Oral membrane pharmaceutical composition and preparation method thereof

Abstract

The invention relates to the technical field of oral membranes, in particular to a multilayer oral membrane and a preparation method thereof. The invention provides an oral membrane composition, which comprises semeglutide and pharmaceutically acceptable auxiliary materials, and is characterized in that the composition is formed by combining a drug-containing biological adhesion layer and a backing layer, and the backing layer mainly comprises a membrane forming material, a solvent and a plasticizer; the drug-containing biological adhesion layer mainly comprises semeglutide, a film-forming material, an adhesive, a pH regulator, a flavoring agent and a solvent. By preparing the double-layer oral membrane, the semeglutide is administrated through the oral cavity, and after the insoluble or slowly eroded / dissolved backing layer (preventing saliva from dissolving the medicine) and the adhesive layer containing the main medicine are combined together, the one-way delivery of the main medicine can be realized; through experiments, it is accidentally found that when temperature-sensitive materials such as poloxamer are added to be combined with a conventional adhesive for use, the residence time of the medicine in the oral mucosa can be remarkably prolonged, the curative effect of the medicine is improved, and the main mechanism is that after the medicine is administered, in the oral temperature environment, after the medicine makes contact with mucus on the surface of the oral mucosa, the oral mucosa does not adhere to the oral mucosa. And after the entanglement and piling effects among poloxamer micelles are intensified to form gel, the gel and a conventional adhesive are cooperated to improve the adhesion between the oral membrane and the oral mucosa. Besides, the medicine can be removed at any time, blood sugar can be better controlled, T2DM complications can be better reduced, a more ideal taking mode is provided for weight loss patients, and a new administration mode is provided for reducing blood sugar and reducing weight. The prepared oral cavity membrane is small in size, light in weight, thin, convenient to apply, carry and transport, safe and environmentally friendly to use and capable of meeting the requirements of old people and travelers.

Description

Technical Field

[0001] The present invention relates to the technical field of oral films, and in particular to a multi-layer oral film and a preparation method thereof. Background Art

[0002] Semaglutide is a new glucagon-like peptide-1 (GLP-1) analog that can stimulate insulin production and inhibit glucagon secretion, reducing appetite and food intake. It is approved in the United States and Europe for the treatment of type 2 diabetes and obesity. The currently marketed products are semaglutide injection and tablets. The injection needs to be stored at low temperature (2-8°C), which is inconvenient to carry. Long-term injection can easily cause pain and damage to the administration site, and compliance is poor. Ordinary oral tablets act on the gastrointestinal tract, causing secondary changes in gastric emptying, intestinal motility, and secretion of other gastrointestinal peptide hormones, or directly or indirectly acting on the central nervous system to affect the normal function of the gastrointestinal tract, thereby causing gastrointestinal discomfort, such as nausea, vomiting, diarrhea, constipation and other adverse reactions. In addition, for patients who only need to lose weight, ordinary tablets need to be taken with water, which is inconvenient to take, and will give patients a psychological suggestion that they are taking medicine, which will cause physical and psychological discomfort. Given the poor patient compliance of semaglutide injection and the low bioavailability of oral dosage forms, there is an urgent need to develop a dosage form with good patient compliance and high bioavailability.

[0003] Oral or transmucosal drug delivery bypasses first-pass metabolism in the gastrointestinal tract and liver through dissolution and absorption through the oral mucosa (usually sublingual administration or oral administration through the inner cheek mucosa). Compared to other methods such as sprays or patches, mucosal administration (sublingual or buccal administration) can quickly decompose tablets or films and is superior to other drug delivery systems in terms of patient compliance. However, like other dosage forms, oral films have their own limitations. The loading of poorly soluble drugs with oral films is still in its infancy. Tablets and capsules can carry dissolved drug components, but oral films are a simpler drug delivery system that mainly relies on polymers to increase drug solubility. Another limitation of oral films is their small drug loading capacity, which is only 10-20 mg. In addition, the large surface area of ​​oral films makes this dosage form more sensitive to humidity and temperature.

[0004] Oral films do not require water to be taken. In terms of use, they only need to be adhered to the mouth and enter the blood circulation through the dense capillaries under the oral mucosa. The buccal mucosal epithelium is a non-keratinized tissue with relatively good permeability. After absorption, the drug enters the jugular vein directly through the blood vessels. This method of administration does not damage normal tissues and can be torn off at any time to interrupt administration. It is especially suitable for the elderly and patients with dysphagia due to gastrointestinal diseases, etc., to improve patient compliance with medication. It can also prevent the drug from being exposed to the acidic and enzymatic environment of the digestive tract, causing drug degradation, promote drug absorption and increase bioavailability. For patients who only need to lose weight, oral films have higher compliance and can greatly reduce the patient's psychological suggestion of suspected medication.

[0005] Existing oral films have poor adhesion, are prone to migration and shedding, and while only a small amount is absorbed through the mucosa, a large amount enters the gastrointestinal tract upon swallowing, where it is absorbed, significantly reducing bioavailability. Drug absorption is highly dependent on the drug's residence time in the mucosa. Therefore, improving the drug's adhesion to the oral mucosa, thereby extending its residence time and increasing its absorption, is an urgent challenge. Summary of the Invention

[0006] To address the above-mentioned problems in the prior art, the semaglutide oral film of the present invention is prepared using a solvent casting method. Compared with traditional preparations, the oral film is easy to carry and can be quickly administered at any time and place. It can effectively avoid the first-pass effect and gastrointestinal degradation, and can quickly exert its drug effect. The oral film of the present invention adds a composite drug-containing bioadhesive layer to the structure of traditional fast-dissolving oral films. Its excellent adhesion properties significantly increase the retention time of the drug in the oral mucosa, overcoming the barrier that prevents polypeptide drugs from completing the digestive journey through the gastrointestinal tract and maintaining their pharmacological effects. In addition, its administration does not require water assistance, and the drug is released by wetting with saliva and adhering to the administration site, thereby improving patient compliance.

[0007] The present invention provides a method for preparing a semaglutide oral film, which comprises the following steps: dissolving a first film-forming material in water or an alcohol solution of a certain concentration, adding an appropriate amount of a plasticizer, uniformly coating the solution, and then drying the solution to obtain a backing layer. A prescribed amount of semaglutide, a second film-forming material, an adhesive, a pH regulator, and a flavoring agent are added to pure water or an ethanol-containing aqueous solution and stirred until completely dissolved, eliminating bubbles. A drug-containing adhesive layer film liquid is prepared, which is uniformly coated on the prepared backing layer and dried to form a double-layer film formed by bonding the backing layer and the drug-containing adhesive layer. The dried film is then cut into desired shapes and sizes, packaged, and the semaglutide oral film is obtained. The preparation method is simple and convenient, and the resulting film has uniform thickness and good physical properties.

[0008] The oral film of the present invention does not require water for delivery and is easy to use. It only needs to be adhered to the oral cavity and enters the blood circulation through the dense capillaries under the oral mucosa. The buccal mucosal epithelium is non-keratinized tissue with relatively good permeability. After the drug is absorbed, it directly enters the jugular vein through the blood vessels. The administration method does not damage normal tissues and can be torn off at any time to interrupt the administration. It is particularly suitable for the elderly and patients with dysphagia due to digestive tract diseases, etc., to improve the patient's compliance with medication. It can also prevent the drug from being exposed to the acidic environment and enzymatic environment of the digestive tract, causing drug degradation, promoting drug absorption and improving bioavailability. For patients who only need to lose weight, the oral film has higher compliance and can greatly reduce the patient's psychological suggestion of suspected medication.

[0009] The present invention provides a semaglutide oral film composition, comprising semaglutide and pharmaceutically acceptable excipients, characterized in that the composition is composed of a drug-containing bioadhesive layer and a backing layer, wherein:

[0010] The backing layer mainly includes film-forming materials, solvents, and plasticizers;

[0011] The drug-containing bioadhesive layer mainly includes semaglutide, film-forming materials, adhesives, pH regulators, flavoring agents, and solvents.

[0012] The drug-containing bioadhesive layer is the active layer, the film-forming material of the adhesive layer is selected from any one or more of hydroxyethyl cellulose and hydroxypropyl cellulose, and the active ingredient semaglutide is incorporated into the bioadhesive layer to exert its medicinal effect.

[0013] The backing layer is an inactive layer, and the film-forming material of the backing layer is selected from any one of cellulose acetate and ethyl cellulose or a combination thereof.

[0014] The composition is administered via the buccal mucosa or sublingual mucosa.

[0015] The composition is composed of the following raw and auxiliary materials in the following weight percentages: 0.1-15% of semaglutide, 10-95% of film-forming material, 1-20% of plasticizer, 1-20% of adhesive, 0.1-5% of pH regulator, and 0.1-5% of flavoring agent.

[0016] More preferably, the composition is composed of the following raw materials and auxiliary materials in the following weight percentages: 0.5-12% semaglutide, 30-90% film-forming material, 2-15% plasticizer, 2-15% adhesive, 0.2-3% pH regulator, and 0.2-3% flavoring agent.

[0017] The plasticizer of the backing layer is selected from any one or more of triethyl citrate, glycerol, hexylene glycol, polyethylene glycol, triacetin, and propylene glycol.

[0018] More preferably, the plasticizer of the backing layer is selected from triethyl citrate.

[0019] The adhesive of the drug-containing bioadhesive layer is selected from any one or more of poloxamer, chitosan, carbomer, polycarbophil, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, carbomer, xanthan gum, hyaluronic acid, dextran sulfate, pectin, and chondroitin sulfate.

[0020] More preferably, the adhesive is selected from any one of poloxamer and polycarbophil, poloxamer and chitosan, and poloxamer and hypromellose, or a combination thereof.

[0021] Conventional technologies often enhance bioadhesion by adding a single-mechanism polymer material. However, the present invention addresses this issue by innovatively incorporating thermosensitive poloxamers. Upon contact with mucus on the oral mucosal surface at oral temperature, the entanglement and stacking of the poloxamer micelles intensify, forming a gel. This gel, in combination with other conventional polymers, synergistically enhances the bioadhesion of the oral film to the oral mucosa, significantly extending the duration of action of the oral film in the oral cavity. This effectively promotes drug absorption, ensures slow release of the drug in the oral cavity, maintains effective blood drug concentrations for a long time, and significantly improves bioavailability.

[0022] The pH regulator of the drug-containing bioadhesive layer is selected from citric acid, disodium phosphate, disodium hydrogen phosphate, sodium hydroxide, sodium dihydrogen phosphate, trisodium phosphate, malic acid, succinic acid, maleic acid, fumaric acid, and tartaric acid.

[0023] More preferably, the pH adjuster is selected from any one or more of citric acid and disodium hydrogen phosphate.

[0024] The flavoring agent of the drug-containing bioadhesive layer is selected from one or more of saccharin sodium, sorbitol, aspartame, acesulfame potassium, xylitol, stevioside, sucrose, sucralose, fructose, essence and the like.

[0025] More preferably, the flavoring agent is selected from any one or more of saccharin sodium or aspartame.

[0026] The solvent is purified water or an aqueous solution containing ethanol.

[0027] The ethanol-containing aqueous solution is a 50% ethanol aqueous solution.

[0028] A method for preparing the semaglutide oral film composition mainly comprises the following steps:

[0029] 1) First, dissolve the film-forming material of the backing layer in water or a certain concentration of alcohol solution according to the various raw materials and auxiliary materials in the oral film formula, add an appropriate amount of plasticizer, stir to dissolve, and evenly apply and dry to obtain the backing layer;

[0030] 2) adding the prescribed amount of semaglutide, the film-forming material of the adhesive layer, the adhesive, the pH adjuster, and the flavoring agent to pure water or an aqueous solution containing ethanol, adjusting the pH value, and stirring until completely dissolved and bubbles are eliminated to prepare a drug-containing adhesive layer film solution;

[0031] 3) The drug-containing film liquid is evenly coated on the prepared backing layer and dried to form a film to obtain a double-layer film formed by bonding the backing layer and the drug-containing adhesive layer. The dried film is then cut into the desired shape and size and packaged to obtain the semaglutide oral film.

[0032] The drying temperature used in the above preparation steps (1) and (3) is 25-50°C, preferably 30°C.

[0033] In the above preparation step (2), the pH adjuster adjusts the pH value of the solution to 5-8, preferably 7.0.

[0034] The oral film prepared by the above method has a size of 1 to 4 cm in length and 1 to 4 cm in width according to the optimal area ratio for oral mucosal administration, and the preferred size of the oral film is 1 cm.

[0035] The preparation method of the composition is simple, and the prepared oral film has a uniform and complete appearance, consistent thickness, uniform color, and no obvious bubbles, which is conducive to industrial batch production.

[0036] The present invention prepares a double-layer oral film so that semaglutide is administered orally. After an insoluble or slowly eroded / dissolved backing layer (preventing saliva from dissolving the drug) is combined with an adhesive layer containing the main drug, unidirectional delivery of the main drug can be achieved. The present invention unexpectedly discovered through experiments that adding a temperature-sensitive material such as poloxamer in combination with a conventional adhesive can significantly prolong the retention time of the drug in the oral mucosa and improve the efficacy of the drug. Its mechanism is mainly that after administration, under an oral temperature environment, after contacting the mucus on the surface of the oral mucosa, the entanglement and stacking effect between the poloxamer micelles is aggravated to form a gel, and then the adhesion between the oral film and the oral mucosa is synergistically improved with a conventional adhesive. In addition, the drug can be removed at any time, better controlling blood sugar and reducing T2DM complications, and providing a more ideal way of taking for weight loss patients, providing a new way of administration for hypoglycemic and weight loss. The oral film prepared by the present invention is small in size, light and thin, easy to use, carry and transport, safe and environmentally friendly to use, and can meet the needs of the elderly and travelers.

[0037] The oral film prepared by the present invention does not require water when taken. By adding a temperature-sensitive material (poloxamer) to the prescription together with a conventional adhesive to synergistically improve adhesion, the retention time of the drug in the oral mucosa is significantly prolonged, the bioavailability is high, and there is a certain sustained-release effect, which also improves the safety and compliance of patients' medication.

[0038] The composition of the present invention can be used to prepare a drug for preventing and / or treating overweight, obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes and / or NASH. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Attachment Figure 1 Cumulative release curves of oral film prescriptions of Examples 6 to 11 DETAILED DESCRIPTION

[0040] Example 1

[0041]

[0042] 1) Dissolve / disperse the film-forming material of the backing layer, cellulose acetate, in 50% ethanol according to the prescription, then add triethyl citrate and glycerin as plasticizers, stir until completely dissolved, and evacuate to eliminate bubbles; pump the film-forming solution onto a conveyor belt using a peristaltic pump, apply it to a uniform film with a doctor blade, and dry it at 30°C. The solvent evaporates during the drying process. After the film is formed, remove it to produce the backing layer;

[0043] 2) Pre-disperse or moisten the film-forming materials for the drug-containing bioadhesive layer, hydroxyethyl cellulose and hydroxypropyl cellulose, with 50% ethanol according to the prescription. Dissolve the film in water and then add the prescribed amount of the adhesive, hypromellose, to form a film-forming solution. Separately, dissolve the prescribed amount of semaglutide, sodium hydrogen phosphate (pH adjuster), and fructose (flavor corrector) in pure water, stirring to dissolve, and adjust the pH to 7.0. Mix the mixture evenly with the film-forming solution, and vacuum to eliminate bubbles to form the drug-containing adhesive layer film solution.

[0044] 3) The drug-containing film liquid is evenly coated on the prepared backing layer and dried at room temperature to form a film to obtain a double-layer film formed by bonding the backing layer and the drug-containing adhesive layer. The film is cut into small films of 1 cm of drug film liquid to obtain semaglutide oral film.

[0045] Example 2

[0046]

[0047]

[0048] 1) Dissolve / disperse the film-forming material of the backing layer, ethyl cellulose, in 50% ethanol according to the prescription, then add triethyl citrate, a plasticizer, and stir until completely dissolved. Vacuum to eliminate bubbles; pump the film-forming solution onto a conveyor belt using a peristaltic pump, apply it to a uniform film with a doctor blade, and dry it at 30°C. The solvent evaporates during the drying process. After the film is formed, remove it to produce the backing layer;

[0049] 2) Pre-disperse or moisten the film-forming materials for the drug-containing bioadhesive layer, hydroxyethyl cellulose and hydroxypropyl cellulose, with 50% ethanol according to the prescription. Dissolve the film in water and then add the prescribed amount of adhesive, polycarbophil, to form a film-forming solution. Separately, dissolve the prescribed amount of semaglutide, the pH adjuster, disodium hydrogen phosphate, and the flavoring agent, saccharin sodium, in pure water, stirring to dissolve, and adjust the pH to 7.0. Mix the solution evenly with the film-forming solution, and vacuum to eliminate bubbles to form the drug-containing adhesive layer film solution.

[0050] 3) The drug-containing film liquid is evenly coated on the prepared backing layer and dried at room temperature to form a film to obtain a double-layer film formed by bonding the backing layer and the drug-containing adhesive layer. The film is cut into small films of 1 cm and 1 cm of drug to obtain semaglutide oral film.

[0051] Example 3

[0052]

[0053]

[0054] 1) Dissolve / disperse the film-forming material of the backing layer, ethyl cellulose, in 50% ethanol according to the prescription, then add triethyl citrate and propylene glycol as plasticizers, stir until completely dissolved, and evacuate to eliminate bubbles; pump the film-forming solution onto a conveyor belt using a peristaltic pump, apply it to a uniform film with a doctor blade, and dry it at 30°C. The solvent evaporates during the drying process. After the film is formed, remove it to produce the backing layer;

[0055] 2) Pre-disperse or moisten the film-forming materials for the drug-containing bioadhesive layer, hydroxyethyl cellulose and hydroxypropyl cellulose, with 50% ethanol according to the prescription. Dissolve the film in water and then add the prescribed amount of chitosan, an adhesive, to form a film-forming solution. Separately, dissolve the prescribed amount of semaglutide, sodium hydrogen phosphate (pH adjuster), and aspartame (flavoring agent) in pure water, stirring to dissolve, and adjust the pH to 7.0. Mix the mixture evenly with the film-forming solution, and vacuum to eliminate bubbles to form the drug-containing adhesive layer film solution.

[0056] 3) The drug-containing film liquid is evenly coated on the prepared backing layer and dried at room temperature to form a film to obtain a double-layer film formed by bonding the backing layer and the drug-containing adhesive layer. The film is cut into small films of 1 cm and 1 cm of drug to obtain semaglutide oral film.

[0057] Analysis of results of Examples 1 to 3

[0058] The film was tested on appearance integrity, film forming properties, toughness, and oral retention time of volunteers (after the film was naturally moistened with saliva, it was adhered to the cheek of the mouth and the time for the film to fall off was recorded).

[0059]

[0060] Note: “×” means poor performance, “√” means good performance

[0061] Based on the results of steps 1 to 3, we will continue to increase the proportion of adhesives and use other adhesive materials in combination to further optimize the adhesives in order to increase the oral adhesion time.

[0062] Example 4

[0063] Based on the prescription of Example 2, the amount of polycarbophil was increased to 15 mg, and semaglutide oral film was prepared according to the following prescription.

[0064]

[0065] 1) Dissolve / disperse the film-forming material of the backing layer, ethyl cellulose, in 50% ethanol according to the prescription, then add triethyl citrate, a plasticizer, and stir until completely dissolved. Vacuum to eliminate bubbles; pump the film-forming solution onto a conveyor belt using a peristaltic pump, apply it to a uniform film with a doctor blade, and dry it at 30°C. The solvent evaporates during the drying process. After the film is formed, remove it to produce the backing layer;

[0066] 2) Pre-disperse or moisten the film-forming materials for the drug-containing bioadhesive layer, hydroxyethyl cellulose and hydroxypropyl cellulose, with 50% ethanol according to the prescription. Dissolve the film in water and then add the prescribed amount of adhesive, polycarbophil, to form a film-forming solution. Separately, dissolve the prescribed amount of semaglutide, pH adjusters, disodium hydrogen phosphate and sodium dihydrogen phosphate, and flavoring agent, saccharin sodium, in pure water, stirring to dissolve, and adjust the pH to 7.0. Mix the solution evenly with the film-forming solution, and vacuum to eliminate bubbles to form a film-forming solution for the drug-containing adhesive layer.

[0067] 3) The drug-containing film liquid is evenly coated on the prepared backing layer and dried at room temperature to form a film to obtain a double-layer film formed by bonding the backing layer and the drug-containing adhesive layer. The film is cut into small films of 1 cm and 1 cm of drug to obtain semaglutide oral film.

[0068] Example 5

[0069] Based on the formulation of Example 4, polycarbophil was replaced with poloxamer, and semaglutide oral film was prepared according to the following formulation.

[0070]

[0071] 1) Dissolve / disperse the film-forming material of the backing layer, ethyl cellulose, in 50% ethanol according to the prescription, then add triethyl citrate, a plasticizer, and stir until completely dissolved. Vacuum to eliminate bubbles; pump the film-forming solution onto a conveyor belt using a peristaltic pump, apply it to a uniform film with a doctor blade, and dry it at 30°C. The solvent evaporates during the drying process. After the film is formed, remove it to produce the backing layer;

[0072] 2) Pre-disperse or moisten the film-forming materials for the drug-containing bioadhesive layer, hydroxyethyl cellulose and hydroxypropyl cellulose, with 50% ethanol according to the prescription. Dissolve the film in water and then add the prescribed amount of the adhesive poloxamer to evenly disperse the mixture to prepare a film-forming solution. Separately, dissolve the prescribed amount of semaglutide, pH adjusters disodium hydrogen phosphate and sodium dihydrogen phosphate, and flavoring agent sodium saccharin in pure water, stirring to dissolve, and adjust the pH to 7.0. Mix the mixture evenly with the film-forming solution and evacuate to eliminate air bubbles to prepare the drug-containing adhesive layer film solution.

[0073] 3) The drug-containing film liquid is evenly coated on the prepared backing layer and dried at room temperature to form a film to obtain a double-layer film formed by bonding the backing layer and the drug-containing adhesive layer. The film is cut into small films of 1 cm and 1 cm of drug to obtain semaglutide oral film.

[0074] Example 6

[0075] Based on the prescriptions of Example 4 and Example 5, polycarbophil and poloxamer were used in combination to prepare semaglutide oral film according to the following prescription.

[0076]

[0077] 1) Dissolve / disperse the film-forming material of the backing layer, ethyl cellulose, in 50% ethanol according to the prescription, then add triethyl citrate, a plasticizer, and stir until completely dissolved. Vacuum to eliminate bubbles; pump the film-forming solution onto a conveyor belt using a peristaltic pump, apply it to a uniform film with a doctor blade, and dry it at 30°C. The solvent evaporates during the drying process. After the film is formed, remove it to produce the backing layer;

[0078] 2) Pre-disperse or moisten the film-forming materials for the drug-containing bioadhesive layer, hydroxyethyl cellulose and hydroxypropyl cellulose, with 50% ethanol according to the prescription. Dissolve the film in water. Add the prescribed amount of adhesives, polycarbophil and poloxamer, and disperse evenly to prepare a film-forming solution. Separately, dissolve the prescribed amount of semaglutide, the pH adjuster, disodium hydrogen phosphate, and the flavoring agent, saccharin sodium, in pure water, stir to dissolve, and adjust the pH to 7.0. Mix evenly with the film-forming solution, and evacuate to eliminate bubbles to prepare the drug-containing adhesive layer film solution.

[0079] 3) The drug-containing film liquid is evenly coated on the prepared backing layer and dried at room temperature to form a film to obtain a double-layer film formed by bonding the backing layer and the drug-containing adhesive layer. The film is cut into small films of 1 cm and 1 cm of drug to obtain semaglutide oral film.

[0080] Example 7

[0081] Based on Example 6, polycarbophil was replaced with other adhesive materials, and semaglutide oral film was prepared according to the following prescription.

[0082]

[0083] 1) Dissolve / disperse the film-forming material of the backing layer, ethyl cellulose, in 50% ethanol according to the prescription, then add triethyl citrate, a plasticizer, and stir until completely dissolved. Vacuum to eliminate bubbles; pump the film-forming solution onto a conveyor belt using a peristaltic pump, apply it to a uniform film with a doctor blade, and dry it at 30°C. The solvent evaporates during the drying process. After the film is formed, remove it to produce the backing layer;

[0084] 2) Pre-disperse or moisten the film-forming materials for the drug-containing bioadhesive layer, hydroxyethyl cellulose and hydroxypropyl cellulose, with 50% ethanol according to the prescription. Dissolve the film in water. Add the prescribed amount of chitosan and poloxamer, the adhesives, and disperse evenly to form a film-forming solution. Separately, dissolve the prescribed amount of semaglutide, sodium hydrogen phosphate (pH adjuster), and sodium saccharin (flavoring agent) in pure water, stirring to dissolve, and adjust the pH to 7.0. Mix evenly with the film-forming solution, and vacuum to eliminate bubbles to form a film-forming solution for the drug-containing adhesive layer.

[0085] 3) The drug-containing film liquid is evenly coated on the prepared backing layer and dried at room temperature to form a film to obtain a double-layer film formed by bonding the backing layer and the drug-containing adhesive layer. The film is cut into small films of 1 cm and 1 cm of drug to obtain semaglutide oral film.

[0086] Example 8

[0087] Based on Example 6, polycarbophil was replaced with other adhesive materials, and semaglutide oral film was prepared according to the following prescription.

[0088]

[0089] 1) Dissolve / disperse the film-forming material of the backing layer, ethyl cellulose, in 50% ethanol according to the prescription, then add triethyl citrate, a plasticizer, and stir until completely dissolved. Vacuum to eliminate bubbles; pump the film-forming solution onto a conveyor belt using a peristaltic pump, apply it to a uniform film with a doctor blade, and dry it at 30°C. The solvent evaporates during the drying process. After the film is formed, remove it to produce the backing layer;

[0090] 2) Pre-disperse or moisten the film-forming materials for the drug-containing bioadhesive layer, hydroxyethyl cellulose and hydroxypropyl cellulose, with 50% ethanol according to the prescription. Dissolve the film in water. Add the prescribed amount of adhesives, hypromellose and poloxamer, and disperse evenly to prepare a film-forming solution. Separately, dissolve the prescribed amount of semaglutide, the pH adjuster, disodium hydrogen phosphate, and the flavoring agent, saccharin sodium, in pure water, stir to dissolve, and adjust the pH to 7.0. Mix evenly with the film-forming solution, and evacuate to eliminate bubbles to prepare the drug-containing adhesive layer film solution.

[0091] 3) The drug-containing film liquid is evenly coated on the prepared backing layer and dried at room temperature to form a film to obtain a double-layer film formed by bonding the backing layer and the drug-containing adhesive layer. The film is cut into small films of 1 cm and 1 cm of drug to obtain semaglutide oral film.

[0092] Analysis of results of Examples 4 to 8

[0093] The appearance integrity, film forming properties, toughness, and oral retention time of volunteers were tested (the oral film was naturally moistened with saliva, adhered to the cheek, and the time it took for the film to fall off was recorded).

[0094] Example 4 Example 5 Example 6 Example 7 Example 8 Integrity √ √ √ √ √ Film-forming properties √ √ √ √ √ toughness √ √ √ √ √ Oral retention time About 10 minutes About 9 minutes About 30 minutes About 26 minutes About 28 minutes

[0095] Note: “×” indicates poor performance, “√” indicates good performance

[0096] Based on the results of Examples 4-8, the oral films of Examples 6, 7, and 8, in which polycarbophil, chitosan, and hypromellose were respectively combined with poloxamer, had significantly longer retention times than the oral films in which either of the two adhesives was used alone, achieving the effect of 1+1>2. Therefore, based on Example 6, the ratio of polycarbophil to poloxamer in the formulation was further optimized to obtain Examples 9, 10, and 11.

[0097] Example 9

[0098]

[0099] 1) Dissolve / disperse the film-forming material of the backing layer, ethyl cellulose, in 50% ethanol according to the prescription, then add triethyl citrate, a plasticizer, and stir until completely dissolved. Vacuum to eliminate bubbles; pump the film-forming solution onto a conveyor belt using a peristaltic pump, apply it to a uniform film with a doctor blade, and dry it at 35°C. The solvent evaporates during the drying process. After the film is formed, remove it to produce the backing layer;

[0100] 2) Pre-disperse or moisten the film-forming materials for the drug-containing bioadhesive layer, hydroxyethyl cellulose and hydroxypropyl cellulose, with 50% ethanol according to the prescription. Dissolve the mixture in water. Add the prescribed amount of adhesives, polycarbophil and poloxamer, and disperse evenly to prepare a film-forming solution. Separately, dissolve the prescribed amount of semaglutide, the pH adjuster, disodium hydrogen phosphate, and the flavoring agent, saccharin sodium, in pure water, stir to dissolve, and adjust the pH to 7.5. Mix the mixture evenly with the film-forming solution, and evacuate to eliminate bubbles. This completes the drug-containing adhesive layer film solution.

[0101] 3) The drug-containing film liquid is evenly coated on the prepared backing layer and dried at room temperature to form a film to obtain a double-layer film formed by bonding the backing layer and the drug-containing adhesive layer. The film is cut into small films of 1 cm and 1 cm of drug to obtain semaglutide oral film.

[0102] Example 10

[0103]

[0104] 1) Dissolve / disperse the film-forming material of the backing layer, ethyl cellulose, in 50% ethanol according to the prescription, then add triethyl citrate, a plasticizer, and stir until completely dissolved. Vacuum to eliminate bubbles; pump the film-forming solution onto a conveyor belt using a peristaltic pump, apply it to a uniform film with a doctor blade, and dry it at 40°C. The solvent evaporates during the drying process. After the film is formed, remove it to produce the backing layer;

[0105] 2) Pre-disperse or moisten the film-forming materials for the drug-containing bioadhesive layer, hydroxyethyl cellulose and hydroxypropyl cellulose, with 50% ethanol according to the prescription. Dissolve the film in water. Add the prescribed amount of adhesives, polycarbophil and poloxamer, and disperse evenly to prepare a film-forming solution. Separately, dissolve the prescribed amount of semaglutide, the pH adjuster, disodium hydrogen phosphate, and the flavoring agent, saccharin sodium, in pure water, stir to dissolve, and adjust the pH to 7.0. Mix evenly with the film-forming solution, and evacuate to eliminate bubbles to prepare the drug-containing adhesive layer film solution.

[0106] 3) The drug-containing film liquid is evenly coated on the prepared backing layer and dried at room temperature to form a film to obtain a double-layer film formed by bonding the backing layer and the drug-containing adhesive layer. The film is cut into small films of 1 cm and 2 cm of drug to obtain the semaglutide oral film.

[0107] Example 11

[0108]

[0109] 1) Dissolve / disperse the film-forming material of the backing layer, ethyl cellulose, in 50% ethanol according to the prescription, then add triethyl citrate, a plasticizer, and stir until completely dissolved. Vacuum to eliminate bubbles; pump the film-forming solution onto a conveyor belt using a peristaltic pump, apply it to a uniform film with a doctor blade, and dry it at 40°C. The solvent evaporates during the drying process. After the film is formed, remove it to produce the backing layer;

[0110] 2) Pre-disperse or moisten the film-forming materials for the drug-containing bioadhesive layer, hydroxyethyl cellulose and hydroxypropyl cellulose, with 50% ethanol according to the prescription. Dissolve the film in water. Add the prescribed amount of adhesives, polycarbophil and poloxamer, and disperse evenly to prepare a film-forming solution. Separately, dissolve the prescribed amount of semaglutide, the pH adjuster, disodium hydrogen phosphate, and the flavoring agent, saccharin sodium, in pure water, stir to dissolve, and adjust the pH to 7.0. Mix evenly with the film-forming solution, and evacuate to eliminate bubbles to prepare the drug-containing adhesive layer film solution.

[0111] 3) The drug-containing film liquid is evenly coated on the prepared backing layer and dried at room temperature to form a film to obtain a double-layer film formed by bonding the backing layer and the drug-containing adhesive layer. The film is cut into small films of 1 cm and 1 cm of drug to obtain semaglutide oral film.

[0112] Analysis of results of Examples 9 to 11

[0113] The appearance integrity, film forming properties, toughness, and oral retention time of volunteers were tested (the oral film was naturally moistened with saliva, adhered to the cheek, and the time it took for the film to fall off was recorded).

[0114] Example 9 Example 10 Example 11 Integrity √ √ √ Film-forming properties √ √ √ toughness √ √ √ Oral retention time About 32 minutes About 34 minutes About 32 minutes

[0115] Note: “×” indicates poor performance, “√” indicates good performance

[0116] Example 12

[0117] Cumulative release profile

[0118] This experiment further refers to the third method (small cup method) of the dissolution and release rate determination method of the Chinese Pharmacopoeia (2020 edition, Part IV, Appendix 0931 General Rules) for in vitro dissolution test. The dissolution medium is 100 ml of artificial saliva, the temperature is 37°C, the rotation speed is 50 rpm, and the sampling points are 15 min 30 min 45 min 60 min 90 min 120 min. The cumulative release curve is as follows Figure 1 As shown, the results show that the oral films of Examples 6-11 have good release and are completely released within 120 minutes.

[0119] Example 13

[0120] Pharmacokinetic studies

[0121] A pharmacokinetic study was conducted on beagle dogs, with 6 dogs in each group. The dogs were administered the semaglutide oral films prepared in Examples 6 to 11 and commercially available semaglutide tablets at a dose of 0.2 mg / kg. Blood was collected before each administration (0 min) and 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 8 h, and 24 h after administration. The plasma semaglutide concentration was determined by LC-MS / MS. The pharmacokinetic parameters of the oral films prepared in Examples 6, 7, 8, 9, 10, and 11 were calculated, and the results are shown in the table below.

[0122]

[0123] The results showed that the pharmacokinetic parameters of Examples 6 to 11 were superior to those of the commercially available semaglutide tablets. Compared with the original oral tablets, the oral film of the present invention has a significant sustained release effect and significantly improves the blood drug concentration.

Claims

1. A semaglutide oral film composition comprising semaglutide and a pharmaceutically acceptable excipient, characterized in that: The composition is composed of a drug-containing bioadhesive layer and a backing layer, wherein: The backing layer mainly includes film-forming materials, solvents, and plasticizers; The drug-containing bioadhesive layer mainly includes semaglutide, film-forming materials, adhesives, pH regulators, flavoring agents, and solvents.

2. The semaglutide oral film composition according to claim 1, characterized in that The film-forming material of the drug-containing bioadhesive layer is selected from any one or more of hydroxyethyl cellulose and hydroxypropyl cellulose.

3. The semaglutide oral film composition according to claim 1, characterized in that The film-forming material of the backing layer is selected from any one of cellulose acetate, ethyl cellulose or a combination thereof.

4. The semaglutide oral film composition according to claim 1, wherein the composition is administered via the buccal mucosa or sublingual mucosa.

5. The semaglutide oral film composition according to claim 1, characterized in that The composition is composed of the following raw and auxiliary materials in the following weight percentages: 0.1-15% of semaglutide, 10-95% of film-forming material, 1-20% of plasticizer, 1-20% of adhesive, 0.1-5% of pH regulator, and 0.1-5% of flavoring agent.

6. The semaglutide oral film composition according to claim 5, characterized in that The composition is composed of the following raw and auxiliary materials in the following weight percentages: 0.5-12% of semaglutide, 30-90% of film-forming material, 2-15% of plasticizer, 2-15% of adhesive, 0.2-3% of pH regulator, and 0.2-3% of flavoring agent.

7. The semaglutide oral film composition according to claim 1, characterized in that The plasticizer of the backing layer is selected from any one or more of triethyl citrate, glycerol, hexylene glycol, polyethylene glycol, triacetin, and propylene glycol.

8. The semaglutide oral film composition according to claim 7, characterized in that The plasticizer of the backing layer is selected from triethyl citrate.

9. The semaglutide oral film composition according to claim 1, characterized in that The adhesive of the drug-containing bioadhesive layer is selected from any one or more of poloxamer, chitosan, carbomer, polycarbophil, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, carbomer, xanthan gum, hyaluronic acid, dextran sulfate, pectin, and chondroitin sulfate.

10. The semaglutide oral film composition according to claim 7, characterized in that The adhesive is selected from any one of poloxamer and polycarbophil, poloxamer and chitosan, and poloxamer and hypromellose, or a combination thereof.

11. The semaglutide oral film composition according to claim 1, characterized in that The pH regulator of the drug-containing bioadhesive layer is selected from citric acid, disodium phosphate, disodium hydrogen phosphate, sodium hydroxide, sodium dihydrogen phosphate, trisodium phosphate, malic acid, succinic acid, maleic acid, fumaric acid, and tartaric acid.

12. The semaglutide oral film composition according to claim 9, characterized in that The pH regulator is selected from any one or more of citric acid and disodium hydrogen phosphate.

13. The semaglutide oral film composition according to claim 1, characterized in that The flavoring agent of the drug-containing bioadhesive layer is selected from one or more of saccharin sodium, sorbitol, aspartame, acesulfame potassium, xylitol, stevioside, sucrose, sucralose, fructose, essence and the like.

14. The semaglutide oral film composition according to claim 11, characterized in that The flavoring agent is selected from any one or more of saccharin sodium or aspartame.

15. The semaglutide oral film composition according to claim 1, characterized in that The solvent is purified water or an aqueous solution containing ethanol.

16. The semaglutide oral film composition according to claim 13, characterized in that The ethanol-containing aqueous solution is a 50% ethanol aqueous solution.

17. A method for preparing the semaglutide oral film composition according to claim 1, comprising the following steps: 1) dissolving the film-forming material of the backing layer in a water solvent, adding a plasticizer, stirring and dissolving, and evenly coating and drying to obtain the backing layer; 2) adding semaglutide, film-forming material, adhesive, pH adjuster and flavoring agent into the solvent, stirring until completely dissolved and eliminating bubbles, thereby preparing a drug-containing bioadhesive layer film solution; 3) The drug-containing film liquid is evenly coated on the prepared backing layer and dried to form a film to obtain a double-layer film formed by bonding the backing layer and the drug-containing bioadhesive layer. The film is dried and cut into film preparations of appropriate sizes and packaged to obtain the semaglutide oral film.

18. The method according to claim 15, characterized in that The drying temperature used in the preparation steps (1) and (3) is 25-50°C.

19. The method according to claim 15, characterized in that The drying temperature used in the preparation steps (1) and (3) is 30°C.

20. The method according to claim 15, wherein In the above preparation step (2), the pH adjuster adjusts the pH value of the solution to 5-8.

21. The method according to claim 15, wherein In the above preparation step (2), the pH value of the solution is adjusted to 7.0 by the pH adjuster.

22. The method according to claim 15, wherein The size of the film is 1 to 4 cm long and 1 to 4 cm wide.

23. The method according to claim 15, wherein The film size is 1cm×1cm.

24. Use of the composition of claim 1 in the preparation of a medicament for preventing and / or treating overweight, obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes and / or NASH.

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