CN117122584A

CN117122584A - Butyl boron compound oral dissolved film and preparation method thereof

Info

Publication number: CN117122584A
Application number: CN202311326679.9A
Authority: CN
Inventors: 刘姝吟; 陈慧; 王炜; 周峰; 张建涛
Original assignee: Ningbo Institute of Material Technology and Engineering of CAS; Cixi Institute of Biomedical Engineering CNITECH of CAS
Current assignee: Ningbo Institute of Material Technology and Engineering of CAS; Cixi Institute of Biomedical Engineering CNITECH of CAS
Priority date: 2023-10-12
Filing date: 2023-10-12
Publication date: 2023-11-28

Abstract

The application provides a butyl boron compound oral solution film and a preparation method thereof. The butyl boron compound oral-soluble film comprises eugenol, borax, a film forming agent, a plasticizer, a thickening agent, an adhesive and a flavoring agent; mixing a film forming agent with a plasticizer and borax solution, adding eugenol oil, stirring until phase separation does not occur, adding other components, degassing and soaking to obtain casting solution, and scraping the casting solution to obtain a butyl boron compound oral solution film; the oral film provided by the application has the effects of inhibiting bacteria and diminishing inflammation, has antibacterial performance superior to that of a spray product under the same drug loading, can be rapidly disintegrated in the mouth, is rapidly absorbed, has good taste, is friendly to patients, is convenient to store and transport, and is a promising substitute for clinically treating diseases such as canker sore and the like; the preparation method provided by the application has the advantages of simple process and low equipment requirement, and is suitable for industrialization.

Description

Butyl boron compound oral dissolved film and preparation method thereof

Technical Field

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a boron-butadiene compound oral solution film and a preparation method thereof.

Background

More and more people are beginning to pay attention to the health status of the oral cavity, which is a mirror reflecting the quality of life health. Canker sores, periodontitis, and the like are among the most common periodontal diseases of the oral mucosa. Wherein periodontitis can destroy hard tissues of teeth and supporting tissues around teeth, if not treated in time, periodontitis can lead to permanent tooth shedding, which not only affects functions such as chewing, speaking, beautiful appearance, but also causes social interaction difficulty and psychological disorder. Infection and inflammatory factors in the oral cavity can cause or aggravate chronic diseases such as cardiovascular and cerebrovascular diseases, diabetes and the like, harm the whole body health and influence the life quality.

Topical antibacterial treatment of periodontal disease is an important aspect of drug treatment of periodontal disease. According to market research: the local administration mode of periodontal disease comprises the following steps: 1 gargle; clinically, gargle can only be used as an auxiliary treatment measure, a patient needs to rinse the mouth for a plurality of times, the gargle is inconvenient to use, the retention time in the oral cavity is short, the curative effect is short, and some gargles such as chlorhexidine solution (spectral antibacterial agent), metronidazole solution (antibiotics), hydrogen peroxide solution (oxidizing agent), compound baical skullcap root gargle and siraitia gum fixing solution (traditional Chinese medicine), stannous fluoride solution and delmopinol solution (surfactant) have certain burning irritation, taste interference, bad mouthfeel and other defects of the oral mucosa. 2, taking medicine by using periodontal pocket; the ioglycerol and the iophenol have the risks of local burn and the like when in use. 3 root surface treatment medicines; at present, more root surface treatment medicines including tetracyclines, fibronectin and the like, such as minocycline hydrochloride ointment, are used in the research, and the root surface is dipped and wiped by cotton balls and then washed by normal saline. The periodontal pocket or root surface treatment is used for medicines, the dosage form is limited, and the using method is complicated. 4, buccal tablets; the local buccal tablet is mainly a metronidazole buccal tablet and a tinidazole buccal tablet, and compared with gargle, the local buccal tablet is slowly contained so that the medicine can stay in the oral cavity for a long time to continuously exert the medicine effect, but the local buccal tablet is an antibiotic medicine, is easy to generate medicine resistance and has great side effect.

The flos Caryophylli is dry bud of Syringa oblongifolia Linn of Myrtaceae, and volatile oil obtained by steam distillation of flos Caryophylli bud is oleum Caryophylli, and its medicinal active ingredient is mainly eugenol. Eugenol has antibacterial, antiinflammatory, local anesthesia, and analgesic effects, and can promote wound healing of canker sore, effectively treat recurrent canker sore, stomatitis, periodontitis, etc., and has special fragrance, and also has effect of refreshing oral cavity. Borax has a certain effect of resisting pathogenic microorganisms and has obvious inhibition effect on escherichia coli, pseudomonas aeruginosa and the like. Can also preserve and protect skin mucosa. The two active ingredients are effectively combined, so that the antibacterial and anti-inflammatory effects can be enhanced. The current medicament for treating oral diseases clinically by using a single component containing eugenol has various dosage forms such as paste, mucilage, cream and the like, and has obvious defects: inconvenient carrying and storage, poor taste, poor patient compliance and poor clinical use effect.

Therefore, the provided product can quickly take effect to reach focus, and is a problem to be solved for treating oral diseases. The orosol film generally has a more accurate drug release rate, is rapidly absorbed through the oral mucosa, and can realize continuous drug delivery, thereby improving the treatment effect, being easier for patients to use, and not requiring water or other auxiliary means, which can improve the convenience of treatment. However, the light and thin texture and smaller volume can lead to generally lower drug loading rate, and the development of an oral film is limited, so that in order to improve the drug loading rate, researchers generally increase the thickness of the film, but also influence the disintegration release and the taste of the oral film, so that in the development of the oral film for treating oral diseases, how to have higher drug effect, faster disintegration rate and better taste under lower drug loading rate is also a key technical challenge.

Disclosure of Invention

The application provides a butyl boron compound oral solution film and a preparation method thereof, which overcome the defects of the prior art.

In order to achieve the above purpose, the technical scheme adopted by the application is as follows:

the application provides a butyl boron compound oral solution film which comprises the following components in parts by mass: 4-10 parts of eugenol, 20-28 parts of borax, 45-60 parts of film forming agent, 12-20 parts of plasticizer, 25-35 parts of thickening agent and 65-76 parts of adhesive.

Further, the preferable proportion comprises the following components in parts by mass: 5-9 parts of eugenol, 20-25 parts of borax, 45-60 parts of film forming agent, 14-18 parts of plasticizer, 25-30 parts of thickening agent, 70-75 parts of adhesive, 0-5 parts of sweetener, 3-12 parts of flavoring agent and 0-3 parts of colorant.

Further, the optimal proportion comprises the following components in parts by mass: 7 parts of eugenol, 25 parts of borax, 52 parts of film forming agent, 16 parts of plasticizer, 36 parts of thickening agent, 70 parts of adhesive, 4 parts of sweetener, 10 parts of flavoring agent and 1 part of colorant.

Further, the film forming agent comprises one or a combination of more of povidone, copovidone, segmented copolymer, cellulose, polyvinyl alcohol, polyethylene glycol, starch and natural polymer; preferably one or more of povidone, copovidone, poloxamer, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene glycol with molecular weight greater than 100000, chitosan, sodium alginate and pullulan; more preferably, it is either one or a combination of two of copovidone and hydroxypropyl methylcellulose.

Further, the plasticizer comprises any one or a combination of a plurality of polyethylene glycol, propylene glycol and glycerin.

Further, the thickener comprises any one or more of methylcellulose, sodium carboxymethylcellulose, gelatin and acacia.

Further, the binder comprises any one of pregelatinized starch and pea starch.

Further, the sweetener comprises any one or more of mannitol, sorbitol, xylitol, sucralose and saccharin sodium, preferably one or two of mannitol and sucralose.

Further, the flavoring agent comprises any one or more of menthol, menthol and edible essence, preferably any one or two of menthol and edible essence.

Further, the colorant comprises any one or a combination of more of titanium dioxide, sunset yellow, lemon yellow, brilliant blue.

The application also provides a preparation method of the butyl boron compound oral solution film, which comprises the steps of mixing a film forming material with a plasticizer, stirring, mixing with borax solution, adding eugenol oil, mechanically stirring until phase separation does not occur, adding an additive, degassing and soaking to obtain a casting solution, and spreading and film scraping the casting solution to obtain the butyl boron compound oral solution film;

wherein the additive comprises any one or more of sweetener, flavoring agent, binder and thickener.

Further, the preparation method comprises the following steps:

s1, after raw materials are weighed, film forming materials with the prescription amount are uniformly mixed and dispersed in pure water, and a plasticizer is added and stirred until the film forming materials are fully dissolved and dispersed;

s2, heating borax in a water bath at 35-45 ℃ and stirring until the borax is completely dissolved to obtain borax solution;

s3, adding the borax solution obtained in the step S2 into the solution obtained in the step S1, uniformly stirring, dropwise adding the eugenol oil solution into the mixed solution after the mixed solution is uniformly dispersed and the temperature is reduced to room temperature, and mechanically stirring until phase separation does not occur and uniform dispersion is achieved;

s4, dispersing the sweetener, the flavoring agent, the adhesive and the thickening agent in pure water, adding the mixed solution obtained in the step S3, and uniformly stirring;

s5, continuously stirring at a lower rotating speed, adding purified water, adjusting the fluidity of the mixed solution, and performing ultrasonic bubble removal for 30-60min after uniform mixing to obtain casting solution.

S6, spreading the casting solution obtained in the step S5 on a plate, scraping the film, and drying to obtain the butyl boron compound oral solution film.

Further, the rotating speed of mechanical stirring in the step S3 is 200-250r/min.

Further, the casting solution film scraping process in S6 specifically comprises the steps of spreading the casting solution on a film spreading machine at a speed of 6-8mm/S, wherein the thickness is 1-1.2mm, and drying at 25-60 ℃ for 4-6 hours to obtain the butyl boron compound oral solution film.

The application provides an application of a butyl boron compound oral dissolved film in preparing medicines for treating canker sore, periodontitis and gingivitis.

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

1. fast onset of action, antibacterial better: the butyl boron compound oral solution film provided by the application can be rapidly disintegrated and released in an oral cavity within 30 seconds, can be taken without drinking water, and is convenient to administer. Under the same drug loading rate, the antibacterial effect of the oral film provided by the application is better than that of a spray product, and the oral film prepared by the application can promote the release of active drugs.

2. Improving bioavailability: the butyl boron compound oral soluble film provided by the application can be delivered to a specific part in an oral cavity in a targeted way, and directly reaches focus parts, the local drug concentration in the oral cavity is high, and the drug is directly delivered into blood through oral mucosa, so that the first pass effect of liver can be avoided, and meanwhile, the drug is allowed to be directly absorbed into the blood through the mucosa, so that the digestion process of stomach and intestines is reduced, and the bioavailability is improved.

3. Patient-friendly: the product has the advantages of rapid dispersion, good taste, no irritation to mucous membrane, no gritty feeling of orally disintegrating tablet and buccal tablet; the medicament is convenient for special crowds such as dysphagia patients, old people, children and the like, and can improve the medicament application adaptability and safety of the special crowds.

4. The dosage is more accurate: the oral dispersion film has thin and uniform texture, can be cut into stamp size, and has flexible administration.

5. The preservation is convenient: the butyl boron compound mouth-soluble film provided by the application enables liquid eugenol to be solidified, is convenient to store and transport, has the average tensile strength of 13.10MPa, the average elastic modulus of 219.64MPa and the average elongation at break of 23%, has proper flexibility, has certain mechanical strength, and is convenient to store, transport and use, and the butyl boron compound mouth-soluble film is cut into a standard dumbbell-shaped film agent

6. The butyl boron compound oral dissolved film provided by the application has good antibacterial and anti-inflammatory effects, and can be used for medicines for treating diseases such as canker sore, periodontitis, gingivitis and the like.

7. The preparation method provided by the application has simple process, no special production equipment requirement and suitability for industrial production.

Drawings

In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments described in the present application, and other drawings may be obtained according to the drawings without inventive effort to those skilled in the art.

Fig. 1 is a diagram of an experiment for evaluating the taste of a butyl boron compound oral film prepared in example 1 of the present application.

FIG. 2 is an experimental diagram for evaluating the antibacterial effect of the butyl boron compound oral dissolved film prepared in the embodiment 1 of the application on escherichia coli.

FIG. 3 is an experimental graph for evaluating the antibacterial effect of the butyl boron compound oral dissolved film prepared in the embodiment 1 of the application on staphylococcus.

Fig. 4 is an experimental diagram of the curative effect of the butyl boron compound oral dissolving membrane canker sore prepared in the embodiment 1 of the application.

Fig. 5 is an external view of a butyl boron compound oral film prepared in example 1 of the present application.

Fig. 6 is a graph showing the comparison of the antibacterial performance of the butyl boron compound oral film prepared in example 1 of the present application and the spraying system product.

Detailed Description

The application will be more fully understood from the following detailed description, which should be read in conjunction with the accompanying drawings. Detailed embodiments of the present application are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the application, which may be embodied in various forms. Therefore, specific functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present application in virtually any appropriately detailed embodiment.

Example 1

The embodiment 1 provides a boron-butadiene compound oral solution film, which mainly comprises main ingredients and additives, wherein the main ingredients comprise eugenol and borax, the additives comprise film forming agents, thickening agents, adhesives, sweeteners, flavoring agents, plasticizers and solvents, and the proportion and the addition amount of each component are shown in the table 1.

Table 1 example 1 formulation and content table

The preparation method comprises the following steps:

(1) Uniformly mixing the two film forming agents in the prescription amount, dispersing in a solvent, adding a plasticizer, and stirring until the two film forming agents are fully dissolved and dispersed;

(2) Heating borax in water bath at 40deg.C, and stirring to dissolve completely;

(3) Adding the borax solution obtained in the step (2) into the mixed solution (1), uniformly stirring, dropwise adding the eugenol oil solution into the mixed solution after the mixed solution is uniformly dispersed and the temperature is reduced to room temperature, and continuously stirring until phase separation does not occur and the mixed solution is uniformly dispersed;

(4) Dispersing the rest ingredients in the formula into pure water, and uniformly stirring the mixed solution obtained in the step (3) after all the mixed solution is added at one time;

(5) Mechanically stirring at 200-250r/min, adding a proper amount of purified water to make the total volume reach 100ml, adjusting the fluidity of the casting solution, and performing ultrasonic bubble removal for 30-60min after uniform mixing to obtain the casting solution.

(6) And (3) coating the casting solution obtained in the step (5) on a bottom plate, coating the casting solution to be 1.2mm thick at the speed of 8mm/s, drying at 40 ℃ to obtain an oral-dissolving film, peeling the film agent from a PET (polyethylene terephthalate) belt, cutting the film agent into a certain size, and sealing and packaging to obtain the butyl boron compound oral-dissolving film.

The film forming agent in the embodiment can be replaced by one or a combination of more of povidone, copovidone, segmented copolymer, cellulose, polyvinyl alcohol, polyethylene glycol, starch and natural polymer; preferably one or more of povidone, copovidone, poloxamer, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene glycol with molecular weight greater than 100000, chitosan, sodium alginate and pullulan; more preferably, it is either one or a combination of two of copovidone and hydroxypropyl methylcellulose.

The plasticizer glycerol in this embodiment may be replaced by any one or a combination of polyethylene glycol, propylene glycol, and the like.

The thickener sodium carboxymethyl cellulose in this embodiment may be replaced by any one or more of methylcellulose, gelatin, and acacia; the binder may be replaced with pea starch in this example.

The sweetener in this embodiment may be replaced by any one or more of mannitol, sorbitol, xylitol, and sodium saccharin; the flavoring agent can be replaced by any one or more of menthol, menthol and edible essence.

The colorant in this embodiment may be replaced with any one or a combination of titanium dioxide, sunset yellow, lemon yellow.

The appearance diagram of the butyl boron compound oral solution film prepared in the embodiment 1 is shown in fig. 1, and the butyl boron compound oral solution film is smooth, complete, glossy, good in flexibility, high in mechanical strength and 30-35 times in folding endurance, and no organic solvent is added in the embodiment 1.

Example 2

Example 2 provides a butyl boron compound oral film, the formula and the content of which are shown in table 2:

table 2 example 2 formulation and content table

Example 2 the preparation process was identical to example 1.

The butyl boron compound oral dissolved film prepared in the embodiment 2 is smooth and complete, good in flexibility, high in mechanical strength and 23-26 times in folding endurance.

Example 3

Example 3 provides a butyl boron compound oral film, the formula and the content of which are shown in table 3:

table 3 example 3 formulation and content table

The preparation of example 3 was identical to that of example 1.

The butyl boron compound oral soluble film prepared in the embodiment 3 is smooth and complete, has certain flexibility and has the folding endurance of 24-26 times.

Example 4

Example 4 provides a butyl boron compound oral film, the formula and the content of which are shown in table 4:

table 4 example 4 formulation and content table

The preparation process was consistent with example 1.

The butyl boron compound oral soluble film prepared in the embodiment 4 is complete, smooth and glossy on the surface and free of bubbles, but low in flexibility and 25-28 times in folding endurance.

Example 5

Example 5 provides a butyl boron compound oral film, the formula and the content of which are shown in table 5:

table 5 example 5 formulation and content table

The preparation process was identical to example 1.

The butyl boron compound oral soluble film prepared in the embodiment 5 is complete, smooth and glossy on the surface and free of bubbles, but low in flexibility and 22-24 times in folding endurance.

Example 6

Example 6 provides a butyl boron compound oral film, the formula and the content of which are shown in table 6:

TABLE 6 example 6 formulation and content table

The preparation process was identical to example 1.

The butyl boron compound oral dissolved film prepared in the embodiment 6 is complete, smooth in surface, free of bubbles, good in flexibility and resistant to folding for 26-28 times.

Comparative examples 1 to 2

Comparative examples 1 and 2 respectively provide a boron-butadiene compound oral solution film, and the formula and the content are shown in table 7:

table 7 comparative examples 1-2 formulations and content tables

Comparative example 1 the preparation was identical to example 1, and comparative example 2 was prepared as follows:

(1) The amounts of each material were weighed as described in table 7;

(2) Dispersing eugenol oil solution in 3ml ethanol solution until phase separation does not occur and uniform dispersion is achieved;

(3) The film-forming material, namely the copovidone Kollidon VA 64, is dissolved in a proper amount of water at 500rpm/min and stirred magnetically until the film-forming material is completely dissolved.

(4) Borax was dissolved in water and heated in a 40 ℃ water bath to completely dissolve the borax.

(5) The rest ingredients of the prescription are mechanically stirred at 600rpm/min and added into the mixed solution of the (2) and the (3), and the mixture is stirred and mixed uniformly for 30min.

(6) And (3) adding the plasticizer in the formula amount in the stirring process, mechanically stirring at 500rpm for 30min, transferring to a bottle rotating machine, continuously rotating and uniformly mixing for 2 hours, standing, and removing bubbles to obtain the oral solution film casting liquid.

(7) Coating the casting solution obtained in the step (6) on a film spreading machine to prepare an oral cavity dispersion film, drying and stripping.

The comparative example 1 and the comparative example 2 can prepare a relatively complete film, the surface is even and smooth, and the eugenol as a main drug can be uniformly dispersed in the whole system without being dispersed in ethanol solution in advance through adjusting the addition sequence. But the whole flexibility of the film is low, the film is not easy to take off, and the folding endurance is only 2-3 times.

Comparative example 3

Comparative example 3 hydroxypropyl methylcellulose HPMC was used as a film former, and the formulation and content are shown in table 8:

table 8 comparative example 3 formulation and content

The preparation method was identical to that of comparative example 2.

The film obtained in comparative example 3 was partially stuck to a plate, and was brittle, and a complete dispersion film could not be obtained.

Comparative example 4

Comparative example 4 the formulation and contents are shown in table 9:

table 9 comparative example 4 formulation and content

The preparation method is the same as that of comparative example 2.

Comparative example 4 did not show any cracking during drying, and the formulation was partially formed and removed, but the removed film was poor in flexibility and brittle, as compared with comparative examples 2 and 3.

Comparative examples 5 to 8

Comparative examples 5-8 formulations and contents are shown in table 10:

table 10 comparative examples 5-8 formulations and content tables

The preparation method was identical to that of comparative example 2.

The comparative examples 5 and 6 did not give a complete film, and the drying process showed dry cracking. The comparative examples 7 and 8 show sticking, and the film is partly detachable, and the film has high elasticity, no supporting strength and is not easy to store.

Comparative examples 9 to 10

Comparative examples 9-10 formulations and contents are shown in Table 11:

table 11 comparative examples 9-10 formulations and contents

Comparative example 9 and comparative example 10 were prepared in the same manner as in example 1.

Comparative example 9 did not give a complete film, and was partially brittle at the time of film release, and comparative example 10 was successful in partial film release with reduced friability compared to comparative example 9.

Performance testing

1. Thickness of (L)

The butyl boron compound oral-dissolving film prepared in examples 1-5 is taken, 5 pieces are cut into 2 x2cm films, and the thickness of each film is measured at five different positions (the center and the four corners) on the 2 x2cm film by a micrometer. Table 12 shows the average of five sample replicates.+ -. SD

Table 12 comparative table for testing thickness of butyl boron compound oral solution film

The test results show that: the average thickness of the butyl boron compound oral dispersion film provided by the application is 0.119mm (+ -0.001), is thin and uniform, and is within the ideal thickness of the oral dispersion film.

2. Sheet weight difference

4 pieces of each of the butyl boron compound oral soluble films (cut to be 1.5x2cm) prepared in examples 1-5 are weighed and recorded, the weight of each piece and the total weight thereof are calculated, the average weight is calculated, and the weight difference is calculated according to the following formula:

weight difference (%) = (monolithic weight-average weight)/monolithic weight 100%

Table 13 film weight difference limit table

Evaluation of weight	Degree of weight difference
		0.02g and less than 0.02g	±15％
0.02g or more to 0.20g	±10％
		0.20g or more	±7.5％

Comparative table of weight difference test of 20 pieces of boron-butadiene compound oral film refer to table 14:

table 1420 weight difference test comparison table of boron-butadiene compound oral solution film

The test results show that: 20 pieces of mouth dissolving films are all in: and the weight difference is more than 0.02g and up to 0.20g, and is less than 10%, and the weight difference is within the limit range.

3. Folding endurance

And repeatedly folding the mouth-soluble film with the proper size (2 x 3 cm) prepared in the embodiment 1-3 at the same position, and turning over the mouth-soluble film along the same crease by 180 degrees until the mouth-soluble film breaks, wherein the folding times when the film agent breaks exactly are the folding endurance.

One of the orosity films prepared in examples 1 to 3 was cut into 2 x 3cm films, which were folded in the horizontal and vertical directions, respectively, and the number of times was recorded, and the data in table 15 are expressed as the average ± SD of repeated measurements of 3 orosity films.

Table 15 fold resistance test of butyl boron compound oral film

	Example 1	Example 2	Example 3	Mean value of	Standard deviation of
						Horizontal level	32	25	28	28	3.5
Vertical and vertical	30	26	26	27	2.3

The test results show that: the folding endurance of the 3-piece mouth-soluble film is 27-28, and the 3-piece mouth-soluble film has certain strength within the error range, and is convenient to store and transport.

4. Mechanical strength

The oral films prepared in examples 1 to 3 were tested for elongation at break, tensile strength, and elastic modulus, and the test results are shown in Table 16.

Table 16 mechanical strength test comparative table for butyl boron compound oral film

The butyl boron compound oral solution film prepared in the embodiment 1 is cut into a standard dumbbell-shaped film, the average tensile strength is 13.10MPa, the average elastic modulus is 219.636MPa, and the average elongation at break is 23%. Has proper flexibility and certain mechanical strength, and is convenient to store, transport and use.

5. Time limit of disintegration

In vitro: taking 2 pieces of oral films prepared in examples 1-3, respectively clamping by clip, taking 900ml of PH=6.8 PBS solution as dissolution medium, measuring at 37 ℃ and rotating speed of 30r/min, starting timing from the time when the oral films contact the dissolution medium, recording the time from the beginning of disintegration of the film to the complete disintegration and dispersion, and repeating the measurement for 3 times.

Table 17 in vivo and in vitro disintegration time test of butyl boron compound oral film

In vitro	Example 1	Example 2	Example 3	Mean value of	Standard deviation of
						Begin to disintegrate(s)	29	30	28	29	1
Complete disintegration(s)	52	55	53	53	2
						In vivo	Volunteer 1	Volunteer 2	Volunteer 3
Complete disintegration(s)	24	23	25	24	1

The test results show that: the in vitro disintegration time of the butyl boron compound oral film accords with European pharmacopoeia regulations, and the butyl boron compound oral film can be disintegrated and released in the oral cavity of a human body within 30 seconds, and has good disintegration performance.

6. Surface pH determination

Alkaline or acidic surface pH causes irritation of the buccal mucosa and therefore the surface pH of the film should be measured. The solution was poured into a d=90 mm dish with 20ml of a ph=6.8 PBS solution, and simultaneously placed into a 1×2cm orodispersible film (n=3) prepared in examples 1 to 3, which was cut out, and floated on the surface, and after the solution was completely immersed for 2 hours, the PH of the solution was measured with a PH meter, and the measurement was repeated 3 times.

Table 18 determination of surface pH of boron-butyrate compound oral solution film

	1	2	3	Mean value of	Standard deviation of
						Example 1	6.84	6.85	6.84	6.84	0.01
Example 2	6.85	6.86	6.86	6.86	0.01
						Example 3	6.87	6.87	6.86	6.87	0.01

Test results show that the pH=6.85+/-0.01 of the butyl boron compound oral dissolving film is close to the pH value of the oral cavity of a human body, and the contact discomfort is not caused.

7. Taste evaluation of butyl boron compound oral film

The butyl boron compound oral film prepared in the example 1 and the butyl boron emulsifiable paste which is a commercial preparation are subjected to taste evaluation, 10 volunteers are selected to adopt a taste method to evaluate the two preparations in the following way: oral irritation, odor, sweetness, mouthfeel, personal preference, etc. were evaluated, and volunteers were asked to score the items on a scale of 1 to 10, indicating their personal acceptance. A score of 1 indicates the lowest acceptance and a score of 10 indicates the highest acceptance. The evaluation results are shown in FIG. 1.

The evaluation result shows that compared with the butyl boron emulsifiable paste, the butyl boron compound oral soluble film obtains higher evaluation of volunteers, and improves the aspects of irritation, bad smell, inconvenient use and the like.

8. Evaluation of antibacterial effect of butyl boron compound oral dissolving film

Diluting the activated bacteria in fresh medium to a desired concentration (1X 10) ⁶ CFU/ml、1X10^ ⁵ CFU/ml、5X10^ ³ CFU/ml). The butyl boron compound oral membrane prepared in example 1 is added into bacterial suspension, incubated for 20 minutes in a 37-degree incubator, and then 100 mu L of mixed solution is taken for plating. The coated agar plates were incubated at 37℃for 8-12 hours. Bacterial growth was then removed and observed to evaluate the inhibition of E.coli and Staphylococcus aureus by orolytic membranes, and the experimental results are shown in FIGS. 2 and 3.

The experimental results show that: the blank control group and the auxiliary material group have dense bacterial colonies, the growth is not inhibited, and the butyl boron compound oral-dissolving membrane group has obvious inhibition effect, thus proving that the antibacterial effect is good.

The minimum inhibitory concentration and minimum bactericidal concentration of two different formulations against e.coli and s.aureus, respectively, were determined using a microdilution method.

100 microliters of medium and 100 microliters of an orosol membrane suspension or an oral spray solution were added to a 96-well plate. The final concentration varies from 7.00 mg/ml to 0.10 mg/ml. Subsequently, 5. Mu.l of E.coli or Staphylococcus aureus suspension was injected into each well at a concentration of 1X 105CFU/mL. After allowing the drug to co-incubate with the bacterial suspension at 37 ℃ for 12 hours, the Optical Density (OD) of the bacteria at 600 nm was measured using an enzyme-labeled instrument. The concentration corresponding to the OD value equal to 0.1 is defined as the minimum inhibitory concentration, and the minimum concentration larger than the minimum inhibitory concentration is defined as the minimum inhibitory concentration of the measured target substance. Each set was set with 6 parallel samples and the experiment was repeated three times.

Test results: referring to fig. 6, a graph showing comparison of antibacterial performance of the oral film and the oral spray system product prepared in example 1 of the present application is calculated based on eugenol as one of the active drugs, and the lowest antibacterial concentration and the smallest antibacterial concentration of the oral film system are measured to be smaller than those of the oral spray system for both escherichia coli and staphylococcus aureus, which indicates that the oral film provided by the present application can promote release of the active drug more under the same active ingredients.

9. Evaluation of effect of butyl boron compound oral dissolving film on treating canker sore disease

The rats were subjected to adaptive breeding for one week in male (180-220 g) groups of A, B, C, D, wherein group A was blank control group, group B was butylboron cream treatment group, group C was modeling control group (physiological saline group), and group D was butylboron compound orolytic membrane treatment group, each group of 4 mice. One week later, molding and administration were started.

The method for molding the canker sore comprises the following steps: the mice are subjected to short-term anesthesia by diethyl ether, a chemical burning method is adopted, a filter paper sheet soaked with a phenol solution is used for burning the mucous membrane of the lower lip of one side of the mice for 1min/30s (the mucous membrane bleeding is the standard, the ulcer surface of each rat is ensured to be consistent in size and depth as much as possible, oral secretion is wiped by a dry cotton ball before each burning), water is forbidden for 2h after molding, and the ulcer formation condition is observed after 24 h.

After molding for 24 hours, the medicines are grouped for administration. The oral ulcer is applied by topical application/smearing three times a day. The number of mice with ulcer healing was recorded for 10 consecutive days by observing and photographing the record, measuring the size of the ulcer area. Referring to fig. 4, fig. 4 is an experimental diagram of the curative effect of the compound oral dissolving film and the oral ulcer of the butyl boron prepared in the embodiment 1 of the application.

The results show that: the butyl boron compound oral dissolving film accelerates the healing speed of the dental ulcer, and the treatment effect of the butyl boron compound oral dissolving film is obviously superior to that of a molding control group and a butyl boron emulsifiable paste administration group.

The various aspects, embodiments, features and examples of the application are to be considered in all respects as illustrative and not intended to limit the application, the scope of which is defined solely by the claims. Other embodiments, modifications, and uses will be apparent to those skilled in the art without departing from the spirit and scope of the claimed application.

Claims

1. The butyl boron compound oral dissolving film is characterized by comprising the following components in parts by mass: 4-10 parts of eugenol, 20-28 parts of borax, 45-60 parts of film forming agent, 12-20 parts of plasticizer, 25-35 parts of thickening agent and 65-76 parts of adhesive.

2. The butyl boron compound oral solution film according to claim 1, which is characterized by comprising the following components in parts by mass: 5-9 parts of eugenol, 20-25 parts of borax, 45-60 parts of film forming agent, 14-18 parts of plasticizer, 25-30 parts of thickening agent, 70-75 parts of adhesive, 0-5 parts of sweetener, 3-12 parts of flavoring agent and 0-3 parts of colorant.

3. The butyl boron compound oral solution film according to claim 2, which is characterized by comprising the following components in parts by mass: 7 parts of eugenol, 25 parts of borax, 52 parts of film forming agent, 16 parts of plasticizer, 36 parts of thickening agent, 70 parts of adhesive, 4 parts of sweetener, 10 parts of flavoring agent and 1 part of colorant.

4. The butyl boron compound oral film according to any one of claims 1-3, wherein the film forming agent comprises: any one or a combination of more of povidone, copovidone, segmented copolymer, cellulose, polyvinyl alcohol, polyethylene glycol, starch and natural polymer; preferably one or more of povidone, copovidone, poloxamer, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene glycol with molecular weight greater than 100000, chitosan, sodium alginate and pullulan; more preferably, it is either one or a combination of two of copovidone and hydroxypropyl methylcellulose.

5. The butyl boron compound oral solution film according to claim 4, wherein: the plasticizer comprises any one or more of polyethylene glycol, propylene glycol and glycerin.

6. The butyl boron compound oral solution film according to claim 4, wherein: the thickener comprises any one or more of methylcellulose, sodium carboxymethylcellulose, gelatin and acacia;

and/or the adhesive comprises any one of pregelatinized starch and pea starch;

and/or the sweetener comprises any one or more of mannitol, sorbitol, xylitol, sucralose and saccharin sodium, preferably one or two of mannitol and sucralose;

and/or the flavoring agent comprises any one or more of menthol, menthol and edible essence, preferably any one or two of menthol and edible essence;

and/or the colorant comprises any one or a combination of more than one of titanium dioxide, sunset yellow, lemon yellow and brilliant blue.

7. The method for preparing the butyl boron compound oral solution film according to any one of claims 1 to 6, which is characterized by comprising the steps of mixing a film forming agent with a plasticizer, stirring, mixing with borax solution, adding eugenol oil, mechanically stirring until phase separation does not occur, adding an additive, degassing and soaking to obtain a casting solution, and then scraping the casting solution to obtain the butyl boron compound oral solution film;

wherein the additive comprises any one or more of sweetener, flavoring agent, binder, thickener, and colorant.

8. The method for preparing the butyl boron compound oral dissolved film according to claim 7, which is characterized by comprising the following steps:

s1, after raw materials are weighed, film forming agents with the prescription amount are uniformly mixed and dispersed in pure water, and plasticizers are added and stirred until the film forming agents are fully dissolved and dispersed;

s2, heating borax at 35-45 ℃ and stirring until the borax is completely dissolved to obtain borax solution;

s3, adding the borax solution obtained in the step S2 into the solution obtained in the step S1, uniformly stirring, dropping the eugenol oil solution into the mixed solution after the mixed solution is uniformly dispersed and the temperature is reduced to room temperature, and mechanically stirring until phase separation does not occur and the mixed solution is uniformly dispersed;

s4, dispersing the sweetener, the flavoring agent, the adhesive, the thickening agent and the coloring agent in pure water, adding the mixed solution obtained in the step S3, and uniformly stirring;

s5, continuously stirring, adding water, adjusting the fluidity of the mixed solution, and performing ultrasonic bubble removal for 30-60min after uniform mixing to obtain casting solution.

9. The method for preparing the butyl boron compound oral dissolved film according to claim 8, which is characterized in that: s3, the rotating speed of mechanical stirring is 200-250r/min;

and/or, the casting solution film scraping process in S6 specifically comprises the steps of spreading the casting solution on a film spreading machine at a speed of 6-8mm/S, wherein the thickness is 1-1.2mm, and drying at 25-60 ℃ to obtain the butyl boron compound oral solution film.

10. Use of the butyl boron compound oral dissolved film according to any one of claims 1-6 in the preparation of a medicament for treating canker sore, periodontitis and gingivitis.