Oral membrane and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to an oral membrane and a preparation method thereof. The oral membrane comprises an adhesive layer, a sustained release layer and a waterproof layer, wherein the adhesive layer comprises 0 wt% to 10 wt% of an antibacterial agent, 50 wt% to 80 wt% of an adhesive material and 10 wt% to 30 wt% of a sustained release material; and the sustained release layer comprises 65 wt% to 85 wt% of an antibacterial agent, 0 wt% to 10 wt% of an adhesive material and 10 wt% to 25 wt% of a sustained release material. Through the special structure comprising the three layers of films and the specific component proportion in each layer of film, the oral film agent is ensured to take effect quickly after administration, the stable long-acting slow-release effect is realized, and the oral film agent also has the advantages of being tightly attached to an affected part, lasting in adhesion, good in mechanical property and the like.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and in particular to an oral film and a preparation method thereof. Background Art

[0002] Oral infection can cause a series of acute and chronic diseases such as bad breath, swollen and painful gums, abscesses, gingivitis, periodontal disease and dental calculus. Compared with systemic medication, local medication is more suitable for the treatment of oral infection diseases. It can not only increase the local drug concentration and reduce the dosage, but also avoid the liver and kidney damage, allergic reactions, dysbacteriosis and other adverse reactions that may be caused by systemic medication. However, due to the special oral environment, there are factors such as lip, cheek and tongue movement and saliva secretion, local medication in the oral cavity has the disadvantages of short residence time, fast loss and difficulty in maintaining effective therapeutic concentration in the affected area for a long time. The preparations used for oral topical administration in the prior art are limited by the special environment in the oral cavity, and it is difficult to achieve long-term and effective administration at a fixed position in the oral cavity, and the treatment effect is not ideal.

[0003] Therefore, there is an urgent need to develop a patch for oral topical administration that takes into account both comfort and stable long-acting sustained-release effects. Summary of the invention

[0004] The present application solves at least one of the problems of the related art from the following aspects.

[0005] To this end, the first aspect embodiment of the present application provides an oral film, comprising: an adhesive layer, a sustained-release layer and a waterproof layer, wherein the adhesive layer comprises 0wt% to 10wt% of an antibacterial agent, 50wt% to 80wt% of an adhesive material and 10wt% to 30wt% of a sustained-release material; and the sustained-release layer comprises 65wt% to 85wt% of an antibacterial agent, 0wt% to 10wt% of an adhesive material and 10wt% to 25wt% of a sustained-release material.

[0006] In some embodiments, the waterproof layer comprises a waterproof material.

[0007] In some embodiments, the waterproof layer further comprises a plasticizer.

[0008] In some embodiments, the waterproof layer comprises 75 wt % to 95 wt % of waterproof material and 5 wt % to 25 wt % of plasticizer.

[0009] In some embodiments, the adhesive layer further comprises 5 to 25 wt % of a plasticizer.

[0010] In some embodiments, the adhesive layer further comprises 0 to 5 wt % flavoring agent.

[0011] In some embodiments, the sustained-release layer further comprises 0 to 10 wt % of a plasticizer.

[0012] In some embodiments, the sustained-release layer further comprises 0 to 3 wt % flavoring agent.

[0013] In some embodiments, in the oral film, the weight percentage of the adhesive layer is 25 wt % to 50 wt %, the weight percentage of the sustained-release layer is 35 wt % to 65 wt %, and the weight percentage of the waterproof layer is 5 wt % to 20 wt %.

[0014] In some embodiments, it is characterized in that the weight ratio of the antibacterial agent in the adhesive layer and the sustained-release layer is 1:(20 to 30).

[0015] In some embodiments, in the adhesive layer, the adhesive material is carbomer and hypromellose, and the weight ratio of the hypromellose to the carbomer is (0.5 to 2):1.

[0016] In some embodiments, in the adhesive layer, the weight ratio of the antibacterial agent to the sustained-release material is 1:(2.5 to 5).

[0017] In some embodiments, in the sustained-release layer, the weight ratio of the antibacterial agent to the sustained-release material is (3 to 6):1.

[0018] In some embodiments, the weight ratio of the antibacterial agent in the adhesive layer to the sustained-release layer is 1:24.

[0019] In some embodiments, in the adhesive layer, the adhesive material is carbomer and hypromellose, and the weight ratio of the hypromellose to the carbomer is 1:1.

[0020] In some embodiments, in the adhesive layer, the weight ratio of the antibacterial agent to the sustained-release material is 1:3.8.

[0021] In some embodiments, in the sustained-release layer, the weight ratio of the antibacterial agent to the sustained-release material is (4 to 5):1.

[0022] In some embodiments, in the sustained-release layer, the weight ratio of the antibacterial agent to the sustained-release material is 4.44:1.

[0023] In some embodiments, the antibacterial agent is ornidazole.

[0024] In some embodiments, the binding material is selected from one or more of carbomer, hydroxypropyl methylcellulose, polycarbophil, hydroxypropyl cellulose, xanthan gum, and polyvinyl pyrrolidone.

[0025] In some embodiments, the sustained-release material is selected from ethyl cellulose and / or acrylic resin.

[0026] In some embodiments, the waterproof material is selected from one or more of ethyl cellulose, polyacrylic acid resin and ethyl acrylate-methyl methacrylate copolymer aqueous dispersion.

[0027] In some embodiments, the plasticizer is selected from one or more of polyethylene glycol, glycerol, propylene glycol, dibutyl phthalate, dioctyl phthalate, tricresyl phosphate, triethyl citrate, triphenyl phosphate and dioctyl sebacate.

[0028] In some embodiments, the flavoring agent is selected from one or more of aspartame, food flavors, vanillin, menthol, stevioside, acesulfame potassium, saccharin sodium and sucralose.

[0029] The second aspect of the present application provides a method for preparing the oral film according to the first aspect of the present application, comprising the following steps S1 to S4:

[0030] S1: mixing the adhesive material and the sustained-release material for preparing the adhesive layer, adding ethanol to soak, then adding the antibacterial agent and the plasticizer for preparing the adhesive layer, and degassing to obtain solution 1;

[0031] S2: mixing the adhesive material and the sustained-release material for preparing the sustained-release layer, adding ethanol to soak, then adding the antibacterial agent and the plasticizer for preparing the sustained-release layer, and degassing to obtain solution 2;

[0032] S3: mixing the sustained-release material and the plasticizer for preparing the sustained-release layer of the waterproof layer, adding ethanol for soaking, and degassing to obtain solution 3; and

[0033] S4: using the solution 1, solution 2 and solution 3 to sequentially apply a film to prepare an oral film comprising the adhesive layer, the sustained-release layer and the waterproof layer.

[0034] In some embodiments, in step S1 and / or step S2, the flavoring agent is added at the same time as the antimicrobial agent and the plasticizer.

[0035] In some embodiments, the concentration of ethanol is 70 wt % to 100 wt %.

[0036] In some embodiments, the soaking time is 8 to 24 hours.

[0037] The embodiments of the present application achieve the following beneficial effects:

[0038] The oral film proposed in the embodiment of the present application ensures that the oral film takes effect quickly after administration and achieves a stable long-term sustained-release effect through its special structure including three layers of film and specific composition ratios in each layer of film, and also has the advantages of close fit with the affected part, long-lasting adhesion and good mechanical properties. The preparation method proposed in the embodiment of the present application adopts a layer-by-layer coating preparation process and combines specific process parameters to prepare an oral film with suitable thickness and good taste. DETAILED DESCRIPTION

[0039] The present invention is further described in detail below in conjunction with specific embodiments. The examples provided are only for illustrating the present invention and are not intended to limit the scope of the present invention. The examples provided below can be used as a guide for further improvements by those of ordinary skill in the art and are not intended to limit the present invention in any way.

[0040] This application is made based on the following knowledge of the inventor:

[0041] Due to the special oral environment, there are factors such as lip, cheek and tongue movement and saliva secretion, local medication in the oral cavity has the disadvantages of short residence time, fast loss and difficulty in maintaining effective therapeutic concentration in the affected area for a long time. The preparations used for oral topical administration in the prior art are limited by the special environment in the oral cavity, and it is difficult to achieve long-term and effective administration at a fixed position in the oral cavity, and the therapeutic effect is not ideal. Traditional oral administration dosage forms (such as solutions and chewable tablets, etc.) and non-adhesive oral administration dosage forms (such as orodisintegrating tablets and lozenges) disappear rapidly in the oral cavity with swallowing action and saliva secretion, and the retention time is too short, resulting in most drugs not playing a role in the oral cavity. Adhesive oral dosage forms, such as oral films, use hypromellose as the main excipient, are water-soluble, easily dissolved by saliva, and can only be adhered to the oral cavity for a short time; and oral patches, although they can be firmly adhered to the affected area of ​​oral ulcers, have poor mechanical properties, obvious foreign body sensation after water absorption and swelling, and bidirectional adhesion.

[0042] In this regard, after extensive research, the inventors designed a three-layer composite structure of the oral film and its component ratio, and achieved a rapid and long-lasting therapeutic effect of the oral film after oral administration. The oral film proposed in the embodiment of the present application has the advantages of close fit with the affected part, long-lasting adhesion and good mechanical properties.

[0043] The embodiment of the first aspect of the present application provides an oral film, comprising an adhesive layer, a sustained-release layer and a waterproof layer, wherein the adhesive layer comprises 0wt% to 10wt% (e.g., 1wt%, 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%) of an antibacterial agent, 50wt% to 80wt% (e.g., 55wt%, 60wt%, 65wt%, 70wt%, 75wt%) of a bonding material and 10wt% to 30wt% (e.g., 15wt%, 20wt%) of a water-resistant layer. the sustained-release layer comprises 65wt% to 85wt% (e.g., 70wt%, 75wt%, 80wt%) of an antibacterial agent, 0wt% to 10wt% (e.g., 1wt%, 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%) of a bonding material and 10wt% to 25wt% (e.g., 12.5wt%, 15wt%, 17.5wt%, 20wt%, 22.5wt%) of a sustained-release material.

[0044] The oral film provided in the embodiment of the present application can adhere to the oral cavity including but not limited to the palate, cheeks, and gums and remain for more than 6 hours (e.g., 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours), and is not affected by factors such as lip, cheek and tongue movement and saliva secretion. The total content of the antibacterial agent in the oral film is 5 to 20 mg / piece (e.g., 7.5 mg / piece, 10 mg / piece, 12.5 mg / piece, 15 mg / piece, 17.5 mg / piece).

[0045] The content of the antibacterial agent in the sustained-release layer of the oral film provided in the embodiment of the present application is as high as 65wt% to 85% of the total weight of the sustained-release layer, which can support the oral film to effectively release the antibacterial agent to the affected area for a long time. The present application achieves both the rapid release and long-term sustained release effects of the antibacterial agent in the oral cavity by adopting a double-layer drug-carrying structure of an adhesive layer and a sustained-release layer and its component composition.

[0046] In some embodiments, the waterproof layer comprises a waterproof material.

[0047] In some embodiments, the waterproof layer further includes a plasticizer.

[0048] In some embodiments, the waterproof layer includes 75wt% to 95wt% (eg, 80wt%, 85wt%, 90wt%) of waterproof material and 5wt% to 25wt% (eg, 10wt%, 15wt%, 20wt%) of plasticizer.

[0049] In some embodiments, the adhesive layer further includes 5 to 25 wt % (eg, 10 wt %, 15 wt %, 20 wt %) of a plasticizer.

[0050] In some embodiments, the adhesive layer further comprises 0 to 5 wt % (eg, 1 wt %, 2 wt %, 3 wt %, 4 wt %) of a flavoring agent.

[0051] In some embodiments, the sustained-release layer further comprises 0 to 10 wt % (eg, 1 wt %, 2 wt %, 3 wt %, 4 wt %, 5 wt %, 6 wt %, 7 wt %, 8 wt %, 9 wt %) of a plasticizer.

[0052] In some embodiments, the sustained-release layer further comprises 0 to 3 wt % (eg, 0.5 wt %, 1 wt %, 1.5 wt %, 2 wt %, 2.5 wt %) of a flavoring agent.

[0053] In some embodiments, in the oral film, the weight percentage of the adhesion layer is 25wt% to 50wt% (e.g., 30wt%, 35wt%, 40wt%, 45wt%), the weight percentage of the sustained-release layer is 35wt% to 65wt% (e.g., 40wt%, 45wt%, 50wt%, 55wt%, 60wt%), and the weight percentage of the waterproof layer is 5wt% to 20wt% (e.g., 7.5wt%, 10wt%, 12.5wt%, 15wt%, 17.5wt%).

[0054] In some embodiments, the weight ratio of the antibacterial agent in the adhesive layer and the sustained-release layer is 1:(20 to 30) (e.g., 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29).

[0055] In some embodiments, the weight ratio of the antibacterial agent in the adhesive layer to the sustained-release layer is 1:24.

[0056] In some embodiments, in the adhesive layer, the binding material is carbomer and hypromellose, and the weight ratio of hypromellose to carbomer is (0.5 to 2):1 (e.g., 0.75:1, 1:1, 1.25:1, 1.5:1, 1.75:1).

[0057] In some embodiments, in the adhesive layer, the adhesive material is carbomer and hypromellose, and the weight ratio of hypromellose to carbomer is 1:1.

[0058] In some embodiments, in the adhesive layer, the weight ratio of the antimicrobial agent to the sustained-release material is 1:(2.5 to 5) (eg, 1:3, 1:3.5, 1:4, 1:4.5).

[0059] In some embodiments, in the adhesive layer, the weight ratio of the antibacterial agent to the sustained-release material is 1:3.8.

[0060] In some embodiments, in the sustained-release layer, the weight ratio of the antibacterial agent to the sustained-release material is (3 to 6):1 (eg, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1).

[0061] In some embodiments, in the sustained-release layer, the weight ratio of the antibacterial agent to the sustained-release material is (4 to 5):1 (e.g., 4.1:1, 4.2:1, 4.3:1, 4.4:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1).

[0062] In some embodiments, in the sustained-release layer, the weight ratio of the antibacterial agent to the sustained-release material is 4.44:1.

[0063] In some embodiments, the antibacterial agent is ornidazole.

[0064] In some embodiments, the binding material is selected from one or more of carbomer, hypromellose, polycarbophil, hydroxypropyl cellulose, xanthan gum, and polyvinyl pyrrolidone.

[0065] In some embodiments, the sustained release material is selected from ethylcellulose and / or acrylic resin.

[0066] In some embodiments, the waterproof material is selected from one or more of ethyl cellulose, polyacrylic acid resin, and ethyl acrylate-methyl methacrylate copolymer aqueous dispersion.

[0067] In some embodiments, the plasticizer is selected from one or more of polyethylene glycol, glycerol, propylene glycol, dibutyl phthalate, dioctyl phthalate, tricresyl phosphate, triethyl citrate, triphenyl phosphate, and dioctyl sebacate.

[0068] In some embodiments, the flavoring agent is selected from one or more of aspartame, food flavors, vanillin, menthol, steviol glycosides, acesulfame potassium, saccharin sodium and sucralose.

[0069] The second aspect of the present application provides a method for preparing the oral film of the first aspect of the present application, comprising the following steps S1 to S4:

[0070] S1: mixing an adhesive material and a sustained-release material for preparing an adhesive layer, adding ethanol to soak, then adding an antibacterial agent and a plasticizer for preparing an adhesive layer, and degassing to obtain a solution 1;

[0071] S2: mixing the adhesive material and the sustained-release material for preparing the sustained-release layer, adding ethanol to soak, then adding the antibacterial agent and the plasticizer for preparing the sustained-release layer, and degassing to obtain solution 2;

[0072] S3: mixing the sustained-release material and the plasticizer for preparing the sustained-release layer of the waterproof layer, adding ethanol for soaking, and degassing to obtain solution 3; and

[0073] S4: using solution 1, solution 2 and solution 3 to sequentially apply a film to prepare an oral film comprising an adhesive layer, a sustained-release layer and a waterproof layer.

[0074] In some embodiments, in step S1 and / or step S2, a flavoring agent is added at the same time as the antimicrobial agent and the plasticizer.

[0075] In some embodiments, the concentration of ethanol is 70 wt % to 100 wt % (eg, 75 wt %, 80 wt %, 85 wt %, 90 wt %, 95 wt %).

[0076] In some embodiments, the soaking time is 8 to 24 hours (eg, 10 hours, 14 hours, 18 hours, 22 hours).

[0077] In some embodiments, the soaking time is 10 to 14 hours (eg, 11 hours, 12 hours, 13 hours).

[0078] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as understood by any technician in the field to which the present invention belongs. The terms used to describe the present invention are intended only to describe specific implementations and are not intended to limit the scope of the teaching. Unless otherwise specified, all numbers indicating quantities, percentages and weight parts and other numerical values ​​used in the specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise specified, the numerical parameters shown in the specification and claims are approximate values ​​and may vary depending on the characteristics to be obtained.

[0079] The technical terms appearing in this application are used according to their common sense or meaning to those skilled in the art. If specific meanings are expressed for certain terms, the definitions of the terms will be given below in the context of using these terms.

[0080] The following examples are used to further illustrate the advantages and features of the present method, but are not intended to limit the present invention. The experimental methods in the following examples, unless otherwise specified, are conventional methods, and are performed according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0081] The materials and reagents used in the following examples, unless otherwise specified, can be obtained from commercial sources. Unless otherwise specified, the quantitative analysis experiments in the following examples were repeated three times, and the results were averaged.

[0082] Example 1

[0083] Ornidazole oral film (625 tablets) was prepared according to the ratio in Table 1 below, with a specification of 1 cm×1 cm. The content of ornidazole in the oral film was 10 mg / tablet.

[0084] Table 1

[0085]

[0086] In Table 1 above, the adhesive layer, the sustained-release layer and the waterproof layer account for 35.75 wt%, 50.05 wt% and 14.2 wt% of the total weight of the oral film, respectively.

[0087] The preparation step includes the following steps S1 to S4.

[0088] S1: The adhesive material and the sustained-release material for preparing the adhesive layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the adhesive layer are added, and the solution 1 is prepared by degassing.

[0089] S2: The adhesive material and the sustained-release material for preparing the sustained-release layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the sustained-release layer are added, and the solution 2 is prepared by degassing.

[0090] S3: The sustained-release material and plasticizer for preparing the sustained-release layer of the waterproof layer were mixed, and 90 wt % ethanol was added to soak for 12 h, and the solution 3 was prepared by degassing.

[0091] S4: using solution 1, solution 2 and solution 3 to apply film in sequence to prepare oral film 1.

[0092] Example 2

[0093] Ornidazole oral film (625 tablets) was prepared according to the ratio in Table 2 below, with a specification of 1 cm×1 cm. The content of ornidazole in the oral film was 6.4 mg / tablet.

[0094] Table 2

[0095]

[0096] In Table 2 above, the adhesive layer, the sustained-release layer and the waterproof layer account for 36.3 wt%, 44.7 wt% and 19 wt% of the total weight of the oral film, respectively.

[0097] The preparation step includes the following steps S1 to S4.

[0098] S1: The adhesive material and the sustained-release material for preparing the adhesive layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the adhesive layer are added, and the solution 1 is prepared by degassing.

[0099] S2: The adhesive material and the sustained-release material for preparing the sustained-release layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the sustained-release layer are added, and the solution 2 is prepared by degassing.

[0100] S3: The sustained-release material and plasticizer for preparing the sustained-release layer of the waterproof layer were mixed, and 90 wt % ethanol was added to soak for 12 h, and the solution 3 was prepared by degassing.

[0101] S4: using solution 1, solution 2 and solution 3 to apply film in sequence to prepare oral film 2.

[0102] Example 3

[0103] Ornidazole oral film (625 tablets) was prepared according to the ratio in Table 3 below, with a specification of 1 cm×1 cm. The content of ornidazole in the oral film was 16 mg / tablet.

[0104] Table 3

[0105]

[0106] In Table 3 above, the adhesive layer, the sustained-release layer and the waterproof layer account for 33.33 wt%, 50 wt% and 16.67 wt% of the total weight of the oral film, respectively.

[0107] The preparation step includes the following steps S1 to S4.

[0108] S1: The adhesive material and the sustained-release material for preparing the adhesive layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the adhesive layer are added, and the solution 1 is prepared by degassing.

[0109] S2: The adhesive material and the sustained-release material for preparing the sustained-release layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the sustained-release layer are added, and the solution 2 is prepared by degassing.

[0110] S3: The sustained-release material and plasticizer for preparing the sustained-release layer of the waterproof layer were mixed, and 90 wt % ethanol was added to soak for 12 h, and the solution 3 was prepared by degassing.

[0111] S4: using solution 1, solution 2 and solution 3 to sequentially apply film to prepare oral film 3.

[0112] Example 4

[0113] Ornidazole oral film (625 tablets) was prepared according to the ratio in Table 4 below, with a specification of 1 cm×1 cm. The content of ornidazole in the oral film was 14.784 mg / tablet.

[0114] Table 4

[0115]

[0116] In Table 4 above, the adhesive layer, the sustained-release layer and the waterproof layer account for 25 wt%, 65 wt% and 10 wt% of the total weight of the oral film, respectively.

[0117] The preparation step includes the following steps S1 to S4.

[0118] S1: The adhesive material and the sustained-release material for preparing the adhesive layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the adhesive layer are added, and the solution 1 is prepared by degassing.

[0119] S2: The adhesive material and the sustained-release material for preparing the sustained-release layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the sustained-release layer are added, and the solution 2 is prepared by degassing.

[0120] S3: The sustained-release material and plasticizer for preparing the sustained-release layer of the waterproof layer were mixed, and 90 wt % ethanol was added to soak for 12 h, and the solution 3 was prepared by degassing.

[0121] S4: using solution 1, solution 2 and solution 3 to apply film in sequence to prepare oral film 4.

[0122] Example 5

[0123] Ornidazole oral film (625 tablets) was prepared according to the ratio in Table 5 below, with a specification of 1 cm×1 cm. The content of ornidazole in the oral film was 6.84 mg / tablet.

[0124] Table 5

[0125]

[0126]

[0127] In Table 5 above, the adhesive layer, the sustained-release layer and the waterproof layer account for 50 wt%, 35 wt% and 15 wt% of the total weight of the oral film, respectively.

[0128] The preparation step includes the following steps S1 to S4.

[0129] S1: The adhesive material and the sustained-release material for preparing the adhesive layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the adhesive layer are added, and the solution 1 is prepared by degassing.

[0130] S2: The adhesive material and the sustained-release material for preparing the sustained-release layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the sustained-release layer are added, and the solution 2 is prepared by degassing.

[0131] S3: The sustained-release material and plasticizer for preparing the sustained-release layer of the waterproof layer were mixed, and 90 wt % ethanol was added to soak for 12 h, and the solution 3 was prepared by degassing.

[0132] S4: using solution 1, solution 2 and solution 3 to apply film in sequence to prepare oral film 5.

[0133] Example 6

[0134] It is basically the same as Example 1, except that the content of ornidazole in the adhesive layer is 0 wt % and the content of ethyl cellulose is 21.66 wt %, wherein the specific amounts are shown in Table 6 below.

[0135] An oral film 6 was prepared, in which the content of ornidazole was 9.6 mg / piece.

[0136] Table 6

[0137]

[0138] Example 7

[0139] It is basically the same as Example 1, except that the amount of hydroxypropyl methylcellulose in the adhesive layer is 68.6wt%, and the amount of carbomer is 0wt%, wherein the specific amounts are shown in Table 7 below.

[0140] An oral film 7 was prepared, in which the content of ornidazole in the oral film was 6.84 mg / piece.

[0141] Table 7

[0142]

[0143] Example 8

[0144] Ornidazole oral film (625 tablets) was prepared according to the ratio in Table 8 below, with a specification of 1 cm×1 cm. The content of ornidazole in the oral film was 14.784 mg / tablet.

[0145] Table 8

[0146]

[0147]

[0148] In Table 8 above, the adhesive layer, the sustained-release layer and the waterproof layer account for 25 wt%, 65 wt% and 10 wt% of the total weight of the oral film, respectively.

[0149] The preparation step includes the following steps S1 to S4.

[0150] S1: The adhesive material and the sustained-release material for preparing the adhesive layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the adhesive layer are added, and the solution 1 is prepared by degassing.

[0151] S2: The adhesive material and the sustained-release material for preparing the sustained-release layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the sustained-release layer are added, and the solution 2 is prepared by degassing.

[0152] S3: The sustained-release material and plasticizer for preparing the sustained-release layer of the waterproof layer were mixed, and 90 wt % ethanol was added to soak for 12 h, and the solution 3 was prepared by degassing.

[0153] S4: using solution 1, solution 2 and solution 3 to apply film in sequence to prepare oral film 8.

[0154] Example 9

[0155] It is basically the same as Example 1, except that the carbomer in the adhesive layer is replaced with hydroxypropyl cellulose, wherein the specific amount is shown in Table 9 below.

[0156] An oral film 9 was prepared, in which the content of ornidazole was 10 mg / piece.

[0157] Table 9

[0158]

[0159] Comparative Example 1

[0160] Ornidazole oral film (625 tablets) was prepared according to the ratio in Table 10 below, with a specification of 1 cm×1 cm. The content of ornidazole in the comparative oral film 1 was 15.504 mg / tablet.

[0161] Table 10

[0162]

[0163] In Table 10 above, the adhesive layer, the sustained-release layer and the waterproof layer account for 20 wt%, 65 wt% and 15 wt% of the total weight of the oral film, respectively.

[0164] The preparation step includes the following steps S1 to S4.

[0165] S1: The adhesive material and the sustained-release material for preparing the adhesive layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the adhesive layer are added, and the solution 1 is prepared by degassing.

[0166] S2: The adhesive material and the sustained-release material for preparing the sustained-release layer are mixed, and 90 wt % ethanol is added to soak for 12 h, and then the antibacterial agent, plasticizer and flavoring agent for preparing the sustained-release layer are added, and the solution 2 is prepared by degassing.

[0167] S3: The sustained-release material and plasticizer for preparing the sustained-release layer of the waterproof layer were mixed, and 90 wt % ethanol was added to soak for 12 h, and the solution 3 was prepared by degassing.

[0168] S4: Solution 1, solution 2 and solution 3 were used to apply films in sequence to prepare a comparative oral film 1.

[0169] The types and proportions of the components in the adhesive layer, sustained-release layer and waterproof layer of the comparative oral film 1 prepared in this comparative example are substantially the same as those of the oral film 4 prepared in Example 4. The main difference between the two is that the adhesive layer, sustained-release layer and waterproof layer in Example 4 account for 25wt%, 65wt% and 10wt% of the total weight of the oral film 4, respectively, while the adhesive layer, sustained-release layer and waterproof layer in this comparative example account for 20wt%, 65wt% and 15wt% of the total weight of the comparative oral film 1, respectively.

[0170] According to Table 14 in the following Test Example 1, since the proportion of the adhesion layer is only 20wt%, the mechanical and adhesion properties of the comparative oral film 1 prepared in this comparative example are significantly reduced compared with those in Example 4; and in the in vitro release experiment, it shows an overall faster release rate than that in Example 1, and the sustained release effect is reduced.

[0171] Comparative Example 2

[0172] A comparative oral film 2 having only a two-layer structure of a sustained-release layer and a waterproof layer was prepared using raw materials having the same formula as those of the sustained-release layer and the waterproof layer in Example 6. The specific dosage is shown in Table 11 below. The content of ornidazole in the comparative oral film 2 is 9.6 mg / tablet.

[0173] Table 11

[0174]

[0175] The comparative oral film 2 prepared in this comparative example does not include an adhesive layer, and the formulations of the sustained-release layer and the waterproof layer are the same as those in Example 6.

[0176] According to Table 14 in the following test example 1, due to the lack of an adhesive layer, the mechanical properties and adhesion of the comparative oral film 2 prepared in this comparative example are significantly reduced compared to Example 6; and in the in vitro sustained release experiment, the cumulative release rate increased sharply from 24% to 52% within 60 to 120 minutes, which means that the long-term sustained release effect in the oral cavity cannot be achieved due to the concentrated release of the active ingredients in the early stage of release. In contrast, the cumulative release rate of the oral film prepared in Example 6 was 18% within 120 minutes, and the overall sustained release effect showed a steady increasing trend.

[0177] Comparative Example 3

[0178] It is basically the same as Example 1, except that the amount of ethyl cellulose in the adhesive layer is 9wt%, and the amount of triethyl citrate is 17.17wt%, wherein the specific amounts are shown in Table 12 below.

[0179] A comparative oral film 3 was prepared, in which the content of ornidazole in the oral film was 10 mg / tablet.

[0180] Table 12

[0181]

[0182]

[0183] In this comparative example, compared with Example 1, only the amounts of ethyl cellulose and triethyl citrate in the adhesive layer were changed.

[0184] According to Table 14 in Test Example 1, the comparative oral film 3 prepared in this comparative example has significantly lower folding resistance and adhesion time than that of Example 1; and the in vitro release rate is unstable, wherein the cumulative release rate increases sharply from 14% to 32% within 30 to 60 minutes, showing a rapid release in the early stage of release and a weak release in the later stage, and cannot achieve a long-term stable sustained release effect.

[0185] Test Example 1

[0186] According to the method in Table 13 below, the mechanical properties, adhesion, in vitro release and water resistance of the oral films 1 to 9 and comparative example oral films 1 to 3 prepared in the above Examples 1 to 9 and Comparative Examples 1 to 3 were tested. The test results are shown in Table 14 below.

[0187] Table 13

[0188]

[0189] Table 14

[0190]

[0191]

[0192]

[0193]

[0194] According to the in vitro release test results in Table 14 above, it can be seen that the sustained release effect of the oral films prepared in Examples 1 to 6 is the most stable, especially showing a stable sustained release effect in the range of 60 to 360 minutes, wherein at 120 minutes, the cumulative release of the oral films prepared in Examples 1 to 6 is stable at 15% to 20%, and at 240 minutes, it is stable at 36% to 43%, and further at 360 minutes, it is stable at 73% to 79%, achieving a long-term stable sustained release effect of the oral film.

[0195] The in vitro release test results of the oral films prepared in Examples 7 to 9 showed that the release rates in the range of 60 to 360 minutes were higher than those of the oral films prepared in Examples 1 to 6, but overall showed a release trend similar to that of the oral films prepared in Examples 1 to 6.

[0196] The in vitro release test results of the oral films prepared in Comparative Examples 1 to 3 show that not only the overall release rate is significantly higher than that of the oral films prepared in Examples 1 to 9, but also the release rates at different time stages vary greatly, not only the overall release is fast, but also shows an unstable trend. For example, the cumulative release of Comparative Example 2 increases sharply from 24% to 52% within 60 to 120 minutes, which means that the oral films prepared in Comparative Examples 1 to 3 cannot achieve a long-term sustained release effect in the oral cavity due to the concentrated release of the active ingredients in the early stage of release, especially the cumulative releases of Comparative Examples 2 and 3 at 120 minutes are 52% and 41%, respectively, while the oral films of Examples 1 to 6 of the present application as described above are all stable at 15% to 20% at 120 minutes.

[0197] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0198] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. An oral film, comprising: an adhesive layer, a sustained-release layer and a waterproof layer, wherein the adhesive layer comprises 0wt% to 10wt% of an antibacterial agent, 50wt% to 80wt% of an adhesive material and 10wt% to 30wt% of a sustained-release material; and the sustained-release layer comprises 65wt% to 85wt% of an antibacterial agent, 0wt% to 10wt% of an adhesive material and 10wt% to 25wt% of a sustained-release material.

2. The oral film according to claim 1, wherein The waterproof layer comprises a waterproof material; preferably, the waterproof layer further comprises a plasticizer, and more preferably, the waterproof layer comprises 75wt% to 95wt% of the waterproof material and 5wt% to 25wt% of the plasticizer.

3. The oral film according to claim 1 or 2, wherein the adhesive layer further comprises 5 to 25 wt% of a plasticizer; Optionally, the adhesive layer further comprises 0 to 5 wt % of a flavoring agent; Optionally, the sustained-release layer further comprises 0 to 10 wt % of a plasticizer; Optionally, the sustained-release layer further comprises 0 to 3 wt % of a flavoring agent.

4. The oral film according to any one of claims 1 to 3, characterized in that In the oral film, the weight percentage of the adhesive layer is 25wt% to 50wt%, the weight percentage of the sustained-release layer is 35wt% to 65wt%, and the weight percentage of the waterproof layer is 5wt% to 20wt%.

5. The oral film according to any one of claims 1 to 4, characterized in that The weight ratio of the antibacterial agent in the adhesive layer and the sustained-release layer is 1:(20 to 30); Optionally, in the adhesive layer, the adhesive material is carbomer and hypromellose, and the weight ratio of the hypromellose to the carbomer is (0.5 to 2):1; Optionally, in the adhesive layer, the weight ratio of the antimicrobial agent to the sustained-release material is 1:(2.5 to 5); Optionally, in the sustained-release layer, the weight ratio of the antibacterial agent to the sustained-release material is (3 to 6):

1.

6. The oral film according to any one of claims 1 to 5, characterized in that The weight ratio of the antibacterial agent in the adhesive layer and the sustained-release layer is 1:24; Optionally, in the adhesive layer, the adhesive material is carbomer and hypromellose, and the weight ratio of the hypromellose to the carbomer is 1:1; Optionally, in the adhesive layer, the weight ratio of the antibacterial agent to the sustained-release material is 1:3.8; Optionally, in the sustained-release layer, the weight ratio of the antibacterial agent to the sustained-release material is (4 to 5):

1.

7. The oral film according to any one of claims 1 to 6, characterized in that In the sustained-release layer, the weight ratio of the antibacterial agent to the sustained-release material is 4.44:

1.

8. The oral film according to any one of claims 1 to 7, characterized in that The antibacterial agent is ornidazole; Optionally, the adhesive material is selected from one or more of carbomer, hydroxypropyl methylcellulose, polycarbophil, hydroxypropyl cellulose, xanthan gum, and polyvinyl pyrrolidone; Optionally, the sustained-release material is selected from ethyl cellulose and / or acrylic resin; Optionally, the waterproof material is selected from one or more of ethyl cellulose, polyacrylic acid resin and ethyl acrylate-methyl methacrylate copolymer aqueous dispersion; Optionally, the plasticizer is selected from one or more of polyethylene glycol, glycerol, propylene glycol, dibutyl phthalate, dioctyl phthalate, tricresyl phosphate, triethyl citrate, triphenyl phosphate and dioctyl sebacate; Optionally, the flavoring agent is selected from one or more of aspartame, edible flavors, vanillin, menthol, stevioside, acesulfame potassium, saccharin sodium and sucralose.

9. The method for preparing the oral film according to any one of claims 3 to 8, comprising the following steps S1 to S4, S1: mixing the adhesive material and the sustained-release material for preparing the adhesive layer, adding ethanol to soak, then adding the antibacterial agent and the plasticizer for preparing the adhesive layer, and degassing to obtain solution 1; S2: mixing the adhesive material and the sustained-release material for preparing the sustained-release layer, adding ethanol to soak, then adding the antibacterial agent and the plasticizer for preparing the sustained-release layer, and degassing to obtain solution 2; S3: mixing the sustained-release material and the plasticizer for preparing the sustained-release layer of the waterproof layer, adding ethanol for soaking, and degassing to obtain solution 3; and S4: using the solution 1, solution 2 and solution 3 to sequentially apply a film to prepare an oral film comprising the adhesive layer, the sustained-release layer and the waterproof layer.

10. The preparation method according to claim 9, characterized in that: In the step S1 and / or step S2, the flavoring agent is added at the same time as the antibacterial agent and the plasticizer; Optionally, the concentration of ethanol is 70wt% to 100wt%; Optionally, the soaking time is 8 to 24 hours.

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