Film agent for treating sleep disorder and preparation method thereof

Abstract

The invention provides a film agent for treating sleep disorder, which at least comprises tasimelteon, a film-forming material, a stabilizing agent, and one or more of a plasticizer and a sweetening agent, and the stabilizing agent is silicon dioxide. The silicon dioxide is added as a stabilizer when the film agent is prepared, so that the tasimelteon keeps amorphous and does not separate out crystals, the stability of the tasimelteon can be kept in the film agent preparation process and the subsequent storage process, the stability of the curative effect is ensured, and the storage is facilitated.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a film preparation for treating sleep disorders and a preparation method thereof. Background Art

[0002] Non-24 sleep-wake rhythm disorder (Non-24) is a rare circadian rhythm disorder in which the patient's biological clock cannot synchronize with the 24-hour day-night cycle, resulting in a gradual delay or advancement of sleep and wake times. This disease is more common in people who are completely blind because their retinas cannot perceive light and thus cannot regulate their biological clocks. However, a small number of people with normal vision may also be affected. Patients usually experience difficulty falling asleep at night and excessive daytime sleepiness, which seriously affects their daily life. Diagnosis usually requires monitoring changes in sleep patterns using a sleep diary or actigraphy.

[0003] Smith-Magenis syndrome (SMS) is a rare genetic disorder caused by a microdeletion in the 11.2 region of the short arm of chromosome 17 (17p11.2) or a mutation in the RAI1 gene. Key features of the syndrome include mild to moderate intellectual disability, delayed language development, distinctive facial features (such as a square face, deep-set eyes, and a short nose), sleep disturbances (such as circadian rhythm disruption), and behavioral problems (such as emotional outbursts, impulsive behavior, and self-injury). Additionally, patients may experience short stature, scoliosis, hearing loss, vision problems, and heart or kidney abnormalities.

[0004] Tasimelteon is a melatonin receptor agonist approved for marketing in the United States on January 31, 2014. It acts on melatonin receptors MT1 and MT2, regulating the body's circadian clock and improving sleep rhythms. Currently, tasimelteon's primary indications include sleep disorders associated with non-24-hour sleep-wake rhythm disorders (Non-24) and Smith-Magenis syndrome (SMS).

[0005] The currently available tasimelteon capsules require water for swallowing, making them inconvenient for patients with swallowing difficulties (such as the elderly or those with uncontrolled behavior). In contrast, orodissolving films do not require water and dissolve rapidly in the mouth, making them more suitable for this specific patient population. Currently, there is no tasimelteon film formulation available.

[0006] Although the already marketed tasimelteon liquid formulation HETLIOZ LQ oral solution does not require water to be taken, the liquid has demanding storage conditions and needs to be stored under refrigerated conditions at a temperature of 2°C to 8°C. Once opened, it can only be stored for 5 to 8 weeks, and unused liquid must be discarded.

[0007] Patent application CN114727978A relates to a liquid tasimelteon formulation comprising a uniform aqueous suspension of tasimelteon, supplemented with suspending agents, taste-masking agents, opacifiers, and surfactants. The formulation aims to address issues such as the physical stability and palatability of tasimelteon in the liquid suspension. However, the liquid formulation described in this patent application presents stability issues. The stability of liquid suspensions is difficult to control, requiring the addition of multiple excipients to ensure uniform dispersion and stability of the drug. Furthermore, different storage conditions may affect the drug's dissolution rate and stability.

[0008] Films can be prepared using either solvent or hot-melt extrusion methods. However, the solvent method requires large amounts of organic solvents, which can leave residual solvents, is environmentally unfriendly, inefficient, and energy-intensive. However, hot-melt extrusion is a challenging method for preparing tasimelteon films, as its melting point is only 78°C. Maintaining its stability during hot-melt extrusion and subsequent storage is extremely challenging, and crystallization can occur during storage. Summary of the Invention

[0009] In order to solve the above technical problems, the purpose of the present invention is to provide a tasimelteon film that is easy to use, quick to take effect, has good stability, and is easy to store.

[0010] In order to achieve the above-mentioned purpose of the present invention, the present invention adopts the following technical solutions: A film preparation for treating sleep disorders comprises at least tasimelteon, a film-forming material, a stabilizer, and one or more of a plasticizer and a sweetener, wherein the stabilizer is silicon dioxide.

[0011] In the film, tasimelteon is in an amorphous form.

[0012] The film comprises, by weight, at least 5-25 parts by weight of tasimelteon, 40-97.5 parts by weight of a film-forming material, 2-15 parts by weight of a plasticizer, 0.0-5 parts by weight of a sweetener, and 0.5-5 parts by weight of a stabilizer.

[0013] Preferably, the film comprises, by weight, at least 5-25 parts by weight of tasimelteon, 68-87 parts by weight of film-forming material, 2-15 parts by weight of plasticizer, 0.5-2 parts by weight of sweetener, and 0.5-5 parts by weight of stabilizer.

[0014] Preferably, in the film preparation, the film-forming materials are polyoxyethylene and copolyvidone.

[0015] Preferably, in the film, the plasticizer is polyethylene glycol.

[0016] Preferably, in the film dosage form, the sweetener is sucralose.

[0017] The film has a thickness of 50-200 μm.

[0018] The preparation method of the film comprises at least the following steps: (1) Weigh tasimelteon, film-forming material, plasticizer, sweetener, and stabilizer and add them into a mixer for mixing; (2) adding the mixture into a hot melt extrusion device at a rate of 0.01-100 kg / h, and stretching it into a film after extrusion; (3) The prepared film is cut into films of different sizes and shapes using a film cutting machine.

[0019] In the preparation method, the die temperature of hot melt extrusion is 120°C to 150°C.

[0020] The melting point of tasimelteon is only 78°C, making it extremely difficult to maintain its stability during hot-melt extrusion and subsequent storage. During the stability storage process, we discovered that crystallization occurred in the tasimelteon sublingual film. After multiple experiments, we unexpectedly discovered that adding silicon dioxide as a stabilizer prevented this crystallization.

[0021] The beneficial effects of the present invention are as follows: (1) The present invention adds silicon dioxide as a stabilizer when preparing the film, so that tasimelteon remains amorphous and does not precipitate crystals, thereby ensuring the stability of the therapeutic effect and facilitating storage; (2) The tasimelteon film of the present invention is dispersed in an amorphous state in the film, has an extremely fast release rate, can be partially or completely absorbed through the oral mucosa, accelerates the onset time, and can make patients fall asleep more quickly; (3) Compared with existing tablets, the tasimelteon film of the present invention is simpler and more convenient to use and is particularly suitable for the elderly, children or patients who are unwilling to take oral medications. DETAILED DESCRIPTION

[0022] Comparative Example 1 Prescription of other stabilizers The prescription is shown in the table below. Assuming the specification of tasimelteon is 10 mg, the tablet weight is 100 mg, and the batch size is 1000 tablets, the weight of each component and the total weight ratio (w / w; %) are as follows:

[0023] Process: Mixing: weigh the raw materials and add them into the mixer for mixing; Hot melt extrusion: The powder was placed in a hot melt extruder and the film was prepared using the hot melt extruder. The extrusion temperatures were set to 80, 100, 130, 145, 145, 145, 145°C and the screw speed was 150 rpm.

[0024] Film formation: The extruded material is stretched to a thickness of 100µm.

[0025] Film cutting: Cut the film agent to the film weight.

[0026] Comparative Example 2 Formulation of other carrier materials The prescription is shown in the table below. Assuming the specification of tasimelteon is 10 mg, the tablet weight is 100 mg, and the batch size is 1000 tablets, the weight of each component and the total weight ratio (w / w; %) are as follows:

[0027] Process: Mixing: weigh the raw materials and add them into the mixer for mixing; Hot melt extrusion: The powder was placed in a hot melt extruder and the film was prepared using the hot melt extruder. The extrusion temperatures were set to 80, 100, 130, 145, 145, 145, 145°C and the screw speed was 150 rpm.

[0028] Film formation: The extruded material is stretched to a thickness of 100µm.

[0029] Film cutting: Cut the film agent to the film weight.

[0030] Example 1 The proportion of different APIs The prescription is shown in the table below. Assuming the specification of tasimelteon is 10 mg, the tablet weight is 100 mg, and the batch size is 1000 tablets, the weight of each component and the total weight ratio (w / w; %) are as follows:

[0031] Process flow: Mixing: tasimelteon, polyoxyethylene, copovidone, polyethylene glycol, sucralose, and silicon dioxide were weighed and added to a mixer for mixing; Hot melt extrusion: the powder was placed in a hot melt extruder, and the experiment was carried out using the hot melt extruder to prepare a film, and the extrusion temperature was set to 80, 100, 130, 140, 140, 140, 140°C and the screw speed was 50 rpm.

[0032] Film formation: The extruded material is stretched to a thickness of 100µm.

[0033] Film cutting: Cut the film agent to the film weight.

[0034] Detection: Tensile strength and disintegration time test Disintegration time: Determined by the disintegration time test method in Appendix 0921 of the 2020 edition of the Chinese Pharmacopoeia; Tensile strength: Use a medical packaging performance tester to conduct tensile tests on different batches of film dosage forms. Cut samples of each batch to a length of 5 cm, set the clamp spacing to 20 mm, and the test speed to 5 mm / min. Test three samples for each batch and record the average tensile strength.

[0035] Dissolution curve: Refer to the second method (paddle method) of 0931 Dissolution and Release Determination Method of the 2020 edition of the "Chinese Pharmacopoeia" to determine the film preparation of the prescription, the water bath temperature is 37±0.1℃, the rotation speed is 75r / min, and the aqueous solution is used as the dissolution medium. 5 ml of liquid is taken at 5, 10, 15, 30, and 45 minutes respectively, and the dissolution medium of the same volume and temperature is supplemented. The liquid is taken out and filtered through a 0.45μm filter membrane, and the dissolution rate is determined by high performance liquid chromatography.

[0036]

[0037] Dissolution curve results

[0038] Example 2 The proportion of silicon dioxide has an impact on stability (see Example 6 for stability test) The prescription is shown in the table below. Assuming the specification of tasimelteon is 10 mg, the tablet weight is 100 mg, and the batch size is 1000 tablets, the weight of each component and the total weight ratio (w / w; %) are as follows:

[0039] Process flow: Same as Example 1.

[0040] Detection: The method is as shown in Example 1

[0041] Dissolution curve results

[0042] Example 3 Plasticizer ratio The prescription is shown in the table below. Assuming the specification of tasimelteon is 10 mg, the tablet weight is 100 mg, and the batch size is 1000 tablets, the weight of each component and the total weight ratio (w / w; %) are as follows:

[0043] Process: Same as Example 1 Detection: The method is as shown in Example 1

[0044] Dissolution curve results

[0045] Among them, the tensile strength of prescription 3-1 is too low, but the others meet the requirements.

[0046] Example 4 Sweetener ratio The prescription is shown in the table below. Assuming the specification of tasimelteon is 10 mg, the tablet weight is 100 mg, and the batch size is 1000 tablets, the weight of each component and the total weight ratio (w / w; %) are as follows:

[0047] Process: Same as Example 1 Detection: The method is as shown in Example 1

[0048] Dissolution curve results

[0049] Example 5 The prescription is shown in the table below. Assuming the specification of tasimelteon is 10 mg, the tablet weight is 100 mg, and the batch size is 1000 tablets, the weight of each component and the total weight ratio (w / w; %) are as follows:

[0050] Process Flow-Formulation 5-1a Mixing: Tasimelteon, polyoxyethylene, copovidone, polyethylene glycol, sucralose, and silicon dioxide were weighed and added to a mixer for mixing. Hot melt extrusion: The powder was placed in a hot melt extruder, and the film was prepared using the hot melt extruder. The extrusion temperatures were set to 80, 100, 120, 120, 120, 120, 120°C (die mouth) and the screw speed was 50 rpm.

[0051] Film formation: The extruded material is stretched to a thickness of 100µm.

[0052] Film cutting: Cut the film to the film weight Process Flow-Formulation 5-1b Mixing: Tasimelteon, polyoxyethylene, copovidone, polyethylene glycol, sucralose, and silicon dioxide were weighed and added to a mixer for mixing. Hot melt extrusion: The powders were placed in a hot melt extruder, and the film was prepared using the hot melt extruder. The extrusion temperatures were set to 80, 100, 145, 145, 145, 145, 145°C (die mouth) and the screw speed was 50 rpm.

[0053] Film formation: The extruded material is stretched to a thickness of 100µm.

[0054] Film cutting: Cut the film to the film weight Process Flow-Prescription 5-1c Mixing: Tasimelteon, polyoxyethylene, copovidone, polyethylene glycol, sucralose, and silicon dioxide were weighed and added to a mixer for mixing. Hot melt extrusion: The powder was placed in a hot melt extruder, and the film was prepared using the hot melt extruder. The extrusion temperatures were set to 80, 100, 150, 150, 150, 150, 150°C (die mouth) and the screw speed was 50 rpm.

[0055] Film formation: The extruded material is stretched to a thickness of 100µm.

[0056] Film cutting: Cut the film to the film weight Process flow-prescription 5-1d Mixing: tasimelteon, polyoxyethylene, copovidone, polyethylene glycol, sucralose, and silicon dioxide were weighed and added to a mixer for mixing. Hot melt extrusion: the powder was placed in a hot melt extruder, and the film was prepared using the hot melt extruder. The extrusion temperatures were set at 80, 110, 130, 160, 160, 160, 160°C (die mouth) and the screw speed was 50 rpm.

[0057] Film formation: The extruded material is stretched to a thickness of 100µm.

[0058] Film cutting: Cut the film to the film weight Process Flow-Formulation 5-1e Mixing: Tasimelteon, polyoxyethylene, copovidone, polyethylene glycol, sucralose, and silicon dioxide were weighed and added to a mixer for mixing. Hot melt extrusion: The powder was placed in a hot melt extruder, and the film was prepared using the hot melt extruder. The extrusion temperatures were set to 80, 100, 110, 110, 110, 110, 110°C (die mouth) and the screw speed was 50 rpm.

[0059] Film formation: The extruded material is stretched to a thickness of 100µm.

[0060] Film cutting: Cut the film to the film weight Detection: The method is as shown in Example 1

[0061] Example 6 Stability test After the samples were placed at 40°C and 75% humidity for 1 month and 3 months, their appearance was examined under a microscope to see if there was any crystallization.

[0062]

[0063] The results show that the present invention adds silicon dioxide as a stabilizer when preparing the film, so that tasimelteon remains in a stable amorphous state, and the stability of tasimelteon can be maintained during the film preparation process and subsequent storage process, and is conducive to storage.

[0064] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention are included in the scope of protection of the present invention.

Claims

1. A film for treating sleep disorders, characterized in that: The film comprises at least tasimelteon, a film-forming material, a stabilizer, and one or more of a plasticizer and a sweetener, wherein the stabilizer is silicon dioxide.

2. The film according to claim 1, characterized in that Tasimelteon is amorphous in the film.

3. The film according to claim 1, characterized in that Calculated by weight, the composition comprises at least 5-25 parts by weight of tasimelteon, 40-97.5 parts by weight of a film-forming material, 2-15 parts by weight of a plasticizer, 0.0-5 parts by weight of a sweetener, and 0.5-5 parts by weight of a stabilizer.

4. The film according to claim 1, characterized in that Calculated by weight, the composition comprises at least 5-25 parts by weight of tasimelteon, 68-87 parts by weight of a film-forming material, 2-15 parts by weight of a plasticizer, 0.5-2 parts by weight of a sweetener, and 0.5-5 parts by weight of a stabilizer.

5. The film according to claim 1, characterized in that The film-forming materials are polyoxyethylene and copolyvidone.

6. The film according to claim 1, characterized in that The plasticizer is polyethylene glycol.

7. The film according to claim 1, characterized in that The sweetener is sucralose.

8. The film according to claim 1, characterized in that The thickness of the film is 50-200 μm.

9. A method for preparing a film according to any one of claims 1 to 8, characterized in that: At least the following steps are included: Weigh tasimelteon, film-forming material, plasticizer, sweetener, and stabilizer, and add them into a mixer for mixing; (2) adding the mixture into a hot melt extrusion device at a rate of 0.01-100 kg / h, and stretching it into a film after extrusion; (3) The prepared film is cut into films of different sizes and shapes using a film cutting machine.

10. The preparation method according to claim 9, characterized in that The die temperature of hot melt extrusion is 120℃~150℃.

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