CN100484573C - Method for preparing floating-biological adhesion synergistic microparticle - Google Patents

Abstract

The invention relates to a preparation method of floating-bioadhesion synergistic microparticles. Firstly, ethyl cellulose floating microspheres are prepared in a water drying system, then coated with sodium alginate in an emulsification system, and finally sodium alginate-ethyl cellulose The cellulose-based microparticles are dispersed in the chitosan solution to undergo ion gelation to form a chitosan film to obtain floating-bioadhesive microparticles. The raw materials for preparing microparticles in the invention are ethyl cellulose, sodium alginate and chitosan, which are widely used in pharmaceutical research and application fields and have good biocompatibility. This floating-bioadhesive synergistic particle can be used to carry small water-soluble or water-insoluble small molecule drugs that function in the stomach, and can also be used to carry many acidic drugs absorbed in the stomach and absorbed in the digestive tract above the duodenum Drug. The preparation can significantly prolong the residence time of the drug in the stomach and improve the bioavailability of the drug.

Description

A preparation method of floating-bioadhesion synergistic particles

technical field

The invention relates to a method for preparing intragastric floating-bioadhesion synergistic microparticle preparations, which adopts the drying-emulsification/internal gelation coupling technology in water, and the raw materials for preparing microparticles are widely used in pharmaceutical research and application fields, and have the advantages of Good biocompatibility biomaterials ethyl cellulose, sodium alginate, chitosan. This floating-bioadhesive synergistic particle can be used to carry small water-soluble or water-insoluble small molecule drugs that function in the stomach, and can also be used to carry many acidic drugs absorbed in the stomach and absorbed in the digestive tract above the duodenum Drug. The preparation can significantly prolong the residence time of the drug in the stomach and improve the bioavailability of the drug.

Background technique

The traditional oral sustained (controlled) release drug delivery system releases the loaded drug into the gastrointestinal tract after administration, and undergoes a change process in the body with gastric emptying and intestinal peristalsis. However, if the drug is absorbed only in a specific part of the gastrointestinal tract or mainly in a certain section (such as in the stomach or the upper part of the small intestine), then this controlled-release drug delivery system will remain in the stomach and small intestine. The time is short (generally 1-2h), so the absorption time is relatively short, the bioavailability is low, and it is difficult to achieve its intended therapeutic purpose.

Gastric retention preparations are a class of new preparations that can prolong the residence time of drugs in the stomach (generally greater than 4 h), thereby prolonging the transport of drugs throughout the gastrointestinal tract, promoting drug absorption, and improving drug bioavailability [Document 1 .Jaspreet K, Kaustubh T, Sanjay G Bioadhesive microspheres as a controlled drugdelivery system.Int.J.Pharm, 2003,255:13-32]; This problem provides a new approach.

Gastric retention preparations are mainly divided into the following types: floating type, bioadhesive type and floating-bioadhesive synergistic type. Dosage forms mainly include tablets, capsules, microspheres, etc. Among them, the floating-bioadhesion synergistic microspheres (particles) exist in multiple tiny units, the specific surface area increases, the bioadhesion area increases, and the small units in the floating state are distributed according to the probability, which increases the chance of floating, significantly Prolong the transit time of the drug in the gastrointestinal tract.

The current method and materials used to prepare floating-bioadhesive synergistic microspheres (microparticles) [Document 2. Huang Jinglin, Lu Jinfang. In vitro drug release and adhesion of metronidazole bioadhesive microspheres. Acta Pharmaceutica Sinica. 2002, 37(3): 226-228; Literature 3. Akiyama Y, Nagahara N, Kashihara T, et al. In vitro and in vivoevaluation of mucoadhesive microspheres prepared for the gastrointestinal tract using polyglycerol esters of fatty acid and a lic derivative.Pharm Res, 1995, 12(3):397-405; literature 4. Umamaheswari RB, Jain S, Tripathi PK, Agrawal GP, Jain NK. Floating-bioadhesive microspheres containing acetohydroxamic acid for clearance of Helicobacter pylori, 20 Delive , 9: 223-231; Literature 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; Literature 6. Yasunori M, Kanako O, Shigeru Y, et al.Invitro and in vivo evaluation of mucoadhesive microspheres consisting of dextranderivatives and cellulose acetate butyrate. 258:21-29; Literature 7. JianW, Yasuhiko T, Dianzhou B, et al.Evaluation of gastric mucoa Dhesive properties ofaminated gelatin microspheres.J Control Release, 2001, 73:223-231] have: 1. Dispersed microspheres (particles), using carbomer as bioadhesive material, and dispersing it in ethyl cellulose organic solvent In , ethyl cellulose bioadhesive microspheres were prepared by drying in oil. Because carbomer swells in water, drying in water cannot be used to prepare microspheres, so the time required is longer and the temperature is higher; at the same time, the high content of carbomer can improve the bioadhesion performance, but at the same time reduce the floating ability of the preparation . 2. Coated microspheres (microparticles), the prepared microspheres are coated or modified with external bioadhesive materials. Commonly used coating materials include carbomer, hydroxypropyl cellulose, acrylic resin Eudragit S, etc. These materials form a gel layer on the surface of the microspheres, but during the transit of the gastrointestinal tract, sometimes they will excessively absorb water and swell when they encounter gastric juice. It is easy to fall off from the microspheres, so that the drug is released prematurely, and the adhesion performance is reduced. The introduction of cross-linking agents such as glutaraldehyde can control the excessive water swelling of the gel layer to a certain extent, but the cross-linking agent has certain toxicity to the body, and sometimes reacts with the drug, reducing the efficacy of the drug.

Contents of the invention

The invention provides a method for preparing gastric floating-bioadhesion synergistic microparticle preparation. The principle is: first prepare hydrophobic floating microspheres with ethyl cellulose as the matrix, and then coat sodium alginate and chitosan bioadhesive materials. By improving the floating performance and bioadhesive performance of the preparation in the stomach, it significantly Prolong the residence time of the drug in the stomach and improve the bioavailability of the drug.

Technical scheme of the present invention is:

A method for preparing floating-bioadhesion synergistic microparticles in the stomach, comprising the following steps: 1) preparing ethylcellulose floating microspheres in a water drying system; 2) coating them with sodium alginate in an emulsified system to form Calcium alginate-ethylcellulose microparticles; 3) Finally, sodium alginate-ethylcellulose microparticles are dispersed in a chitosan solution to undergo ion gelation to form a chitosan film to obtain floating-bioadhesive microparticles.

Specific steps are as follows:

(1) liquid paraffin is that dispersion medium and Span 80 are tensio-active agent at the dispersion system that drying method adopts in the oil, and the cleaning process of the microsphere that obtains is loaded down with trivial details, therefore, the present invention adopts new dispersion system that water is dispersion medium and Polyvinyl alcohol (PVA) was used as a surfactant, and the drug and ethyl cellulose were dissolved in dichloromethane and other solvents, and ethyl cellulose microspheres with good sphericity were prepared by drying in water.

Specifically: the ethyl cellulose solution with dichloromethane, chloroform, carbon tetrachloride or n-hexane, etc. as a solvent with a weight concentration of 1 to 15% (w/v) as the dispersed phase (O), with a weight concentration of 0.5 to 10% (w/v) polyvinyl alcohol (PVA) or 0.01%-0.2% (w/v) aqueous solution of sodium dodecylsulfonate as the continuous phase (W), disperse the dispersed phase into the continuous phase, O The /W volume ratio is 1:40~1:10, the temperature is controlled at 20~40°C, and stirred at a speed of 600~1200rpm for 2~5h to prepare ethyl cellulose microspheres with different particle sizes (50~200μm). .

(2) Using sodium alginate as a coating material, disperse the dried ethylcellulose microspheres in the sodium alginate solution, and prepare calcium alginate-ethylcellulose microparticles by emulsification/internal gelation method. The principle of the emulsification/internal gelation method is to disperse sodium alginate solution and insoluble calcium salts: calcium carbonate, calcium lactate, calcium oxalate particles into liquid paraffin in the oil phase, and form under the action of a suitable surfactant Span 80 Water-in-oil (W/O) emulsion. Then, by lowering the pH of the system, the calcium ions in the insoluble calcium salt are dissociated to trigger the gelation reaction of sodium alginate to generate calcium alginate gel beads.

Specifically: uniformly disperse the prepared ethylcellulose microspheres and 0.05-0.3mol/L insoluble calcium salt (can be calcium carbonate, calcium lactate, calcium oxalate) to a weight concentration of 0.5-3% (w/v) Sodium alginate solution, and then disperse the mixture into liquid paraffin containing 0.5-2.5% (w/v) Span 80 (Span80) and 0.5-2.5% (w/v) Tween 20 (Tween20) by weight , the volume ratio of the water-oil phase is 1:4-1:10, stirring at a speed of 600-1200rpm for 15-40min; using glacial acetic acid as the gel initiator to adjust the pH of the system to 3.0-6.5 (usually adding 10-50% (v/v) 0.2-10ml of glacial acetic acid), and continue to stir for 5-20 minutes to obtain AE particles (calcium alginate-ethylcellulose particles); the mass of ethylcellulose microspheres and sodium alginate solution The ratio is 1:1-4.

(3) In order to enhance the bioadhesion performance of calcium alginate-ethylcellulose microparticles, chitosan-calcium alginate-ethylcellulose microparticles were prepared by ion cross-linking: the prepared AE microparticles (calcium alginate - ethylcellulose microparticles) dispersed in chitosan solution, shaken for 5-30 minutes to react to obtain chitosan-calcium alginate-ethylcellulose microparticles. The pH of the chitosan used is between 3.0-6.5, the weight concentration is between 0.25-5%, and the temperature is controlled at 20-40°C.

The advantages of the present invention are:

1. The preparation process and operation of the present invention are simple, the temperature is low, and the required time is short. The overall time is about 3-10 hours, and the prepared particles have the characteristics of floating and biological adhesion.

2. The present invention uses sodium alginate and calcium ions to carry out ionic cross-linking to prepare microparticles, the reaction conditions are mild, and the introduction of toxic cross-linking agents such as glutaraldehyde is avoided, so the toxicity is reduced and the biocompatibility is better. Avoid adverse reactions caused by the use of chemical cross-linking agents.

3. The chitosan-calcium alginate-ethylcellulose microparticles of the present invention have good floating performance in the acetate buffer solution of pH 5.0, and the floating time of 70% of the microparticles is greater than 4h.

4. The present invention uses chitosan and sodium alginate for ion cross-linking, and chitosan coats calcium alginate-ethyl cellulose particles, which enhances the bioadhesion performance of the system and has better in vitro bioadhesion performance , washed at a speed of 22ml/min for 5min, and more than 90% of the particles adhered to the surface of the gastric mucosa.

Description of drawings

Fig. 1 is the micrograph of calcium alginate-ethyl cellulose particle of the present invention; Wherein A is calcium alginate-ethyl cellulose particle × 4, B is calcium alginate-ethyl cellulose particle × 10;

Fig. 2 is the microscope photo * 10 of chitosan-calcium alginate-ethylcellulose particle of the present invention;

Fig. 3 is the floating time curve of chitosan-calcium alginate-ethylcellulose microparticles in pH 5.0 acetate buffer of the present invention.

Detailed ways

As shown in Figure 1 and Figure 2, the particle size of the floating-bioadhesive particles prepared by this technology is 150-1000 μm, and chitosan wrapped with 1-6 or more ethylcellulose microspheres can be prepared according to different needs - Calcium Alginate - Ethyl Cellulose Microparticles.

The specific implementation method is as follows:

Embodiment 1: take dichloromethane as solvent, the ethyl cellulose solution of concentration 4% (w/v) is as dispersed phase (O), with concentration 0.5% (w/v) polyvinyl alcohol (PVA) and concentration 0.01 % (w/v) sodium dodecylsulfonate aqueous solution is used as the continuous phase (W), the O/W ratio is 1:40, the temperature is controlled at 20°C, the stirring speed is 1200rpm, and the stirring time is 5h, and the particle size is 50 ~100 μm ethylcellulose microspheres. Evenly disperse the prepared ethylcellulose microspheres and 0.05mol/L insoluble calcium salt into a 0.5% (w/v) sodium alginate solution, and then disperse the mixed solution to a solution containing 0.5% (w/v) sodium In the liquid paraffin of Span80 (Span80) and 0.5% (w/v) Tween 20 (Tween20), the volume ratio of water to oil phase is between 1:4, add 0.2ml of 10% (v/v) glacial acetic acid, continue Stir for 20 minutes and control the temperature at 20°C to obtain sodium alginate-ethylcellulose microparticles. Disperse the prepared sodium alginate-ethylcellulose microparticles in the chitosan solution and shake for 5 minutes to obtain the chitosan-sodium alginate-ethylcellulose microparticles. The chitosan used has a pH of 3.0 , the concentration is 0.25%, and the temperature is controlled at 20°C.

Embodiment 2: take chloroform as solvent, the ethyl cellulose solution of concentration 15% (w/v) is as dispersed phase (O), with concentration 10% (w/v) polyvinyl alcohol (PVA) and concentration 0.2% ( w/v) Sodium dodecylsulfonate aqueous solution is used as the continuous phase (W), the O/W ratio is 1:10, the temperature is controlled at 40°C, the stirring speed is 600rpm, the stirring time is 2h, and the particle size is 100-200μm ethylcellulose microspheres. Evenly disperse the prepared ethylcellulose microspheres and 0.3mol/L insoluble calcium salt into a 3% (w/v) sodium alginate solution, and then disperse the mixed solution into a solution containing 2.5% (w/v) sodium alginate In the liquid paraffin of Pan 80 (Span80) and 2.5% (w/v) Tween 20 (Tween20), the volume ratio of water to oil phase is between 1:10, add 10ml of 50% (v/v) glacial acetic acid, and continue stirring 5min, the temperature is controlled at 20°C, and sodium alginate-ethylcellulose microparticles can be obtained. Disperse the prepared sodium alginate-ethylcellulose microparticles in the chitosan solution and shake for 30 minutes to obtain chitosan-sodium alginate-ethylcellulose microparticles. The pH of the chitosan used is 6.5 , the concentration is 5%, and the temperature is controlled at 20°C.

Embodiment 3: take normal hexane as solvent, the ethyl cellulose solution of concentration 1% (w/v) is as dispersed phase (O), with concentration 2% (w/v) polyvinyl alcohol (PVA) and concentration 0.1% (w/v) Sodium dodecylsulfonate aqueous solution is used as the continuous phase (W), the O/W ratio is 1:6, the temperature is controlled at 30°C, the stirring speed is 900rpm, and the stirring time is 4h. The prepared particle size is 100～ 150 μm ethylcellulose microspheres. Evenly disperse the prepared ethylcellulose microspheres and 0.2mol/L insoluble calcium salt into a 1.5% (w/v) sodium alginate solution, and then disperse the mixed solution into a solution containing 1% (w/v) sodium alginate In the liquid paraffin of Span80 (Span80) and 1% (w/v) Tween 20 (Tween20), the volume ratio of water to oil phase is between 1:6, add 5ml of 30% (v/v) glacial acetic acid, and continue stirring After 15 minutes, the temperature is controlled at 30°C to obtain sodium alginate-ethylcellulose microparticles. Disperse the prepared sodium alginate-ethylcellulose microparticles in the chitosan solution and shake for 15 minutes to obtain chitosan-sodium alginate-ethylcellulose microparticles. The pH of the chitosan used is 5.0 , the concentration is 2.5%, and the temperature is controlled at 30°C.

Implementation effect of the present invention:

1. In vitro simulation of the floating situation of chitosan-calcium alginate-ethylcellulose particles in the acetate buffer solution of pH 5.0, which basically reflects the floating of chitosan-calcium alginate-ethylcellulose particles in the stomach , the longer the floating time, the longer the drug stays in the body, which is more conducive to the absorption of the drug. As shown in the curve in Figure 3.

2. To investigate the residual amount of chitosan-calcium alginate-ethylcellulose microparticles in gastric mucosal tissue in vitro, the more the residual amount of microparticles in gastric mucosal tissue, the higher the drug concentration in mucosal tissue. As in Table 1.

Table 1 Retention rate of different microparticles on isolated rat gastric mucosa

The experimental conditions were as follows: the rats fed with fasting and water supply for 24 hours were randomly divided into 3 groups, their stomachs were taken after sacrifice, and spread flat on the stage. Take 100 grains of ethyl cellulose microspheres, sodium alginate-ethyl cellulose micro-particles and chitosan-sodium alginate-ethyl cellulose micro-particles, sprinkle them evenly on the surface of the gastric mucosa, and place them in saturated sodium chloride solution In an airtight container, take it out after moisturizing for 20 minutes, and place the stage at an oblique angle of 45°. Rinse with pH 5 acetate buffer at 22ml·min-1 for 5min, record the number of particles remaining on the gastric mucosal tissue after rinsing, and obtain the retention percentage.

Claims (3)

1. a preparation method of floating-bioadhesion synergistic microparticles in the stomach has the following steps: 1) medicine and ethyl cellulose are dissolved in methylene chloride, chloroform, carbon tetrachloride or normal hexane solvent, first The step of preparing ethylcellulose floating microspheres with the water drying system, 2) and then coating with sodium alginate in the emulsification system to form the step of calcium alginate-ethylcellulose particles, 3) finally adding sodium alginate- A step in which ethyl cellulose particles are dispersed in chitosan solution and undergo ion gelation to form a chitosan film; In the step 2), the emulsification system is to uniformly disperse the prepared ethylcellulose microspheres and 0.05-0.1mol/L insoluble calcium salt into a sodium alginate solution with a weight concentration of 0.5-3%, The mass ratio of ethyl cellulose microspheres to sodium alginate solution is 1:1-4, and then the mixed solution is dispersed into liquid paraffin containing 0.5-2.5% Span 80 and 0.5-2.5% Tween 20 by weight, The water-oil phase volume ratio is 1:4-1:10, using glacial acetic acid as the gel initiator, adding glacial acetic acid, adjusting the pH value of the overall system to 4.0-6.5, and stirring at a speed of 600-1200rpm for 5-20min to obtain Sodium alginate-ethylcellulose microparticles; In said step 1), the drying system in water is that the weight concentration of dichloromethane, chloroform, carbon tetrachloride or n-hexane as a solvent is 1 to 15% ethyl cellulose solution as a dispersed phase, and the weight concentration is The aqueous solution of 0.5-10% polyvinyl alcohol or 0.01%-0.2% sodium dodecylsulfonate is used as the continuous phase, and the volume ratio of the dispersed phase to the continuous phase is 1:40-1:10. ball; The ionic gelation is to disperse the prepared sodium alginate-ethyl cellulose particles in the chitosan aqueous solution, shake and react for 5-30 minutes, and obtain the chitosan-sodium alginate-ethyl cellulose The particle, the weight concentration of chitosan in the chitosan aqueous solution is 0.25-5%, and the pH value of the chitosan solution is 3.0-6.5. 2. According to the preparation method of intragastric floating-bioadhesion synergistic microparticles according to claim 1, it is characterized in that: the insoluble calcium salt is calcium carbonate, calcium lactate or calcium oxalate. 3. The method for preparing intragastric floating-bioadhesion synergistic microparticles according to claim 1, characterized in that: the temperature of the reaction process is controlled at 20-40°C.

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