% (w/v), and the solubility of antiplastering aid also can be regulated between 0.1-3% (w/v).
Further experiment shows, the concentration that improves rotating speed in above-mentioned scope, reduce the concentration of acrylic resin or improve antiplastering aid all can improve the rate of releasing drug of small-molecule drug.
The particle diameter of chitosan/gelatine microsphere can be controlled by the amount of rotating speed and emulsifying agent, and mixing speed generally can be controlled in 400-900 rev/min, and lower emulsifier concentration can reach good balling-up effect, and is more excellent with 0.1-0.5% (w/v).
The mass ratio of acrylic resin nuclear core microsphere and chitosan/gelatin substrate material was generally 1: 2～1: 10, be preferably 1: 3～1: 6, the amount of acrylic resin nuclear core can make drug loading on the low side very little, and amount too much can make the microsphere form that is become relatively poor and coat not exclusively.
The advantage that multinuclear core provided by the invention adheres to microsphere is:
1. earlier medicine is wrapped in the acrylic resin nuclear core microsphere by emulsion-solvent evaporation method in the preparation process of the present invention, and then this nuclear core microsphere wrapped in the chitosan microball, can be reduced in the seepage of water soluble drug when the preparation chitosan microball greatly, improve drug loading.
2. enteric solubility that center core microsphere of the present invention is used or water-insoluble acrylic resin be insoluble and swelling seldom in the environment of gastric acid, is good slow-release material, so the medicine that carries for bag can obtain good slow release effect under sour environment.Simultaneously, parameters such as rotating speed, solubility can be easy to regulate release rate of drugs, thereby make the scope of application broad of this system when examining the core microsphere by regulating the preparation acrylic resin, can be used for the water soluble drug of different solubility.
3. chitosan/the gelatine microsphere of preparation of the present invention carries out ionomer to it again by the method molding of condensation, and mild condition is simple to operate, and it is good to make the microsphere form, and particle diameter is controlled.The formation of microsphere is by cooling, and the dispersed phase drop in the emulsifying systems is solidified direct balling, and the acrylic resin of suspendible nuclear core can effectivelyly be wrapped among chitosan/gelatine microsphere substrate in the decentralized photo.
4. the multinuclear core of the present invention preparation adheres to microsphere, because the ratedeterming step that be released to its release of medicine from nuclear core microsphere, so regardless of the crosslink density of chitosan/gelatin skeleton, microsphere all can well be controlled the release of medicine.The present invention adopts gentle ionomer; the adverse effect of having avoided steps such as chemical crosslinking, reacetylation and coating other materials to bring; simultaneously because ionomer does not relate to chemical reaction; it only is ionic bond effect between chitosan or gelatin and the anion and reversible; so the freedom of chitosan molecule chain with and surface amino groups content can keep significantly, make it have good sticking property.
Description of drawings
Fig. 1 represents that the multinuclear core adheres to microsphere surface form scanning electron microscope (SEM) photo.
Fig. 2 represents that the multinuclear core adheres to microsphere transverse section stereoscan photograph
Fig. 3 represents the medicine accumulative total releasing curve diagram of medicine carrying microballoons in simulated gastric fluid.
The specific embodiment
Embodiment 1 prescription is to the influence of rate of release
Prescription 1
200mg berberine hydrochloride and 200mg aluminium stearate are dispersed in acrylic resin II number of 10ml 1% the acetone soln that contains 5% water, this mixture is joined in the 80ml acetone saturated liquid paraffin speed with 900rpm to be stirred and forms oily oil-in Emulsion, stir 5 hours under the room temperature with interior complete to the solvent evaporates thing, the centrifugal acrylic resin that obtains is examined the core microsphere and is washed three times to remove residual liquid paraffin, drying with normal hexane.
The acrylic resin microsphere of the above-mentioned preparation of 200mg joined in 40 ℃ 2% the acetum that contains 3% (w/v) chitosan and 3% (w/v) gelatin, stir and make its homodisperse and standing and defoaming, as water; With 80ml liquid paraffin and 0.16g Span80 mixing as oil phase; Water and oil phase all remain on 40 ℃, and water is joined in the oil phase, and 600 rev/mins are stirred 20min and obtain emulsion.Under agitation by the cryosel bath the above-mentioned emulsion temperature that obtains being dropped to below 4 ℃ solidifies gelatin, leaves standstill and treat that the microsphere post precipitation separates oil phase with microsphere.The microsphere that separation is obtained joins in 4 ℃ 0.5% the sodium tripolyphosphate solution and carries out ionomer, 300 rev/mins are stirred behind the 3min microsphere and ionomer solution separating, the microsphere that obtains washs three times with 50ml distilled water and 50ml normal hexane successively, and with 30ml acetone dehydration, vacuum drying 12h obtains the finished product microsphere under the room temperature.Resulting multinuclear core adheres to microsphere surface form scanning electron microscope (SEM) photo as shown in Figure 1, its transverse section stereoscan photograph as shown in Figure 2, the accumulative total release profiles of simulated gastric fluid Chinese medicine is as shown in Figure 3.
Prescription 2
400mg berberine hydrochloride and 200mg aluminium stearate are dispersed in acrylic resin II number of 10ml1% the acetone soln that contains 5% water, this mixture is joined in the 80ml acetone saturated liquid paraffin speed with 900rpm to be stirred and forms oily oil-in Emulsion, stir 5 hours under the room temperature with interior complete to the solvent evaporates thing, the centrifugal acrylic resin that obtains is examined the core microsphere and is washed three times to remove residual liquid paraffin, drying with normal hexane.
The acrylic resin microsphere of the above-mentioned preparation of 200mg joined in 40 ℃ 2% the acetum that contains 3% (w/v) chitosan and 3% (w/v) gelatin, stir and make its homodisperse and standing and defoaming, as water; With 80ml liquid paraffin and 0.16gSpan80 mixing as oil phase; Water and oil phase all remain on 40 ℃, and water is joined in the oil phase, and 600 change a part clock stirring 20min obtains emulsion.Under agitation by the cryosel bath the above-mentioned emulsion temperature that obtains being dropped to below 4 ℃ solidifies gelatin, leaves standstill and treat that the microsphere post precipitation separates oil phase with microsphere.The microsphere that separation is obtained joins in 4 ℃ 0.5% the sodium tripolyphosphate solution and carries out ionomer, 300 rev/mins are stirred behind the 3min microsphere and ionomer solution separating, the microsphere that obtains washs three times with 50ml distilled water and 50ml normal hexane successively, and with 30ml acetone dehydration, vacuum drying 12h obtains the finished product microsphere under the room temperature.The accumulative total release profiles of simulated gastric fluid Chinese medicine as shown in Figure 3.
Comparative example 1
Non-nuclear core ionomer microsphere: the 200mg berberine hydrochloride is distributed in 40 ℃ 2% the acetum that contains 3% (w/v) chitosan and 3% (w/v) gelatin, stirs and make its homodisperse and standing and defoaming, as water; With 80ml liquid paraffin and 0.16gSpan80 mixing as oil phase; Water and oil phase all remain on 40 ℃, and water is joined in the oil phase, and 600 change a part clock stirring 20min obtains emulsion.Under agitation by the cryosel bath the above-mentioned emulsion temperature that obtains being dropped to below 4 ℃ solidifies gelatin, leaves standstill and treat that the microsphere post precipitation separates oil phase with microsphere.The microsphere that separation is obtained joins in 4 ℃ 0.5% the sodium tripolyphosphate solution and carries out ionomer, 300 rev/mins are stirred behind the 3min microsphere and ionomer solution separating, the microsphere that obtains washs three times with 50ml distilled water and 50ml normal hexane successively, and with 30ml acetone dehydration, vacuum drying 12h obtains non-nuclear core ionomer microsphere under the room temperature.The accumulative total release profiles of simulated gastric fluid Chinese medicine as shown in Figure 3.
Comparative example 2
Non-nuclear core glutaraldehyde cross-linking microsphere: the 200mg berberine hydrochloride is distributed in 40 ℃ 2% the acetum that contains 3% (w/v) chitosan and 3% (w/v) gelatin, stirs and make its homodisperse and standing and defoaming, as water; With 80ml liquid paraffin and 0.16gSpan80 mixing as oil phase; Water and oil phase all remain on 40 ℃, and water is joined in the oil phase, and 600 rev/mins are stirred 20min and obtain emulsion.The toluene saturated solution of 5ml glutaraldehyde is added dropwise to above-mentioned emulsion, descended crosslinked 24 hours at 40 ℃.Leave standstill and treat that the microsphere post precipitation separates oil phase with microsphere, the microsphere that obtains washs three times with the 50ml normal hexane, and dewaters with 30ml acetone, and vacuum drying 12h obtains non-nuclear core glutaraldehyde cross-linking microsphere under the room temperature.The accumulative total release profiles of simulated gastric fluid Chinese medicine as shown in Figure 3.
The invention process effect: in-vitro simulated multinuclear core adheres to microsphere (embodiment 1, embodiment 2), non-nuclear core ionomer microsphere (comparative example 1) and non-nuclear core glutaraldehyde cross-linking microsphere (comparative example 2) in pH1.2 simulated gastric fluid Chinese medicine release conditions.Medicine lasting release under one's belt will help the elimination of helicobacter pylori.The slow release effect of multinuclear core adhesion microsphere Chinese medicine is much better than the microsphere with the crosslinked no acrylic resin nuclear core of method.The result is shown in curve among Fig. 3.As can be seen from the figure the multinuclear core adheres to microsphere and can realize good slow release effect to the soluble small molecular medicine, and by the medicine in the adjusting nuclear core microsphere and the ratio of acrylic resin, release rate of drugs can be regulated within a large range, and this scope has comprised the slow release effect that the microsphere of glutaraldehyde cross-linking can reach.And the non-nuclear core ionomer microsphere with same ionomer density, the medicine above 80% discharged in 2 hours, and the introducing of this explanation acrylic resin nuclear core is to the importance of control drug release.
Embodiment 2 multinuclear cores adhere to microsphere in the research of body adhesiveness
Experiment condition is: the Wistar rat fasting 12h of 200g-250g, anesthesia back is opened an osculum and is linked to each other with polyethylene tube respectively in distal esophagus and the nearly section of duodenum.Wash away with normal saline and to pour into 100 microspheres and 0.2ml water in the stomach behind the remaining content.After ten minutes, the simulated gastric fluid with the 1.5ml/min flow velocity in the stomach washes 1.5h.The microsphere number of removing from stomach after the record drip washing is calculated the delay percentage rate.
Choose prescription 2, comparative example 1 and comparative example 2 among the embodiment 1, investigate at the gastric mucosa retention rate at body, microgranule is high more at the gastric mucosa retention rate, and the microsphere adhesion property is good more, and the gastric mucosa drug level is high more.As table 1
Table 1. microsphere is retention rate under one's belt
Embodiment 3
100mg amoxicillin and 200mg magnesium stearate are dispersed in acrylic resin III number of 10ml1% the acetone soln that contains 5% water, this mixture is joined in the 80ml acetone saturated liquid paraffin speed with 900rpm to be stirred and forms oily oil-in Emulsion, stir 5 hours under the room temperature with interior complete to the solvent evaporates thing, centrifugal obtain acrylic resin nuclear core microsphere and with petroleum ether three times to remove residual liquid paraffin, drying.
The interior olefin(e) acid resin microsphere of the above-mentioned preparation of 75mg joined in 40 ℃ 2% the acetum that contains 3% (w/v) chitosan and 1.5% (w/v) gelatin, stir and make its homodisperse and standing and defoaming, as water; With 80ml liquid paraffin and 0.16gSpan85 mixing as oil phase; Water and oil phase all remain on 40 ℃, and water is joined in the oil phase, and 600 rev/mins are stirred 20min and obtain emulsion.Under agitation by the cryosel bath the above-mentioned emulsion temperature that obtains being dropped to below 4 ℃ solidifies gelatin, leaves standstill and treat that the microsphere post precipitation separates oil phase with microsphere.The microsphere that separation is obtained joins in 4 ℃ 2% the sodium tripolyphosphate solution and carries out ionomer, 300 rev/mins are stirred behind the 3min microsphere and ionomer solution separating, the microsphere that obtains is used 50ml distilled water and 50ml petroleum ether three times successively, and with 30ml acetone dehydration, vacuum drying 12h obtains the finished product microsphere under the room temperature.
Embodiment 4
100mg ampicillin and 200mg magnesium stearate are dispersed in acrylic resin II number of 10ml1% the acetone soln that contains 5% water, this mixture is joined in the 80ml acetone saturated liquid paraffin speed with 900rpm to be stirred and forms oily oil-in Emulsion, stir 5 hours under the room temperature with interior complete to the solvent evaporates thing, centrifugal obtain acrylic resin nuclear core microsphere and with petroleum ether three times to remove residual liquid paraffin, drying.
The acrylic resin microsphere of the above-mentioned preparation of 200mg joined in 40 ℃ 2% the acetum that contains 3% (w/v) chitosan and 3% (w/v) gelatin, stir and make its homodisperse and standing and defoaming, as water; With 80ml liquid paraffin and 0.16gSpan80 mixing as oil phase; Water and oil phase all remain on 40 ℃, and water is joined in the oil phase, and 600 rev/mins are stirred 20min and obtain emulsion.Under agitation by the cryosel bath the above-mentioned emulsion temperature that obtains being dropped to below 4 ℃ solidifies gelatin, leaves standstill and treat that the microsphere post precipitation separates oil phase with microsphere.The microsphere that separation is obtained joins in 4 ℃ 0.5% the sodium tripolyphosphate solution and carries out ionomer, 300 rev/mins are stirred behind the 3min microsphere and ionomer solution separating, the microsphere that obtains is used 50ml distilled water and 50ml petroleum ether three times successively, and with 30ml acetone dehydration, vacuum drying 12h obtains the finished product microsphere under the room temperature.
Embodiment 5
100mg tetracycline and 50mg magnesium stearate are dispersed in 10ml1%'s
The alcoholic solution that contains 5% water in, this mixture is joined in the 80ml liquid paraffin speed with 900rpm to be stirred and forms oily oil-in Emulsion, stir 5 hours under the room temperature with interior complete to the solvent evaporates thing, the centrifugal acrylic resin that obtains is examined the core microsphere and is washed three times to remove residual liquid paraffin, drying with normal hexane.
The acrylic resin microsphere of the above-mentioned preparation of 200mg joined in 40 ℃ 2% the acetum that contains 3% (w/v) chitosan and 3% (w/v) gelatin, stir and make its homodisperse and standing and defoaming, as water; With 80ml liquid paraffin and 0.24gSpan85 mixing as oil phase; Water and oil phase all remain on 40 ℃, and water is joined in the oil phase, and 600 rev/mins are stirred 20min and obtain emulsion.Under agitation by the cryosel bath the above-mentioned emulsion temperature that obtains being dropped to below 4 ℃ solidifies gelatin, leaves standstill and treat that the microsphere post precipitation separates oil phase with microsphere.The microsphere that separation is obtained joins in 4 ℃ 0.5% the sodium tripolyphosphate solution and carries out ionomer, 300 rev/mins are stirred behind the 3min microsphere and ionomer solution separating, the microsphere that obtains washs three times with 50ml distilled water and 50ml normal hexane successively, and with 30ml acetone dehydration, vacuum drying 12h obtains the finished product microsphere under the room temperature.
Claims (10)
1. a multinuclear core that can be used for load soluble small molecular medicine adheres to microsphere, it is characterized in that including the microsphere substrate of the chitosan/gelatin of ionomer, and is scattered in the acrylic resin nuclear core that is used for carrying medicament in this microsphere substrate.
2. multinuclear core according to claim 1 adheres to microsphere, and the microsphere substrate that it is characterized in that the chitosan/gelatin of described ionomer mainly is by the mixture of chitosan and gelatin and the formed ionomer attitude of sodium tripolyphosphate (TPP) structure.
3. the acrylic resin nuclear core that is used for carrying medicament according to claim 1 is characterized in that by enteric solubility or water-insoluble acrylic resin, comprise acrylic resin II number, III number,
Wait one or more acrylic resin that is mixed with the medicine carrying that forms nuclear core microspheres.
4. adhere to microsphere according to each described multinuclear core of claim 1 to 2, it is characterized in that the weight ratio that the described acrylic resin that is used for carrying medicament is examined the chitosan/gelatine microsphere host material of core and ionomer was generally 1: 3～1: 6.
5. one kind prepares the method that each described multinuclear core of claim 1 to 4 adheres to microsphere, it is characterized in that may further comprise the steps:
(1) soluble small molecular medicine and antiplastering aid adding are contained in the organic solvent solution of acrylic resin, gained solution is joined oiliness to be become in the oil phase be grouped into and fully stirs to form Emulsion, under agitation make the organic solvent volatilization in the inner phase complete then, separate oil phase and obtain acrylic acid nuclear core microsphere and use the volatile nonpolar organic solvent washing;
(2) the acrylic resin nuclear core microsphere that forms is scattered in 30～50 ℃ the acid solution of chitosan/gelatin, again this mixture solution is joined under 30～50 ℃ condition by in emulsifying agent and the oil phase that oiliness becomes to be grouped into and stir, form the water-in-oil emulsion system;
(3) the water-in-oil emulsion system that forms under agitation is cooled to below 10 ℃, preferred-10～4 ℃,, separates oil phase and the microsphere that solidifies so that microsphere solidifies;
(4) microsphere of gained is joined in the cold sodium tripolyphosphate crosslinker solution carry out ionomer, obtain the described multinuclear core that is used for the load water soluble drug and adhere to microsphere, at last microsphere is isolated after scouring, dehydration and dry from ionomer solution.
6. preparation method according to claim 5 is characterized in that described oiliness composition is general to select pharmaceutically acceptable alkanes Hydrocarbon, as one or more mixture of liquid paraffin, olive oil, sunflower seed wet goods.
7. preparation method according to claim 6, the acid solution that it is characterized in that described chitosan/gelatin for acid solutions such as acetic acid or hydrochloric acid as solvent, be dissolved with the mixture solution of the gelatin of the chitosan of 0.5-10% (w/v) and 0.5-10% (w/v).
8. preparation method according to claim 7, it is characterized in that described water-in-oil emulsion system, be that chitosan/gelatin acid solution of thinking the acrylic resin microsphere that is dispersed with 0.5-5% (w/v) is a decentralized photo, with oiliness become be grouped into and to contain HLB value be that the oil mixture of the non-ionic surface active agent of 4-7 is its continuous phase, the water-in-oil type mixture of composition.
9. preparation method according to claim 8 is characterized in that described water-in-oil emulsion system, its decentralized photo be 1 to volume ratio continuously: 20-1: 5.
10. preparation method according to claim 9, it is characterized in that: after the described multinuclear core that obtains adheres to microsphere and crosslinker solution separates, wash successively with distilled water, volatile nonpolar organic solvent respectively, and with comprising ethanol, isopropyl alcohol, the dehydration of acetone volatile organic solvent, drying.
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