CN100484573C - Method for preparing floating-biological adhesion synergistic microparticle - Google Patents
Method for preparing floating-biological adhesion synergistic microparticle Download PDFInfo
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- CN100484573C CN100484573C CNB2005100468188A CN200510046818A CN100484573C CN 100484573 C CN100484573 C CN 100484573C CN B2005100468188 A CNB2005100468188 A CN B2005100468188A CN 200510046818 A CN200510046818 A CN 200510046818A CN 100484573 C CN100484573 C CN 100484573C
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- sodium alginate
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Abstract
The present invention relates to a preparation method of floatation-bioadhesion synergistic type microgranules. Said preparation method includes the following steps: firstly, utilizing drying system in the water to prepare ethyl cellulose floatation microspheres, then using sodium alginate to make coating in the emulsification system, finally the sodium alginate and ethyl cellulose microparticles are dispersed in chitosan solution to produce ion gelatification and form chitosan film so as to obtain the invented floatation-bioadhesion synergistic type microgranules.
Description
Technical field
The present invention relates to a kind of method for preparing floating in stomach-biological adhesion synergistic microparticle preparation, it adopts drying-emulsifying/internal gelatinizing coupled process in the water, and the raw material of preparation microgranule is to be widely used in biomaterial ethyl cellulose study of pharmacy and application, that have excellent biological compatibility, sodium alginate, chitosan.This floating-biological adhesion synergistic microparticle can be used for delivering water slightly soluble or the insoluble small-molecule drug of water that gastric plays a role, and also can be used for delivering many acidic drugs of stomach absorption and the medicine that absorbs with the upper digestive tract position at duodenum.Said preparation energy significant prolongation medicine improves bioavailability of medicament in the holdup time of gastric.
Background technology
Traditional oral slow (control) releases drug-supplying system, and its contained medicine of release and along with the wriggling of gastric emptying and intestinal, is experiencing the transition process in vivo after the administration in gastrointestinal tract.But, if the epimere of gastric or small intestinal (for example) only carried out or mainly carried out at a certain section in the absorption of medicine at the gastrointestinal specific part, so this controlled release drug induction system, holdup time is short (generally 1-2h) in gastric and small intestinal, thereby soak time is shorter relatively, bioavailability is low, is difficult to realize the therapeutic purposes of its expection.
The Entogastric lingering preparation is that class energy prolong drug is in the holdup time of gastric (generally greater than 4h), thereby prolong drug is transported at whole gastrointestinal, promote the absorption of medicine, improve new formulation [the document 1.Jaspreet K of bioavailability of medicament, Kaustubh T, Sanjay G Bioadhesive microspheres as a controlled drugdelivery system.Int.J.Pharm, 2003,255:13-32]; Said preparation can reduce administration frequency, makes things convenient for administration, provides a new way for solving low this problem of drug bioavailability.
The Entogastric lingering preparation mainly is divided into following several: float type, bioadhesion type and floating-biological adhesion synergistic type.Dosage form mainly contains tablet, capsule, microsphere etc.Wherein floating-biological adhesion synergistic type microsphere (microgranule) exists with a plurality of small units, specific surface area increases, and the bioadhesion area increases, and the subsection that is floating state is by probability distribution, increased buoyant chance, the significant prolongation medicine is transported the time at gastrointestinal.
Prepare at present the method for floating-biological adhesion synergistic type microsphere (microgranule) and the material of use [document 2. yellow quiet beautiful jades, Lu Jinfang. the external release and the adhesiveness thereof of metronidazole bioadhesion microsphere. Acta Pharmaceutica Sinica .2002,37 (3): 226-228; Document 3.Akiyama Y, Nagahara N, KashiharaT, et al.In vitro and in vivoevaluation of mucoadhesive microspheres prepared for the gastrointestinal tract usingpolyglycerol esters of fatty acids and a poly (acrylic acid) derivative.Pharm Res, 1995,12 (3): 397-405; Document 4.Umamaheswari RB, Jain S, Tripathi PK, Agrawal GP, Jain NK.Floating-bioadhesive microspheres containing acetohydroxamic acid for clearance ofHelicobacter pylori.Drug Delivery, 2002,9:223-231; Document 5.Lehr CM, Bbounstra JA, Tukker J, et al.Intestinal transit of bioadhesive microspheres in an situ loop in the rat-acomparative study with copolymers and blends and based on poly (acrylic acid) .JControl Release, 1990,13:51-62; Document 6.Yasunori M, Kanako O, Shigeru Y, et al.Invitro and in vivo evaluation of mucoadhesive microspheres consisting of dextranderivatives and cellulose acetate butyrate.Int.J.Pharm, 2003,258:21-29; Document 7.JianW, Yasuhiko T, Dianzhou B, et al.Evaluation of gastric mucoadhesive properties ofaminated gelatin microspheres.J Control Release, 2001,73:223-231] have: 1, decentralized microsphere (microgranule), with carbomer as bioadhesive material, it is dispersed in the ethyl cellulose organic solvent, and seasoning prepares ethyl cellulose bioadhesion microsphere in the employing oil.Because of carbomer swelling in water, can not adopt that seasoning prepares microsphere in the water, so required time is longer, temperature is higher; Carbomer content is big simultaneously, though can improve the bioadhesion performance, reduces the floating ability of preparation simultaneously.2, coating type microsphere (microgranule), with the microsphere for preparing, the external bioadhesive material is carried out coating or modification to its surface.Coating material commonly used has carbomer, hydroxypropyl cellulose, Eudragit E udragit S etc., these materials form gel layer at microsphere surface, but in the gastrointestinal tract transport process, meet the excessive sometimes water absorption and swelling of gastric juice, easy and microsphere comes off, thereby medicine is discharged too early, and adhesion property descend.Introduce cross-linking agent such as glutaraldehyde, though can control the excessive water absorption and swelling phenomenon of gel layer to a certain extent, cross-linking agent produces certain toxicity to body, reacts with medicine sometimes, has reduced drug effect.
Summary of the invention
The invention provides a kind of method for preparing floating in stomach-biological adhesion synergistic microparticle preparation.Its principle is: be that substrate prepares the floating microsphere of hydrophobicity with the ethyl cellulose earlier, coating sodium alginate, chitosan bioadhesive material then, by improving flotation property and the bioadhesion performance of preparation at gastric, the significant prolongation medicine improves bioavailability of medicament in the holdup time of gastric.
Technical scheme of the present invention is:
A kind of preparation method of floating in stomach-biological adhesion synergistic microparticle has following steps: 1) prepare the floating microsphere of ethyl cellulose with dry system in the water earlier; 2) in emulsification system, form calcium alginate-microparticles by using then with the sodium alginate coating; 3) at last sodium alginate-microparticles by using is dispersed in generation ionic gel formation chitosan film in the chitosan solution, makes the floating-biological adhesion microgranule.
Concrete steps are as follows:
(1) dispersion that adopts at seasoning in the oil is that liquid paraffin is that disperse medium and Span 80 are surfactant, the cleaning process of the microsphere that obtains is loaded down with trivial details, therefore, it is that water is that disperse medium and polyvinyl alcohol (PVA) are surfactant that the present invention adopts new dispersion, medicine and ethyl cellulose are dissolved in the dichloromethane equal solvent, have prepared sphericity ethyl cellulose microsphere preferably with seasoning in the water.
Be specially: is that the ethyl cellulose solution of 1～15% (w/v) is as decentralized photo (O) with dichloromethane, chloroform, carbon tetrachloride or normal hexane etc. as the weight concentration of solvent, the aqueous solution of weight concentration 0.5～10% (w/v) polyvinyl alcohol (PVA) or 0.01%-0.2% (w/v) dodecyl sodium sulfate is as continuous phase (W), decentralized photo is distributed in the continuous phase, the O/W volume ratio is 1:40～1:10, temperature is controlled at 20～40 ℃, under the rotating speed of 600～1200rpm, stir 2～5h, prepare the ethyl cellulose microsphere of different-grain diameter (50～200 μ m).
(2) again with sodium alginate as coating material, exsiccant ethyl cellulose microsphere is dispersed in the sodium alginate soln, adopt the emulsifying/internal gelling technique to prepare calcium alginate-microparticles by using.The principle of emulsifying/internal gelation method is with sodium alginate soln and slightly solubility calcium salt: calcium carbonate, calcium lactate, calcium oxalate Dispersion of Particles form Water-In-Oil (W/O) type emulsion under suitable surfactant Span 80 effects in the liquid paraffin of oil phase.Dissociate the gelation reaction that calcium ion in the slightly solubility calcium salt causes sodium alginate by the pH that reduces system then, generate calcium alginate gel beads.
Be specially: the ethyl cellulose microsphere and the 0.05～0.3mol/L insoluble calcium salts (can be calcium carbonate, calcium lactate merit calcium oxalate) that prepare are evenly spread in weight concentration 0.5～3% (w/v) sodium alginate soln, then mixed liquor is distributed in the liquid paraffin that contains weight concentration 0.5～2.5% (w/v) sorbester p17 (Span80) and 0.5～2.5% (w/v) polysorbas20 (Tween20), water oil phase volume ratio stirs 15～40min at 1:4～1:10 under the rotating speed of 600～1200rpm; With the glacial acetic acid is pH=3.0～6.5 (adding 10～50% (v/v) glacial acetic acid 0.2-10ml usually gets final product) of gel initiator regulation system, continues to stir 5～20min, can obtain AE microgranule (calcium alginate-microparticles by using); The mass ratio of ethyl cellulose microsphere and sodium alginate soln is 1:1-4.
(3) for strengthening the bioadhesion performance of calcium alginate-microparticles by using, adopt ionic cross-linking to prepare chitin-alginic acid calcium-microparticles by using: the AE microgranule (calcium alginate-microparticles by using) for preparing is dispersed in the chitosan solution, jolting reaction 5～30min promptly gets chitin-alginic acid calcium-microparticles by using.The chitosan pH that uses is between 3.0～6.5, and weight concentration is between 0.25～5%, and temperature is controlled at 20～40 ℃.
Advantage of the present invention is:
1. preparation process of the present invention and simple to operate, temperature is low, and required time is short, and the whole time, the microgranule of preparation had the characteristics of floating and bioadhesion about 3-10h.
2. the present invention's method of adopting sodium alginate and calcium ion to carry out ionomer prepares microgranule, the reaction condition gentleness has been avoided virose cross-linking agent such as introducing glutaraldehyde, therefore reduces toxicity, and biocompatibility is better, avoids the untoward reaction of using chemical cross-linking agent to bring.
3. chitin-alginic acid calcium-microparticles by using of the present invention has good flotation property in the acetate buffer solution of pH5.0, the showy time of 70% microgranule is greater than 4h.
4. the present invention adopts chitosan and sodium alginate to carry out ionomer, chitosan coating calcium alginate-microparticles by using, strengthened the bioadhesion performance of system, has good in-vitro bioadhesion performance, with the speed flushing 5min of 22ml/min, the microgranule more than 90% sticks to gastric mucosa surface.
Description of drawings
Fig. 1 is the microphotograph of calcium alginate-microparticles by using of the present invention; Wherein A is calcium alginate-microparticles by using * 4, and B is calcium alginate-microparticles by using * 10;
Fig. 2 is microphotograph * 10 of chitin-alginic acid calcium-microparticles by using of the present invention;
Fig. 3 is the showy time graph of chitin-alginic acid calcium-microparticles by using of the present invention in the acetate buffer solution of pH5.0.
The specific embodiment
As shown in Figure 1 and Figure 2, the floating-biological adhesion diameter of particle of present technique preparation is prepared the chitin-alginic acid calcium-microparticles by using of 1～6 of parcel or more a plurality of ethyl cellulose microspheres at 150～1000 μ m according to different needs.
Concrete implementing method is as follows:
Embodiment 1: be solvent with the dichloromethane, the ethyl cellulose solution of concentration 4% (w/v) is as decentralized photo (O), with concentration 0.5% (w/v) polyvinyl alcohol (PVA) and concentration 0.01% (w/v) sodium dodecyl sulfate aqueous solution as continuous phase (W), O/W is than being 1:40, temperature is controlled at 20 ℃, mixing speed 1200rpm, mixing time 5h, preparing particle diameter is the ethyl cellulose microsphere of 50～100 μ m.The ethyl cellulose microsphere and the 0.05mol/L insoluble calcium salts that prepare are evenly spread in 0.5% (w/v) sodium alginate soln, then mixed liquor is distributed in the liquid paraffin that contains 0.5% (w/v) sorbester p17 (Span80) and 0.5% (w/v) polysorbas20 (Tween20), water oil phase volume ratio is between 1:4, add 10% (v/v) glacial acetic acid 0.2ml, continue to stir 20min, temperature is controlled at 20 ℃, can obtain sodium alginate-microparticles by using.Sodium alginate-the microparticles by using for preparing is dispersed in the chitosan solution, and jolting reaction 5min promptly gets chitin-sodium alginate-microparticles by using, and the chitosan pH of use is 3.0, and concentration is 0.25%, and temperature is controlled at 20 ℃.
Embodiment 2: be solvent with the chloroform, the ethyl cellulose solution of concentration 15% (w/v) is as decentralized photo (O), with concentration 10% (w/v) polyvinyl alcohol (PVA) and concentration 0.2% (w/v) sodium dodecyl sulfate aqueous solution as continuous phase (W), O/W is than being 1:10, temperature is controlled at 40 ℃, mixing speed 600rpm, mixing time 2h, preparing particle diameter is the ethyl cellulose microsphere of 100～200 μ m.The ethyl cellulose microsphere and the 0.3mol/L insoluble calcium salts that prepare are evenly spread in 3% (w/v) sodium alginate soln, then mixed liquor is distributed in the liquid paraffin that contains 2.5% (w/v) sorbester p17 (Span80) and 2.5% (w/v) polysorbas20 (Tween20), water oil phase volume ratio is between 1:10, add 50% (v/v) glacial acetic acid 10ml, continue to stir 5min, temperature is controlled at 20 ℃, can obtain sodium alginate-microparticles by using.Sodium alginate-the microparticles by using for preparing is dispersed in the chitosan solution, and jolting reaction 30min promptly gets chitin-sodium alginate-microparticles by using, and the chitosan pH of use is 6.5, and concentration is 5%, and temperature is controlled at 20 ℃.
Embodiment 3: be solvent with the normal hexane, the ethyl cellulose solution of concentration 1% (w/v) is as decentralized photo (O), with concentration 2% (w/v) polyvinyl alcohol (PVA) and concentration 0.1% (w/v) sodium dodecyl sulfate aqueous solution as continuous phase (W), O/W is than being 1:6, temperature is controlled at 30 ℃, mixing speed 900rpm, mixing time 4h, preparing particle diameter is the ethyl cellulose microsphere of 100～150 μ m.The ethyl cellulose microsphere and the 0.2mol/L insoluble calcium salts that prepare are evenly spread in 1.5% (w/v) sodium alginate soln, then mixed liquor is distributed in the liquid paraffin that contains 1% (w/v) sorbester p17 (Span80) and 1% (w/v) polysorbas20 (Tween20), water oil phase volume ratio is between 1:6, add 30% (v/v) glacial acetic acid 5ml, continue to stir 15min, temperature is controlled at 30 ℃, can obtain sodium alginate-microparticles by using.Sodium alginate-the microparticles by using for preparing is dispersed in the chitosan solution, and jolting reaction 15min promptly gets chitin-sodium alginate-microparticles by using, and the chitosan pH of use is 5.0, and concentration is 2.5%, and temperature is controlled at 30 ℃.
The invention process effect:
1, the showy situation of in-vitro simulated chitin-alginic acid calcium-microparticles by using in the acetate buffer solution of pH5.0, basic reflection chitin-alginic acid calcium-microparticles by using floating at gastric, flotation time is long more, medicine in vivo the holdup time long more, be beneficial to the absorption of medicine more.Shown in curve among Fig. 3.
2, external investigation chitin-alginic acid calcium-microparticles by using is in the residual quantity of mucosa tissue, and microgranule is many more in the residual quantity of mucosa tissue, and medicine is high more in the concentration of mucosa.As table 1.
The retention rate of the different microgranules of table 1 on the isolated rat gastric mucosa
Experiment condition is: the rat behind the fasting water supply raising 24h is divided into 3 groups at random, gets stomach after the execution, be tiled on the object stage.Get each 100 of ethyl cellulose microsphere, sodium alginate-microparticles by using and chitin-sodium alginate-microparticles by using respectively, evenly be sprinkling upon gastric mucosa surface, place the hermetic container of saturated nacl aqueous solution, take out behind the 20min that preserves moisture, make object stage be 45 ° of oblique angles and place.Wash 5min with the pH5 acetate buffer solution with 22mlmin-1, be retained in the microgranule number on the mucosa tissue after the record drip washing respectively, obtain the delay percentage rate.
Claims (3)
1. the preparation method of a floating in stomach-biological adhesion synergistic microparticle, have following steps: 1) medicine and ethyl cellulose are dissolved in dichloromethane, chloroform, carbon tetrachloride or the normal hexane solvent, the step for preparing the floating microsphere of ethyl cellulose earlier with dry system in the water, 2) in emulsification system, use the sodium alginate coating then, form the step of calcium alginate-microparticles by using, 3) at last sodium alginate-microparticles by using is dispersed in the step that ionic gel formation chitosan film takes place in the chitosan solution;
In described step 2) in, described emulsification system is, the ethyl cellulose microsphere and the 0.05～0.1mol/L insoluble calcium salts that prepare are evenly spread in weight concentration 0.5～3% sodium alginate soln, the mass ratio of ethyl cellulose microsphere and sodium alginate soln is 1:1～4, then mixed liquor is distributed in the liquid paraffin that contains weight concentration 0.5～2.5% sorbester p17 and 0.5～2.5% polysorbas20, water oil phase volume ratio is at 1:4～1:10, with the glacial acetic acid is the gel initiator, adjust total system pH value to 4.0～6.5 after adding glacial acetic acid, under the rotating speed of 600～1200rpm, stir 5～20min, obtain sodium alginate-microparticles by using;
Dry system is in water described in the described step 1), is that 1～15% ethyl cellulose solution is as decentralized photo with dichloromethane, chloroform, carbon tetrachloride or normal hexane as the weight concentration of solvent, the aqueous solution of weight concentration 0.5～10% polyvinyl alcohol or 0.01%～0.2% dodecyl sodium sulfate is as continuous phase, the volume ratio of decentralized photo and continuous phase is 1:40～1:10, prepares the ethyl cellulose microsphere;
Described ionic gelization is, sodium alginate-the microparticles by using for preparing is dispersed in the chitosan aqueous solution, jolting reaction 5～30min, promptly get chitin-sodium alginate-microparticles by using, the weight concentration of chitosan is 0.25～5% in the chitosan aqueous solution, and the chitosan solution pH value is 3.0～6.5.
2. according to the preparation method of the described floating in stomach-biological adhesion synergistic microparticle of claim 1, it is characterized in that: described insoluble calcium salts is calcium carbonate, calcium lactate or calcium oxalate.
3. according to the preparation method of the described floating in stomach-biological adhesion synergistic microparticle of claim 1, it is characterized in that: described course of reaction temperature is controlled at 20～40 ℃.
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| CN102406595B (en) * | 2011-11-02 | 2013-05-29 | 沈阳药科大学 | Floating microorganism adhesive porous hydrogel and preparation method thereof |
| CN105326811B (en) * | 2015-12-02 | 2018-05-08 | 沈阳药科大学 | A kind of anthocyanidin floating in stomach microballoon and preparation method thereof |
| CN107418998B (en) * | 2016-09-14 | 2020-02-28 | 四川蓝光英诺生物科技股份有限公司 | Microparticle manipulation method, bioprinting method and biological construct |
| CN114130165B (en) * | 2020-09-03 | 2023-03-24 | 中国科学院大连化学物理研究所 | Recyclable ionic gel dehumidifying bag |
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