CN109953984A - A kind of compound tetracaine hydrochloride film and preparation method thereof - Google Patents

Abstract

The invention discloses a compound tetracaine hydrochloride film and a preparation method thereof. The compound tetracaine hydrochloride film is prepared from tetracaine hydrochloride, gentamicin sulfate, hydrocortisone, sodium carboxymethyl cellulose (CMC-Na), polyvinyl alcohol (PVA), glycerin and purified water. to make. When adding the drug into the film-forming material, the FLUKO FA25 high-shear dispersing emulsifier is used for stirring. Compared with the traditional manual stirring, the texture of the drug liquid is uniform and fine, and the work efficiency is high. In the film laying process, the electric film laying device is used to replace the original manual film laying method, which solves the problems of low production efficiency, uneven thickness of the drug film, and the weight difference limit in the quality inspection does not meet the regulations. The electric film spreader is easy to operate and can precisely control the film laying rate and the thickness of the film agent. The film laying is uniform, the flatness is good, the thickness is controllable and the production efficiency is greatly improved. The local application of the present invention is used to treat oral ulcers, has anti-inflammatory and analgesic effects, strong pertinence, obvious curative effect, easy acceptance by patients, and is an ideal oral ulcer treatment drug.

Description

A kind of compound tetracaine hydrochloride film and preparation method thereof

technical field

The invention relates to a compound tetracaine hydrochloride film and a preparation method thereof. The invention belongs to the technical field of pharmaceutical production.

Background technique

Recurrent oral ulcer (ROU) is a common oral mucosal disease, which is painful at the onset and lasts for a long time. Because of its recurring characteristics, it brings great pain to patients. ROU may be related to local trauma, stress, diet, drugs, hormones, and lack of vitamins and trace elements, and the main causes are still under study.

Films are film-like dosage forms made by dissolving or uniformly dispersing drugs in film-forming materials, which can be used for oral or mucosal applications. Oral films (OFs), also known as oral dispersing films (Oradispersible films), oral fast dissolving films (Oral Fast dissolving Films, Fast dissolving films, Oraldissolvable films, Orally dissolving strips), etc., are characterized by direct action on On the affected area, the effect is fast and the effect is long-lasting; the drug content is accurate, the stability is good; the weight is light, the volume is small, and the application is convenient.

The film can be firmly adhered to the mucous membrane through the adhesive component, which resists the clearing effect of saliva and swallowing to a certain extent, which is beneficial to protect the ulcer surface, prolong the action time of the drug, exert the drug effect better, and reduce the occurrence of ulcers. The frequency and severity of ulceration are currently the first-line treatment for ROU.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a compound tetracaine hydrochloride film and a preparation method thereof.

In order to achieve the above object, the present invention has adopted the following technical means:

A compound tetracaine hydrochloride film of the present invention is composed of tetracaine hydrochloride, gentamicin sulfate, hydrocortisone, sodium carboxymethyl cellulose (CMC-Na), polyvinyl alcohol (PVA), glycerin and purified water.

Among them, preferably, the weight parts of each raw material are: tetracaine hydrochloride 0.3-0.5 weight part, gentamicin sulfate 0.1-0.3 weight part, hydrocortisone 0.1-0.3 weight part, sodium carboxymethyl cellulose (CMC-Na) 0.5-2 parts by weight, polyvinyl alcohol (PVA) 5-15 parts by weight, glycerol 1-4 parts by weight, and purified water 70-90 parts by weight.

The oral film prepared by the present invention takes the dosage of sodium carboxymethyl cellulose (CMC-Na), polyvinyl alcohol (PVA) and glycerin as the investigation factors, and takes the appearance, release degree and residence time in the oral cavity of the film as the comprehensive evaluation According to the index, the orthogonal test analysis was carried out, and the best formula and preparation process of the drug film were screened out. Among them, preferably, the mass ratio of polyvinyl alcohol to purified water is 10:100, the mass ratio of sodium carboxymethyl cellulose to purified water is 2:100, and the mass ratio of glycerol to purified water is 5:100.

Wherein, preferably, the parts by weight of each raw material are: 0.4 part by weight of tetracaine hydrochloride, 0.2 part by weight of gentamicin sulfate, 0.2 part by weight of hydrocortisone, 1.6 part by weight of sodium carboxymethyl cellulose (CMC-Na) parts by weight, 8 parts by weight of polyvinyl alcohol (PVA), 4 parts by weight of glycerin, and 80 parts by weight of purified water.

Further, the present invention also proposes a method for preparing the compound tetracaine hydrochloride film, comprising the following steps:

(1) respectively take by weighing tetracaine hydrochloride, gentamicin sulfate, hydrocortisone, sodium carboxymethyl cellulose (CMC-Na), polyvinyl alcohol (PVA) according to the parts by weight described in any one of the above ), glycerin and purified water;

(2) The weighed sodium carboxymethyl cellulose (CMC-Na) and polyvinyl alcohol (PVA) are soaked in an appropriate amount of purified water and fully swollen, and then heated and dissolved in a water bath, avoiding stirring, so that the natural dissolution is complete, Obtain the film slurry, cool it for later use;

(3) tetracaine hydrochloride, gentamicin sulfate and hydrocortisone that were weighed were dissolved by ultrasonic wave with an appropriate amount of purified water to obtain medicinal liquid;

(4) mixing the weighed glycerol, the medicinal liquid obtained in step (3) and the membrane slurry obtained in step (2), adding remaining purified water, stirring evenly, and placing it in 60° C. water for thermal insulation and degassing to obtain medicinal slurry;

(5) Putting the medicinal slurry obtained in step (4) into an electric film spreader, adjusting the required thickness of the film agent, laying the film, naturally drying, stripping the film, dividing into pieces, and sterilizing and packaging.

Wherein, preferably, the temperature of the water bath in step (2) is 85-90°C.

Among them, preferably, in step (4), a FLUKO FA25 high-shear dispersing emulsifier is used to stir uniformly at a rotational speed of 10000-28000 rpm.

Among them, preferably, each tablet contains 6 mg of tetracaine hydrochloride.

Further, the present invention also proposes the application of the compound tetracaine hydrochloride film in preparing a medicine for treating oral ulcers.

Wherein, preferably, the drug is an oral film.

Compared with the prior art, the beneficial effects of the present invention are:

1. A compound tetracaine hydrochloride film and a preparation method thereof provided by the present invention are made into a film with anti-inflammatory and analgesic effects, and are mainly used for oral ulcers.

2. When the compound tetracaine hydrochloride film is added with drugs into the film-forming material, the FLUKO FA25 high-shear dispersing emulsifier is used for stirring at 10000-28000 rpm, and the film is laid after standing. Compared with the traditional manual stirring, the emulsification is uniform, the texture of the liquid medicine is uniform and delicate, and the work efficiency is high.

3. In the film laying process of compound tetracaine hydrochloride film, an electric film laying device is used to replace the original manual film laying method, which solves the problem of low production efficiency, uneven film thickness, and the weight difference limit in quality inspection does not meet the regulations, etc. Happening. The electric film spreader is easy to operate and can precisely control the film laying rate and the thickness of the film agent. The film laying is uniform, the flatness is good, the thickness is controllable and the production efficiency is greatly improved.

Detailed ways

In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention, but not to limit the present invention.

Example 1 Preparation of compound tetracaine hydrochloride film

Include the following steps:

(1) respectively take by weighing tetracaine hydrochloride, gentamicin sulfate, hydrocortisone, sodium carboxymethyl cellulose (CMC-Na), polyvinyl alcohol (PVA), glycerin according to the following parts by weight and purified water:

0.4 parts by weight of tetracaine hydrochloride, 0.2 parts by weight of gentamicin sulfate, 0.2 parts by weight of hydrocortisone, 1.6 parts by weight of sodium carboxymethyl cellulose (CMC-Na), 8 parts by weight of polyvinyl alcohol (PVA), 4 parts by weight of glycerol, 80 parts by weight of purified water.

(2) The weighed sodium carboxymethyl cellulose (CMC-Na) and polyvinyl alcohol (PVA) are soaked in an appropriate amount of purified water and fully swollen, and then heated and dissolved in a water bath at 85-90°C, avoiding stirring, so that the Naturally dissolve completely, obtain film slurry, cool for standby;

(3) tetracaine hydrochloride, gentamicin sulfate and hydrocortisone that were weighed were dissolved by ultrasonic wave with an appropriate amount of purified water to obtain medicinal liquid;

(4) Mix the weighed glycerol, the medicinal liquid obtained in step (3) and the membrane slurry obtained in step (2), add the remaining purified water, stir evenly with a FLUKO FA25 high shear dispersing emulsifier rotating speed of 10000 rpm, and set it to 60°C Heat preservation and de-bubbling in water to obtain medicinal slurry;

(5) Put the obtained medicinal slurry into an electric film spreader, adjust the required thickness of the film, lay the film, dry it naturally, remove the film, and cut it into pieces. Each piece contains 6 mg of tetracaine hydrochloride. After sterilization, the Pack.

Example 2 Preparation of Compound Tetracaine Hydrochloride Film

Include the following steps:

(1) respectively take by weighing tetracaine hydrochloride, gentamicin sulfate, hydrocortisone, sodium carboxymethyl cellulose (CMC-Na), polyvinyl alcohol (PVA), glycerin according to the following parts by weight and purified water:

0.5 part by weight of tetracaine hydrochloride, 0.2 part by weight of gentamicin sulfate, 0.1 part by weight of hydrocortisone, 1 part by weight of sodium carboxymethyl cellulose (CMC-Na), 15 part by weight of polyvinyl alcohol (PVA), 12 parts by weight of glycerin and 90 parts by weight of purified water.

(2) The weighed sodium carboxymethyl cellulose (CMC-Na) and polyvinyl alcohol (PVA) are soaked in an appropriate amount of purified water and fully swollen, and then heated and dissolved in a water bath at 85-90°C, avoiding stirring, so that the Naturally dissolve completely, obtain film slurry, cool for standby;

(3) tetracaine hydrochloride, gentamicin sulfate and hydrocortisone that were weighed were dissolved by ultrasonic wave with an appropriate amount of purified water to obtain medicinal liquid;

(4) Mix the weighed glycerol, the medicinal liquid obtained in step (3) and the membrane slurry obtained in step (2), add remaining purified water, stir evenly with a FLUKO FA25 high shear dispersing emulsifier rotating speed of 20000 rpm, and set it to 60°C Heat preservation and de-bubbling in water to obtain medicinal slurry;

(5) Put the obtained medicinal slurry into an electric film spreader, adjust the required thickness of the film, lay the film, dry it naturally, remove the film, and cut it into pieces. Each piece contains 6 mg of tetracaine hydrochloride. After sterilization, the Pack.

Example 3 Preparation of Compound Tetracaine Hydrochloride Film

Include the following steps:

(1) respectively take by weighing tetracaine hydrochloride, gentamicin sulfate, hydrocortisone, sodium carboxymethyl cellulose (CMC-Na), polyvinyl alcohol (PVA), glycerin according to the following parts by weight and purified water:

0.3 parts by weight of tetracaine hydrochloride, 0.3 parts by weight of gentamicin sulfate, 0.3 parts by weight of hydrocortisone, 2 parts by weight of sodium carboxymethyl cellulose (CMC-Na), 5 parts by weight of polyvinyl alcohol (PVA), 4 parts by weight of glycerol, 70 parts by weight of purified water.

(2) The weighed sodium carboxymethyl cellulose (CMC-Na) and polyvinyl alcohol (PVA) are soaked in an appropriate amount of purified water and fully swollen, and then heated and dissolved in a water bath at 85-90°C, avoiding stirring, so that the Naturally dissolve completely, obtain film slurry, cool for standby;

(3) tetracaine hydrochloride, gentamicin sulfate and hydrocortisone that were weighed were dissolved by ultrasonic wave with an appropriate amount of purified water to obtain medicinal liquid;

(4) Mix the weighed glycerin, the medicinal liquid obtained in step (3) and the membrane slurry obtained in step (2), add the remaining purified water, stir evenly with a FLUKO FA25 high shear dispersing emulsifier rotating speed of 25000 rpm, and set it to 60°C Heat preservation and de-bubbling in water to obtain medicinal slurry;

(5) Put the obtained medicinal slurry into an electric film spreader, adjust the required thickness of the film, lay the film, dry it naturally, remove the film, and cut it into pieces. Each piece contains 6 mg of tetracaine hydrochloride. After sterilization, the Pack.

Experimental Example 1 Screening of the Best Formula

1. Experimental method:

1. Take the prescription amount of PVA and CMC-Na, add an appropriate amount of purified water to soak and fully swell, and place it in a water bath of 85-90°C and heat it to clarify to obtain a membrane slurry for later use.

2. Take tetracaine hydrochloride, gentamicin sulfate, and hydrocortisone in the prescribed amount, and dissolve them with an appropriate amount of purified water ultrasonically to obtain a medicinal liquid.

3. Take the prescribed amount of glycerin, then mix the medicinal liquid with the above-mentioned membrane slurry, add the remaining purified water, stir evenly with a FLUKO FA25 high shear dispersing emulsifier at a speed of 25000 rpm, and place it in 60 ℃ water for thermal insulation and debubbling to obtain the medicinal slurry;

4. Put the obtained medicinal slurry into an electric film spreader, adjust the required thickness of the film, lay the film, dry it naturally, remove the film, and cut into pieces, each containing tetracaine hydrochloride 6mg.

2. Optimization of film formulation

1. Orthogonal experimental design

On the basis of the single factor investigation, the three main factors affecting the quality of the film agent were optimized by an orthogonal design with 3 factors and 3 levels. The experimental factors and levels are shown in Table 1, of which the A factor is the quality of PVA and purified water. The B factor is the mass ratio of CMC-Na to purified water, and the C factor is the mass ratio of glycerol to purified water.

The formulations were optimized using the appearance evaluation scores (film formation, uniformity and flexibility), oral residence time and 60min release (F60min) as indicators. The orthogonal test scheme is shown in Table 2.

Table 1 Test factor level table

Table 2 L9( ³⁴ ) Orthogonal Test Scheme

2. Appearance evaluation

Film formation: the full score is 10 points, and the weight coefficient is 0.3. Investigate the difficulty of film laying and the loss degree of the slurry (reflected by the residual amount of the machine), the easier the film laying and the less loss, the higher the score.

Uniformity: The full score is 10 points, and the weight coefficient is 0.4. Check whether the film has bubbles and whether the thickness is uniform (reflected by the thickness of different sites), the less bubbles and the smaller the thickness difference, the higher the score.

Flexibility: the full score is 10 points, and the weight coefficient is 0.3. The softness of the film agent and the ultimate strength against tensile load (reflected by the maximum load and elongation at break of the universal testing machine) were investigated.

The appearance comprehensive score results are shown in Table 3.

Table 3 Appearance evaluation results

3. Residence time

In order to examine this indicator, 18 volunteers were selected, including 9 males and 9 females, all of whom were physically and oral healthy. They were divided into 9 groups, numbered, with 1 male and 1 female in each group. The drug films prepared by 9 prescriptions were pasted on any side of the oral cavity of the subjects in the corresponding groups, fasting during the test, and recording the duration of the drug film completely dissolving or disappearing at the administration site, and calculating the average value. . The results are shown in Table 4, and the results of variance analysis are shown in Table 5.

4. Determination of release rate

The release was determined by the paddle-disc method. Add the artificial saliva to the dissolution cup, clip the medicinal film (3cm×4cm per piece) into the mesh plate, and then place the mesh plate in the lower part of the beaker, parallel to the rotating surface of the pulp bottom, adjust the temperature to 37±0.5℃, and rotate the speed 50r·min ^{- 1} , 60min sampling, with blank film as control, measure the amount of tetracaine hydrochloride by titration method, calculate the release degree of tetracaine hydrochloride. The results are shown in Table 4. The analysis of variance results are shown in Table 5.

Table 4L9(3 ⁴ ) Orthogonal test results

Table 5 Analysis of variance of orthogonal test results

It can be seen from Table 4 and Table 5 that the mass ratio of PVA to water is the main factor affecting the appearance of the film and the residence time in the oral cavity. When the ratio is 10:100, the various indicators of the appearance of the film are good. The mass ratio of glycerol to water is a secondary factor affecting the appearance of the film and residence time in the oral cavity. The main factor affecting the release of the film is the mass ratio of PVA to water. When the ratio is less than 10:100, the release of the film at 60min is greater than 75%. The optimized prescription determined by orthogonal design is A2B2C2.

Claims (10)

1. a compound tetracaine hydrochloride film, is characterized in that, described compound tetracaine hydrochloride film is made of tetracaine hydrochloride, gentamicin sulfate, hydrocortisone, sodium carboxymethyl cellulose (CMC- Na), polyvinyl alcohol (PVA), glycerin and purified water. 2. compound tetracaine hydrochloride film as claimed in claim 1, is characterized in that, the parts by weight of each raw material are: tetracaine hydrochloride 0.3-0.5 weight part, gentamicin sulfate 0.1-0.3 weight part, hydrogenation 0.1-0.3 parts by weight of cortisone, 0.5-2 parts by weight of sodium carboxymethyl cellulose (CMC-Na), 5-15 parts by weight of polyvinyl alcohol (PVA), 1-4 parts by weight of glycerin, 70-90 parts by weight of purified water parts by weight. 3. compound tetracaine hydrochloride film as claimed in claim 1 is characterized in that, the mass ratio of polyvinyl alcohol and purified water is 10:100, the mass ratio of sodium carboxymethyl cellulose and purified water is 2:100, glycerol The mass ratio with purified water is 5:100. 4. compound tetracaine hydrochloride film as claimed in claim 1 is characterized in that, the parts by weight of each raw material are: 0.4 weight part of tetracaine hydrochloride, 0.2 weight part of gentamicin sulfate, 0.2 weight part of hydrocortisone In parts by weight, 1.6 parts by weight of sodium carboxymethyl cellulose (CMC-Na), 8 parts by weight of polyvinyl alcohol (PVA), 4 parts by weight of glycerin, and 80 parts by weight of purified water. 5. a method for preparing compound tetracaine hydrochloride film as described in any one of claims 1-4, is characterized in that, comprises the following steps: (1) respectively take by weighing tetracaine hydrochloride, gentamicin sulfate, hydrocortisone, sodium carboxymethyl cellulose (CMC-Na), poly Vinyl alcohol (PVA), glycerin and purified water; (2) The weighed sodium carboxymethyl cellulose (CMC-Na) and polyvinyl alcohol (PVA) are soaked in an appropriate amount of purified water and fully swollen, and then heated and dissolved in a water bath, avoiding stirring, so that the natural dissolution is complete, Obtain the film slurry, cool it for later use; (3) tetracaine hydrochloride, gentamicin sulfate and hydrocortisone that were weighed were dissolved by ultrasonic wave with an appropriate amount of purified water to obtain medicinal liquid; (4) mixing the weighed glycerol, the medicinal liquid obtained in step (3) and the membrane slurry obtained in step (2), adding remaining purified water, stirring evenly, and placing it in 60° C. water for thermal insulation and degassing to obtain medicinal slurry; (5) Putting the medicinal slurry obtained in step (4) into an electric film spreader, adjusting the required thickness of the film agent, laying the film, naturally drying, stripping the film, dividing into pieces, and sterilizing and packaging. 6. The method of claim 5, wherein the temperature of the water bath in step (2) is 85-90°C. 7. The method according to claim 5, characterized in that, in step (4), a FLUKO FA25 high shear dispersing emulsifier rotating speed of 10000-28000rpm is used to stir evenly. 8. The method of claim 5, wherein each tablet contains 6 mg of tetracaine hydrochloride. 9. The application of the compound tetracaine hydrochloride film described in any one of claims 1-4 in the preparation of a medicament for the treatment of oral ulcers. 10. The use according to claim 9, wherein the medicine is an oral film.