Smeglutide buccal membrane agent and preparation method thereof

Abstract

The invention discloses a semeglutide buccal membrane agent and a preparation method thereof, the semeglutide buccal membrane agent comprises a drug layer and a backing layer, the drug layer comprises 2.0-4.0% of semeglutide, 15.0-20.0% of an absorption enhancer, 9.6-14.5% of a first film forming material, 1.0-2.0% of an adhesive, 0.2-0.8% of an opacifying agent, 0.8-1.4% of a first plasticizer and the balance of a second film forming material, and the total mass percentage of the semeglutide buccal membrane agent is 100%. And the backing layer comprises 60.92%-62.36% of a second film forming material, 0.3%-0.6% of a coloring agent and 1.6%-3.4% of a second plasticizer. The semeglutide buccal membrane agent disclosed by the invention is a parenteral administration, is directly absorbed into systemic circulation through a buccal mucosa in an oral cavity, can avoid a first-pass effect of a liver and damage and degradation of an acid environment and an enzyme environment of a gastrointestinal tract, improves the bioavailability of a medicine, and is relatively loose in control conditions and few in process steps during preparation.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a semaglutide buccal film and a preparation method thereof. Background Art

[0002] Semaglutide tablets contain 35 amino acids and are analogs of human glucagon-like peptide 1 (GLP-1). Semaglutide can selectively bind to and activate the GLP-1 receptor, which is the target of natural GLP-1. GLP-1 is a peptide hormone secreted by intestinal L cells. Its mechanism of action is to act on pancreatic β cells, promote the synthesis and secretion of insulin, stimulate the proliferation and differentiation of pancreatic β cells, inhibit the apoptosis of pancreatic β cells, increase the number of pancreatic β cells, and protect pancreatic islet function. It can also act on pancreatic α cells to inhibit the release of glucagon and reduce the release of liver glycogen. It acts on pancreatic δ cells to promote the secretion of somatostatin and participate in the inhibition of glucagon secretion. It enhances insulin sensitivity, slows down gastric emptying, acts on the hypothalamus to suppress appetite, reduces body weight, and achieves the effect of lowering blood sugar through these actions.

[0003]

[0004] In December 2017, the US Food and Drug Administration (FDA) approved the once-weekly subcutaneous injection formulation of semaglutide (brand name: Ozempic) for marketing, for the blood glucose control of adult patients with type 2 diabetes. In January 2020, it was approved by the FDA to reduce the risk of major adverse cardiovascular events in adult patients with type 2 diabetes complicated with cardiovascular diseases. On December 4, 2020, Novo Nordisk submitted a marketing application to the FDA for once-weekly subcutaneous injection of 2.4 mg semaglutide for weight loss. On June 5, 2021, Novo Nordisk announced that the FDA approved Wegovy (once-weekly subcutaneous injection of 2.4 mg semaglutide) for marketing, for chronic weight management, applicable to obese (BMI≥30 kg / m 2 ) or overweight (BMI≥27 kg / m 2 ) adults. In April 2021, it was approved by the National Medical Products Administration (NMPA) for the treatment of adult type 2 diabetes and reducing the risk of cardiovascular adverse events in patients with T2DM complicated with cardiovascular diseases.

[0005] On September 20, 2019, the FDA officially approved the marketing application of Novo Nordisk's Rybelsus (oral semaglutide tablets). The specifications of the oral semaglutide tablets are 3mg, 7mg, and 14mg, and are used in combination with diet and exercise to improve blood glucose control in patients with type II diabetes. The once-daily oral semaglutide tablets are the first FDA-approved oral glucagon-like peptide-1 receptor agonist (GLP-1RA). Its emergence has broken the pattern that patients with type II diabetes need to receive GLP-1RA injections daily or weekly, providing a less invasive and convenient treatment option for them to control blood glucose. Although the oral absorption rate (bioavailability) of semaglutide is only 0.5-1.0%, the oral dose is still very low, 100-200 times that of the injectable form of the same drug, but this is already the highest among oral formulations of polypeptide and protein drugs since 1992.

[0006] SNAC is used as an absorption enhancer in semaglutide tablets to increase the bioavailability of semaglutide. Its mechanism of action is to open the small intestinal cell wall through SNAC to improve its permeability. Although this absorption-promoting effect is transient and instantaneous, for safety reasons, it is required not to eat during the time of taking the medicine. Because of this, it is necessary to fast for 6 hours and half an hour before and after taking oral semaglutide, respectively.

[0007] There are only two original formulations of semaglutide available currently. One is an injection (subcutaneous injection), and the other is an oral tablet (absorbed through the gastrointestinal tract), but both have drawbacks. Injection (subcutaneous injection): ① It causes pain during injection, and patients have poor compliance with the medication. ② Injection administration is inconvenient. It requires disinfection before use, the needle needs to be changed each time, and the drug needs to be stored refrigerated, which is not conducive to carrying. ③ The quality and dosage requirements for injections are more stringent, and improper use is more likely to pose risks. ④ The research and production process is complex. Since injections require sterility and pyrogen-free conditions, the production process is strict, with many steps, and requires high equipment conditions. Moreover, the drugs in injections are generally dispersed in water in molecular states, micron-sized solid small molecules, or oil droplets, with a relatively large degree of dispersion. During moist heat sterilization, stability problems such as hydrolysis, oxidation, aggregation and enlargement of solid particles, or coalescence and rupture of oil droplets often occur. Oral preparations (absorbed through the gastrointestinal tract): ① The complex acidic and enzymatic environment in the gastrointestinal tract has a great impact on the stability of semaglutide, which in turn leads to a low oral bioavailability of semaglutide. ② Semaglutide absorbed through the gastrointestinal tract needs to undergo the first-pass effect of the liver, further reducing its bioavailability. ③ Absorbed through the gastrointestinal tract, the drug cannot quickly enter the systemic blood circulation, and the onset of the drug is relatively slow. ④ The permeability of semaglutide is poor, and the gastrointestinal barrier has a greater impact on its bioavailability. Therefore, the original oral tablet of semaglutide adds SNAC as an absorption enhancer to increase the absorption of semaglutide. SNAC increases the transmembrane transport of semaglutide by disturbing the phospholipid bilayer of epithelial cells, thereby improving the bioavailability of semaglutide. Therefore, this tablet requires patients to take it on an empty stomach after getting up, with no more than 120 mL of water, and no food intake within 30 minutes to ensure safety and effectiveness. From this perspective, the restrictions on oral semaglutide tablets are relatively large. ⑤ Solid oral medications such as tablets are extremely inconvenient for administration and have poor compliance for patients such as the elderly, children, Parkinson's patients, those prone to nausea, and those under anesthesia. Summary of the Invention

[0008] To solve the problems in the prior art, the present invention aims to provide a buccal film of semaglutide and its preparation method. The buccal film of semaglutide has a high bioavailability, can avoid the first-pass effect of the liver and the influence of the acidic and enzymatic environment in the gastrointestinal tract, the drug can quickly enter the systemic blood circulation, and the administration is convenient, without medication restrictions, and patients have relatively high compliance.

[0009] The specific technical solutions of the present invention are as follows:

[0010] The present invention provides a semaglutide buccal film, which is composed of a drug layer and a backing layer. Calculated based on 100% of the total mass percentage of the semaglutide buccal film, the drug layer contains 2.0 - 4.0% of semaglutide, 15.0 - 20.0% of an absorption enhancer, 9.6 - 14.5% of a first film-forming material, 1.0 - 2.0% of an adhesive, 0.2 - 0.8% of a light-shielding agent, and 0.8 - 1.4% of a first plasticizer. The backing layer contains 60.92 - 62.36% of a second film-forming material, 0.3 - 0.6% of a coloring agent, and 1.6 - 3.4% of a second plasticizer.

[0011] Further, the absorption enhancer is selected from at least any one of sodium caprylate, N-(8-[2-hydroxybenzoyl]-amino) sodium octanoate, sucrose laurate, dodecylphosphocholine, and sodium octanoate;

[0012] and / or, the first film-forming material is selected from at least any one of hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, hypromellose, poly(lactic-co-glycolic acid), and polyacrylate;

[0013] and / or, the adhesive is selected from at least any one of polycarbophil, xanthan gum, guar gum, soluble starch, gelatin, and sodium alginate;

[0014] and / or, the light-shielding agent is selected from at least any one of titanium dioxide, iron oxide red, and zinc oxide;

[0015] and / or, the first plasticizer is selected from at least any one of glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, and polyethylene glycol 600.

[0016] Further, the absorption enhancer is at least one of dodecylphosphocholine and sodium octanoate;

[0017] and / or, the first film-forming material is at least one of hydroxypropyl cellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose;

[0018] and / or, the adhesive is polycarbophil;

[0019] and / or, the light-shielding agent is titanium dioxide;

[0020] and / or, the first plasticizer is propylene glycol.

[0021] Further, the second film-forming material is selected from at least any one of hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, hypromellose, poly(lactic-co-glycolic acid), and polyacrylate;

[0022] And / or, the colorant is selected from at least one of carmine, brilliant blue, lemon yellow, sunset yellow;

[0023] And / or, the second plasticizer is selected from at least one of glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600.

[0024] Furthermore, the second film-forming material is at least one of hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose;

[0025] The colorant is carmine;

[0026] The second plasticizer is propylene glycol.

[0027] Furthermore, the thickness of the drug layer is 0.140 - 0.170 mm, and the thickness of the backing layer is 0.180 - 0.210 mm.

[0028] The present invention also provides a preparation method of the semaglutide buccal film, comprising the following steps:

[0029] Weigh the components of the backing layer and the drug layer;

[0030] Stir purified water and ethanol until in a vortex state, add the colorant and the second plasticizer, and slowly add the second film-forming material after uniform dispersion to obtain the backing layer formulation solution;

[0031] Stir part of the purified water and ethanol until in a vortex state, add the light-shielding agent, semaglutide, and absorption promoter, add the first film-forming material after uniform dispersion, and stir until the materials are completely dissolved to obtain mixture 1; stir the remaining purified water and ethanol until in a vortex state, add the first plasticizer and the adhesive, and stir until the materials are completely dissolved to obtain mixture 2; mix mixture 1 and mixture 2 together and stir evenly to obtain the drug layer formulation solution;

[0032] Remove the bubbles in the backing layer formulation solution and the drug layer formulation solution;

[0033] Coat the backing layer formulation solution, set the coating thickness to 1.2 mm, and set the drying temperature to 40 - 50 °C, preferably 45 °C;

[0034] Coat the drug layer formulation solution on the backing layer, set the coating thickness to 1.7 mm, the drying temperature to 40 - 50 °C, preferably 45 °C, and dry until the water content is 3.0% - 8.0%;

[0035] Peel off the double-layer film and cut it to obtain the semaglutide buccal film.

[0036] Furthermore, the solid content concentration in the drug layer formulation solution is 17% - 18%, preferably 17.5%.

[0037] Further, the solid content concentration in the backing layer formulation is 19-21%, preferably 20%.

[0038] The beneficial effects of the present invention are as follows:

[0039] (1) The oral tablets of semaglutide need to be absorbed through the intestine and are extremely vulnerable to the destruction of the gastric acid environment and gastrointestinal hydrolytic enzymes, resulting in the affected stability of semaglutide. In addition, the first-pass effect of the liver will further reduce the amount of semaglutide absorbed into the blood circulation and lower the bioavailability. However, the administration route of the semaglutide buccal film of the present invention is a parenteral route, which directly enters the systemic circulation through the buccal mucosa in the oral cavity, avoiding the first-pass effect of the liver and the destruction and degradation of the acidic environment and enzyme environment in the gastrointestinal tract, improving the bioavailability of the drug and reducing adverse reactions.

[0040] (2) The administration method of the semaglutide injection is subcutaneous injection, and the acupuncture during administration will cause pain, and the compliance of patients with drug use is poor. For the oral tablets of semaglutide, it is also extremely inconvenient to administer drugs to the elderly, children, Parkinson's patients, patients prone to nausea and those under anesthesia, and the compliance is poor. Moreover, since SNAC is used as an absorption promoter in the oral tablets of semaglutide, in order to ensure safety and effectiveness, fasting is required before drug use, and diet is prohibited within half an hour after drug use, and the administration is extremely inconvenient. Once the semaglutide injection and the oral tablets of semaglutide are administered, it is an irreversible state. If strong side effects or adverse reactions occur, it is difficult to stop the drug in time. However, the administration route of the semaglutide buccal film of the present invention is simple and easy to perform. Compared with injection, there is no pain caused by acupuncture. It only needs to stick the film on the buccal mucosa of the patient's oral cavity. Moreover, once adverse effects are found, they can be removed in time, greatly enhancing the safety of drug use; compared with oral tablets, there is no need to control diet, and it will not cause nausea, vomiting and dysphagia. For the elderly, children, Parkinson's patients, patients prone to nausea and those under anesthesia, the compliance of taking medicine is better.

[0041] (3) Compared with other non-oral administration routes, due to the high vascularization of the oral buccal mucosa and the absence of a stratum corneum on the surface, the onset speed of semaglutide buccal film administration is relatively fast.

[0042] (4) The semaglutide buccal film of the present invention can adhere to the oral buccal mucosa, prolong the residence time of the drug, and make the drug absorption more sufficient.

[0043] (5) The semaglutide buccal film of the present invention uses choline dodecyl phosphate and sodium caprylate as absorption promoters, which can instantaneously open the tight junctions between cells, promote the paracellular transport of semaglutide, increase the bioavailability of semaglutide, and the tight junctions of oral buccal mucosal epithelial cells can be quickly restored, and the self-repair speed of the mucosa is relatively fast, without causing damage to the buccal mucosa, and both the safety and effectiveness are good.

[0044] (6) The development and production process of semaglutide injection is complex. Since the injection requires sterility and pyrogen-free, the production process is strict, with many steps, requiring high equipment conditions. Moreover, semaglutide is dispersed in water in molecular state in the injection, with a large dispersion degree, and stability problems such as hydrolysis, oxidation, and aggregation of the drug often occur during heat and moisture sterilization. However, the semaglutide buccal film of the present invention acts on the oral mucosa, its production and preparation are relatively simple, the control conditions are more relaxed, the process steps are fewer, the requirements for production equipment are lower, the production cost is reduced, and it is conducive to the industrial production of the product.

[0045] (7) The semaglutide buccal film of the present invention is a film agent and can be stored at room temperature, which is extremely convenient for carrying and transportation. Description of the Drawings

[0046] Figure 1 Schematic diagram of the action mechanism of the buccal film.

[0047] Figures 2 to 7 Cross-sectional optical microscope images of the buccal films obtained in Examples 1 to 6, respectively.

[0048] Figure 8 Plasma concentration-time curve of the semaglutide buccal film of Example 1 after delivery through the oral buccal mucosa of beagle dogs.

[0049] Figure 9 Plasma concentration-time curve of the semaglutide buccal film of Example 2 after delivery through the oral buccal mucosa of beagle dogs.

[0050] Figure 10 Plasma concentration-time curve of the semaglutide injection after subcutaneous injection into beagle dogs. Detailed Description of the Invention

[0051] To better understand the present invention, the present invention is further described below with reference to the following examples and drawings. The examples are for explanation only and do not limit the present invention in any way. In the examples, all the original reagent materials can be obtained commercially, and the experimental methods without specific conditions are the conventional methods and conventional conditions well-known in the art, or the conditions recommended by the instrument manufacturers.

[0052] The semaglutide buccal film of the present invention is a double-layer film agent, which is composed of a drug layer containing the drug and the absorption promoter and a backing layer for isolation. Figure 1It is a schematic diagram of the mechanism of action of the buccal film. The drug layer has good adhesiveness and can closely adhere to the oral buccal mucosa. Among them, the absorption promoter is released and opens the tight junctions between the buccal mucosa epithelial cells. At the same time, the drug is released and passively transported through the intercellular spaces, which is called paracellular transport. The backing layer is mainly to prevent the drug from being dissolved by saliva and diffusing into the oral cavity, thereby causing drug loss. At the same time, the backing layer can prevent the degradation of the drug by enzymes in saliva. After the drug layer is completely dissolved and released, the backing layer also dissolves accordingly. After the drug in the preparation of the present invention is released, it is absorbed through the buccal mucosa and enters the systemic circulation, avoiding gastric acid destruction and protease hydrolysis. In addition, it avoids the first-pass effect of the liver, greatly improving the stability of the drug.

[0053] The semaglutide buccal film of the present invention has the main prescription components as shown in the following table:

[0054]

[0055] In a specific embodiment, the absorption promoter is selected from at least one of sodium caprate, sodium N-(8-[2-hydroxybenzoyl]-amino) octanoate, sucrose laurate, dodecylphosphocholine, and sodium caprylate. Preferably, the absorption promoter is selected from at least one of dodecylphosphocholine and sodium caprylate.

[0056] In a specific embodiment, the film-forming materials of the drug layer and the backing layer are selected from at least one of hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, poly(lactic-co-glycolic acid), and polyacrylate. Preferably, the film-forming materials of the drug layer and the backing layer are selected from at least one of hydroxypropyl cellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose.

[0057] In a specific embodiment, the adhesive is selected from at least one of polycarbophil, xanthan gum, guar gum, soluble starch, gelatin, and sodium alginate. Preferably, the adhesive is polycarbophil.

[0058] In a specific embodiment, the opacifier is selected from at least one of titanium dioxide, iron oxide red, and zinc oxide. Preferably, the opacifier is titanium dioxide.

[0059] In a specific embodiment, the plasticizers of the drug layer and the backing layer are selected from at least one of glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, and polyethylene glycol 600. Preferably, the plasticizers of the drug layer and the backing layer are propylene glycol.

[0060] In a specific embodiment, the colorant is selected from at least one of carmine, brilliant blue, lemon yellow, and sunset yellow. Preferably, the colorant is selected from carmine.

[0061] The present invention will be described in detail below with reference to specific embodiments.

[0062] Example 1:

[0063] The formulation of the semaglutide buccal film in this example is shown in the following table:

[0064]

[0065] The preparation process steps of the semaglutide buccal film in this example are as follows:

[0066] 1) Weighing of the backing layer: Weigh the prescribed amounts of hydroxypropyl cellulose Klucel EF, hydroxyethyl cellulose Natrosol 250L, carmine, propylene glycol, ethanol, and purified water;

[0067] 2) Preparation of the backing layer solution: Stir the prescribed amounts of ethanol and purified water with a stirring paddle until in a vortex state, and sequentially add the prescribed amounts of carmine and propylene glycol. After uniform dispersion, slowly add the prescribed amounts of hydroxypropyl cellulose Klucel EF and hydroxyethyl cellulose Natrosol 250L, and stir until the materials are completely dissolved;

[0068] 3) Weighing of the drug layer: Weigh the prescribed amounts of semaglutide, dodecylphosphocholine, hydroxypropyl cellulose Klucel EF, hydroxyethyl cellulose Natrosol 250L, polycarbophil Noveon AA-1, sodium carboxymethyl cellulose Blanose 7LF, propylene glycol, titanium dioxide, ethanol, and purified water;

[0069] 4) Preparation of the drug layer solution: Stir 1 / 2 of the ethanol and purified water with a stirring paddle until in a vortex state, and add the prescribed amounts of titanium dioxide, semaglutide, and dodecylphosphocholine. After uniform dispersion, sequentially add the prescribed amounts of hydroxypropyl cellulose Klucel EF, hydroxyethyl cellulose Natrosol 250L, and sodium carboxymethyl cellulose Blanose 7LF, and stir until the materials are completely dissolved; Stir the remaining ethanol and purified water until in a vortex state, add the prescribed amounts of propylene glycol and polycarbophil Noveon AA-1 and dissolve completely. After the solution is uniform, mix the two together and stir evenly;

[0070] 5) Degassing of the solution: After leveling the weights of the drug layer solution and the backing layer solution, centrifuge to remove bubbles, set the centrifuge speed to 4000 rpm, and set the centrifugation time to 10 min;

[0071] 6) Coating of the backing layer: Perform the first coating of the backing solution with a film coater, set the coating thickness to 1.2 mm, and set the drying temperature to 45 °C;

[0072] 7) Coating of the drug layer: The drug layer solution was coated on the backing layer using a film coater, with the coating thickness set at 1.7 mm and the drying temperature at 45 °C;

[0073] 8) Slitting: After peeling the double-layer film, it was slit into 2×3 cm and packaged.

[0074] Example 2:

[0075] The formulation of the semaglutide buccal film in this example is shown in the following table:

[0076]

[0077]

[0078] The preparation process steps of the semaglutide buccal film in this example are as follows:

[0079] 1) Weighing of the backing layer: Weigh the prescribed amounts of hydroxypropyl cellulose Klucel EF, hydroxyethyl cellulose Natrosol 250L, carmine, propylene glycol, ethanol, and purified water;

[0080] 2) Preparation of the backing layer solution: Stir the prescribed amounts of ethanol and purified water with a stirring paddle until in a vortex state, and sequentially add the prescribed amounts of carmine and propylene glycol. After uniform dispersion, slowly add the prescribed amounts of hydroxypropyl cellulose Klucel EF and hydroxyethyl cellulose Natrosol 250L, and stir until the materials are completely dissolved;

[0081] 3) Weighing of the drug layer: Weigh the prescribed amounts of semaglutide, sodium caprylate, hydroxypropyl cellulose Klucel EF, hydroxyethyl cellulose Natrosol 250L, polycarbophil Noveon AA-1, sodium carboxymethyl cellulose Blanose 7LF, propylene glycol, titanium dioxide, ethanol, and purified water;

[0082] 4) Preparation of the drug layer solution: Stir 1 / 2 of the ethanol and purified water with a stirring paddle until in a vortex state, and add the prescribed amounts of titanium dioxide, semaglutide, and sodium caprylate. After uniform dispersion, sequentially add the prescribed amounts of hydroxypropyl cellulose Klucel EF, hydroxyethyl cellulose Natrosol 250L, and sodium carboxymethyl cellulose Blanose 7LF, and stir until the materials are completely dissolved; Stir the remaining ethanol and purified water until in a vortex state, add the prescribed amounts of propylene glycol and polycarbophil Noveon AA-1 and dissolve completely. After the solution is uniform, mix the two together and stir evenly;

[0083] 5) Degassing of the solution: After leveling the weights of the drug layer solution and the backing layer solution, use a centrifuge to remove bubbles, set the centrifuge speed at 4000 rpm, and set the centrifugation time at 10 min;

[0084] 6) Backing layer coating: The backing solution is coated for the first time with a film coater, setting the coating thickness to 1.2 mm and the drying temperature to 45 °C;

[0085] 7) Drug layer coating: The drug layer solution is coated on the backing layer with a film coater, setting the coating thickness to 1.7 mm and the drying temperature to 45 °C;

[0086] 8) Slitting: After peeling the double-layer film, it is slit into 2×3 cm and packaged.

[0087] Examples 3 to 6:

[0088] The prescriptions of semaglutide buccal films in Examples 3 to 6 are shown in the following table:

[0089]

[0090] The preparation process steps of semaglutide buccal films in Examples 3 to 6 are as follows:

[0091] 1) Backing layer weighing: Weigh the prescribed amounts of hydroxypropyl cellulose Klucel EF, hydroxyethyl cellulose Natrosol 250L, carmine, propylene glycol, ethanol and purified water;

[0092] 2) Backing layer solution preparation: Stir the prescribed amounts of ethanol and purified water with a stirring paddle until in a vortex state, and successively add the prescribed amounts of carmine and propylene glycol. After uniform dispersion, slowly add the prescribed amounts of hydroxypropyl cellulose Klucel EF and hydroxyethyl cellulose Natrosol 250L, and stir until the materials are completely dissolved;

[0093] 3) Drug layer weighing: Weigh the prescribed amounts of semaglutide, dodecylphosphocholine, hydroxypropyl cellulose Klucel EF, hydroxyethyl cellulose Natrosol 250L, polycarbophil Noveon AA-1, sodium carboxymethyl cellulose Blanose 7LF, propylene glycol, titanium dioxide, ethanol and purified water;

[0094] 4) Drug layer solution preparation: Stir 1 / 2 of the ethanol and purified water with a stirring paddle until in a vortex state, and add the prescribed amounts of titanium dioxide, semaglutide and dodecylphosphocholine. After uniform dispersion, successively add the prescribed amounts of hydroxypropyl cellulose Klucel EF, hydroxyethyl cellulose Natrosol 250L and sodium carboxymethyl cellulose Blanose 7LF, and stir until the materials are completely dissolved; Stir the remaining ethanol and purified water until in a vortex state, add the prescribed amounts of propylene glycol and polycarbophil Noveon AA-1 and dissolve completely. After the solutions are uniform, mix the two together and stir evenly;

[0095] 5) Solution degassing: After leveling the weights of the drug layer solution and the backing layer solution, centrifuge to remove air bubbles using a centrifuge. Set the centrifuge speed to 4000 rpm and the centrifugation time to 10 min;

[0096] 6) Coating of the backing layer: Perform the first coating of the backing solution using a film coater. Set the coating thickness to 1.2 mm and the drying temperature to 45 °C;

[0097] 7) Coating of the drug layer: Coat the drug layer solution on the backing layer using a film coater. Set the coating thickness to 1.7 mm and the drying temperature to 45 °C;

[0098] 8) Slitting: After peeling the double-layer film, slit it into 2 × 3 cm and package.

[0099] Experimental examples:

[0100] 1. Content determination

[0101] 1) Chromatographic conditions

[0102]

[0103] 2) Solution preparation

[0104] 10 mmol / L phosphate buffer: Take 1.56 g of sodium dihydrogen phosphate dihydrate, dissolve it in 1000 mL of water, and adjust the pH to 7.5 with 1 mol / L sodium hydroxide solution to obtain.

[0105] 50 mM ammonium dihydrogen phosphate solution: Take 5.75 g of ammonium dihydrogen phosphate, dissolve it in 1000 mL of water, adjust the pH to 3.0 with phosphoric acid, and filter by suction to obtain.

[0106] Test solution of semaglutide buccal film: Put the semaglutide buccal film into a 50 mL volumetric flask, dilute it to the mark with 10 mmol / L phosphate buffer, shake for 30 min, centrifuge for 30 min (7800 rpm / min), and take the supernatant to obtain the test solution. Prepare 2 portions in parallel.

[0107] Reference solution of semaglutide: Weigh accurately about 20 mg of semaglutide reference substance in a 20 mL volumetric flask, dilute it to the mark with 10 mmol / L phosphate buffer as the stock solution. Then take 2 mL of the stock solution to a 20 mL volumetric flask and dilute it to the mark with 10 mmol / L phosphate buffer to obtain (prepared into a reference solution with a concentration of 0.1 mg / mL). Prepare 2 portions in parallel.

[0108] 3) Sample detection

[0109] Respectively take 10 μL of the blank solution, reference solution, and test solution, and record the chromatogram according to the high performance liquid chromatography method.

[0110] 4) Content Results

[0111]

[0112] 2. Dissolution Determination

[0113] 1) Chromatographic Conditions

[0114]

[0115]

[0116] 2) Dissolution Conditions

[0117]

[0118] 3) Solution Preparation and Determination

[0119] 50 mM Ammonium Dihydrogen Phosphate Solution: Take 5.75 g of ammonium dihydrogen phosphate, dissolve it in 1000 mL of water, adjust the pH to 3.0 with phosphoric acid, and filter by suction to obtain.

[0120] Dissolution Medium of pH 6.4: Weigh 27.2 g of potassium dihydrogen phosphate and 1.86 g of sodium hydroxide, dissolve them in water and dilute to 8 L, adjust the pH value to 6.4, mix well, and degas at 40 °C to obtain.

[0121] Semaglutide Reference Solution: Weigh accurately about 20 mg of semaglutide reference substance in a 20 mL volumetric flask, dilute to the mark with 10 mmol / L phosphate buffer solution as the stock solution. Take 1 mL of the stock solution into a 100 mL volumetric flask, dilute to the mark with the dissolution medium to obtain (prepared into a reference solution with a concentration of 10 μg / mL). Prepare 2 portions in parallel.

[0122] Test Solution: Moisten the buccal film backing layer and stick it on a glass plate, add 500 mL of dissolution medium, rotate at 50 revolutions per minute, operate according to the law, and take samples at 10, 15, 20, 30, 45, and 60 minutes; as the test solution;

[0123] 4) Sample Detection

[0124] Take 50 μL of the blank solution, reference solution, and test solution respectively, and record the chromatogram according to the high performance liquid chromatography method.

[0125] 5) Dissolution Results

[0126]

[0127]

[0128] 3. Observation of Double-Layer Membrane Structure

[0129] The cross-sections of the buccal films obtained in Examples 1 to 6 were observed under an optical microscope to measure the thickness of the drug layer and the backing layer, and to observe the uniformity of the two layers and the smoothness of the film surfaces on both sides. Figures 2 - 7 shown.

[0130] 4. Weight, thickness and moisture

[0131] The weight, thickness and moisture content of the buccal films obtained in Examples 1 to 6 were measured using an electronic balance, a vernier caliper and a halogen moisture meter, respectively. The results are shown in the following table:

[0132]

[0133]

[0134] 5. Pharmacokinetic study in beagle dogs

[0135] 5.1 Pharmacokinetic study plan

[0136] 1) Animal drug preparations

[0137] The formulations administered to the animals are shown in the following table:

[0138] Table 5.1-1 Information of drug delivery preparations for pharmacokinetic tests

[0139]

[0140] 2) Animal information

[0141] The animal information table of pharmacokinetic test is as follows:

[0142] Table 5.1-2 Pharmacokinetic test animal information

[0143]

[0144] 3) Animal experiment design

[0145] The pharmacokinetic study design is as follows:

[0146] Table 5.1-3 Pharmacokinetic test design

[0147]

[0148]

[0149] 4) Samples of the test solution

[0150] The prepared preparation samples were stored in a refrigerator at 2-10℃.

[0151] 5) Collection and Storage of Biological Samples

[0152] Approximately 0.5 mL of blood was collected and placed in a labeled EDTA-2K anticoagulant tube. After gently inverting the tube up and down to fully mix the anticoagulant (EDTA-2K) with the blood, it was immediately placed on wet ice and centrifuged to separate plasma within 1 hour after blood collection. The centrifugation conditions were set at 4°C, 6800 g, and 6 minutes. The separated plasma after centrifugation was placed in a labeled EP tube and stored in an ultra-low temperature freezer as soon as possible until sample analysis.

[0153] 6) Sample Analysis

[0154] According to the requirements of the relevant SOP, an LC-MS / MS analytical method for determining the concentration of the drug prototype in canine plasma was established and used for the concentration determination of the biological samples obtained in this experiment. The pretreatment process of the biological samples was carried out in an ice-water bath.

[0155] 5.2 Pharmacokinetic Test Results

[0156] 1) Administration of the Drug

[0157] The administration of the drug in the pharmacokinetic test and the experimental phenomena are shown in the following table:

[0158] Table 5.2-1 Administration of the Drug in the Pharmacokinetic Test and Experimental Phenomena

[0159]

[0160]

[0161]

[0162] 2) Pharmacokinetic Parameters of Example 1

[0163] After the buccal mucosa of beagle dogs was delivered with the buccal film of semaglutide in Example 1 batch, the blood drug concentration and PK parameters were as follows, and the concentration-time curve was as Figure 8 shown:

[0164] Table 5.2-2 Blood Drug Concentration and PK Parameters of Semaglutide in Example 1

[0165]

[0166]

[0167] Note: ① BQL: Below the quantification limit (10.0 ng / mL in Beagle dog plasma)

[0168] ② Tmax reports the median

[0169] ③F = (AUC0-inf-PO / AUC0-inf-IV mean) / (DosePO / DoseIV) * 100%, due to the incomplete blood sampling period, AUC0-t is used for F calculation here.

[0170] 3) Pharmacokinetic parameters of Example 2

[0171] The blood drug concentrations and PK parameters of Example 2 batch of semaglutide buccal film after being delivered through the oral buccal mucosa of beagle dogs are as follows, and the concentration-time curve is as Figure 9 shown:

[0172] Table 5.2-3 Blood drug concentrations and PK parameters of semaglutide in Example 2

[0173]

[0174] Note: ① BQL: Below the lower limit of quantification (Beagle dog plasma 10.0 ng / mL)

[0175] ② Tmax reports the median

[0176] ③ F = (AUC0-inf-PO / AUC0-inf-IV mean) / (DosePO / DoseIV) * 100%, due to the incomplete blood sampling period, AUC0-t is used for F calculation here, for reference only.

[0177] 4) Pharmacokinetic parameters of semaglutide injection

[0178] The blood drug concentrations and PK parameters of semaglutide injection batch after subcutaneous injection in beagle dogs are as follows, and the concentration-time curve is as Figure 10 shown:

[0179] Table 5.2-4 Blood drug concentrations and PK parameters of semaglutide

[0180]

[0181] Note: ① BQL: Below the lower limit of quantification (Beagle dog plasma 10.0 ng / mL)

[0182] ② Tmax reports the median

[0183] ③ F = (AUC0-inf-PO / AUC0-inf-IV mean) / (DosePO / DoseIV) * 100%, due to the incomplete blood sampling period, AUC0-t is used for F calculation here, for reference only.

[0184] Obviously, the above embodiments are merely examples for clear illustration and not limitations on the implementation manners. For those of ordinary skill in the art, other different forms of changes or variations can be made based on the above description. It is not necessary and impossible to enumerate all implementation manners here. And the obvious changes or variations derived therefrom still fall within the protection scope of the present invention.

Claims

1. A semaglutide buccal film, characterized in that, The semaglutide buccal film is composed of a drug layer and a backing layer. Calculated based on 100% of the total mass of the semaglutide buccal film, the drug layer contains 2.0 - 4.0% of semaglutide, 15.0 - 20.0% of absorption enhancer, 9.6 - 14.5% of the first film-forming material, 1.0 - 2.0% of adhesive, 0.2 - 0.8% of light-shielding agent, and 0.8 - 1.4% of the first plasticizer. The backing layer contains 60.92 - 62.36% of the second film-forming material, 0.3 - 0.6% of colorant, and 1.6 - 3.4% of the second plasticizer.

2. The semaglutide buccal film according to claim 1, wherein The absorption enhancer is selected from at least one of sodium caprate, sodium N-(8-[2-hydroxybenzoyl]-amino) octanoate, sucrose laurate, dodecylphosphocholine, and sodium caprylate; and / or, the first film-forming material is selected from at least one of hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, hypromellose, poly(lactic-co-glycolic acid), and polyacrylate; and / or, the adhesive is selected from at least one of polycarbophil, xanthan gum, guar gum, soluble starch, gelatin, and sodium alginate; and / or, the light-shielding agent is selected from at least one of titanium dioxide, iron oxide red, and zinc oxide; and / or, the first plasticizer is selected from at least one of glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, and polyethylene glycol 600.

3. The semaglutide buccal film according to claim 1, wherein The absorption enhancer is at least one of dodecylphosphocholine and sodium caprylate; and / or, the first film-forming material is at least one of hydroxypropyl cellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose; and / or, the adhesive is polycarbophil; and / or, the light-shielding agent is titanium dioxide; and / or, the first plasticizer is propylene glycol.

4. The semaglutide buccal film according to claim 1, wherein, The second film-forming material is selected from at least one of hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, hypromellose, poly(lactic-co-glycolic acid), and polyacrylate; and / or, the colorant is selected from at least one of carmine, brilliant blue, lemon yellow, and sunset yellow; and / or, the second plasticizer is selected from at least one of glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, and polyethylene glycol 600.

5. The semaglutide buccal film according to claim 1, wherein The second film-forming material is at least one of hydroxypropyl cellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose; The colorant is carmine; The second plasticizer is propylene glycol.

6. The semaglutide buccal film according to claim 1, wherein The thickness of the drug layer is 0.140 - 0.170 mm, and the thickness of the backing layer is 0.180 - 0.210 mm.

7. A method for preparing the semaglutide buccal film according to claim 1, characterized in that, Including the following steps: Weigh the components of the backing layer and the drug layer; Stir purified water and ethanol until in a vortex state, add the colorant and the second plasticizer, and slowly add the second film-forming material after uniform dispersion to obtain the backing layer formulation solution; Stir part of the purified water and ethanol until in a vortex state, add the light-shielding agent, semaglutide, and absorption promoter. After dispersing evenly, add the first film-forming material and stir until the materials are completely dissolved to obtain mixture 1; stir the remaining purified water and ethanol until in a vortex state, add the first plasticizer and adhesive, and stir until the materials are completely dissolved to obtain mixture 2; mix mixture 1 and mixture 2 together and stir evenly to obtain the drug layer formulation solution; Remove the bubbles in the backing layer formulation solution and the drug layer formulation solution; Coat the backing layer formulation solution, set the coating thickness to 1.2 mm, and set the drying temperature to 40 - 50 °C; Coat the drug layer formulation solution on the backing layer, set the coating thickness to 1.7 mm, the drying temperature to 40 - 50 °C, and dry until the water content is 3.0% - 8.0%; After peeling and cutting the double-layer film, the semaglutide buccal film as described in claim 1 is obtained.

8. The preparation method according to claim 7, characterized in that, The solid content concentration in the drug layer formulation solution is 17% - 18%.

9. The preparation method according to claim 7, characterized in that, The solid content concentration in the backing layer formulation solution is 19 - 21%.

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