Melatonin / buspiron hydrochloride oral fast dissolving film and preparation method thereof

Abstract

This invention discloses a melatonin / buspirone hydrochloride oral instant-dissolving film and its preparation method, belonging to the field of pharmaceutical technology. The preparation process of the melatonin / buspirone hydrochloride oral instant-dissolving film of this invention is as follows: Film-forming material is weighed, added to water, and stirred until fully swollen. Plasticizer, inclusion agent / solvent, melatonin, buspirone hydrochloride, crystallization inhibitor, opacifier, and flavoring agent are added sequentially, stirred until homogeneous, degassed, and a gel solution is obtained. This solution is then evenly coated onto a backing using a coating machine to form a film. After drying, the film is lifted and cut to the required size. The film of this invention is administered sublingually, allowing the drug to be directly absorbed into the bloodstream through the sublingual mucosa. It has a rapid onset of action, achieving both anxiety relief and quick sleep induction. The film does not require swallowing with water, making it convenient to use and suitable for children, the elderly, and patients with swallowing difficulties. Furthermore, the preparation process of this invention is simple, quick, and low-cost, offering good economic benefits.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to a melatonin / buspirone hydrochloride oral instant-dissolving film and its preparation method. Background Technology

[0002] Nowadays, due to the fast pace of life, many people are troubled by insomnia and anxiety. Insomnia is usually manifested as difficulty falling asleep or poor sleep quality; while anxiety is a mood disorder characterized by excessive and persistent worry and unease. Although they seem different, they are closely related: anxiety patients often experience insomnia because anxiety can cause abnormal excitation of the cerebral cortex, making it difficult to fall asleep; at the same time, prolonged sleep deprivation can reduce a person's ability to regulate emotions, leaving them in a state of unease, thus exacerbating anxiety symptoms.

[0003] Melatonin, also known as melanocyte lectin, is a hormone secreted by the pineal gland in the brain and is an essential natural hormone for the human body. Domestic and international research indicates that it has physiological functions such as promoting sleep, delaying aging, and regulating the body's circadian rhythm, and is mainly used for primary insomnia. Buspirone hydrochloride is a new generation of non-benzodiazepine selective anxiolytic drug used to treat acute and chronic anxiety states. It has a short half-life, does not produce self-dependence or euphoric effects with long-term use, and has a low tendency to become addicted.

[0004] The most common treatment for insomnia and anxiety is to administer medication separately, namely melatonin and buspirone hydrochloride, with no studies on combining the two. In addition, the marketed dosage forms of melatonin and buspirone hydrochloride are mainly tablets, which need to be swallowed with water. For insomnia patients who are already in bed, getting up to drink water and other actions may make them more awake and unable to fall asleep. Furthermore, it is inconvenient for the elderly, bedridden patients, and patients with swallowing difficulties to take the medication.

[0005] Film-forming preparations refer to solid dosage forms made from raw drug substances and suitable film-forming polymers. They are typically single-layer or multi-layer composite drug-loaded films, intended for oral or mucosal use, to exert local or systemic therapeutic effects. Oral films dissolve rapidly in the mouth, requiring no water for administration, offering advantages such as rapid onset of action, portability, and ease of use. Furthermore, their small size and pleasant taste make them particularly suitable for children, the elderly, and patients with swallowing difficulties. Summary of the Invention

[0006] Therefore, the purpose of this invention is to provide a melatonin / buspirone hydrochloride oral fast-dissolving film and its preparation method. The drug is directly absorbed into the blood through the sublingual mucosa via sublingual administration, has a rapid onset of action, and allows the two drugs to work together to achieve the effect of relieving anxiety and falling asleep quickly.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0008] This invention provides an oral instant-dissolving film, composed of the following components by weight percentage: drug: 0.5-15%; film-forming material: 10-60%; plasticizer: 2-10%; encapsulating agent / solvent: 20-50%; crystallization inhibitor: 0-10%; opacifier: 0-3%; flavoring agent: 0-10%; the drug is one or a combination of two of melatonin and buspirone hydrochloride.

[0009] Based on the above technical solution, the composition of the oral instant film is further as follows: melatonin: 2-5%, buspirone hydrochloride: 4-7%, film-forming material: 20-40%, plasticizer: 5-10%, encapsulating agent / solvent: 30-40%, crystallization inhibitor: 3-10%, light-blocking agent: 1-3%, and flavoring agent: 1-8%.

[0010] Based on the above technical solution, the film-forming material further includes one or more of hydroxypropyl methylcellulose E-5, hydroxypropyl methylcellulose E-15, polyvinyl alcohol, and polyvinylpyrrolidone.

[0011] Based on the above technical solution, the film-forming material is further described as polyvinyl alcohol 17-88.

[0012] Based on the above technical solution, the plasticizer further includes one or more of glycerol, propylene glycol and polyethylene glycol 400.

[0013] Based on the above technical solution, the inclusion agent / solvent further includes one or more of hydroxypropyl-β-cyclodextrin, polysorbate 80, and sodium dodecyl sulfate.

[0014] Based on the above technical solution, the crystallization inhibitor further includes one or a combination of two of polyvinylpyrrolidone K30 and hydroxypropyl methylcellulose.

[0015] Based on the above technical solution, the light-blocking agent further includes one or a combination of two of titanium dioxide and calcium carbonate.

[0016] Based on the above technical solution, the flavoring agent further includes one or more of sucralose, aspartame, sorbitol and cherry flavoring.

[0017] The present invention also provides a method for preparing the above-mentioned oral quick-dissolving film, comprising the following steps:

[0018] (1) Weigh the film-forming material, add it to water, stir to make it completely swollen, add plasticizer, inclusion agent / solvent, melatonin and / or buspirone hydrochloride, crystallization inhibitor, opacifier and flavoring agent in sequence, continue to stir to mix it evenly, degas it, and obtain the adhesive solution.

[0019] (2) The adhesive obtained in step (1) is evenly coated onto the backing using a coating machine to form a film. After drying, the film is removed and cut to the required size to obtain the oral quick-dissolving film.

[0020] Based on the above technical solution, further, the mass ratio of the film-forming material to water in step (1) is 1:50 to 1:5; the swelling temperature of the film-forming material is 30 to 90°C; the stirring speed is 500 to 2000 rpm; and the degassing method is ultrasonic degassing.

[0021] Based on the above technical solution, further, in step (2), the coating speed is 5 to 20 rpm, the coating thickness is such that the film thickness is 90±5 μm, and the drying temperature is 40±5℃.

[0022] The advantages of this invention over the prior art are as follows:

[0023] The melatonin / buspirone hydrochloride oral instant-dissolving film of the present invention simultaneously encapsulates melatonin and buspirone hydrochloride in a film for the treatment of transient insomnia caused by anxiety. Administered sublingually, the drugs are directly absorbed into the bloodstream through the sublingual mucosa, resulting in rapid onset of action and allowing both drugs to work synergistically to relieve anxiety and promote rapid sleep. Furthermore, the film dissolves rapidly in the mouth without the need for drinking water, overcoming the difficulties caused by swallowing disorders in oral solid dosage forms. The preparation process of the present invention is simple, time-saving, and low-cost, facilitating packaging, transportation, and storage, thus offering significant economic benefits. Attached Figure Description

[0024] To more clearly illustrate the embodiments of the present invention, the accompanying drawings involved in the embodiments will be briefly described below.

[0025] Figure 1 The in vitro release curve of the melatonin / buspirone hydrochloride oral instant film prepared in Example 3 is shown. Detailed Implementation

[0026] To further illustrate the present invention, the melatonin / buspirone hydrochloride oral instant film and its preparation method provided by the present invention are described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0027] Example 1

[0028] This embodiment provides a melatonin / buspirone hydrochloride oral instant dissolving film, comprising:

[0029] Melatonin 0.9g, buspirone hydrochloride 1.5g

[0030] Hydroxypropyl methylcellulose E5 4g

[0031] 2g of propylene glycol

[0032] Hydroxypropyl-β-cyclodextrin 9g, polysorbate 80 1.5g

[0033] Polyvinylpyrrolidone K30 1.5g

[0034] 0.5g of titanium dioxide

[0035] 0.5g of sucralose

[0036] Cherry flavoring 1.5g

[0037] 100mL of purified water

[0038] Preparation method: Accurately weigh the prescribed amount of hydroxypropyl methylcellulose E5 and add it to the prescribed amount of purified water. Stir thoroughly to allow it to swell. Then, slowly add the prescribed amounts of propylene glycol, hydroxypropyl-β-cyclodextrin, polysorbate 80, melatonin, buspirone hydrochloride, polyvinylpyrrolidone K30, titanium dioxide, sucralose, and cherry flavoring sequentially. Stir at 1000 rpm for 1 hour to obtain the adhesive solution. Coat the film using a coating machine, install the backing material, adjust the coating thickness to make the film thickness approximately 90±5 μm, set the coating speed to 10 rpm, and evenly coat the adhesive solution onto the backing to form a film. Dry at 40±5℃. After drying, the film is intact and has a smooth and uniform appearance, but its flexibility (evaluated by the number of bends) is poor, with a bend count of 69.

[0039] Example 2

[0040] This embodiment provides a melatonin / buspirone hydrochloride oral instant dissolving film, comprising:

[0041] Melatonin 0.9g, buspirone hydrochloride 1.5g

[0042] Hydroxypropyl methylcellulose E15 4g

[0043] 2g of propylene glycol

[0044] Hydroxypropyl-β-cyclodextrin 9g, polysorbate 80 1.5g

[0045] Polyvinylpyrrolidone K30 1.5g

[0046] 0.5g of titanium dioxide

[0047] 0.5g of sucralose

[0048] Cherry flavoring 1.5g

[0049] 100mL of purified water

[0050] Preparation method: Accurately weigh the prescribed amount of hydroxypropyl methylcellulose E15 and add it to the prescribed amount of purified water. Stir thoroughly to allow it to swell. Then, slowly add the prescribed amounts of propylene glycol, hydroxypropyl-β-cyclodextrin, polysorbate 80, melatonin, buspirone hydrochloride, polyvinylpyrrolidone K30, titanium dioxide, sucralose, and cherry flavoring sequentially. Stir at 1000 rpm for 1 hour to obtain the adhesive solution. Coat the film using a coating machine, install the backing material, adjust the coating thickness to make the film thickness approximately 90±5 μm, set the coating speed to 10 rpm, and evenly coat the adhesive solution onto the backing material to form a film. Dry at 40±5℃. After drying, the film is complete and has a smooth and uniform appearance, but its flexibility is poor, with a bending count of 77 times.

[0051] Example 3

[0052] This embodiment provides a melatonin / buspirone hydrochloride oral instant dissolving film, comprising:

[0053] Melatonin 0.9g, buspirone hydrochloride 1.5g

[0054] Polyvinyl alcohol 17-88 10g

[0055] 2g of propylene glycol

[0056] Hydroxypropyl-β-cyclodextrin 9g, polysorbate 80 1.5g

[0057] Polyvinylpyrrolidone K30 1.5g

[0058] 0.5g of titanium dioxide

[0059] 0.5g of sucralose

[0060] Cherry flavoring 1.5g

[0061] 100mL of purified water

[0062] Preparation method: Accurately weigh the prescribed amount of polyvinyl alcohol 17-88 and add it to the prescribed amount of purified water, stirring thoroughly to allow it to swell. Then, slowly add the prescribed amounts of propylene glycol, hydroxypropyl-β-cyclodextrin, polysorbate 80, melatonin, buspirone hydrochloride, polyvinylpyrrolidone K30, titanium dioxide, sucralose, and cherry flavoring sequentially, stirring at 1000 rpm for 1 hour to obtain the adhesive solution. Coat the film using a coating machine, install the backing material, adjust the coating thickness to approximately 90±5 μm, set the coating speed to 10 rpm, and evenly coat the adhesive solution onto the backing material to form a film. Dry at 40±5℃. After drying, the film is complete, with a smooth and uniform appearance, good flexibility and mechanical strength (evaluated by tensile strength and elongation at break), and a bending cycle >100 times. Tensile strength = 48.33±1.44 N / mm. 2 Elongation at break = 87.87 ± 6.94%.

[0063] Example 4

[0064] This embodiment provides a melatonin / buspirone hydrochloride oral instant dissolving film, comprising:

[0065] Melatonin 0.9g, buspirone hydrochloride 1.5g

[0066] Polyvinyl alcohol 17-88 2g

[0067] 2g of propylene glycol

[0068] Hydroxypropyl-β-cyclodextrin 9g, polysorbate 80 1.5g

[0069] Polyvinylpyrrolidone K30 1.5g

[0070] 0.5g of titanium dioxide

[0071] 0.5g of sucralose

[0072] Cherry flavoring 1.5g

[0073] 100mL of purified water

[0074] Preparation method: Accurately weigh the prescribed amount of polyvinyl alcohol 17-88 and add it to the prescribed amount of purified water. Stir thoroughly to allow it to swell (the resulting solution is extremely dilute and highly fluid). Then, slowly add the prescribed amounts of propylene glycol, hydroxypropyl-β-cyclodextrin, polysorbate 80, melatonin, buspirone hydrochloride, polyvinylpyrrolidone K30, titanium dioxide, sucralose, and cherry flavoring sequentially. Stir at 1000 rpm for 1 hour to obtain the adhesive solution. Coat the solution using a coating machine, install a backing material, adjust the coating thickness to make the film thickness approximately 90±5 μm, set the coating speed to 10 rpm, and evenly coat the adhesive solution onto the backing to form a film. Dry at 40±5℃. After drying, it is difficult to form a film.

[0075] Example 5

[0076] This embodiment provides a melatonin / buspirone hydrochloride oral instant dissolving film, comprising:

[0077] Melatonin 0.9g, buspirone hydrochloride 1.5g

[0078] Polyvinyl alcohol 17-88 14g

[0079] 2g of propylene glycol

[0080] Hydroxypropyl-β-cyclodextrin 9g, polysorbate 80 1.5g

[0081] Polyvinylpyrrolidone K30 1.5g

[0082] 0.5g of titanium dioxide

[0083] 0.5g of sucralose

[0084] Cherry flavoring 1.5g

[0085] 100mL of purified water

[0086] Preparation method: Accurately weigh the prescribed amount of polyvinyl alcohol 17-88 and add it to the prescribed amount of purified water. Stir thoroughly to allow it to swell (the resulting solution is viscous and contains many bubbles). Then, slowly add the prescribed amounts of propylene glycol, hydroxypropyl-β-cyclodextrin, polysorbate 80, melatonin, buspirone hydrochloride, polyvinylpyrrolidone K30, titanium dioxide, sucralose, and cherry flavoring sequentially. Stir at 1000 rpm for 1 hour to obtain the adhesive solution. Coat the film using a coating machine, install the backing material, adjust the coating thickness to make the film thickness approximately 90±5 μm, set the coating speed to 10 rpm, and evenly coat the adhesive solution onto the backing material to form a film. Dry at 40±5℃. After drying, the film is intact, but the surface is uneven and contains many bubbles.

[0087] The melatonin / buspirone hydrochloride oral instant-dissolving film prepared in Examples 1-5 was evaluated based on its film-forming properties, release properties, and film appearance. Polyvinyl alcohol 17-88 was selected as the optimal film-forming material for subsequent experiments.

[0088] Example 6

[0089] This embodiment provides a melatonin / buspirone hydrochloride oral instant dissolving film, comprising:

[0090] Melatonin 0.9g, buspirone hydrochloride 1.5g

[0091] Polyvinyl alcohol 17-88 4g

[0092] 2g of propylene glycol

[0093] Hydroxypropyl-β-cyclodextrin 9g, polysorbate 80 1.5g

[0094] Polyvinylpyrrolidone K30 1.5g

[0095] 0.5g of titanium dioxide

[0096] 0.5g of sucralose

[0097] Cherry flavoring 1.5g

[0098] 100mL of purified water

[0099] Preparation method: Accurately weigh the prescribed amount of polyvinyl alcohol 17-88 and add it to the prescribed amount of purified water, stirring thoroughly to allow it to swell. Then, slowly add the prescribed amounts of propylene glycol, hydroxypropyl-β-cyclodextrin, polysorbate 80, melatonin, buspirone hydrochloride, polyvinylpyrrolidone K30, titanium dioxide, sucralose, and cherry flavoring sequentially, stirring at 1000 rpm for 1 hour to obtain the adhesive solution. Apply the adhesive solution using a coating machine, install a backing material, adjust the coating thickness to approximately 90±5 μm, set the coating speed to 10 rpm, and evenly coat the adhesive solution onto the backing material to form a film. Dry at 40±5℃. After drying, the film is intact, with good flexibility and mechanical strength, bending cycles >100 times, and tensile strength = 39.26±7.13 N / mm. 2 Elongation at break = 75.83 ± 9.56%.

[0100] Example 7

[0101] This embodiment provides a melatonin / buspirone hydrochloride oral instant dissolving film, comprising:

[0102] Melatonin 0.9g, buspirone hydrochloride 1.5g

[0103] Polyvinyl alcohol 17-88 12g

[0104] 2g of propylene glycol

[0105] Hydroxypropyl-β-cyclodextrin 9g, polysorbate 80 1.5g

[0106] Polyvinylpyrrolidone K30 1.5g

[0107] 0.5g of titanium dioxide

[0108] 0.5g of sucralose

[0109] Cherry flavoring 1.5g

[0110] 100mL of purified water

[0111] Preparation method: Accurately weigh the prescribed amount of polyvinyl alcohol 17-88 and add it to the prescribed amount of purified water, stirring thoroughly to allow it to swell. Then, slowly add the prescribed amounts of propylene glycol, hydroxypropyl-β-cyclodextrin, polysorbate 80, melatonin, buspirone hydrochloride, polyvinylpyrrolidone K30, titanium dioxide, sucralose, and cherry flavoring sequentially, stirring at 1000 rpm for 1 hour to obtain the adhesive solution. Coat the film using a coating machine, install the backing material, adjust the coating thickness to approximately 90±5 μm, set the coating speed to 10 rpm, and evenly coat the adhesive solution onto the backing material to form a film. Dry at 40±5℃. After drying, the film is intact, with slight bubbles on the surface, exhibiting good flexibility and tensile strength, with a bending cycle >100 times and a tensile strength of 43.37±3.05 N / mm. 2 Elongation at break = 82.64 ± 5.77%.

[0112] Example 8

[0113] This embodiment provides a melatonin / buspirone hydrochloride oral instant dissolving film, comprising:

[0114] Melatonin 0.9g, buspirone hydrochloride 1.5g

[0115] Polyvinyl alcohol 17-88 10g

[0116] 2g of glycerin

[0117] Hydroxypropyl-β-cyclodextrin 9g, polysorbate 80 1.5g

[0118] Polyvinylpyrrolidone K30 1.5g

[0119] 0.5g of titanium dioxide

[0120] 0.5g of sucralose

[0121] Cherry flavoring 1.5g

[0122] 100mL of purified water

[0123] Preparation method: Accurately weigh the prescribed amount of polyvinyl alcohol 17-88 and add it to the prescribed amount of purified water, stirring thoroughly to allow it to swell. Then, slowly add the prescribed amounts of glycerol, hydroxypropyl-β-cyclodextrin, polysorbate 80, melatonin, buspirone hydrochloride, polyvinylpyrrolidone K30, titanium dioxide, sucralose, and cherry flavoring sequentially, stirring at 1000 rpm for 1 hour to obtain the adhesive solution. Coat the film using a coating machine, install a backing material, adjust the coating thickness to approximately 90±5 μm, set the coating speed to 10 rpm, and evenly coat the adhesive solution onto the backing material to form a film. The drying temperature is 40±5℃. After drying, the film is not completely intact, has high viscosity, and exhibits surface wrinkling.

[0124] Example 9

[0125] This embodiment provides a melatonin / buspirone hydrochloride oral instant dissolving film, comprising:

[0126] Melatonin 0.9g, buspirone hydrochloride 1.5g

[0127] Polyvinyl alcohol 17-88 10g

[0128] Polyethylene glycol 400 2g

[0129] Hydroxypropyl-β-cyclodextrin 9g, polysorbate 80 1.5g

[0130] Polyvinylpyrrolidone K30 1.5g

[0131] 0.5g of titanium dioxide

[0132] 0.5g of sucralose

[0133] Cherry flavoring 1.5g

[0134] 100mL of purified water

[0135] Preparation method: Accurately weigh the prescribed amount of polyvinyl alcohol 17-88 and add it to the prescribed amount of purified water, stirring thoroughly to allow it to swell. Then, slowly add the prescribed amounts of polyethylene glycol 400, hydroxypropyl-β-cyclodextrin, polysorbate 80, melatonin, buspirone hydrochloride, polyvinylpyrrolidone K30, titanium dioxide, sucralose, and cherry flavoring sequentially, stirring at 1000 rpm for 1 hour to obtain the adhesive solution. Coat the film using a coating machine, install a backing material, adjust the coating thickness to approximately 90±5 μm, set the coating speed to 10 rpm, and evenly coat the adhesive solution onto the backing material to form a film. Dry at 40±5℃. After drying, the film is complete, with a smooth and uniform appearance, good flexibility and tensile strength, bending cycles > 100 times, and tensile strength = 45.69±1.87 N / mm. 2 Elongation at break = 89.34 ± 7.01%.

[0136] The melatonin / buspirone hydrochloride oral instant-dissolving film prepared in Examples 6-9 was evaluated based on its film-forming properties, release properties, and film appearance. Propylene glycol and polyethylene glycol 400 can both be good plasticizers. However, since melatonin is poorly soluble in water, an inclusion agent or solubilizer needs to be added to increase its solubility. The combined use of hydroxypropyl-β-cyclodextrin and propylene glycol can effectively increase the solubility of melatonin. Therefore, propylene glycol was used as the best plasticizer in subsequent experiments in this invention.

[0137] Example 10

[0138] This embodiment provides a melatonin / buspirone hydrochloride oral instant dissolving film, comprising:

[0139] Melatonin 0.9g, buspirone hydrochloride 1.5g

[0140] Polyvinyl alcohol 17-88 10g

[0141] 2g of propylene glycol

[0142] Hydroxypropyl-β-cyclodextrin 9g

[0143] Polyvinylpyrrolidone K30 1.5g

[0144] 0.5g of titanium dioxide

[0145] 0.5g of sucralose

[0146] Cherry flavoring 1.5g

[0147] 100mL of purified water

[0148] Preparation method: Accurately weigh the prescribed amount of polyvinyl alcohol 17-88 and add it to the prescribed amount of purified water, stirring thoroughly to allow it to swell. Then, slowly add the prescribed amounts of propylene glycol, hydroxypropyl-β-cyclodextrin, melatonin, buspirone hydrochloride, polyvinylpyrrolidone K30, titanium dioxide, sucralose, and cherry flavoring sequentially, stirring at 1000 rpm for 1 hour to obtain the adhesive solution. Apply the adhesive solution using a coating machine, install a backing material, adjust the coating thickness to achieve a film thickness of approximately 90±5 μm, set the coating speed to 10 rpm, and evenly coat the adhesive solution onto the backing material to form a film. Dry at 40±5℃.

[0149] Example 11

[0150] This embodiment provides a melatonin / buspirone hydrochloride oral instant dissolving film, comprising:

[0151] Melatonin 0.9g, buspirone hydrochloride 1.5g

[0152] Polyvinyl alcohol 17-88 10g

[0153] 2g of propylene glycol

[0154] 3g of sodium dodecyl sulfate

[0155] Polyvinylpyrrolidone K30 1.5g

[0156] 0.5g of titanium dioxide

[0157] 0.5g of sucralose

[0158] Cherry flavoring 1.5g

[0159] 100mL of purified water

[0160] Preparation method: Accurately weigh the prescribed amount of polyvinyl alcohol 17-88 and add it to the prescribed amount of purified water, stirring thoroughly to allow it to swell. Then, slowly add the prescribed amounts of propylene glycol, sodium dodecyl sulfate, melatonin, buspirone hydrochloride, polyvinylpyrrolidone K30, titanium dioxide, sucralose, and cherry flavoring sequentially, stirring at 1000 rpm for 1 hour to obtain the adhesive solution. Apply the adhesive solution using a coating machine, install a backing material, adjust the coating thickness to approximately 90±5 μm, set the coating speed to 10 rpm, and evenly coat the adhesive solution onto the backing material to form a film. Dry at 40±5℃.

[0161] Example 12

[0162] This embodiment provides a melatonin / buspirone hydrochloride oral instant dissolving film, comprising:

[0163] Melatonin 0.9g, buspirone hydrochloride 1.5g

[0164] Polyvinyl alcohol 17-88 10g

[0165] 2g of propylene glycol

[0166] Polysorbate 80 3g

[0167] Polyvinylpyrrolidone K30 1.5g

[0168] 0.5g of titanium dioxide

[0169] 0.5g of sucralose

[0170] Cherry flavoring 1.5g

[0171] 100mL of purified water

[0172] Preparation method: Accurately weigh the prescribed amount of polyvinyl alcohol 17-88, add it to the prescribed amount of purified water, and stir thoroughly to allow it to swell. Then, slowly add the prescribed amounts of propylene glycol, polysorbate 80, melatonin, buspirone hydrochloride, polyvinylpyrrolidone K30, titanium dioxide, sucralose, and cherry flavoring sequentially, stirring at 1000 rpm for 1 hour to obtain the adhesive solution. Apply the adhesive solution using a coating machine, install a backing material, adjust the coating thickness to achieve a film thickness of approximately 90±5 μm, set the coating speed to 10 rpm, and evenly coat the adhesive solution onto the backing material to form a film. Dry at 40±5℃.

[0173] Comparative Example 1

[0174] This comparative example provides a melatonin / buspirone hydrochloride oral instant dissolving film, comprising:

[0175] Melatonin 0.9g, buspirone hydrochloride 1.5g

[0176] Polyvinyl alcohol 17-88 10g

[0177] 2g of propylene glycol

[0178] Hydroxypropyl-β-cyclodextrin 9g, polysorbate 80 1.5g

[0179] 0.5g of titanium dioxide

[0180] 0.5g of sucralose

[0181] Cherry flavoring 1.5g

[0182] 100mL of purified water

[0183] Preparation method: Accurately weigh the prescribed amount of polyvinyl alcohol 17-88, add it to the prescribed amount of purified water, and stir thoroughly to allow it to swell. Then, slowly add the prescribed amounts of propylene glycol, hydroxypropyl-β-cyclodextrin, polysorbate 80, melatonin, buspirone hydrochloride, titanium dioxide, sucralose, and cherry flavoring sequentially, stirring at 1000 rpm for 1 hour to obtain the adhesive solution. Apply the adhesive solution using a coating machine, install a backing material, adjust the coating thickness to achieve a film thickness of approximately 90±5 μm, set the coating speed to 10 rpm, and evenly coat the adhesive solution onto the backing material to form a film. Dry at 40±5℃.

[0184] Example 13

[0185] The mixed adhesive and melatonin / buspirone hydrochloride oral quick-dissolving film prepared in Examples 3, 10-12 and Comparative Example 1 were tested for appearance, film-forming properties, release properties, melting time, thickness, and water content (according to the 2020 edition of the Chinese Pharmacopoeia). The results are shown in Table 1.

[0186] Table 1. Performance test results of the mixed adhesive and melatonin / buspirone hydrochloride oral instant film.

[0187]

[0188] The level indicators in the table are as follows: + indicates that the film is partially intact and demolding is slightly difficult; ++ indicates that the film is intact and demolding is easy; / indicates that it was not measured.

[0189] According to the results in Table 1, the melatonin / buspirone hydrochloride oral instant film prepared in Example 3 is the best.

[0190] Example 14

[0191] In vitro release test

[0192] The melatonin / buspirone hydrochloride oral instantaneous membrane prepared in Example 3 was used to investigate its in vitro permeation using a Franz vertical diffusion cell. The diffusion cell had an upper and lower structure, with a supply cell on top and a receiving cell on the bottom. Equal weights of the membrane were fixed onto the supply cell. Simulated artificial saliva (2.38 g disodium hydrogen phosphate, 0.19 g potassium dihydrogen phosphate, and 8.00 g sodium chloride dissolved in 1 L of purified water) was added to the receiving cell as the release medium, with a volume of 7 mL. The measurement was performed at 37°C and a stirring speed of 200 rpm. Sampling was conducted at 1, 3, 5, 7, 10, 15, 20, 30, and 60 min, with 2 mL of sample taken each time, followed by the addition of 2 mL of artificial saliva. The analysis was performed using HPLC (based on the analytical methods for buspirone hydrochloride tablets in the 2020 edition of the Chinese Pharmacopoeia and melatonin in the USP-NF). The results were measured in triplicate, and the cumulative release curve was obtained by plotting the data.

[0193] The in vitro release results of melatonin / buspirone hydrochloride oral instant film are as follows: Figure 1 As shown. By Figure 1 It can be seen that melatonin and buspirone hydrochloride in the film can be released simultaneously, with a cumulative release rate of 90% in 7 minutes and 100% in 10 minutes. This verifies its rapid dissolution characteristics, which can quickly dissolve and release the drug simultaneously.

[0194] Example 15

[0195] 1. Influencing Factors Test—High Temperature Test

[0196] The melatonin / buspirone hydrochloride oral instant film prepared in Example 3 was weighed and recorded. After removing the outer packaging, it was placed at 40°C for 10 days. Samples were taken on days 0, 5, and 10, and analyzed using HPLC.

[0197] 2. Influencing Factors Test—High Humidity Test

[0198] The melatonin / buspirone hydrochloride oral instant film prepared in Example 3 was weighed and recorded. After removing the outer packaging, it was placed under a relative humidity of 75±5% for 10 days. Samples were taken on days 0, 5, and 10, and analyzed using HPLC.

[0199] 3. Influencing Factors Experiment—Light Irradiation Experiment

[0200] The melatonin / buspirone hydrochloride oral instant film prepared in Example 3 was weighed and recorded. After removing the outer packaging, it was placed under a light intensity of 4500±500 Lx for 10 days. Samples were taken on day 0, day 5, and day 10, and analyzed using HPLC.

[0201] Table 2. Influencing factors of melatonin in melatonin / buspirone hydrochloride oral film: test results

[0202]

[0203] Table 3. Influencing factors of buspirone hydrochloride in melatonin / buspirone hydrochloride oral film: experimental results

[0204]

[0205] As shown in Tables 2-3, no impurities were detected in the melatonin / buspirone hydrochloride oral instant dissolving film prepared in Example 3 under high temperature, high humidity and light conditions, indicating good stability. However, its physical properties changed; the film became brittle under high temperature and light conditions, and softened under high humidity conditions. This suggests that the melatonin / buspirone hydrochloride oral instant dissolving film should be stored in a suitable temperature and sealed environment, avoiding high temperature, high humidity and strong light exposure.

[0206] Example 16

[0207] Accelerated testing

[0208] Melatonin / buspirone hydrochloride oral instant dissolving film was prepared according to Example 3. Three batches of film were taken, weighed and recorded, packaged in "self-sealing bags + aluminum foil bags", and placed at a temperature of 40±2℃ for 6 months. Samples were taken at the end of the 1st, 2nd, 3rd and 6th months respectively, and analyzed by HPLC. The data were compared with the data from the 0th month.

[0209] Table 4. Accelerated test results of melatonin in melatonin / buspirone hydrochloride oral film.

[0210]

[0211] Table 5. Accelerated test results of buspirone hydrochloride in melatonin / buspirone hydrochloride oral film.

[0212]

[0213] Accelerated testing results showed that the prepared melatonin / buspirone hydrochloride oral instant film was relatively stable under accelerated conditions. Only a small amount of unknown melatonin impurity was detected in the 3rd and 6th months, with contents of 0.22% ± 0.01 and 0.26% ± 0.02, respectively, which met the pharmacopoeia impurity limit requirements. However, the film became brittle under these conditions, further indicating that it should be stored in a suitable temperature and sealed environment.

[0214] Long-term trial

[0215] Melatonin / buspirone hydrochloride oral instant dissolving film was prepared according to Example 3. Three batches of film were taken, weighed and recorded, and packaged in "self-sealing bags + aluminum foil bags". They were placed at a temperature of 25±2℃ and a relative humidity of 60±5% for 12 months. Samples were taken at the end of the 3rd, 6th, 9th and 12th months respectively, and analyzed by HPLC.

[0216] Table 6. Long-term test results of melatonin in melatonin / buspirone hydrochloride oral film.

[0217]

[0218] Table 7. Long-term test results of buspirone hydrochloride in melatonin / buspirone hydrochloride oral film.

[0219]

[0220] Long-term test results show that no impurities were detected after the prepared melatonin / buspirone hydrochloride oral instant film was placed under these conditions for 9 months; at the same time, the appearance of the film did not show any significant changes, indicating that the prepared film has good stability and should be stored in a suitable temperature and sealed environment.

[0221] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. An oral instant-dissolving film, characterized in that, Composed of the following components by weight percentage Composition: Melatonin: 2-5%, Buspirone hydrochloride: 4-7%, Film-forming material: 20-40%, Plasticizer: 5-10%, Inclusion agent / Solubilizer: 30-40%, Crystallization inhibitor: 3-10%, Opacifier: 1-3%, Flavoring agent: 1-8%; The drug is a combination of melatonin and buspirone hydrochloride. The film-forming material is polyvinyl alcohol 17-88, the plasticizer is propylene glycol, the inclusion agent / solvent is hydroxypropyl-β-cyclodextrin and polysorbate 80; the crystallization inhibitor is polyvinylpyrrolidone K30; the light-blocking agent is titanium dioxide; and the flavoring agent is sucralose and cherry flavoring. The preparation method of the oral instant-dissolving film includes the following steps: (1) Weigh the film-forming material, add it to water, stir to make it completely swollen, add plasticizer, inclusion agent / solvent, melatonin and buspirone hydrochloride, crystallization inhibitor, opacifier and flavoring agent in sequence, continue to stir to mix it evenly, degas it, and obtain the adhesive solution; (2) The adhesive obtained in step (1) is evenly coated onto the backing to form a film. After drying, the film is removed and cut into the required size to obtain the oral quick-dissolving film. The mass ratio of the film-forming material to water in step (1) is 1:50 to 1:5; the swelling temperature of the film-forming material is 30 to 90°C. In step (2), the coating speed is 5~20 rpm, and the coating thickness is such that the film thickness is 90±5 μm.

2. The oral instant-dissolving film according to claim 1, characterized in that, The stirring speed in step (1) is 500~2000 rpm; the degassing method is ultrasonic degassing.

3. The oral instant-dissolving film according to claim 1, characterized in that, The drying temperature in step (2) is 40±5℃.

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