Oral instant film liquid based on nano-carrier and preparation method of oral instant film

Abstract

The invention provides an oral cavity soluble film solution based on a nano-carrier and a preparation method of an oral cavity soluble film. According to the method, a nano-carrier technology, microcapsule multilayer coating, a low-temperature electrochemical polymerization method and an ultrasonic dispersion technology are utilized, and uniform distribution and multi-stage slow release of a medicine in an oral instant film are achieved. According to the invention, active pharmaceutical ingredients are firstly wrapped by a nano-carrier, and then a multi-layer composite coating structure is formed by a microcapsule technology, so that drug release effects at different stages are realized. And then, uniformly mixing the microcapsule nano-drug particles with a film-forming substrate, depositing layer by layer to form a film through a low-temperature electrochemical polymerization method, and carrying out low-temperature drying treatment. The soluble film disclosed by the invention has good biocompatibility and mechanical strength, and can be gradually dissolved in an oral cavity, and the medicine is released according to a set stage, so that a long-acting oral care or treatment effect is realized. The method avoids the use of high temperature and organic solvents, is environment-friendly and safe, and is suitable for delivery systems of various oral drugs.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of oral fast-dissolving films, and in particular to an oral fast-dissolving film liquid based on nano-carriers and a preparation method of the oral fast-dissolving film. Background Art

[0002] Traditional oral care or drug delivery mostly relies on oral tablets, lozenges or mouthwashes, but these forms usually have a slow onset of action, limited duration of efficacy, and low absorption rate. Oral fast-dissolving film is a new drug delivery method that forms a thin film in the mouth to achieve sustained release and direct absorption of drugs or active ingredients. It has the advantages of fast effect and convenient operation. As a new oral drug delivery system, oral fast-dissolving film has the advantages of directly acting on the local oral cavity, avoiding gastrointestinal decomposition, high drug bioavailability, and rapid onset of action. Therefore, it has broad application potential in many fields such as oral health, antibacterial, anti-inflammatory, and analgesia.

[0003] In recent years, oral fast-dissolving film has gradually received attention as a new drug delivery system in academic research and practical applications. The preparation methods mentioned in existing patents and academic literature mainly include solvent evaporation method, hot melt extrusion method and gel molding method, but these methods have many shortcomings in application, which limits the wide application and performance optimization of oral fast-dissolving film. The solvent evaporation method dissolves the polymer and the drug in a solvent, and then coats or sprays it on the surface of the substrate to form a film. There are problems such as uneven film formation, solvent residue, high cost and environmental pollution. In particular, the toxicity risk of solvent residue affects the safety of oral fast-dissolving film. The hot melt extrusion method heats the polymer and the drug to a molten state and then extrudes the film to avoid the use of solvents, but high temperature easily leads to inactivation or decomposition of active ingredients (such as vitamins, antibacterial ingredients, etc.), especially temperature-sensitive biological molecules. In addition, the hot melt extrusion equipment is expensive, the distribution of the drug in the polymer matrix is ​​difficult to control evenly, and it is difficult to achieve accurate drug release. Moreover, the film dissolution rate of this method is slow, which is not suitable for the administration needs of short-acting drugs. The gel forming method gels the polymer solution under low temperature conditions and then dries it into a film, avoiding high temperature and organic solvents, but the production cycle is long and the drug distribution is prone to migration. The film has low mechanical strength, which makes the film easy to break in the oral cavity, which is not conducive to the stable release of the drug. In addition, these methods mostly use a single-layer film-forming process, and the drug release is difficult to control in stages. It often shows rapid release in the early stage and slowdown in the later stage, which cannot meet the needs of long-term stable drug efficacy, especially for oral care products that require sustained release. There are also defects in biocompatibility and taste. The existing oral dissolving film often uses synthetic polymers such as hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA). Although it has certain film-forming properties, the biocompatibility and user experience are not ideal, and sometimes even cause oral irritation or allergies. After the film is dissolved, sticky substances may remain, affecting the user's experience. Therefore, improving the preparation method of oral dissolving film, improving drug release control, enhancing biocompatibility and improving user experience are still the current research difficulties and important development directions. In summary, the existing oral dissolving film preparation methods have obvious deficiencies in terms of film uniformity, drug release control, biocompatibility and safety of use. Summary of the invention

[0004] In order to solve the technical defects and shortcomings of the prior art, the present invention provides a novel oral fast-dissolving film liquid based on nano-carriers and a method for preparing an oral fast-dissolving film, which mainly includes the following parts:

[0005] 1. Nanocarrier Preparation

[0006] Active pharmaceutical ingredients: antibacterial ingredients, anti-inflammatory ingredients or analgesic ingredients are selected as active pharmaceutical ingredients, and the amount added accounts for 5% to 10% of the total mass of the dissolved film.

[0007] Nanocarrier matrix: Chitosan or polylactic acid-glycolic acid copolymer (PLA-PLGA) is used as the nanocarrier matrix, and the added amount accounts for 15% to 20% of the total mass of the dissolved film. The hydrophilic polyethylene glycol (PEG) group is modified on the surface of the nanocarrier to enhance its dispersibility in the oral dissolved film matrix. The amount of PEG added accounts for 1% to 2% of the total mass of the dissolved film. The combination of the drug and the carrier is controlled by reaction, the temperature is controlled at 15°C to 20°C, the reaction time is 30 to 60 minutes, and nanocarrier particles with a particle size controlled at 100 to 200 nanometers are formed. Finally, a uniform nano drug carrier dispersion is obtained by centrifugation and freeze-drying.

[0008] 2. Microcapsule multilayer coating

[0009] Coating material: The outer coating material of the microcapsule is chitosan and sodium alginate, which are deposited layer by layer to form a multi-layer composite structure. The ratio of chitosan and sodium alginate is 1:1, and the total amount accounts for 5% to 8% of the total mass of the dissolved film. Sustained-release control layer: The inner coating sustained-release layer is prepared with polylactic acid-glycolic acid copolymer (PLA-PLGA), and its proportion is 3% to 5% of the total mass of the dissolved film.

[0010] Preparation method: First, disperse the nano drug carrier particles in deionized water, and alternately deposit chitosan and sodium alginate on the surface of the nano carrier particles by layer-by-layer deposition to form a multilayer structure. During the deposition process, the pH value is controlled between 6 and 7 to ensure the stability of the coating material. The deposition time for each layer is 10 minutes, and 4 layers are deposited in total. Then, the sustained-release layer is coated on the inner layer, PLA-PLGA is dissolved in a low-concentration organic solvent, and a uniform sustained-release layer is formed on the surface of the nanoparticles by spray coating.

[0011] 3. Film-forming matrix and ultrasonic dispersion

[0012] Film-forming matrix: The film-forming matrix is ​​mainly composed of chitosan and sodium alginate. The mass ratio of chitosan to sodium alginate is 1:1, and the total amount accounts for 50% to 60% of the total mass of the film.

[0013] Plasticizer: Glycerol is added as a plasticizer in an amount of 5% of the total mass of the film-forming matrix to improve the flexibility and taste of the film.

[0014] Stabilizer: Vitamin E is used as an antioxidant stabilizer, and the added amount is 0.5% to 1% of the total mass of the film-forming matrix.

[0015] Ultrasonic dispersion process: Add microcapsule nano drug carriers to the film-forming matrix solution, and use ultrasonic dispersion treatment to ensure uniform distribution of particles. The ultrasonic frequency is set to 20kHz and the treatment time is 15 minutes. Ultrasonic dispersion can effectively break the aggregation state of microcapsule particles, ensure their dispersibility in the film-forming solution, and form an oral film-dissolving solution with uniform thickness.

[0016] Low temperature electrochemical polymerization

[0017] Electrolyte: Deionized water is used as the basic solution, and salts (such as sodium chloride) are appropriately added as conductive electrolytes.

[0018] Polymer material: A composite material of sodium alginate and chitosan is used to form a multilayer composite membrane structure through a low-temperature electrochemical reaction, and the proportion of the polymer material accounts for 20% to 25% of the total mass of the dissolved membrane.

[0019] Specific method: Place the film solution in an electrochemical reaction tank and deposit the polymer material layer by layer through low-temperature electrochemical polymerization to form a film. The current density is 1.5 mA / cm 2 , the temperature is controlled at 10℃~15℃, and the reaction time is 30~45 minutes. Through electrolytic reaction, the film-forming material is polymerized layer by layer around the nano drug carrier to form a composite film structure, thereby ensuring the uniform thickness of the film and multi-layer sustained release characteristics. The final film thickness is controlled at 50~100 microns to ensure the strength and dissolution rate of the film.

[0020] 4. Drying and styling

[0021] After low-temperature electrochemical polymerization, the dissolved film is taken out and dried at a temperature below 30-60°C to ensure that the activity of the film-forming matrix and the drug is not affected by high temperature. The drying process is generally controlled within 3 hours to ensure that the water in the film is completely evaporated to form a flexible dissolved film with good mechanical strength.

[0022] Effect:

[0023] The oral dissolving film prepared by the present invention has a multi-layer composite structure, which can realize the staged sustained release of drugs. The initial rapid release layer enables the drug to be quickly released in the early stage of dissolving the dissolving film, providing an efficient drug concentration; the intermediate sustained release layer can prolong the drug action time, so that the drug effect is sustained and stable; the deep sustained release layer ensures the long-term sustained release of the drug, reducing the frequency of repeated use. The combination of nanocarrier and microcapsule technology improves the bioavailability of the drug, while avoiding the influence of organic solvents and high temperature on the drug components in the traditional process, ensuring the activity and safety of the drug. Ultrasonic dispersion technology ensures the uniform distribution of drug microcapsules in the film-forming liquid, avoids the aggregation of drugs in the film or the formation of uneven areas, and ensures the consistency of drug content and controllability of the release rate of each dissolving film. Natural polymer materials are selected as film-forming materials and carriers, which have good biocompatibility and degradability, avoid oral irritation or discomfort that may be caused by synthetic polymer materials, and are safer to use. The entire preparation process avoids organic solvents and high-temperature treatment, uses water as a solvent, and meets green environmental protection requirements. At the same time, the process flow is simple and easy to industrialize and scale up production. The prepared oral dissolving film is thin and soft. After being put into the mouth, it can quickly adhere to the oral mucosa. The dissolution rate is controllable and there is no residual foreign body sensation, which improves the patient's medication compliance. DETAILED DESCRIPTION

[0024] Embodiment 1: Dissolve 10g of chlorhexidine, an antibacterial drug, in 30mL of ethanol and stir until completely dissolved. Add 15g of polylactic acid-glycolic acid copolymer (PLA-PLGA) and 2g of surface modification material polyethylene glycol (PEG, molecular weight 6000) to the solution and continue stirring. Inject the mixed solution into an emulsifier, use a probe ultrasonic emulsifier, and ultrasonically disperse for 10 minutes at a power of 100W and a frequency of 20kHz to form nanoparticles. Adjust the pH of the emulsion to 5-6, centrifuge, collect the precipitate, freeze-dry, and obtain nanocarrier drug particles with a particle size of 150nm. Obtain stable nanocarrier particles, the drug encapsulation rate reaches more than 95%, and the particle size is evenly distributed at about 150nm, providing a basis for subsequent microcapsule coating.

[0025] Dissolve 30g chitosan and 30g sodium alginate in 100mL deionized water and stir until uniform. Add 5g glycerol and 1g vitamin E and stir again to ensure uniform dissolution. Add 10g microcapsule nano drug particles to the above solution and treat it with an ultrasonic disperser. The ultrasonic frequency is set to 20kHz, the power is 100W, and the treatment time is 15 minutes to obtain a uniformly dispersed film solution. The microcapsule drug particles are evenly distributed in the film-forming matrix to avoid aggregation. The film-forming solution can form a uniform oral film after coating. Pour the film solution into an electrochemical reaction tank and add 0.5g sodium chloride as a conductive electrolyte. Set the current density to 1.5mA / cm 2, the electrolysis temperature is controlled at 12°C. The electrochemical polymerization reaction is carried out in the electrolytic cell, and the reaction time is controlled at 40 minutes to form a multi-layer composite film structure. Low-temperature drying treatment is carried out at an environment below 40°C, and the drying time is 3 hours to ensure that the moisture in the film is completely evaporated.

[0026] Through electrolytic polymerization, the film-forming matrix is ​​deposited layer by layer under low temperature conditions to form a film of uniform thickness. The film thickness can be controlled at 60 microns, with good mechanical strength and biocompatibility. It meets the requirements of multi-stage sustained release. After dissolving in the mouth, the drug can be gradually released to achieve a sustained therapeutic effect.

[0027] Example 2: Dissolve 10g of lidocaine, an antibacterial drug, in 30mL of ethanol and stir until completely dissolved. Add 20g of polylactic acid-glycolic acid copolymer (PLA-PLGA) and 3g of surface modification material polyethylene glycol (PEG, molecular weight 6000) to the solution and continue stirring. Inject the mixed solution into an emulsifier, use a probe ultrasonic emulsifier, and ultrasonically disperse for 15 minutes at a power of 100W and a frequency of 10kHz to form nanoparticles. Adjust the pH of the emulsion to 5-6, centrifuge, collect the precipitate, freeze-dry, and obtain nanocarrier drug particles with a particle size of 200nm. Obtain stable nanocarrier particles, the drug encapsulation rate reaches more than 95%, and the particle size is evenly distributed at about 150nm, providing a basis for subsequent microcapsule coating.

[0028] Dissolve 20g gelatin and 20g sodium carboxymethyl cellulose in 100mL deionized water and stir until uniform. Add 5g propylene glycol and 1g vitamin E and stir again to ensure uniform dissolution. Add 10g microcapsule nano drug particles to the above solution and treat it with an ultrasonic disperser. The ultrasonic frequency is set to 20kHz, the power is 100W, and the treatment time is 15 minutes to obtain a uniformly dispersed film solution.

[0029] Pour the film solution into the electrochemical reaction tank and add 0.5g sodium chloride as a conductive electrolyte. Set the current density to 1.5mA / cm 2 , the electrolysis temperature is controlled at 15°C. The electrochemical polymerization reaction is carried out in the electrolytic cell, and the reaction time is controlled at 30 minutes to form a multi-layer composite film structure. Low-temperature drying treatment is carried out at an environment below 30°C, and the drying time is 4 hours to ensure that the moisture of the film is completely evaporated.

[0030] Through electrolytic polymerization, the film-forming matrix is ​​deposited layer by layer under low temperature conditions to form a film of uniform thickness. The film thickness can be controlled at 50 microns, with good mechanical strength and biocompatibility. It meets the requirements of multi-stage sustained release. After dissolving in the mouth, the drug can be gradually released to achieve a sustained therapeutic effect.

[0031] Example 3: Dissolve 10g of hydrogen peroxide, an antibacterial drug, in 30mL of deionized water and stir until completely dissolved. Add 18g of polylactic acid-glycolic acid copolymer (PLA-PLGA) and 1g of surface modification material polyethylene glycol (PEG, molecular weight 6000) to the solution and continue stirring. Inject the mixed solution into an emulsifier, use a probe ultrasonic emulsifier, and ultrasonically disperse for 10 minutes at a power of 100W and a frequency of 20kHz to form nanoparticles. Adjust the pH of the emulsion to 5-6, centrifuge, collect the precipitate, freeze-dry, and obtain nanocarrier drug particles with a particle size of 300nm. Stable nanocarrier particles are obtained, the drug encapsulation rate reaches more than 90%, and the particle size is evenly distributed at about 200nm, providing a basis for subsequent microcapsule coating.

[0032] Dissolve 15g of polyvinyl alcohol and 15g of pectin in 100mL of deionized water and stir until uniform. Add 4g of glycerol and 1g of vitamin E and stir again to ensure uniform dissolution. Add 10g of microcapsule nanoparticles to the above solution and treat it with an ultrasonic disperser. The ultrasonic frequency is set to 20kHz, the power is 100W, and the treatment time is 15 minutes to obtain a uniformly dispersed film solution.

[0033] Pour the film solution into the electrochemical reaction tank and add 0.5g sodium chloride as a conductive electrolyte. Set the current density to 1.5mA / cm 2 , the electrolysis temperature is controlled at 12°C. The electrochemical polymerization reaction is carried out in the electrolytic cell, and the reaction time is controlled at 40 minutes to form a multi-layer composite film structure. Low-temperature drying treatment is carried out at an environment below 40°C, and the drying time is 3 hours to ensure that the moisture in the film is completely evaporated.

[0034] Through electrolytic polymerization, the film-forming matrix is ​​deposited layer by layer under low temperature conditions to form a film of uniform thickness. The film thickness can be controlled at 80 microns, with good mechanical strength and biocompatibility. It meets the requirements of multi-stage sustained release. After dissolving in the mouth, the drug can be gradually released to achieve a sustained therapeutic effect.

[0035] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing an oral fast-dissolving film solution and an oral fast-dissolving film based on nanocarriers, characterized in that: The method comprises the following steps: The active pharmaceutical ingredient is encapsulated by a nanocarrier, wherein the mass ratio of the active pharmaceutical ingredient to the nanocarrier matrix is ​​1:1.5 to 1:2; The nano drug carrier particles are coated with microcapsules in multiple layers, wherein the outer coating material of the microcapsules is a biocompatible polymer, including but not limited to chitosan, gelatin, and polyvinyl alcohol; The microcapsule nano drug particles are added to the film-forming matrix solution and uniformly distributed by ultrasonic dispersion technology to form a film-dissolving solution; The film was deposited layer by layer in the film solution by low-temperature electrochemical polymerization, and the current density was controlled at 1.5 mA / cm 2 Below, the temperature is controlled between 12℃ and 30℃; The final oral fast-dissolving film is obtained by low-temperature drying.

2. The method according to claim 1, wherein the nanocarrier matrix is ​​polylactic acid-co-glycolic acid (PLA-PLGA), polycaprolactone (PCL), polyglycolide (PLGA), polyethyleneimine (PEI), lipid nanoparticles, etc., and the surface is modified with polyethylene glycol (PEG) to improve the biocompatibility and dispersibility of the drug.

3. The method according to claim 1, wherein the coating material of the microcapsule is formed into a multilayer structure by a layer-by-layer deposition method, each coating layer has a uniform thickness and has a different drug release rate to achieve the effect of releasing the drug in stages.

4. The method according to claim 1, wherein the film-forming matrix solution comprises 30% to 60% chitosan, sodium alginate, polyvinyl alcohol or pectin, and a plasticizer and a stabilizer are added to enhance the flexibility and antioxidant properties of the film.

5. The method according to claim 1, wherein an ultrasonic dispersion technique with an ultrasonic frequency of 20 to 40 kHz and a power of 100 to 150 W is used in the film-forming matrix to make the microcapsule nanoparticles evenly distributed in the film-forming liquid to avoid drug aggregation.

6. The method according to claim 1, wherein the film is formed layer by layer by low-temperature electrochemical polymerization, and the final oral fast-dissolving film has a thickness of 50 to 100 microns and has a multi-layer composite structure, thereby achieving the effect of phased sustained release of the drug.

7. An oral fast-dissolving film product prepared by the preparation method according to claims 1 to 6, characterized in that: The dissolving film has good biocompatibility, mechanical strength and a multi-layer composite sustained-release structure. It can gradually dissolve in the oral cavity and release drugs in stages for use in oral care and treatment.