Oral soluble film for treating insomnia and preparation method thereof

Abstract

The invention provides an oral soluble film for treating insomnia and a preparation method thereof, and the oral soluble film at least comprises suvorexant, a film forming material, and one or more of a plasticizer, a disintegrating agent, a flavoring agent or a sweetening agent, and a stabilizer. Wherein the film forming material is hydroxy propyl cellulose and a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol grafted copolymer. Compared with existing tablets, the suvorexant oral soluble film is more suitable for old people, children or patients with dysphagia, can be rapidly disintegrated and dissolved out, is constant in release speed, is moderate in maximum blood concentration Cmax, and reduces side effects caused by too high blood concentration.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to an orally dissolving film for treating insomnia and a preparation method thereof. Background Art

[0002] According to the "2024 White Paper on Sleep Health of Chinese Residents" and related research, the incidence of insomnia among the elderly in China is relatively high. Among them, the insomnia rate of the elderly over 60 years old can reach 54.1%, and the insomnia rate of the elderly over 80 years old is as high as 72.7%. This indicates that with the increase of age, the insomnia problem of the elderly becomes more and more serious, seriously affecting their quality of life.

[0003] With the increase of age, the chewing and swallowing ability of the elderly declines, resulting in difficulty in taking medicine. In addition, when the elderly have insomnia at night, if they need to take ordinary tablets, they also need to get out of bed to get water to take medicine, which is not only inconvenient but also may increase the risk of falling. This inconvenient medication experience seriously affects the medication compliance of patients and thus affects the treatment effect.

[0004] Suvorexant, with the trade name Belsomra, is a new type of insomnia treatment drug developed by Merck & Co., Inc., and belongs to the world's first orexin receptor antagonist. It blocks orexin receptors and inhibits the action of endogenous orexin neuropeptides that promote wakefulness, thereby increasing the drowsiness of patients, helping patients fall asleep and improving sleep quality.

[0005] Suvorexant was approved for marketing by the US Food and Drug Administration (FDA) in August 2014. The drug has a unique mechanism of action. Compared with traditional sedative-hypnotic drugs (such as benzodiazepines), it has lower physical dependence and fewer adverse reactions.

[0006] Patent CN114344269B provides a suvorexant tablet and a preparation method thereof. By using a hot melt process to prepare a solid dispersion of suvorexant micropowder and copovidone, and then mixing it with excipients such as lactose and microcrystalline cellulose to make tablets. This method improves the dissolution of suvorexant and enhances the bioavailability of the drug, and is suitable for industrial production. However, suvorexant tablets need to be swallowed, which is inconvenient for those with swallowing difficulties; the onset speed is slower than that of orally dissolving films, and the preparation process is complex, with a relatively high production cost.

[0007] Suvorexan orodispersible film has the characteristics of rapid absorption and can exert its efficacy in a short time, which is especially suitable for the elderly patient population. This dosage form does not require water, can be quickly dissolved in the mouth, and is easy to use. However, although Suvorexan has a high oral bioavailability (up to 80%), absorption through the oral mucosa does not significantly increase its bioavailability or AUC (area under the curve). However, it should be noted that the rapid disintegration and dissolution characteristics of the orodispersible film may lead to a significant increase in the maximum blood drug concentration (Cmax), thereby causing unnecessary side effects. Therefore, it is of great clinical value to develop an orodispersible film preparation that can both quickly take effect and effectively control blood drug concentration.

[0008] "Preparation and in vitro and in vivo evaluation of Suvorex orodispersible film" (Acta Pharmaceutica Sinica 2024, 59(9): 2659−2664) prepared Suvorex orodispersible film by hot melt extrusion technology, and comprehensively evaluated its in vitro and in vivo performance. The results showed that the orodispersible film had the advantages of rapid disintegration and high mechanical strength. In vivo pharmacokinetic studies also showed that it had a faster onset of action, simple preparation process, stable quality, and good application prospects. However, the study also found that the Cmax of the orodispersible film was much higher than that of the original tablets. Excessively high Cmax may bring many potential risks: on the one hand, the risk of drug toxicity may increase, and high concentrations of drugs may have toxic effects on important organs; on the other hand, the drug concentration in the body quickly reaches a peak and then drops rapidly, which may cause large fluctuations in blood drug concentration, affecting the stability and duration of efficacy. In addition, excessively high Cmax may also increase the risk of drug interaction with other drugs, thereby affecting the metabolism and efficacy of other drugs.

[0009] In summary, the prior art suvorexant preparations mainly have the following disadvantages: (1) Suvorexan tablets need to be swallowed with water, which is inconvenient for patients with swallowing difficulties (such as the elderly or patients with uncontrolled autonomous behavior); (2) The production process of suvorexan tablets is complex and the production cost is high; (3) The Cmax of the existing Suvorex orodispersible film is much higher than that of the original tablets, which may bring many potential risks. Summary of the invention

[0010] In view of the above-mentioned shortcomings of the prior art, the purpose of the present invention is to provide a Suvorex orodispersible film that can disintegrate and dissolve quickly, has a consistent release rate, and has a moderate maximum blood drug concentration Cmax, thereby reducing side effects caused by excessive blood drug concentration.

[0011] In order to achieve the above-mentioned purpose of the present invention, the present invention adopts the following technical scheme: An orally disintegrating film for treating insomnia, which at least comprises suvorexant, a film-forming material, and one or more of a plasticizer, a disintegrant, a flavoring agent or a sweetening agent, and a stabilizer, wherein the film-forming material is hydroxypropyl cellulose and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0012] In the orally disintegrating film described above, the particle size of suvorexant is 5-20 μm.

[0013] In the orally disintegrating film described above, the weight ratio of hydroxypropyl cellulose to polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 1:3-3:1.

[0014] In the orally disintegrating film described above, the weight percentage content of suvorexant is 5-20%.

[0015] In the orally disintegrating film described above, calculated by weight, it at least comprises 5-20 parts by weight of suvorexant, 10-90 parts by weight of the film-forming material, 5-20 parts by weight of the plasticizer, and 0-5 parts by weight of the flavoring agent or the sweetening agent.

[0016] The plasticizer is polyethylene glycol or triethyl citrate, preferably triethyl citrate, and the flavoring agent or the sweetening agent is sucralose. In the orally disintegrating film described above, the thickness of the film agent is 5-1000 μm, preferably 50-200 μm.

[0017] The preparation method of the orally disintegrating film described above is a hot melt extrusion method, and the die temperature of the hot melt extrusion is 120°C-140°C.

[0018] The preparation method of the orally disintegrating film described above at least comprises the following steps: (1) Weigh suvorexant, the film-forming material, the plasticizer, the disintegrant, the flavoring agent or the sweetening agent, and the stabilizer and add them to a mixer for mixing; (2) Add the mixture to a hot melt extrusion device at a speed of 0.01-100 kg / h, and after extrusion, stretch it into a film; (3) Cut the prepared film into film agents of different sizes and shapes through a film cutting machine.

[0019] It was unexpectedly found through a large number of experiments and studies in the present invention that using hydroxypropyl cellulose and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as the film-forming material can slow down the drug release of suvorexant, but does not affect the complete release of the drug, can reduce Cmax, increase Tmax, and does not change AUC.

[0020] The beneficial effects of the present invention are as follows: (1) The present invention creatively uses a combination of hydroxypropyl cellulose and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as a film-forming material, and controls its ratio to slow down the drug release of suvorexant, but without affecting the complete release of the drug, which can reduce Cmax, increase Tmax, and not change AUC. Compared with the existing oral soluble film in the prior art, the present invention has a more stable blood drug concentration to maintain the effectiveness throughout the sleep period, helps to improve the curative effect, and reduces the side effects caused by too high blood drug concentration. (2) For the suvorexant oral soluble film of the present invention, by controlling the temperature of hot melt extrusion during preparation and controlling the particle size of suvorexant, it is ensured that the film disintegrates rapidly but the drug is not released too quickly. Suvorexant is dispersed in the film in a microcrystalline state, and the release rate is stable. Tmax is 2 times faster than that of the commercially available tablets, and Cmax is basically the same as that of the market tablets. (3) The suvorexant oral soluble film of the present invention is simple to use and more convenient than the existing tablets, especially suitable for the elderly, children or patients who are unwilling to take oral drugs or have difficulty swallowing, significantly improving the medication compliance. The oral soluble film can induce sleep in a short time by rapidly releasing the drug and maintain an effective concentration for about 6 hours to cover the entire sleep cycle. At the same time, its non-invasive and sustained release characteristics give it unique advantages in home care. Specific embodiments

[0021] Comparative example 1 Prescription

[0022] Process: Mixing: Suvorexant, polyethylene oxide, copovidone, poloxamer, and neotame are weighed and added to a mixer for mixing; hot melt extrusion: The powder is placed in a hot melt extruder, and a film agent is prepared using the hot melt extruder. The extrusion temperatures are set at 80, 100, 130, 160, 160, 160, 160, 160 °C, and the screw speed is 150 rpm.

[0023] Film forming: The extruded material is stretched to a thickness of 100 µm.

[0024] Film cutting: The film agent is cut to the film weight.

[0025] Example 1 The prescription is shown in the following table. Taking the specification of suvorexant as 10 mg, the tablet weight as 100 mg, and the batch size as 1000 tablets, the weight and the proportion of the total weight (w / w; %) of each component are:

[0026] Process flow: Mixing: Suvorexant, Soluplus, hydroxypropyl cellulose, triethyl citrate, and sucralose were weighed and added to a mixer for mixing; Hot melt extrusion: The powder was placed in a hot melt extruder to prepare a film agent using the hot melt extruder. The extrusion temperatures were set at 80, 100, 130, 135, 135, 135, 135, 135 °C, and the screw speed was 50 rpm.

[0027] Film formation: The extruded material was stretched to a thickness of 100 µm.

[0028] Film cutting: The film agent was cut to the film weight.

[0029] Detection: Tensile strength and disintegration time limit test Disintegration time limit: Determined by the disintegration time limit inspection method in Appendix 0921 of the Chinese Pharmacopoeia 2020 Edition; Tensile strength: Using a medical packaging performance tester, tensile tests were carried out on film agents of different batches. Cut 5 cm long samples from each batch, set the clamp spacing at 20 mm, the test speed was 5 mm / min, and 3 samples were tested for each batch. Record the average value of the tensile strength.

[0030] Dissolution curve: Refer to the second method (paddle method) of the dissolution and release determination method in General Chapter 0931 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition to determine the orally disintegrating film prepared by the prescription. The water bath temperature was 37 ± 0.1 °C, the rotation speed was 75 r / min, 0.5% SDS solution was used as the dissolution medium. Take 5 ml of liquid at 10, 20, 30, 45, and 60 min respectively and supplement the same volume and temperature of the dissolution medium. Filter the taken liquid through a 0.45 μm filter membrane, and use high performance liquid chromatography to determine the dissolution degree.

[0031]

[0032] Dissolution curve results

[0033] Example 2 The prescription is shown in the following table. Taking the specification of suvorexant as 10 mg, the tablet weight as 100 mg, and the batch size as 1000 tablets, the weight and total weight percentage (w / w; %) of each component are:

[0034] Process flow: The same as Example 1.

[0035] Detection: The method is as shown in Example 1

[0036] Dissolution curve results

[0037] Result description: Under the sustained-release materials and specific preparation temperature conditions adopted in this product, the suvorexant API with a particle size of 5 - 20 µm can be evenly dispersed in the film agent, with a stable dissolution rate and good appearance of the film agent. However, when the particle size of suvorexant increases to 30 µm, obvious granularity appears on the surface of the film agent, and the appearance no longer meets the quality standards, and the dissolution also fails to reach the expectation. On the contrary, when the particle size of suvorexant is only 2 µm, its dissolution rate significantly accelerates. It is speculated that due to the too small particle size, part of the API may have transformed into an amorphous state during the hot melt process, thus unable to maintain the expected sustained-release characteristics.

[0038] Example 3 The prescription is shown in the following table. Taking the specification of suvorexant as 10 mg, the tablet weight as 100 mg, and the batch size as 1000 tablets, the weight and the proportion of the total weight (w / w; %) of each component are:

[0039] Process: Same as Example 1 Detection: The method is as shown in Example 1

[0040] Dissolution curve results

[0041] Example 4 The prescription is shown in the following table. Taking the specification of suvorexant as 10 mg, the tablet weight as 100 mg, and the batch size as 1000 tablets, the weight and the proportion of the total weight (w / w; %) of each component are:

[0042] Process: Same as Example 1 Detection: The method is as shown in Example 1

[0043] Example 5 The prescription is shown in the following table. Taking the specification of suvorexant as 10 mg, the tablet weight as 100 mg, and the batch size as 1000 tablets, the weight and the proportion of the total weight (w / w; %) of each component are:

[0044] Process: Same as Example 1 Detection: The method is as shown in Example 1

[0045] Example 6 The prescription is shown in the following table. Taking the specification of suvorexant as 10 mg, the tablet weight as 100 mg, and the batch size as 1000 tablets, the weight and the proportion of the total weight (w / w; %) of each component are as follows:

[0046] Process flow - Prescription 6 - 1a Mixing: Suvorexant, Soluplus, hydroxypropyl cellulose, triethyl citrate, and sucralose are weighed and added to a mixer for mixing; hot melt extrusion: The powder is placed in a hot melt extruder, and a film agent is prepared using the hot melt extruder. The extrusion temperature is set at 80, 100, 120, 120, 120, 120, 120, 120 °C (die orifice), and the screw speed is 50 rpm.

[0047] Film forming: The extruded material is stretched to a thickness of 100 µm.

[0048] Film cutting: The film agent is cut to the film weight Process flow - Prescription 6 - 1b Mixing: Suvorexant, Soluplus, hydroxypropyl cellulose, triethyl citrate, and sucralose are weighed and added to a mixer for mixing; hot melt extrusion: The powder is placed in a hot melt extruder, and a film agent is prepared using the hot melt extruder. The extrusion temperature is set at 80, 100, 135, 135, 135, 135, 135, 135 °C (die orifice), and the screw speed is 50 rpm.

[0049] Film forming: The extruded material is stretched to a thickness of 100 µm.

[0050] Film cutting: The film agent is cut to the film weight Process flow - Prescription 6 - 1c Mixing: Suvorexant, Soluplus, hydroxypropyl cellulose, triethyl citrate, and sucralose are weighed and added to a mixer for mixing; hot melt extrusion: The powder is placed in a hot melt extruder, and a film agent is prepared using the hot melt extruder. The extrusion temperature is set at 80, 100, 140, 140, 140, 140, 140, 140 °C (die orifice), and the screw speed is 50 rpm.

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

[0052] Film cutting: The film agent is cut to the film weight Process flow - Prescription 6 - 1d Mixing: Suvorexant, Soluplus, hydroxypropyl cellulose, triethyl citrate, and sucralose were weighed and added to a mixer for mixing; Hot melt extrusion: The powder was placed in a hot melt extruder to prepare a film agent using the hot melt extruder. The extrusion temperature was set at 80, 100, 150, 150, 150, 150, 150, 150 °C (die orifice), and the screw speed was 50 rpm.

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

[0054] Film cutting: The film agent was cut to the film weight Process flow - Prescription 6 - 1e Mixing: Suvorexant, Soluplus, hydroxypropyl cellulose, triethyl citrate, and sucralose were weighed and added to a mixer for mixing; Hot melt extrusion: The powder was placed in a hot melt extruder to prepare a film agent using the hot melt extruder. The extrusion temperature was set at 80, 100, 110, 110, 110, 110, 110, 110 °C (die orifice), and the screw speed was 50 rpm.

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

[0056] Film cutting: The film agent was cut to the film weight Detection: The method is as shown in Example 1

[0057] The results showed that: The properties and tensile strength of the orally disintegrating film could meet the qualified standards within the temperature range of 120 °C to 140 °C. However, when the temperature dropped to 110 °C, due to the too low temperature, the hot melt extruded material would break immediately during the stretching process and could not form a complete film agent. When the temperature rose to 150 °C, the formed film agent showed a light yellow color and was a transparent film. It was speculated that this might be due to a relatively high impurity content, and Suvorexant could no longer maintain its microcrystalline form, and its properties also did not meet the requirements.

[0058] Dissolution results:

[0059] The results showed that: Since Prescription 6 - 1d could no longer form microcrystals, the dissolution rate was much greater than that of Prescription 6 - 1d, 6 - 1b, and Prescription 6 - 1c.

[0060] Example 7 Animal experiment Six beagle dogs were randomly and evenly divided into two experimental groups, with 3 dogs in each group. They were respectively administered the prescription 1-1 of Example 1, the control group 1, and the commercial tablets, and the dosage was uniformly 10 mg. Among them, the administration method of the oral soluble film was: placing the oral soluble film on the tongue surface of the beagle dog, moistening it with a small amount of normal saline, then holding the dog's mouth for about 5 minutes, waiting for it to completely dissolve and be swallowed.

[0061] At 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours after administration, 0.5 mL of blood was collected from the anterior limb vein of the beagle dog, and the blood drug concentrations of the self-made oral soluble film group and the commercial tablet group were detected by LC-MS / MS technology.

[0062] The results showed that the present invention could significantly accelerate Tmax, reduce Cmax. Tmax was 2 times faster than that of the commercial tablets, and Cmax was basically the same as that of the market tablets. It could achieve a more stable blood drug concentration, reduce side effects, and was safer to use. At the same time, compared with the existing tablets, this product was also more suitable for the elderly, children, or patients with difficulty in swallowing.

[0063] The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention are all included in the protection scope of the present invention.

Claims

1. An orally disintegrating film for treating insomnia, characterized in that, The orally disintegrating film at least comprises suvorexant, a film-forming material, and one or more of a plasticizer, a disintegrant, a flavoring agent or a sweetening agent, and a stabilizer, wherein the film-forming material is hydroxypropyl cellulose and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

2. The orally dissolving film according to claim 1, characterized in that The weight ratio of hydroxypropyl cellulose to polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 1:3 - 3:

1.

3. The orally dissolving film according to claim 1, characterized in that The particle size of suvorexant is 5 - 20 μm.

4. The orally dissolving film according to claim 1, wherein The weight percentage content of suvorexant is 5 - 20%.

5. The orally disintegrating film according to claim 1, wherein, Calculated by weight parts, it at least comprises 5 - 20 weight parts of suvorexant, 10 - 90 weight parts of the film-forming material, 5 - 20 weight parts of the plasticizer, and 0 - 5 weight parts of the flavoring agent or the sweetening agent.

6. The orally disintegrating film according to claim 5, wherein The plasticizer is polyethylene glycol or triethyl citrate, preferably triethyl citrate, and the flavoring agent or the sweetening agent is sucralose.

7. The orally disintegrating film according to claim 1, wherein The thickness of the film agent is 5 - 1000 μm, preferably 50 - 200 μm.

8. A method for preparing an orally disintegrating film according to any one of claims 1-7, characterized in that, The preparation method is the hot melt extrusion method, and the die temperature of the hot melt extrusion is 120°C - 140°C.

9. The preparation method of the orally disintegrating film according to claim 8, wherein It at least comprises the following steps: (1) Weigh suvorexant, the film-forming material, the plasticizer, the disintegrant, the flavoring agent or the sweetening agent, and the stabilizer and add them to a mixer for mixing; (2) Add the mixture to a hot melt extrusion device at a speed of 0.01 - 100 kg / h, and after extrusion, stretch it into a film; (3) Cut the prepared film into film agents of different sizes and shapes through a film cutting machine.

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