Briracetam oral soluble film and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a briracetam oral soluble film and a preparation method thereof. The composition provided by the invention comprises an active component, namely, the distriburacetam, a film-forming agent, a crystal inhibitor and the like, and the film-forming agent is selected from a combination of polyvinyl alcohol and hydroxypropyl cellulose. The composition provided by the invention has better in-vivo bioavailability, overcomes the defects of conventional oral solid and liquid preparations, is very suitable for administration of epilepsy patients, particularly greatly improves the compliance of the patients, and has better economic benefits and social benefits.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a bricetrast oral disintegrating film pharmaceutical composition and its preparation method. Background Technology

[0002] Brivaceratam is a second-generation antiepileptic drug developed by UCB (UCB Pharmaceuticals) in Belgium. It is a highly selective and affinity synaptic vesicle protein 2A ligand with higher affinity for SV2A and the ability to inhibit synaptic transmission and vesicle release. It is mainly used to treat epilepsy patients aged 16 years and older in adolescents and adults.

[0003] Bricetane has the molecular formula C11H20N2O2 and the chemical name (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide. It is a BCS Class I (highly soluble and highly permeable) drug. Its chemical structure is as follows:

[0004]

[0005] Currently, brucetan is available in tablet, oral solution, and injection forms. While the approved oral solution and injection can compensate for the inconvenience of tablets for epilepsy patients, epileptic seizures are usually acute, and patients often lack the awareness to take medication or have difficulty swallowing. Although injections can take effect quickly, administration is extremely inconvenient, requiring patients to be taken to a medical institution for professional medical care, which greatly delays treatment time. Oral solutions are prone to spilling from the corners of the mouth during administration, making it difficult to control the dosage and leading to inaccurate dosage.

[0006] Therefore, there is an urgent need to develop a new formulation of brucetain that is convenient to take and has a rapid onset of action, in order to meet the clinical medication needs of patients and improve the convenience and compliance of patient medication.

[0007] Oral instant dissolving film is a new dosage form that dissolves rapidly in the oral cavity. It is a thin film solid preparation made by dissolving or uniformly dispersing the drug in a film-forming material. Oral instant dissolving film has the following advantages and characteristics: (1) It can dissolve in a few seconds, release rapidly, and take effect quickly; (2) It can quickly dissolve with saliva and be swallowed into the stomach with voluntary or involuntary swallowing movements to take effect. It does not require chewing or water to take, is convenient to take, has good patient compliance, and does not pose a risk of choking; (3) It is lightweight and compact, individually packaged, and easy to carry.

[0008] It is evident that developing briracetam into an orally disintegrating film solves the problems of inconvenient administration of injectable formulations, difficulty in swallowing or choking on tablets, and easy dripping and inaccurate dosage of oral solutions. However, orally disintegrating films have the following drawbacks: due to their small size and light weight, and the limited requirements for thickness, length, and span, their drug loading is often lower compared to other oral dosage forms. They are also soft, hygroscopic, and have poor release properties. Therefore, research on orally disintegrating films for briracetam is relatively scarce. Furthermore, due to the different properties of the drug, considering the solubility of briracetam, the tendency for white crystals to precipitate during preparation, and the requirements for drug loading, solubility, release properties, hygroscopicity, physical properties, and taste, existing orally disintegrating film formulations cannot solve the above technical problems. Therefore, research on orally disintegrating films for briracetam still needs further development and improvement.

[0009] In view of this, the present invention provides an orally disintegrating film formulation of briceracetam and its preparation method, aiming to fill the global gap in orally disintegrating film formulations of briceracetam and provide epilepsy patients with a convenient, well-compliant, accurately dosed, and rapidly acting drug. Simultaneously, the orally disintegrating film formulation of briceracetam provided by the present invention has the advantages of high drug loading, excellent desiccation and mechanical properties, and no drug precipitation. It can disintegrate rapidly, and its related substances are of good quality and stability, making it suitable for large-scale industrial production and effectively overcoming the shortcomings of existing technologies. Summary of the Invention

[0010] The present invention aims to provide a bricetrastant oral dissolving film formulation with high drug loading, excellent mechanical properties, no drug precipitation, rapid disintegration, good stability, and suitable for large-scale industrial production, as well as its preparation method.

[0011] A first aspect of the present invention provides a pharmaceutical composition comprising brisexiantan, a film-forming agent, and a crystallization inhibitor.

[0012] In some embodiments, the crystallization inhibitor in the pharmaceutical composition is selected from poloxamer, povidone, and eutectic, preferably povidone.

[0013] In some embodiments, the pharmaceutical composition is an orally disintegrating film.

[0014] In some embodiments, the film-forming agent is selected from one or more of polyvinyl alcohol, polyoxyethylene, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, pullulan, gelatin, gum arabic, modified starch, carrageenan, gum arabic, guar gum, locust bean gum, xanthan gum, sodium carboxymethyl cellulose, povidone K30, gelatan gum, and agar.

[0015] Preferably, the film-forming agent is one or more of polyvinyl alcohol, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and povidone K30.

[0016] More preferably, the film-forming agent is one or more of polyvinyl alcohol and hydroxypropyl cellulose.

[0017] More preferably, the film-forming agent is a combination of polyvinyl alcohol and hydroxypropyl cellulose.

[0018] This invention does not impose any particular limitation on the molecular weight of polymers such as polyvinyl alcohol and povidone, and those skilled in the art can select them according to actual needs. In some specific embodiments, polyvinyl alcohol with a molecular weight of 20,000 Da to 220,000 Da can be selected, such as 20,000 Da, 25,000 Da, 30,000 Da, 35,000 Da, 120,000 Da, 130,000 Da, 10140,000 Da, 200,000 Da, 210,000 Da, and 220,000 Da, with polyvinyl alcohol with a molecular weight of 20,000 Da to 75,000 Da being preferred. In some specific implementation schemes, polyvinyl chloride with a molecular weight of 25,000 Da to 1,500,000 Da can be selected, such as 25,000 Da, 28,000 Da, 30,000 Da, 34,000 Da, 50,000 Da, 400,000 Da, and 1,000,000 Da, with polyvinyl chloride with a molecular weight of 25,000 Da to 40,000 Da being preferred.

[0019] Optionally, the weight ratio of polyvinyl alcohol to hydroxypropyl cellulose is 1-50:1, preferably 2-30:1, and more preferably 6-25:1.

[0020] In some embodiments, the bricetan is present in 15-65 parts by weight, preferably 20-60 parts, more preferably 35-55 parts, such as 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, and 55 parts.

[0021] In some embodiments, the crystal inhibitor is present in 2-20 parts by weight, preferably 5-15 parts, more preferably 7-10 parts, such as 7 parts, 8 parts, 9 parts, or 10 parts.

[0022] In some embodiments, the film-forming agent is 15-50 parts by weight, preferably 20-40 parts, for example 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 29 parts, 30 parts, 31 parts, 32 parts, 33 parts, 34 parts, 35 parts, 36 parts, 37 parts, 38 parts, 39 parts, or 40 parts.

[0023] In some embodiments, the orally disintegrating film agent includes bricetam, a film-forming agent, and a crystallization inhibitor, wherein the film-forming agent is selected from one or more of polyvinyl alcohol, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and povidone K30, and the crystallization inhibitor is selected from one or more of poloxamer, povidone, and eutectic.

[0024] In some embodiments, the orally disintegrating film agent comprises 20-60 parts by weight of bricetan, 20-40 parts by weight of a film-forming agent, and 5-15 parts by weight of a crystal-inhibiting agent. The film-forming agent is selected from one or more of polyvinyl alcohol, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and povidone K30, and the crystal-inhibiting agent is selected from one or more of poloxamer, povidone, and eutectic.

[0025] In some embodiments, the orally disintegrating film contains 25-100 mg of bricetramine.

[0026] In some embodiments, the oral dissolving film agent has bricetan as its active ingredient, a film-forming agent that is a combination of polyvinyl alcohol and hydroxypropyl cellulose, and a crystallization inhibitor that is povidone.

[0027] In some embodiments, the bricetan orally dissolving film agent comprises 20-60 parts by weight of bricetan, 20-40 parts by weight of polyvinyl alcohol and hydroxypropyl cellulose, and 5-15 parts by weight of povidone.

[0028] In some embodiments, the oral dissolving film agent further includes a plasticizer selected from one or more of glycerin, polyethylene glycol series, diethylene glycol, tripropylene glycol, ethylene glycol, 1,3-butanediol and 1,4-butanediol, and polysorbate.

[0029] In some embodiments, the plasticizer is preferably one or more of polyethylene glycol 400, polyethylene glycol 1000, and glycerin.

[0030] In some embodiments, the plasticizer is more preferably a combination of polyethylene glycol 400 or polyethylene glycol 1000 and glycerin.

[0031] In some embodiments, the weight ratio of polyethylene glycol 400 to glycerin is 0.1-5:1, preferably 1-3:1, for example 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3.0:1.

[0032] In some embodiments, the weight ratio of polyethylene glycol 1000 to glycerin in the plasticizer is 0.1-5:1, preferably 1-3:1, for example 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3.0:1.

[0033] In some embodiments, the plasticizer is present in 1-22 parts by weight, preferably 5-18 parts, for example 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, or 18 parts.

[0034] In some embodiments, the orally disintegrating film agent further includes a disintegrant.

[0035] In some embodiments, the disintegrant is selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, and microcrystalline cellulose.

[0036] In some embodiments, the disintegrant is preferably crospovidone.

[0037] In some embodiments, the disintegrant is present in 1-20 parts by weight, preferably 3-15 parts, more preferably 3-6 parts, such as 3 parts, 4 parts, 5 parts, or 6 parts.

[0038] In some embodiments, the oral dissolving film agent also includes a flavoring agent.

[0039] In some embodiments, the flavoring agent is selected from one or more of aspartame, sodium saccharin, sucrose, glucose, fructose, sucralose, menthol, nutmeg oil, and flavoring.

[0040] In some embodiments, the flavoring agent is preferably sucralose, flavoring, and menthol.

[0041] In some embodiments, the flavoring agent is present in an amount of 0.1-10 parts by weight, preferably 0.5-5 parts.

[0042] In some embodiments, the bricetan orally dissolving film agent has bricetan as its active ingredient, a film-forming agent consisting of a combination of polyvinyl alcohol and hydroxypropyl cellulose, a crystallization inhibitor consisting of povidone, a plasticizer consisting of a combination of polyethylene glycol 400 or polyethylene glycol 1000 and glycerin, a disintegrant consisting of cross-linked povidone, and flavoring agents consisting of sucralose, flavorings, and menthol.

[0043] In some embodiments, in addition to the excipients mentioned above, other excipients known in the art may also be added to the bricetan orally dissolving film agent according to the characteristics of the product requirements.

[0044] In some embodiments, the bricetam orally dissolving film contains 20-60 parts by weight of bricetam, 20-40 parts by weight of polyvinyl alcohol and hydroxypropyl cellulose, 5-15 parts by weight of povidone, 5-18 parts by weight of a combination of polyethylene glycol 400 or polyethylene glycol 1000 and glycerin, 3-15 parts by weight of crospovidone, and 0.5-5 parts by weight of sucralose, flavoring, and menthol.

[0045] In some embodiments, the bricetan orally dissolving film contains 50 parts by weight of bricetan, 42 parts by weight of polyvinyl alcohol and hydroxypropyl cellulose, 10 parts by weight of povidone, 14 parts by weight of the combination of polyethylene glycol 400 and glycerin, 4 parts by weight of cross-linked povidone, and 2 parts by weight of sucralose, flavoring and menthol.

[0046] In some embodiments, the bricetan orally dissolving film agent comprises 50 parts by weight of bricetan, 21 parts by weight of polyvinyl alcohol and hydroxypropyl cellulose, 10 parts by weight of povidone, 18 parts by weight of the combination of polyethylene glycol 400 and glycerin, 6 parts by weight of cross-linked povidone, and 5 parts by weight of sucralose, flavoring, and menthol.

[0047] In some embodiments, the bricetam oral dissolving film agent comprises 100 parts by weight of bricetam, 51 parts by weight of polyvinyl alcohol and hydroxypropyl cellulose, 15 parts by weight of povidone, 18 parts by weight of the combination of polyethylene glycol 1000 and glycerin, 15 parts by weight of cross-linked povidone, and 5 parts by weight of sucralose, flavoring and menthol.

[0048] A second aspect of the present invention provides a method for preparing a bricetan orally dissolving membrane, the method comprising the following steps:

[0049] (1) Heat the film-forming agent, disintegrant and crystal inhibitor in a certain solvent and stir until dissolved to obtain solution I.

[0050] Optionally, the solvent used in step (1) is an alcohol-water solvent, wherein the alcohol-water solvent contains ethanol, preferably 10-20% by weight of ethanol.

[0051] In some embodiments, the preparation method may further include the following steps:

[0052] (2) Add brucetan, plasticizer and flavoring agent to solution I, stir and dissolve to obtain matrix solution II.

[0053] Optionally, the solid content (i.e., the mass percentage concentration of solid material in matrix liquid II) in step (2) needs to be controlled at 15-60%, preferably 25-45%.

[0054] The weight percentage of bricetan added, and the types and weight percentages of the film-forming agent, crystal inhibitor, disintegrant, plasticizer, and flavoring agent added are as described in any of the above descriptions.

[0055] In some embodiments, the preparation method may further include the following steps:

[0056] (3) Apply matrix liquid II using a coating machine and dry it.

[0057] Optionally, the drying process in step (3) requires controlling the weight loss to ≤15%, preferably 6-12%; the wet adhesive coating thickness is controlled to 100-600μm.

[0058] In some embodiments, the preparation method may further include the following steps:

[0059] (4) Cut the winding film and control the weight difference to obtain the finished product.

[0060] In some embodiments, the method for preparing the oral dissolving film further includes a vacuum degassing operation, with the vacuum level controlled between -0.05 MPa and -0.10 MPa. Preferably, the vacuum degassing operation is performed after obtaining the matrix liquid II.

[0061] By employing the technical solution of this invention, the amount of bubble generation can be effectively controlled, resulting in a smooth, flat, and aesthetically pleasing oral dissolution film.

[0062] A third aspect of the present invention provides that, in some embodiments, any of the foregoing orally disintegrating film preparations or orally disintegrating film preparations obtained by the above methods can be used to prepare a drug for treating epilepsy.

[0063] In some embodiments, any of the aforementioned orally disintegrating films or orally disintegrating films prepared by the above methods can be used to treat epilepsy.

[0064] In some embodiments, the present invention provides a method for treating epilepsy, the method comprising administering to a patient a therapeutically effective amount of any of the aforementioned orally disintegrating film agents or an orally disintegrating film agent prepared by the above method.

[0065] Compared with the prior art, the present invention has the following beneficial effects:

[0066] (1) This invention provides a bricesteran oral disintegrating film, which adds a new dosage form to bricesteran, enabling industrial production and filling a market gap. At the same time, it achieves good bioavailability in vivo, disintegrates rapidly in the oral cavity without water, and has a good taste, no obvious odor, no gritty feeling, etc., which helps to improve patient compliance and provides more dosage form options for epilepsy patients.

[0067] (2) Since bricetan has good solubility and easily precipitates white transparent crystals, the present invention finally solved this problem. The oral soluble film obtained does not crystallize and has excellent quality, smooth appearance, excellent toughness / folding resistance, low content of related substances, and good drug stability, disintegration and dissolution.

[0068] (3) The bricetane orally disintegrating film provided by the present invention is convenient to take. It does not require water or chewing. It disintegrates rapidly with saliva and can be swallowed into the stomach with voluntary or involuntary swallowing movements to take effect. Furthermore, the orally disintegrating film of the present invention can disintegrate rapidly in the mouth, has a fast onset of action, and allows the drug to dissolve extremely quickly. The dosage is accurate, and the onset of action is comparable to that of oral solutions. However, it is more beneficial for epilepsy patients than oral solutions. Compared with ordinary tablets, capsules, oral solutions and injections, it has better patient compliance and is especially suitable for epilepsy patients. For example, the orally disintegrating film dosage form is significantly superior to or comparable to ordinary tablets in terms of content, dissolution, disintegration time, stability and related substances.

[0069] (4) The bricetrastran orally disintegrating film provided by this invention has a high drug loading (API content can reach more than 20%, preferably more than 40%), a uniform and beautiful appearance, and no excessive thickness that is not conducive to drying. Furthermore, the quality of the prepared orally disintegrating film, including toughness, folding resistance, appearance, disintegration, and dissolution, is excellent. This invention can prepare bricetrastran orally disintegrating films with high drug loading, meaning that the preparation of orally disintegrating films can be achieved with fewer excipients, and the quality meets the requirements. The highest drug loading of this invention reaches 55.7%. As is generally known to those skilled in the art, the higher the drug loading of an orally disintegrating film, the greater the difficulty in its preparation. Within a limited area of ​​the orally disintegrating film, if there are too few excipients, it is difficult to form; if there are too many, the thickness of the orally disintegrating film will inevitably increase. However, the industrialization of orally disintegrating films is a dynamic, automated drying process with limited drying temperature and time. An excessively thick orally disintegrating film is difficult to dry for industrial production. This invention greatly improves the drug loading, enabling the preparation of orally disintegrating film agents with high drug loading, and making it easier to achieve industrial-scale production of orally disintegrating films.

[0070] (5) This invention provides a method for preparing bricipital orally soluble film, which is simple to operate, allows for easy demolding and peeling, and ensures that the orally soluble film adheres firmly to the coating material during subsequent cutting, making it difficult to separate and easy to scale up production. The process of developing orally soluble film from laboratory to industrial application presents certain challenges, especially in the processes of dissolution, coating, drying, cutting, and packaging. It is essential to ensure that the intermediates in each process meet the requirements. For example, the viscosity of the dissolved adhesive should be appropriate, with no excessive air bubbles; the coating should not exhibit "flowing" or "film-hanging" phenomena; and the coating thickness should be appropriate to facilitate subsequent continuous dynamic drying and match the coating speed. The dried orally soluble film has appropriate adhesion to the backing carrier material and suitable "demolding properties." Detailed Implementation

[0071] To more clearly illustrate the technical solution of this invention, further explanation is provided below with reference to specific embodiments and comparative examples. However, these are not intended to limit the invention and are merely some embodiments of the invention. Simple improvements to the invention based on its technical solution are all within the scope of protection of this invention. Unless otherwise stated, the instruments, reagents, materials, experimental animals, etc., used in this invention can all be obtained through conventional commercial means. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply.

[0072] The quality evaluation method used in the experimental examples of this invention is as follows:

[0073] 1. Disintegration time limit

[0074] Place the unit formulation into a beaker containing 50 ml of pH 6.4 phosphate buffer at (37±0.5)℃, gently shake, and record the time it takes for the sample to completely disintegrate as the disintegration time limit. Record the longest disintegration time.

[0075] 2. Dissolution rate

[0076] Take the formulation prepared according to the present invention, and perform the dissolution test according to the method (Chinese Pharmacopoeia 2020 General Chapter 0931 Method II), using pH 6.4 phosphate buffer as the dissolution medium, a rotation speed of 50 rpm, and a volume of 900 ml. After 5 min, 10 min, 15 min, 20 min, and 30 min, take an appropriate amount of solution, filter it, and take the filtrate as the test solution; perform the content determination according to the content determination method, and calculate the dissolution amount per tablet.

[0077] 3. Content determination

[0078] High performance liquid chromatography (HPLC) (Appendix to Part II of the Chinese Pharmacopoeia 2015 Edition), chromatographic conditions: SB-C18 column: 4.6 mm × 250 mm, 5 μm; acetonitrile:NaH2PO4 (0.02 mol / L, pH = 2) = 45:55 (v / v); isogradient elution, elution time 30 min; flow rate: 1.0 mL / min; column temperature: 25 ℃; UV detector wavelength: 210 nm; injection volume: 10 μL; calculated by peak area using the external standard method.

[0079] 4. Content uniformity determination

[0080] According to the content uniformity test method in Appendix II of the 2020 edition of the Chinese Pharmacopoeia, take 10 tablets of this product and place them in separate 25ml volumetric flasks. Add an appropriate amount of phosphate buffer, shake to disintegrate, and then shake for 10 minutes to dissolve briracetam. Dilute to the mark with phosphate buffer, shake well, centrifuge, and take the supernatant as the test solution. Determine the content according to the method under the content determination section, calculate the content of each tablet, and calculate the mean and standard deviation S of the relative content X of each tablet with the labeled amount as 100%, as well as the absolute value A of the difference between the labeled content and the mean. If A + 2.2S ≤ 15.0, the content uniformity of the test sample meets the requirements.

[0081] 5. Mechanical properties

[0082] The following methods were used to determine the film release properties, tensile strength, elongation, and folding endurance of the film prepared according to the present invention.

[0083] (1) Demolding properties

[0084] After the film coating dries, assess the ease with which the film can be peeled off from the coated carrier material PET (i.e., polyester film). Take a 40mm x 50mm film, gently peel off the film coating by hand, and evaluate the ease of peeling.

[0085] (2) Tensile strength and elongation

[0086] The prepared bricipitan orally soluble membrane was cut into strips of 20 mm x 5 mm. Tensile stress and elongation at fracture were measured using a universal DE material testing instrument at a speed of 50 mm / min. The measurements were recorded, and the results were repeated three times. Tensile strength and elongation were calculated using the following formulas: Tensile strength (N·mm⁻²) = Tensile stress / Cross-sectional area; Elongation (%) = Elongation / Initial length x 100%.

[0087] (3) Flexural endurance

[0088] Take a suitable size of 10 x 20 mm bricipital oral fusion film and repeatedly fold it manually in the same position until it breaks. Record the number of folds and evaluate the folding resistance of the oral fusion film.

[0089] Examples 1-3: Prescriptions and their preparation methods

[0090] Table 1 Prescriptions for Examples 1-3

[0091]

[0092] Note: " / " indicates that the ingredient was not added.

[0093] Examples 1-3 were prepared using the following process:

[0094] (1) Heat the prescribed amounts of polyvinyl alcohol, hydroxypropyl cellulose, povidone (if any), and crospovidone in suitable water, stir and disperse evenly, and cool to room temperature to obtain solution I;

[0095] (2) Add the prescribed amount of brucetam, polyethylene glycol 400 or polyethylene glycol 1000, and glycerin to solution I, stir until dissolved, and obtain matrix solution II;

[0096] (3) After the matrix liquid II has settled and there are basically no bubbles, it is coated on the polyester film, the wet adhesive thickness is controlled at 400-450um, and then dried in an oven;

[0097] (5) Cut the film to a width of 3×4cm. 2 The tablet weight difference was controlled within ±10% to obtain the sample. Comparative Examples 1-12: Formulations and Preparation Methods.

[0098] Table 2-1 Comparative Examples 1-6 Prescriptions

[0099]

[0100] Table 2-2 Comparative Example 7-12 Prescriptions

[0101]

[0102]

[0103] Note: " / " indicates that the ingredient was not added.

[0104] Comparative Examples 1-12 were prepared using the following process:

[0105] (1) Heat the corresponding prescription and dosage of polyvinyl alcohol or hydroxypropyl cellulose or sodium carboxymethyl cellulose or povidone K30 or polyvinyl alcohol + hydroxypropyl cellulose, crospovidone or crospovidone sodium carboxymethyl cellulose or sodium carboxymethyl starch, and / or povidone or poloxamer or eutectic in an appropriate amount of water, stir and disperse evenly, and cool to room temperature to obtain solution I.

[0106] (2) Add the prescribed amount of brucetam, polyethylene glycol 400 or polyethylene glycol 1000 or polyethylene glycol 4000, and / or glycerin to solution I, stir until dissolved, and obtain matrix solution II;

[0107] (3) After the matrix liquid II has settled and there are basically no bubbles, it is coated on the polyester film, the wet adhesive thickness is controlled at 400-450um, and then dried in an oven;

[0108] (4) Cut the film to a width of 3×4cm. 2 The sample is obtained by controlling the weight difference to ±10%.

[0109] Experiment Example 1: Screening Experiment for Film-Forming Materials

[0110] Films were prepared according to the formulations of Example 1 and Comparative Examples 1-4. The appearance, release properties, toughness, and mechanical properties of the samples were studied. The experimental results are shown in the table below:

[0111] Table 3-1 Comparison of appearance between Samples from Example 1 and Comparative Examples 1-3

[0112]

[0113] Table 3-2 Comparison of demolding properties of samples from Example 1 and Comparative Examples 1 and 3-4

[0114]

[0115] Table 3-3 Comparison of mechanical properties of Example 1 and Comparative Examples 1-3

[0116]

[0117] Table 3-4 Toughness Comparison Results of Example 1 and Comparative Examples 1-3

[0118] serial number Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 toughness good generally Difference Difference

[0119] Table 3-5 Comparison of disintegration time between Example 1 and Comparative Example 2

[0120] serial number Example 1 Comparative Example 2 Disintegration time limit 35s 126s

[0121] The experimental results show that the membrane prepared by Comparative Example 1 (hydroxypropyl cellulose) has poor film-forming properties, moderate toughness, and is difficult to peel off from the carrier material, which is not conducive to production operations. The membrane prepared by Comparative Example 2 (sodium carboxymethyl cellulose) has poor film-forming properties, but poor toughness. Further investigation revealed that the membrane prepared by Comparative Example 2 has a relatively long disintegration time. The membrane prepared by Comparative Example 3 (povidone K30) has poor film-forming properties and poor toughness, and is also difficult to peel off from the carrier material, failing to meet the film-forming requirements. The membrane prepared by Comparative Example 4 (polyvinyl alcohol) is too easy to demold, and falls off before it can be bagged. The membrane prepared in Example 1 has a delicate appearance, good film-forming properties, good toughness, and suitable demolding properties. All indicators meet the film-forming requirements and industrial production requirements, and the disintegration time is about 35 seconds, which is very beneficial for the rapid disintegration and dissolution of the membrane in the oral cavity.

[0122] Experiment Example 2: Plasticizer Screening Experiment

[0123] Films were prepared according to the formulations of Examples 1-2 and Comparative Examples 5-8. The appearance, release properties, and toughness of the samples were studied. The experimental results are shown in the table below:

[0124] Table 4-1 Comparison of Demolding Properties of Examples 1-2 and Comparative Example 5

[0125] serial number Example 1 Example 2 Comparative Example 5 Demolding Suitable for peeling from PET film Suitable for peeling from PET film Too easy to peel off from PET film

[0126] Table 4-2 Comparison of mechanical properties between Examples 1-2 and Comparative Examples 5-8

[0127]

[0128] Table 4-3 Comparison of toughness between Examples 1-2 and Comparative Examples 6-8

[0129] serial number Example 1 Example 2 Comparative Example 6 Comparative Example 7 Comparative Example 8 toughness good good generally generally generally

[0130] The above experimental results show that the film prepared by Comparative Example 5 (polyethanol 4000) has too good demolding properties, which is not conducive to the cutting process; the films prepared by Examples 1-2 have better mechanical properties and a higher number of folding cycles than the films prepared by Comparative Examples 5-8. When polyethylene glycol 1000, polyethylene glycol 400, or glycerol (i.e., Comparative Examples 6-8) are used as a single plasticizer, the toughness of the prepared film is generally average; when the plasticizers of Examples 1-2 (i.e., polyethylene glycol 400 or polyethylene glycol 1000 combined with glycerol) are used as a mixed plasticizer, the film-forming properties, toughness, and demolding properties of the oral solution film are all excellent, meeting product requirements and industrial production.

[0131] Experiment Example 3: Disintegrant Screening Experiment

[0132] Films were prepared according to the formulations of Example 1 and Comparative Examples 9-10, and the effects of different disintegrants on disintegration time, film-forming properties, toughness, and release properties were investigated. The experimental results are shown in the table below:

[0133] Table 5. Comparison results of disintegration time, film-forming properties, toughness, and release properties of samples from Example 1 and Comparative Examples 9-10.

[0134] serial number Example 1 Comparative Example 9 Comparative Example 10 Disintegration time limit 35s 200s 120s Demolding Suitable for peeling from PET film Difficult to peel from PET film Too easy to peel off from PET film Mechanical properties 230-240 folding cycles 42-51 folding cycles 4-7 folding cycles toughness good generally Difference

[0135] Using croscarmellose sodium (Comparative Example 9) as a disintegrant, the resulting membrane had a disintegration time of about 200 seconds, was difficult to demold, and had poor peelability. Using croscarmellose sodium (Comparative Example 10) as a disintegrant, the resulting membrane had a disintegration time of 120 seconds, poor toughness, and was too easy to peel off. Using croscarmellose polyvinylpyrrolidone (Example 1) as a disintegrant, the resulting membrane had a delicate appearance, good film-forming properties, good toughness, suitable demolding properties, and a disintegration time of only 35 seconds, with all indicators meeting the requirements.

[0136] Experiment Example 4: Screening Experiment for Crystallization Inhibitors

[0137] Films were prepared according to the formulations of Example 3 and Comparative Examples 11-12. The effects of different anti-crystallization agents on solving the crystallization problem were investigated, as well as the influence of the addition of anti-crystallization agents on film formation, toughness, and release properties. The experimental results are shown in the table below:

[0138] Table 6. Comparison results of film-forming properties, toughness, and release properties of samples from Example 3 and Comparative Examples 11-12.

[0139]

[0140] Studies have found that after the oral dissolution film of this product is prepared, it has a good appearance and no crystals are precipitated on day 0. However, after being left at room temperature for 1 month, almost all of the active ingredients are precipitated into crystals, which seriously affects the appearance and product quality.

[0141] The above experimental results show that when povidone (Example 3) is used as a crystal inhibitor, the film prepared does not exhibit crystal precipitation during stable storage, has good release properties, and is suitable for peeling from PET film. In contrast, when poloxamer and eutectic (Comparative Examples 11-12) are used, crystals precipitate after one month at room temperature. Furthermore, the addition of the crystal inhibitor does not affect other quality indicators of the orally disintegrating film, such as excellent toughness / folding endurance, suitable release properties, and good disintegration time (approximately 36 seconds).

[0142] Examples 4-10 (10,000 tablets produced)

[0143] Table 7 Prescriptions for Examples 4-10

[0144]

[0145] Note: " / " indicates that the ingredient was not added.

[0146] The bricetam orally disintegrating film provided in Examples 4-10 has a drug loading (calculated as: drug loading (%) = weight of API in the film / weight of the film × 100%) greater than 20%, preferably greater than 40%, and even reaching 55.7%. At high drug loadings, when the film area is fixed, the thickness is usually thicker and disintegration is slower. However, this invention can produce orally disintegrating films with high drug loading, suitable thickness, and the ability to be dried industrially. Furthermore, compared to other methods with the same drug loading specifications, this invention uses less excipients, effectively reducing production costs.

[0147] Berizetan oral dissolving film formulations, with high drug loading, can reduce the frequency of patient dosing and improve patient compliance. Furthermore, the film formulation exhibits good stability and tolerability even at high drug loading levels, demonstrating that the formulation provided by this invention can tolerate high proportions of the API.

[0148] Preparation methods of Examples 4-10

[0149] (1) Heat the prescribed amounts of polyvinyl alcohol, hydroxypropyl cellulose, povidone, and crospovidone in alcohol-water to 40-60°C, stir and disperse evenly, and cool to room temperature to obtain solution I;

[0150] (2) Add the prescribed amounts of brucetam, polyethylene glycol, glycerin, sucralose, flavoring and menthol to solution I, stir until dissolved, and obtain matrix solution II;

[0151] (3) Remove air bubbles and control solid content under vacuum conditions of -0.05Mpa to -0.10Mpa;

[0152] (4) Apply the matrix liquid II using a coating machine, control the thickness of the wet adhesive, and dynamically dry and rewind it in the oven section of the coating machine at 60-90℃.

[0153] (5) Cut the winding film and control the weight difference of the sheet to ±10% to obtain the finished product.

[0154] The preparation processes for Examples 4-10 are as described above, differing only in the amount of alcohol-water solvent, ethanol concentration, degassing time, control of solid content, wet coating thickness, and film cutting width. Specifically:

[0155]

[0156] Comparative Example 13: Bricestane orally dissolving membrane (prepared into 1000 membranes)

[0157] Table 8 Comparative Example 13 Prescriptions

[0158]

[0159] Preparation method of Comparative Example 13

[0160] (1) Weigh out all the components according to the prescription in the table and set aside;

[0161] (2) Preparation of flavoring agent solution: Add flavoring agent sucralose and flavoring to purified water, stir, and obtain flavoring agent solution;

[0162] (3) Preparation of polymer material mixture: Add film-forming agent hydroxypropyl cellulose and xanthan gum to the above flavoring agent solution, stir, and continue to add plasticizer glycerin to obtain polymer material mixture;

[0163] (4) Preparation of drug solution: Add brucetan to the above polymer mixture and stir to obtain drug solution.

[0164] (5) Use a coating machine to evenly coat the drug solution onto the PET backing with a coating thickness of 70-80μm, dry at 60-65℃, demold, and obtain the oral dissolving film.

[0165] Experimental Example 5

[0166] The appearance, release properties, tensile strength, ductility, and flexural endurance of samples from Examples 4-10 were studied, and the data are shown in the table below:

[0167] Table 9 Comparison results of appearance, release properties, tensile strength, ductility, and flexural endurance of samples from Examples 4-10

[0168]

[0169] Note: Scores are based on a comprehensive evaluation, with higher scores indicating better overall performance. Demolding properties: Easy to peel is better than peelable.

[0170] The above data show that bricetan orally dissolving films of the present invention can be prepared according to the embodiments of the present invention, and the orally dissolving films prepared in Examples 4, 7, 8 and 9 have excellent overall quality indicators.

[0171] Experimental Example 6

[0172] The content, content uniformity, disintegration time, dissolution rate, and related substances of samples from Examples 4-10 and Comparative Example 13 were studied, and the data are shown in the table below:

[0173] (1) Results of the 0-day measurement

[0174] Table 10-1 Results of day 0 measurements for samples from Examples 4-10 and Comparative Example 13

[0175]

[0176]

[0177] Table 10-2 Results of day 0 measurements for samples from Examples 4-10 and Comparative Example 13

[0178]

[0179] The above results indicate that the orally disintegrating films prepared in Examples 4-10 of this invention meet the requirements for content and related substances, and the disintegration time is no more than 45 seconds. Furthermore, the orally disintegrating films of this invention dissolve very rapidly, reaching over 100% dissolution within 5 minutes, far faster than gastric emptying, essentially equivalent to a solution, thus rapidly promoting drug release, absorption, and efficacy.

[0180] (2) Stability (accelerated test for 6 months) results

[0181] Samples from Examples 4-10 of this invention and sample from Comparative Example 13 were placed under conditions of 40 minutes and 75% RH for 6 months. Samples were then taken to examine their quality changes. The results are shown in the table below:

[0182] Table 11-1 Results of accelerated testing of samples from Examples 4-10 and Comparative Example 13 over 6 months

[0183]

[0184] Table 11-2 Results of accelerated testing of samples from Examples 4-10 and Comparative Example 13 over 6 months

[0185]

[0186] The results showed that, after being placed under the above-mentioned test conditions for 6 months, the contents and related substances of the samples in each embodiment of the present invention did not change significantly, indicating good stability and meeting the product quality requirements.

[0187] (3) Results of crystallization under various stability testing conditions of oral dissolution film samples

[0188] Table 12 Crystallization of Samples 4-10 under Various Stability Conditions Table 12 Crystallization of Samples 4-10 under Various Stability Conditions

[0189]

[0190] The above data shows that the anti-crystallization agent used in this invention can effectively inhibit the precipitation of crystals from the raw materials during the preparation process, ensuring that the 0-day sample meets the quality requirements, and also ensuring that the product will not crystallize during long-term storage under various temperature conditions, effectively guaranteeing product quality, and further proving that the use of anti-crystallization agent in the oral dissolution film of this invention has substantial and significant advantages.

Claims

1. A bricetam oral dissolving film agent, characterized in that, The orally disintegrating film-forming agent contains bricetan, a film-forming agent, and a crystal-inhibiting agent.

2. The oral dissolving film agent according to claim 1, characterized in that, The crystallization inhibitor is selected from one of poloxamer, povidone, and eutectic, preferably povidone.

3. The oral dissolving film agent according to any one of claims 1-2, characterized in that, The film-forming agent is selected from one or more of polyvinyl alcohol, polyoxyethylene, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, pullulan polysaccharide, gelatin, gum arabic, modified starch, carrageenan, gum arabic, guar gum, locust bean gum, xanthan gum, sodium carboxymethyl cellulose, povidone K30, glucan gum, and agar, preferably one or more of polyvinyl alcohol, hydroxypropylcellulose, sodium carboxymethyl cellulose, and povidone K30, more preferably one or more of polyvinyl alcohol and hydroxypropylcellulose, and even more preferably a combination of polyvinyl alcohol and hydroxypropylcellulose; Choose any location The weight ratio of polyvinyl alcohol to hydroxypropyl cellulose is 1-50:1, preferably 2-30:1, and more preferably 6-25:

1.

4. The oral dissolving film agent according to any one of claims 1-3, characterized in that, The oral dissolving film further includes one or more of the following components 1)-3): 1) Plasticizer: selected from one or more of glycerin, polyethylene glycol series, diethylene glycol, tripropylene glycol, ethylene glycol, 1,3-butanediol and 1,4-butanediol, and polysorbate; preferably one or more of polyethylene glycol 400, polyethylene glycol 1000 and glycerin; 2) Disintegrant: selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch and microcrystalline cellulose, preferably crospovidone; 3) Flavoring agent: selected from one or more of aspartame, sodium saccharin, sucrose, glucose, fructose, sucralose, menthol, nutmeg oil, and flavoring, preferably sucralose, flavoring, and menthol.

5. The oral dissolving film agent according to claim 4, characterized in that, The bricetam is present in parts by weight of 20-60; the film-forming agent is present in parts by weight of 20-40; the crystal inhibitor is present in parts by weight of 5-15; the plasticizer is present in parts by weight of 5-18; the disintegrant is present in parts by weight of 3-15; and the flavoring agent is present in parts by weight of 0.5-5.

6. The oral dissolving film agent according to any one of claims 4-5, wherein the plasticizer is a combination of polyethylene glycol 400 and glycerin, wherein the weight ratio of polyethylene glycol 400 to glycerin is 0.1-5:1, preferably 1-3:1; or The plasticizer is a combination of polyethylene glycol 1000 and glycerin, wherein the weight ratio of polyethylene glycol 1000 to glycerin is 0.1-5:1, preferably 1-3:

1.

7. The orally dissolving film according to any one of claims 1-6, characterized in that, The drug loading of the bricetramine orally dissolving membrane is greater than 20%, preferably greater than 40%.

8. A method for preparing an orally dissolving film according to any one of claims 1-7, characterized in that, The method includes the following steps: (1) Heat the film-forming agent, disintegrant and crystal inhibitor in a certain solvent and stir until dissolved to obtain solution I; (2) Add brucetan, plasticizer and flavoring agent to solution I, stir until dissolved, and obtain matrix solution II; (3) Apply matrix liquid II using a coating machine and dry it.

9. The method for preparing the orally dissolving film agent according to claim 8, characterized in that, The solvent used in step (1) is an alcohol-water solvent, which contains ethanol, preferably 10-20% ethanol; And / or, The solid content (i.e., the mass percentage concentration of solid materials) in the matrix liquid in step (2) needs to be controlled at 15-60%, preferably 25-45%. And / or, The drying step (3) requires controlling the weight loss to ≤15%, preferably 6-12%; And / or, The method for preparing the oral dissolution membrane further includes a vacuum degassing operation, with the vacuum degree controlled between -0.05 MPa and -0.10 MPa. Preferably, the vacuum degassing operation is performed after obtaining the matrix liquid II.

10. Use of the orally disintegrating film according to any one of claims 1-7 or the orally disintegrating film prepared according to the preparation method of claim 8 or 9 in the preparation of a medicament for treating epilepsy.

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