阅读说明：本技术 一种新型的单向释药口腔溃疡双层膜及其制备方法 (Novel one-way drug release oral ulcer double-layer film and preparation method thereof ) 是由 罗国平 闫梦茹 陈程 陈格 于 2021-06-24 设计创作，主要内容包括：本发明公开了一种新型单向释药的口腔溃疡双层膜,其特征在于,口腔溃疡双层膜具有双层结构,一层为与口腔溃疡面接触的载药层；一层为具有单向释药和防粘作用的疏水保护层,两层之间通过粘合剂粘合；所述载药层由药物、亲水成膜材料、促渗剂、第一增塑剂和第一溶剂组成；所述疏水保护层由疏水成膜材料、第二增塑剂和第二溶剂组成。本发明还提供了上述口腔溃疡双层膜的制备方法,本发明提供的新型单向释药的口腔溃疡双层膜,药物分散或者溶解于载药层内,疏水保护层中不包含药物,载药层遇水能产生黏性,载药层中的亲水生物黏附材料可黏附于溃疡面上,随着水分的渗透,药物会逐渐释放出来,具有较好的治疗效果。(The invention discloses a novel oral ulcer double-layer film capable of releasing medicine in one direction, which is characterized in that the oral ulcer double-layer film has a double-layer structure, and one layer is a medicine-carrying layer which is in contact with an oral ulcer surface; one layer is a hydrophobic protective layer with the functions of unidirectional drug release and anti-sticking, and the two layers are bonded by an adhesive; the drug-loaded layer consists of a drug, a hydrophilic film-forming material, a penetration enhancer, a first plasticizer and a first solvent; the hydrophobic protective layer is composed of a hydrophobic film forming material, a second plasticizer and a second solvent. The novel one-way drug release oral ulcer double-layer film provided by the invention has the advantages that the drugs are dispersed or dissolved in the drug-carrying layer, the hydrophobic protective layer does not contain the drugs, the drug-carrying layer can generate viscosity when meeting water, the hydrophilic biological adhesive material in the drug-carrying layer can be adhered to the ulcer surface, the drugs can be gradually released along with the penetration of the water, and the better treatment effect is realized.)

1. A novel oral ulcer double-layer film with unidirectional drug release is characterized in that the oral ulcer double-layer film has a double-layer structure, one layer is a drug-loaded layer (1) which is contacted with an oral ulcer surface (3); one layer is a hydrophobic protective layer (2) with the functions of unidirectional drug release and anti-sticking, and the two layers are bonded by an adhesive;

the drug-loaded layer (1) consists of a drug, a hydrophilic film-forming material, a penetration enhancer, a first plasticizer and a first solvent, wherein the mass ratio of the drug to the hydrophilic film-forming material to the penetration enhancer to the first plasticizer to the first solvent is 1: 12-13: 1.48-2.12: 2.52-5.04: 80-120;

the hydrophobic protective layer (2) is composed of a hydrophobic film forming material, a second plasticizer and a second solvent, and the mass ratio of the hydrophobic film forming material to the second plasticizer to the second solvent is 1: 0.096-0.19: 7.90-9.48.

2. The novel unidirectional release canker sore bilayer membrane according to claim 1 wherein the drug is metronidazole.

3. The novel one-way release oral ulcer double-layer membrane as claimed in claim 1, wherein the hydrophilic membrane-forming material is chitosan and bletilla polysaccharide, and the mass ratio of the chitosan to the bletilla polysaccharide is 1: 70-136.

4. The novel unidirectional release oral ulcer bilayer membrane according to claim 1, wherein the penetration enhancer is polysorbate 80.

5. The novel unidirectional release canker sore bilayer membrane according to claim 1 wherein the first plasticizer is glycerol.

6. The novel unidirectional release canker sore bilayer membrane according to claim 1 wherein the first solvent is an acetic acid solution with a mass concentration of 1%.

7. The novel unidirectional release canker sore bilayer membrane according to claim 1 wherein the hydrophobic film forming material is ethyl cellulose, the second plasticizer is castor oil and the second solvent is absolute ethanol.

8. The novel unidirectional release canker sore bilayer membrane according to claim 1 wherein the adhesive is a chitosan acetic acid solution with a mass concentration of 2%.

9. A method for preparing the novel unidirectional drug release canker sore bilayer membrane according to any one of claims 1-8, which comprises the following steps:

s1, adding the medicine into a first solvent, adding a penetration enhancer, adding a hydrophilic film forming material after ultrasonic dissolution, heating to dissolve at 75 ℃, adding a first plasticizer, stirring, defoaming, coating and drying to obtain a medicine carrying layer (1);

the mass ratio of the medicine to the hydrophilic film forming material to the penetration enhancer to the first plasticizer to the first solvent is 1: 12-13: 1.48-2.12: 2.52-5.04: 80-120;

s2, adding the hydrophobic film-forming material and a second plasticizer into a second solvent, stirring for dissolving, coating, and drying to obtain a hydrophobic protective layer (2);

the mass ratio of the hydrophobic film forming material to the second plasticizer to the second solvent is 1: 0.096-0.19: 7.90-9.48;

s3, adding chitosan into an acetic acid solution with the mass concentration of 1%, and stirring to dissolve to obtain an adhesive;

s4, coating the adhesive obtained in the step S3 on the hydrophobic protective layer (2) obtained in the step S2, then adhering the drug-loaded layer (1) obtained in the step S1 on the surface of the hydrophobic protective layer (2) through the adhesive, drying, and then carrying out closed packaging by adopting aluminum-plastic composite paper to obtain the novel one-way drug release oral ulcer double-layer film.

10. The method for preparing the novel unidirectional drug release oral ulcer bilayer membrane is characterized in that in the step S4, the drying time is 2-3 h.

Technical Field

The invention belongs to the technical field of medicinal preparations, and particularly relates to a novel one-way drug release oral ulcer double-layer film and a preparation method thereof.

Background

Oral mucosal ulcer is a very common ulcerative lesion occurring in the oral mucosa, and is mostly seen in the inner lip, vestibular groove, tongue, buccal mucosa, soft palate and other positions, and the mucosa in these positions has poor keratinization or lacks of a cutinized layer. The oral mucosa ulcer is usually accompanied with severe pain during the onset, obvious burning pain exists on the local part, the speaking and eating can be influenced under the serious condition, the general complications such as halitosis, chronic pharyngitis, constipation, dysphoria, dizziness, headache, nausea, fever, hypodynamia, lymphadenectasis and the like also exist, and the normal life of people is greatly influenced.

The etiology of oral ulcers may be a combination of factors including mental stress, topical trauma, malnutrition, medications, food, altered hormone levels, vitamin or trace element deficiencies. Generally, the western medicine considers that the disease is caused by the deficiency of vitamins and trace elements, and particularly, the iron deficiency and the B vitamins are more susceptible to the disease. At present, the clinical treatment of symptoms such as inflammation diminishing, antibiosis, pain relieving and the like is still mainly performed, and the dosage forms of the commonly used medicinal preparations are as follows: solution, aerosol, powder spray, patch, topical powder, etc., and the administration method comprises oral administration, gargle, topical mucosa topical application, etc. Wherein, the external film pasting agent is most commonly used, and is directly acted on the affected part of ulcer mucosa, and has the advantages that: can cover the surface of a wound, avoid repeatedly stimulating the ulcer surface and facilitate the healing of the surface of the wound; direct action of the medicine, small side effect and the like. However, most of the oral ulcer films on the market are single-layer films, the biological adhesion performance is poor, the residence time at the focus part is short, and the curative effect is not ideal; most of the drugs are released in saliva, but the amount of the drugs actually absorbed by ulcer surfaces only accounts for a small part, and some drugs can generate side effects after being absorbed by non-ulcer oral mucosa.

Clinically, the commonly used external film-sticking agent mainly comprises an antibiotic film, a traditional Chinese medicine film, a hormone film and the like. However, the antibiotic membrane has an insignificant effect on oral ulcer caused by local immune abnormality, the traditional Chinese medicine membrane has a poor effect on inflammatory reaction, and the hormone membrane cannot promote tissue repair well. Most of the existing oral ulcer films on the market are single-layer films, the biological adhesion performance is poor, the detention time at the focus part is short, and the curative effect is not ideal; most of the drugs are released in saliva, but the amount of the drugs actually absorbed by the ulcer surface is only a small part (the drug release is not unidirectional), and some drugs can generate side effects after being absorbed by non-ulcer oral mucosa.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a novel oral ulcer double-layer film releasing drugs in one direction and a preparation method thereof.

The first purpose of the invention is to provide a novel oral ulcer double-layer film with unidirectional drug release, which has a double-layer structure, wherein one layer is a drug-loaded layer which is in contact with an oral ulcer surface; one layer is a hydrophobic protective layer with protective effect, and the two layers are bonded through an adhesive;

the drug-loaded layer consists of a drug, a hydrophilic film-forming material, a penetration enhancer, a first plasticizer and a first solvent, and the mass ratio of the drug to the hydrophilic film-forming material to the penetration enhancer to the first plasticizer to the first solvent is 1: 12-13: 1.48-2.12: 2.52-5.04: 80-120;

the hydrophobic protective layer is composed of a hydrophobic film forming material, a second plasticizer and a second solvent, and the mass ratio of the hydrophobic film forming material to the second plasticizer to the second solvent is 1: 0.096-0.19: 7.90-9.48.

Preferably, the drug of the drug-loaded layer is metronidazole.

Preferably, the hydrophilic film-forming material is chitosan and bletilla polysaccharide, and the mass ratio of the chitosan to the bletilla polysaccharide is 1: 136-1: 70.

Preferably, the penetration enhancer is polysorbate 80.

Preferably, the first plasticizer is glycerol.

Preferably, the first solvent is an acetic acid solution with a mass concentration of 1%.

Preferably, the hydrophobic film-forming material is ethyl cellulose.

Preferably, the second plasticizer is castor oil.

Preferably, the second solvent is absolute ethyl alcohol.

The adhesive is chitosan acetic acid solution with the mass concentration of 2%.

The second purpose of the invention is to provide a preparation method of the oral ulcer double-layer film, which comprises the following steps:

s1, adding the medicine into a first solvent, adding a penetration enhancer, adding a hydrophilic film forming material after ultrasonic dissolution, heating to dissolve at 75 ℃, adding a first plasticizer, stirring, defoaming, coating and drying to obtain a medicine carrying layer;

the mass ratio of the medicine to the hydrophilic film forming material to the penetration enhancer to the first plasticizer to the first solvent is 1: 12-13: 1.48-2.12: 2.52-5.04: 80-120;

s2, adding the hydrophobic film forming material and a second plasticizer into a second solvent, stirring for dissolving, defoaming, coating and drying to obtain a hydrophobic protective layer;

the mass ratio of the hydrophobic film forming material to the second plasticizer to the second solvent is (1: 0.096) - (0.19: 7.90) - (9.48):

s3, adding chitosan into an acetic acid solution with the mass concentration of 1%, and stirring to dissolve to obtain an adhesive solution;

s4, coating the adhesive solution obtained in the step S3 on the hydrophobic protective layer obtained in the step S2, then adhering the drug-loaded layer obtained in the step S1 on the surface of the hydrophobic protective layer through the adhesive solution, drying, and then carrying out closed packaging by adopting aluminum-plastic composite paper to obtain the novel one-way drug-release oral ulcer double-layer film.

Preferably, in step S4, the drying time is 2 to 3 hours.

Compared with the prior art, the invention has the beneficial effects that:

(1) the novel one-way-release oral ulcer double-layer membrane provided by the invention has an upper layer structure and a lower layer structure, the medicines are dispersed or dissolved in the medicine carrying layer, the hydrophobic protective layer does not contain the medicines, the medicine carrying layer generates viscosity when meeting water, the hydrophilic biological adhesion material in the medicine carrying layer can be adhered to the ulcer surface, the medicines can be gradually released along with the permeation of water, and the hydrophobic protective layer is made of a material which is difficult to dissolve in water, so that the medicines are only released towards the ulcer surface in one way, can be absorbed by the ulcer surface in a large amount, and has a better treatment effect;

(2) the hydrophilic biological adhesive material in the drug-loaded layer has the functions of resisting bacteria, covering and protecting ulcer surfaces and promoting the repair of the ulcer surfaces besides being used as a film-forming material, and has the characteristic of 'drug-assisted integration';

(3) the hydrophilic bioadhesive material in the medicine-carrying layer can delay the release speed of the medicine, so that the medicine is slowly released, the local action time is long, and the pain can be relieved, the wound healing can be promoted, and the wound infection can be prevented;

(4) according to the invention, the drug-loaded layer and the hydrophobic protective layer are bonded together through the adhesive solution, so that when the oral ulcer double-layer film is used in an oral cavity, the drug-loaded layer and the hydrophobic protective layer of the oral ulcer double-layer film can not be separated, the oral ulcer double-layer film can be kept flat all the time, and the use comfort is improved;

(5) the novel one-way drug release canker sore double-layer film provided by the invention has the advantages of uniform thickness, white appearance, good viscosity, capability of generating viscosity within 3 minutes when meeting water, good film release degree and capability of releasing most of drugs within 30 minutes.

Drawings

FIG. 1 is a schematic view of the contact between a bilayer membrane of a canker sore and a canker sore surface provided in example 1 of the present invention;

FIG. 2 is a graph showing the dissolution rate of the bilayer membrane for oral ulcer provided in example 1 of the present invention and the bilayer membrane provided in comparative example 9;

FIG. 3 is a graph of the dissolution profiles of the bilayer films provided in examples 1 and 2 of the present invention and the bilayer film provided in comparative example 11;

FIG. 4 is a graph showing the dissolution profiles of the bilayer films provided in example 1 of the present invention and comparative examples 1 and 2;

FIG. 5 is a dissolution rate graph of the bilayer film provided in example 1 of the present invention and the drug-loaded layer in example 1 of the present invention;

in the figure: 1. a drug-loaded layer; 2. a hydrophobic protective layer; 3. oral ulcer surface.

Detailed Description

Exemplary embodiments of the present disclosure will be described in more detail below with reference to the accompanying drawings. While exemplary embodiments of the present disclosure are shown in the drawings, it should be understood that the present disclosure may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.

The test methods not specifically described in the following examples were carried out according to conventional methods and conditions in the art, and the starting materials were commercially available.

Example 1

The embodiment of the invention provides a novel oral ulcer double-layer film with unidirectional drug release, which has a double-layer structure, wherein one layer is a drug-loaded layer 1 which is in contact with an oral ulcer surface 3; one layer is a hydrophobic protective layer 2 with protective effect, and the two layers are bonded through an adhesive;

the drug-loaded layer 1 is composed of a drug, a hydrophilic film-forming material, a penetration enhancer, a first plasticizer and a first solvent, and the mass ratio of the drug, the hydrophilic film-forming material, the penetration enhancer, the first plasticizer and the first solvent is 1:12.5:1.59:3.02: 89. The medicine is metronidazole, the hydrophilic film-forming material is chitosan and bletilla polysaccharide, the mass ratio of the chitosan to the bletilla polysaccharide is 1:136, the penetration enhancer is polysorbate 80, the first plasticizer is glycerol, the first solvent is acetic acid with the mass concentration of 1%, and the adhesive is a chitosan acetic acid solution with the mass concentration of 2%;

the hydrophobic protective layer 2 is composed of a hydrophobic film forming material, a second plasticizer and a second solvent, and the mass ratio of the hydrophobic film forming material to the second plasticizer to the second solvent is 1:0.096: 7.90.

Wherein the hydrophobic film forming material is ethyl cellulose, the second plasticizer is castor oil, and the second solvent is absolute ethyl alcohol.

The embodiment of the invention also provides a preparation method of the oral ulcer double-layer film, which comprises the following steps:

s1, adding 167.8mg of metronidazole into 15mL of acetic acid solution with the mass concentration of 1%, then adding 0.25mL of polysorbate 80, ultrasonically dissolving at 250W and 40kHz, respectively adding 15.4mg of chitosan and 2092mg of bletilla striata polysaccharide, heating and dissolving at 75 ℃, adding 0.4mL of glycerol, stirring, defoaming, coating and drying to obtain a drug-loaded layer 1;

s2, adding 1.00g of ethyl cellulose and 0.1mL of castor oil into 10mL of absolute ethyl alcohol, stirring to dissolve, coating, and drying to obtain a hydrophobic protective layer;

s3, adding 2g of chitosan into 100mL of acetic acid solution with the mass concentration of 1% to obtain chitosan acetic acid solution with the mass concentration of 2%;

s4, coating the chitosan acetic acid solution obtained in the step S3 on the hydrophobic protective layer obtained in the step S2, then adhering the drug-loaded layer obtained in the step S1 on the surface of the hydrophobic protective layer through the chitosan acetic acid solution, drying for 2 hours at 60 ℃, and then carrying out closed packaging by adopting aluminum-plastic composite paper to obtain the novel one-way drug release oral ulcer double-layer film.

Example 2

The structure and the preparation method of the novel unidirectional-release oral ulcer double-layer membrane provided by the embodiment of the invention are the same as those of the embodiment 1, and the differences are only that the mass ratio of the drug, the hydrophilic film-forming material, the penetration enhancer, the first plasticizer to the first solvent is 1:12:1.48:2.52:80, the mass ratio of the hydrophobic film-forming material, the second plasticizer to the second solvent is 1:0.15:8.65, and the mass ratio of chitosan to bletilla striata polysaccharide is 1: 90.

Example 3

The structure and the preparation method of the novel unidirectional-release oral ulcer double-layer membrane provided by the embodiment of the invention are the same as those of the embodiment 1, and the differences are only that the mass ratio of the drug, the hydrophilic film-forming material, the penetration enhancer, the first plasticizer to the first solvent is 1:13:2.12:5.04:120, the mass ratio of the hydrophobic film-forming material, the second plasticizer to the second solvent is 1:0.19:9.48, and the mass ratio of chitosan to bletilla striata polysaccharide is 1: 70.

Example 4

The structure and preparation method of the novel unidirectional-release oral ulcer double-layer film provided by the embodiment of the invention are the same as those of the embodiment 1, and the difference is that in the step S4, the drying time is 3 h.

Comparative example 1

The comparative example provides a novel oral ulcer double-layer film with unidirectional drug release, the oral ulcer double-layer film has a double-layer structure, and one layer is a drug-loaded layer which is contacted with an oral ulcer surface; one layer is a hydrophobic protective layer with protective effect, and the two layers are bonded through an adhesive solution;

the drug-loaded layer consists of a drug, a film-forming material, a penetration enhancer, a plasticizer and a solvent, and the mass ratio of the drug to the film-forming material to the penetration enhancer to the plasticizer to the solvent is 1:11.4:1.59:3.024: 89.

The medicine is metronidazole, the film-forming materials are chitosan and bletilla polysaccharide, the mass ratio of the chitosan to the bletilla polysaccharide is 1:63, the penetration enhancer is polysorbate 80, the plasticizer is glycerol, the solvent is acetic acid with the mass concentration of 1%, and the adhesive solution is chitosan solution.

The comparative example also provides a preparation method of the oral ulcer double-layer film, which comprises the following steps:

s1, adding 167.2mg of metronidazole into 15mL of 1% acetic acid, then adding 0.25mL of polysorbate 80, respectively adding 29.9mg of chitosan and 1908.5mg of bletilla striata polysaccharide after ultrasonic dissolution, heating and dissolving at 75 ℃, adding 0.4mL of glycerin, stirring, defoaming, coating and drying to obtain a drug-loaded layer;

s2, adding 1.00g of ethyl cellulose and 0.1ml of castor oil into 10ml of absolute ethyl alcohol, stirring to dissolve, coating, and drying to obtain a hydrophobic protective layer;

s3, adding chitosan into 1% acetic acid to obtain 2% chitosan acetic acid solution; (ii) a

S4, coating chitosan solution on the hydrophobic protective layer obtained in the step S2, then covering the drug-loaded layer obtained in the step S1 on the surface of the coated chitosan solution, drying for 2 hours at 60 ℃ to obtain the novel oral ulcer double-layer film releasing drugs in a single direction, and carrying out closed packaging by adopting aluminum-plastic composite paper.

Comparative example 2

The comparative example provides a drug-loaded layer, which consists of a drug, a film-forming material, a penetration enhancer, a plasticizer and a solvent, wherein the mass ratio of the drug to the film-forming material to the penetration enhancer to the plasticizer to the solvent is 1:11.1:1.59:3.024: 89.

The medicine is metronidazole, the film-forming materials are chitosan and bletilla polysaccharide, the mass ratio of the chitosan to the bletilla polysaccharide is 1:41, the penetration enhancer is polysorbate 80, the plasticizer is glycerol, the solvent is acetic acid with the mass concentration of 1%, and the adhesive solution is 2% chitosan acetic acid solution.

The preparation method of the drug-loaded layer specifically comprises the following steps:

adding 168.0mg of metronidazole into 15mL of 1% acetic acid, then adding 0.25mL of polysorbate 80, respectively adding 45.1mg of chitosan and 1688.4mg of bletilla striata polysaccharide after ultrasonic dissolution, heating and dissolving at 75 ℃, then adding 0.40mL of glycerin, stirring, defoaming, coating and drying to obtain a drug-loaded layer;

comparative example 3

A drug-loaded layer is prepared by the following method:

adding 170.0mg metronidazole into 15mL of 1% acetic acid, adding 0.25mL polysorbate 80, ultrasonically dissolving, adding 400mg chitosan, heating to dissolve at 75 deg.C, adding 0.40mL glycerin, stirring, defoaming, coating, and drying to obtain drug-loaded layer.

Comparative example 4

A drug-loaded layer is prepared by the following method:

adding 168.2mg metronidazole into 15mL of 1% acetic acid, adding 0.25mL polysorbate 80, ultrasonically dissolving, adding 1201.5mg rhizoma Bletillae polysaccharide, heating at 75 deg.C for dissolving, adding 0.40mL glycerol, stirring, defoaming, coating, and drying to obtain drug-loaded layer.

Comparative example 5

A hydrophobic protective layer is prepared by the following method:

adding 0.50g of ethyl cellulose and 0.1mL of castor oil into 10mL of absolute ethyl alcohol, stirring for dissolving, coating, and drying to obtain the hydrophobic protective layer.

Comparative example 6

A hydrophobic protective layer is prepared by the following method:

adding 1.50g of ethyl cellulose and 0.1mL of castor oil into 10mL of absolute ethyl alcohol, stirring for dissolving, coating, and drying to obtain the hydrophobic protective layer.

Comparative example 7

This comparative example is the same as the preparation method of the oral ulcer bilayer membrane provided in example 1 except that, in step S4, the hydrophobic protective layer and the drug-loaded layer are not adhered by an adhesive, but the drug-loaded layer is directly coated on the hydrophobic protective layer to obtain the oral ulcer bilayer membrane.

Comparative example 8

This comparative example is the same as the preparation method of the oral ulcer bilayer membrane provided in example 1 except that the adhesive is replaced with absolute ethanol in step S3.

Comparative example 9

This comparative example is the same as the preparation method of the oral ulcer bilayer membrane provided in example 1 except that, in step S3, the binder was replaced with a mixture of chitosan and bletilla polysaccharide, and the mass ratio of chitosan to bletilla polysaccharide was 10: 90.

Comparative example 10

A drug-loaded layer is prepared by the following method:

respectively adding 15.4mg of chitosan and 2091.7mg of bletilla striata polysaccharide into 15mL of 1% acetic acid, ultrasonically dissolving, adding 168.0mg of metronidazole, then adding 0.25mL of polysorbate 80, heating to dissolve at 75 ℃, adding 0.40mL of glycerin, stirring, defoaming, coating and drying to obtain a drug-loaded layer.

Comparative example 11

This comparative example was identical to the preparation method of the oral ulcer bilayer membrane provided in example 1, except that the drying time was 4 hours in step S4.

First, the novel unidirectional drug release oral ulcer double-layer film provided in example 1 of the present invention and the films provided in comparative examples 1 to 11 are taken as examples, and various physicochemical properties thereof are studied respectively.

1. State evaluation criteria

(1) Film forming property

TABLE 1 film formation evaluation criteria

(2) Film forming property

TABLE 2 evaluation criteria for film formability

(3) Ductility of the alloy

TABLE 3 ductility evaluation criteria

2. Preparation of artificial saliva

According to ISO/TR 10271 standard, the pH is adjusted to 6.8 with sodium hydroxide, and the artificial saliva components comprise sodium chloride 0.4g, potassium chloride 0.4g, calcium chloride dihydrate 0.795g, sodium dihydrogen phosphate dihydrate 0.78g, sodium sulfide dihydrate 0.005g, urea 1g, and distilled water 1L.

3. Dissolution rate

(1) Selection of dissolution method

The pulp method is selected, and according to the regulation of Chinese pharmacopoeia (2020 edition), the dissolution medium is artificial saliva, the temperature is 32 ℃, and the rotating speed is 50 r/min.

(2) Determination of dissolution

The oral ulcer membranes prepared in the invention in the example 1, the example 2, the comparative example 1, the comparative example 2, the comparative example 9 and the comparative example 11 are respectively taken, the oral ulcer membranes are wetted and attached to the bottom of a dissolution cup by water, 1L of artificial saliva with the temperature of 32 ℃ is added to be taken as a dissolution medium, the set rotating speed is 50r/min, 2mL of the oral ulcer membranes are sucked at different time points, the oral ulcer membranes are centrifuged at 15000r/min for 15min, and the contents of the oral ulcer membranes are measured by an HPLC method.

4. Swelling test

The films prepared in example 1, comparative example 2, comparative example 3 and comparative example 4 were placed in a beaker containing 100ml of artificial saliva and observed for swelling.

5. Test results and analysis

(1) Study of conditions

The states of the drug-loaded layer in example 1 of the present invention and the drug-loaded layers prepared in comparative examples 1 to 4 were evaluated, respectively, and the evaluation results are shown in table 4 below.

TABLE 4 evaluation of the state of the drug-loaded layers prepared in inventive example 1 and comparative examples 1 to 4

The results in Table 4 show that the swelling time is too long for comparative example 3 using chitosan as a film forming material, while the swelling time is too short for comparative example 4 using bletilla polysaccharide as a film forming material, and when chitosan and bletilla polysaccharide are selected as film forming materials, drug-loaded layers having a suitable swelling time can be obtained (example 1 and comparative example 1).

(2) Influence of the sequence of drug addition on the physicochemical properties of the drug-loaded layer

The physicochemical properties of the drug-loaded layer provided in example 1 of the present invention and the drug-loaded layer prepared in comparative example 10 were studied, and it was found through the study that when a drug was added before the addition of the film-forming material (example 1), the drug was uniformly dissolved, the solution was clear and transparent, and after the dissolution of the film-forming material, the gum solution was uniform, easy to coat, and the film-forming material was transparent and tough, whereas when a drug was added after the addition of the film-forming material (comparative example 10), the drug was not uniformly dissolved and distributed, and there was an apparently undissolved solid after the film-forming, therefore, the order of addition of the drug in example 1 of the present invention had a critical influence on the properties of the drug-loaded layer obtained by the preparation, and the drug should be added before the addition of the film-forming material, and after the dissolution, the film-forming material was added.

(3) Influence of ethyl cellulose addition on hydrophobic protective layer film formation

The film forming properties of the hydrophobic protective layer provided in example 1 of the present invention and the hydrophobic protective layers provided in comparative examples 5 and 6 were investigated, and the film forming results are shown in table 5 below.

TABLE 5 hydrophobic protective layer formation

	Comparative example 5	Example 1	Comparative example 6
				Film formation conditions	Poor and incomplete membrane	Good taste	Generally, the film is hard

The results in Table 5 show that the hydrophobic protective layer formed relatively well when the amount of ethylcellulose added was 1.00g, and that the hydrophobic protective layer formed not well when other amounts were used.

(4) Influence of composite mode of drug-loaded layer and hydrophobic protective layer on stability and flatness of oral ulcer double-layer film

The canker sore double-layer film provided in example 1 of the present invention and the canker sore double-layer films provided in comparative examples 1 to 9 were put in artificial saliva in the same size, and whether separation occurred or not was observed, and the stability and flatness thereof were investigated, and the results are shown in table 6 below.

TABLE 6 evaluation of different compounding methods

As can be seen from the results of table 6, the double-layer film (comparative example 7) obtained by directly coating the drug-loaded layer on the hydrophobic protective layer was not separated in artificial saliva but was not flat, and the double-layer film obtained by using the chitosan provided in example 1 of the present invention and the mixture of chitosan and bletilla polysaccharide provided in comparative example 9 as binders was not separated in artificial saliva and was flat.

(5) Effect of different binders on dissolution of the prepared bilayer films

The dissolution rates of the canker sore bilayer membrane provided in example 1 of the present invention and the bilayer membrane provided in comparative example 9 were measured, respectively, and the measurement results are shown in table 7 below and fig. 2.

Table 7 dissolution of bilayer films prepared with different binders

As can be seen from the results of table 7 and fig. 2, the dissolution rates of the bilayer films prepared in example 1 and comparative example 9 of the present invention are not much different, but the operation is simple by using chitosan as the binder, and chitosan is selected as the binder for the drug-loaded layer and the hydrophobic protective layer based on the combination of the process simplification and the cost.

(6) Effect of different drying times on dissolution of bilayer films

The dissolution rates of the two-layer films provided in examples 1 and 2 of the present invention and the two-layer film provided in comparative example 11 were measured, respectively, and the results are shown in table 8 and fig. 3 below.

As can be seen from the results of table 8 and fig. 3, different drying times affect the dissolution rates of the bilayer films, and the dissolution rates of the bilayer films provided in examples 1 and 2 of the present invention are superior to the dissolution rate of the bilayer film provided in comparative example 11.

(6) Influence of ratio of chitosan and bletilla polysaccharide in film-forming material on dissolution rate of double-layer film

Dissolution rates of the bilayer films provided in example 1 of the present invention and comparative examples 1 and 2 were measured, respectively, and the results of the measurements are shown in the following table 9 and fig. 4.

As can be shown from the results of table 9 and fig. 4, at the same time, the dissolution rate of the bilayer membrane provided in example 1 of the present invention is significantly better than that of the bilayer membrane provided in comparative example 1 and comparative example 2, which indicates that the smaller the ratio of chitosan to bletilla polysaccharide, i.e., the less chitosan, the higher the dissolution rate of the bilayer membrane.

(7) Dissolution comparative analysis of Single-layer film and double-layer film

The dissolution rates of the bilayer film provided in example 1 of the present invention and the drug-loaded layer in example 1 of the present invention were respectively studied, and the results of the studies are shown in table 10 below and fig. 5.

Table 10 dissolution rates of bilayer film and drug-loaded layer provided in example 1 of the present invention

As can be seen from the results in Table 10 and FIG. 5, the release rate of the single-layer film is greater than that of the double-layer film at the same time, and the release rate of the single-layer film is about twice that of the double-layer film in the first five minutes, the single-layer film can release most of the drugs within 15 minutes, and the double-layer film can release most of the drugs within 30 minutes, which indicates that the double-layer film has the effect of unidirectional drug release.

Secondly, the following is a preliminary drug effect test study by taking the novel one-way drug release oral ulcer double-layer film provided in example 1 of the invention as an example

1. Test method

(1) Criteria for recurrent oral ulcer cases:

the oral ulcer has obvious pain, periodic attack, self-limiting course and repeated attack of ulcer. The ulcer is started for less than 48 hours, the diameter of the ulcer is 2-4 mm, the center of the ulcer surface is sunken, the base is not hard, a hyperemia and halation zone with the thickness of about 1mm is arranged at the periphery, and a light yellow or grey-white false membrane is arranged on the surface.

(2) Subject: in the school, 35 samples are collected in an accumulated way for oral ulcer patients in teachers, family members, students and friends and relatives.

(3) The test formulation: the metronidazole single-direction drug release double-layer film provided by the embodiment 1 of the invention, the drug-carrying layer provided by the embodiment 1 of the invention and the traditional metronidazole single-layer film are prepared by the following method: adding 167.8mg metronidazole into 15mL of 1% acetic acid, adding 0.25mL of polysorbate 80, ultrasonic dissolving, adding 2107.4mg polyvinyl alcohol (05-88) respectively, heating at 75 deg.C for dissolving, adding 0.40mL of glycerin, stirring, defoaming, coating, and drying.

(4) Grouping and administration methods:

(41) grouping: the subjects were divided into a one-way drug release two-layer film treatment group, a single-layer film treatment group and a control group.

(42) The administration method comprises: the subject is allowed to open his mouth to expose the affected part, and the medicinal film is cut into suitable size according to the area of the ulcer surface, and applied on the ulcer surface 4 times a day, namely, once in the morning, in the middle of the day, and once before sleep. Wherein, the double-layer film treatment group is used for administering the novel oral ulcer double-layer film with unidirectional drug release provided by the embodiment 1 of the invention, the single-layer film treatment group is used for administering the drug-loaded layer provided by the embodiment 1 of the invention, and the control group is used for administering the traditional metronidazole single-layer film.

(5) The curative effect judgment:

the effect is shown: 4d, ulcer healing, pain symptom disappearance of the patient and ulcer recurrence intermittence period prolonging;

the method has the following advantages: 4 days, the ulcer is about to heal or shrink obviously, the pain symptom is relieved obviously, and the recurrence intermission period of the ulcer is prolonged.

And (4) invalidation: the ulcer does not shrink obviously or pain symptoms are not relieved obviously at 4 days, and the recurrence interval of the ulcer is not prolonged obviously.

(6) Subject medication compliance score

And 5, dividing: convenient application, good adhesiveness, good protection for covering ulcer surface and long duration

And 4, dividing: convenient application, general adhesiveness, good protection for covering ulcer surface and long duration

And 3, dividing: the plaster is not convenient to apply, has general adhesiveness, general protective property for covering ulcer surfaces and short duration

And 2, dividing: the paste is not convenient to apply, has poor adhesion, has poor covering protection on ulcer surfaces and has short duration

2. Test results and analysis

(1) Efficacy comparison: the results of the three groups are shown in Table 11 below.

TABLE 11 comparison of efficacy of three groups of subjects

The results in table 11 show that the total effective rates of the double-layer membrane treatment group and the control group are compared, and through Ridit analysis, the difference between the two groups has statistical significance (P <0.05), which indicates that the double-layer membrane treatment group is superior to the control group; the total effective rate of the single-layer membrane treatment group is compared with that of the control group, and through Ridit analysis, the difference between the two groups has statistical significance (P <0.05), which indicates that the single-layer membrane treatment group is superior to the control group; the total effective rate of the double-layer film treatment group is compared with that of the single-layer film treatment group, and through Ridit analysis, the difference between the two groups has statistical significance (P is less than 0.10), which indicates that the double-layer film treatment group is superior to the single-layer film treatment group. The data analysis shows that the one-way drug release double-layer film has more obvious advantages compared with a single-layer film for treating the oral ulcer, and the film-forming materials, namely the bletilla polysaccharide and the chitosan, have a certain treatment effect on the oral ulcer.

(2) Subject medication compliance comparison: the subject medication compliance results for the three groups are shown in table 12 below.

TABLE 12 statistics of medication compliance scores for three groups of subjects

As can be seen from the results in table 12, the difference between the scores of the double-layer membrane treated group and the control group was statistically significant (P <0.05) by Ridit analysis; the total effective rate of the single-layer membrane treatment group is compared with that of the control group, and through Ridit analysis, the difference between the single-layer membrane treatment group and the control group has no statistical significance (P is more than 0.05); the total effective rate of the double-layer film treatment group and the single-layer film treatment group is compared, and the difference between the two groups has statistical significance (P <0.10) through Ridit analysis. The data analysis shows that the bletilla polysaccharide and the chitosan have strong biological adhesion to the oral ulcer, and the double-layer film has good covering protection to the ulcer surface and longer duration.

In summary, the two-layer films prepared in examples 1 to 4 of the present invention have uniform film thickness, white appearance and good adhesiveness, and can generate adhesiveness within 3 minutes when meeting water. The membrane release degree is better.

It should be noted that when the following claims refer to numerical ranges, it should be understood that both ends of each numerical range and any value between the two ends can be selected, and since the steps and methods used are the same as those in embodiments 1-4, the present invention describes preferred embodiments in order to prevent redundancy, but once the basic inventive concept is known, those skilled in the art can make other changes and modifications to these embodiments. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention. It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.