A tablet for treating insomnia and its preparation method

Abstract

The present invention belongs to the field of pharmaceutical technology and relates to a tablet for treating insomnia and its preparation method. Disclosed are YZG-331 tablets, a drug for treating insomnia, as represented by Formula I, and its preparation method. Specifically disclosed are the formulation composition and preparation process of YZG-331 tablets. #imgabs0#

Description

Technical Field

[0001] The present invention relates to a pharmaceutical preparation and a preparation method thereof, in particular to a YZG-331 tablet for treating insomnia and a preparation method thereof, belonging to the technical field of pharmaceuticals. Background Art

[0002] Sleep is a crucial physiological process regulated by the brain. It promotes brain development, allows the body to rest, restore physical strength, stop mental activity, restore mental capacity, and consolidate memory. It plays a vital role in human brain development, physical and mental health, and cognitive function. Insomnia is a condition characterized by frequent and persistent difficulty falling asleep and / or maintaining sleep, leading to decreased sleep satisfaction. According to epidemiological surveys, approximately 29% of people worldwide suffer from varying degrees of insomnia. The 2021 White Paper on Exercise and Sleep shows that 300 million people in China suffer from sleep disorders. Insomnia seriously affects work and quality of life. Long-term insomnia not only aggravates conditions such as hypertension, coronary heart disease, and diabetes, but also increases the risk of related diseases. China is currently experiencing an aging population and a growing number of elderly people. As the number of elderly people increases, the number of people with sleep disorders is also expanding. At the same time, as the pace of life accelerates, work and life pressures are also increasing, making sleep disorders more likely to occur [1,2]. These current situations have increased the clinical demand for sedative hypnotics.

[0003] Ideal sedatives and hypnotic drugs in clinical practice should have the advantages of being easy to use, quickly inducing sleep, having no effect on physiological sleep structure, being eliminated quickly, having no residual effect the next day, having no effect on memory function, having no respiratory depression, having few drug interactions, and having no dependence or withdrawal symptoms after long-term use. Given the complexity of the causes of insomnia, existing drugs all have problems such as dependence, tolerance, and rebound after discontinuation to varying degrees. Even though the development of sedatives and hypnotic drugs has a long history, from the earliest chloral hydrate to the widely used benzodiazepines, class, until today's highly efficient and selective 5-HT 2A Receptor antagonists, orexin receptor antagonists, or GABAa receptor agonists still cannot meet the needs of patients [3]. In particular, there are no original sedative and hypnotic drugs in my country.

[0004] The diversity of natural product structures and bioactivities, as well as their bioadaptability, are the driving forces behind modern small molecule drug development. Research on active ingredients from traditional Chinese herbal medicines and folk medicinal bioresources has received considerable attention. Gastrodia elata (Gastrodiaelata Bl.) is a perennial herbaceous plant of the genus Gastrodia in the Orchidaceae family. Its dried tubers are used as medicine and are a traditional and precious Chinese medicine. It is primarily used to treat a variety of neurological disorders, including convulsions, insomnia, headaches, and vertigo. It also has the potential to strengthen the body, improve memory, and promote blood circulation [4,5]. Domestic and international scholars have conducted extensive research on the chemical composition of Gastrodia elata extracts. The reported chemical components are primarily p-hydroxybenzyl derivatives and compounds with p-hydroxybenzyl as a substituent [6-10]. Pharmacological activity studies have shown that p-hydroxybenzyl derivatives and gastrodin have various pharmacological effects on the nervous system. However, there are also reports that the components of Gastrodia elata extracts after removing gastrodin retain significant pharmacological effects, such as sedation and hypnosis, while gastrodin, at higher doses under the same conditions, does not exhibit sedative and hypnotic effects [6,11,12]. This shows that the pharmacological effects of gastrodin cannot reflect the main pharmacological effects of Gastrodia elata.

[0005] Therefore, considering the traditional application of Chinese medicine such as Gastrodia elata, which is mainly based on water decoction, we carried out research on the water extract of Gastrodia elata, from which a series of components such as p-hydroxybenzyl alcohol phenols, p-hydroxybenzyl alcohol glycosides and citrate benzyl ester glycosides have been isolated and identified [13-22]. A trace component N 6 -(p-Hydroxybenzyl)-adenosine (NHBA) has a yield of about 0.4 parts per 100,000 and a very significant sedative effect. When administered intraperitoneally, its sedative effect is more than a thousand times that of ingredients such as gastrodin [23,24]. Given the low oral bioavailability of NHBA (the effective dose difference between oral administration and intraperitoneal injection is more than 200 times), we confirmed that NHBA is the key active ingredient in the sedative and hypnotic effects of Gastrodia elata. After repeated synthesis and drugability evaluation, including preliminary drug metabolism and toxicity tests, we finally obtained the sedative and hypnotic candidate drug YZG-331 and conducted a series of studies on N-terminal NHBA containing YZG-331 and its analogs. 6 -Adenosine derivatives and N 6Patents have been filed for substituted purine derivatives, their preparation methods, pharmaceutical compositions, and uses [25-28] and have been granted U.S. patents in China and the United States. According to the "Guidelines for Estimating the Maximum Recommended Starting Dose of Drugs for Initial Clinical Trials in Healthy Adult Volunteers" issued by the National Medical Product Administration (NMPA), based on the no-observed-adverse-effect-level (NOAEL) from animal toxicology studies and using the human equivalent dose (HED) derivation method, the maximum recommended starting dose (MRSD) of 11.2 mg was obtained. Considering the ease of clinical operation, the MRSD dose of 10 mg was ultimately selected for clinical trials. Given the characteristics of YZG-331, the clinical dosage is relatively small and it has some hygroscopicity, which affects its clinical application. Taking into account the characteristics of oral preparations, tablets are more suitable.

[0006] References:

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[0017] 11. Huang Junhua, Wang Guilian. Preliminary study on the pharmacological effects of Tianma injection and gastrodin[J]. Journal of the Chinese Academy of Medical Sciences, 1985, 7:399.

[0018] 12. Huang Junhua, Wang Guilian. Comparison of the pharmacological effects of the gastrodin-free fraction and gastrodin of Tianma injection[J]. Journal of the Chinese Academy of Medical Sciences, 1989, 11: 147.

[0019] 13. Wang Yanan. Study on chemical components and biological activities of Gastrodia elata[D]. Peking Union Medical College, 2012.

[0020] 14. Guo Qinglan. Study on the chemical components and biological activities of Gastrodia elata[D]. Peking Union Medical College, 2014.

[0021] 15. Zhou Xue. Study on chemical components of water extract of Gastrodia elata[D]. Peking Union Medical College, 2017.

[0022] 16. Wang Yanan, Lin Sheng, Chen Minghua, et al. Chemical constituents of aqueous extract of Gastrodia elata[J]. China Journal of Traditional Chinese Medicine, 2012, 37:1775.

[0023] 17.Guo QL; Wang YN; Zhu CG; et al. 4-Hydroxybenzyl-substitutedglutathione derivatives from Gastrodia elata[J].J.Asian Nat.Prod.Res.2015,17:439.

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[0025] 19. Guo QL; Lin S.; Wang YN; et al. Gastrolatathioneine, an unusualergothioneine derivative from an aqueous extract of “tian ma”: A natural product co-produced by plant and symbiotic fungus. Chin. Chem. Lett. 2016, 27: 1577.

[0026] 20.Zhou

[0027] 21.Xu CB; Guo QL; Wang YN; et al.Gastrodin derivatives from Gastrodia elata[J].Nat.Prod.Bioprospect.2019,9:393.

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[0029] 23.Zhang Y.; Li M.; Kang RX; at al.NHBA isolated from Gastrodia elataexerts sedative and hypnotic effects in sodium pentobarbital-treated mice[J].Pharm.Biochem.Behav.2012,102:450.

[0030] 24.He J.; Luo Z.; Huang L.; et al.Ambient mass spectrometry imagingmetabolomics method provides novel insights into the action mechanism of drugcandidates[J]. Anal.Chem.2015,87:5372.

[0031] 25. Shi Jiangong, Zhang Jianjun, Yue Zhenggang, et al. 6 -substituted adenosine derivatives and N 6 -Substituted adenine derivatives and their uses [P]. ZL200980162826.5.

[0032] 26. Zhang Jianjun, Shi Jiangong, Li Min, et al. 6 -Substituted adenosine derivatives, their preparation methods, pharmaceutical compositions and uses [p]. ZL 200810114594.3.

[0033] 27. Shi Jiangong, Zhang Jianjun, Yue Zhenggang, et al. 6 -substituted adenosine derivatives and N 6 -Substituted adenine derivatives and their uses[p].ZL201410539423.0.

[0034] 28.Shi Jiangong,Zhang Jianjun,Yue Zhenggang,et al.N 6 -substitutedadenosine derivatives and N 6 -sustituted adenine derivatives and uses thereof[p].US 10174033 B2. Summary of the Invention

[0035] The technical problem to be solved by the present invention is to provide a new type of drug YZG-331 tablets with sedative and hypnotic effects.

[0036] In order to solve the technical problems of the present invention, the present invention provides the following technical solutions:

[0037] The first aspect of the technical solution of the present invention is to provide a tablet composition of the sedative and hypnotic drug candidate YZG-331 or a pharmaceutically acceptable salt thereof.

[0038] The present invention provides a YZG-331 tablet, wherein the active pharmaceutical ingredient is YZG-331 or a pharmaceutically acceptable salt thereof, and the weight proportion of the tablet is 5% to 15%, preferably 7% to 10%.

[0039] The YZG-331 tablet filler of the present invention is one or more of lactose, microcrystalline cellulose, corn starch, and mannitol, and more preferably a mixture of lactose, microcrystalline cellulose, and corn starch. More preferably, a mixture of lactose (monohydrate), microcrystalline cellulose 101, and corn starch is used. The preferred weight proportion of the filler in the tablet is 65% to 85%, and more preferably, the weight range is 75% to 85%.

[0040] The adhesive of the present invention is preferably povidone K30, and the usage range of the adhesive is 3% to 6%, preferably 4% to 5%.

[0041] The disintegrant of the present invention is crospovidone, and the dosage of the disintegrant is in the range of 1.5% to 2.5%, preferably in the range of 1.7% to 2.2%.

[0042] The lubricant of the present invention is one or a mixture of magnesium stearate, calcium stearate, talc, and stearic acid, and more preferably magnesium stearate. The preferred weight ratio of magnesium stearate in the tablet is 0.4% to 1.0%, and the more preferred amount is 0.45% to 0.65%.

[0043] The film coating premix of the present invention is one or more of titanium dioxide, soybean lecithin, talc, and polyvinyl alcohol. More preferably, the premix is a mixture of titanium dioxide, soybean lecithin, talc, and polyvinyl alcohol. The preferred weight proportion of the film coating premix in the tablet is 3.0% to 8.0%, and the more preferred amount is 4.2% to 5.5%.

[0044] The wetting agent of the present invention is a 30% to 70% ethanol aqueous solution, and a more preferred wetting agent is a 40% to 60% ethanol aqueous solution.

[0045] The second aspect of the present invention is to provide a method for preparing the drug YZG-331 tablet, which is characterized by being prepared by a powder direct tableting method, comprising the following steps:

[0046] Weigh YZG-331 or its pharmaceutically acceptable salt, filler, binder, and disintegrant;

[0047] Mix evenly by adding equal amounts gradually;

[0048] Add appropriate amount of binder solution for wet granulation, dry and size the granules, then add wetting agent and lubricant, mix well and press into tablets;

[0049] Coating.

[0050] The third aspect of the present invention provides the use of the drug YZG-331 tablet in the preparation of a drug for preventing or treating insomnia.

[0051] Beneficial technical effects

[0052] YZG-331 tablets are original candidate psychiatric drugs that have not been marketed domestically or abroad. Its API, YZG-331, has many advantages, including clear sedative and hypnotic effects, rapid onset, no effect on physiological sleep structure at low doses, rapid elimination, no next-day residual effects, effective compound prototype, ineffective metabolites, no significant inhibitory and inductive effects on liver enzymes, good safety, no respiratory depression, no potential for physical and mental dependence, and its target of action is different from the most commonly used clinical drugs, zolpidem tartrate and diazepam. It is expected that YZG-331 tablets may reduce the common adverse reactions of clinical insomnia treatment drugs, such as rebound after withdrawal, tolerance, and dependence. YZG-331 tablets are easy to use and have good stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1, YZG-331 tablet preparation process flow chart DETAILED DESCRIPTION

[0054] The following experimental examples are provided to further illustrate the present invention but are not intended to limit the present invention in any way.

[0055] Example 1, Prescription screening of YZG-331 tablets:

[0056] Table 1: Prescription screening summary table

[0057]

[0058] Conclusion: Based on the above experimental results, prescription 5 has the best comprehensive performance, among which the dosage of binder PVPk30 accounts for 4.6%; the dosage of disintegrant accounts for 2.0%; and the dosage of lubricant accounts for 0.5%, all of which are within the commonly used dosage range of oral solid preparations. The tablet core prescription composition is preliminarily confirmed as prescription 5.

[0059] Example 2: Screening of coating powder for YZG-331 tablets

[0060] Taking into account the hygroscopicity of the raw materials, a moisture-proof film coating is applied to the surface of the tablets to improve the moisture-proof performance of the preparation.

[0061] Table 2: Coating formulation design

[0062]

[0063] Result analysis: The film coating is complete, the dissolution rate meets the requirements, and the coating has little effect on the dissolution rate of the tablets. The coating powder and coating process are suitable, so it is preliminarily confirmed that the film coating premix ( 81W680001).

[0064] Example 3, Prescription of YZG-331 Tablets

[0065] The tablet formulation of YZG-331 was determined, as shown in Table 4 below:

[0066] Table 4: Prescription composition of YZG-331 tablets per unit dose

[0067]

[0068] Note 1: 50% ethanol solution is the solvent for the binder during wet granulation and is removed during the process.

[0069] Note 2: Film coating premix ingredients: titanium dioxide, soybean lecithin, talc, polyvinyl alcohol.

[0070] Note 3: Purified water is the solvent of the coating solution during film coating and is removed during the process.

[0071] Example 4: Development and Optimization of Tablet Preparation Process

[0072] Based on the formulation of this product, wet granulation tableting and film coating processes were selected. The specific process steps are as follows:

[0073] ① Preparation of adhesive: First prepare a 50% (W / W) ethanol solution, then weigh the prescribed amount of povidone K30, dissolve and dilute it with 50% (W / W) ethanol solution to prepare a 24% povidone K30 solution.

[0074] ② Mixing: Pass the API and excipients through a 60-mesh sieve, place them in a wet granulator, stir at 100 rpm, and mix for 10 minutes.

[0075] ③Preparing soft material: Turn on the stirring speed to 125 rpm and the cutting speed to 360 rpm, add the prescribed amount of adhesive / wetting agent at a uniform speed, and continue granulating for 1 minute.

[0076] ④ Granulation: 20 mesh screen, swing granulator to obtain wet granules.

[0077] ⑤ Drying: Spread the wet granules on a tray and place them in a drying oven. Adjust the oven temperature to 60°C and dry them, turning them manually every 30 minutes. The drying endpoint is when the granules lose ≤ 5% weight. Once the granules reach the drying endpoint, stop drying and remove them from the oven and allow them to cool naturally.

[0078] ⑥ Granulation: 20 mesh sieve, oscillating granulator for granulation.

[0079] ⑦Total mixing: According to the yield of dry granules, the amount of magnesium stearate is converted proportionally, added to the dry granules, and manually shaken up and down in a ziplock bag for 2 minutes.

[0080] ⑧ Tablet pressing: Adjust the tablet weight and hardness within the appropriate range and use electric tablet pressing.

[0081] ⑨Coating:

[0082] Instrument startup: Turn on the instrument, set the inlet air temperature to 45°C, the inlet air speed to 1000 rpm, the exhaust air speed to 1300 rpm, and start heating.

[0083] Preheating of slices: After the air inlet temperature rises to 45℃ and stabilizes, put the slices into the pot and start preheating at a speed of 6r / min.

[0084] Liquid spraying: When the temperature of the tablets is preheated to 43-46°C, adjust the inlet air temperature to 55°C, the atomization pressure to 0.23-0.25 MPa, open the spray gun, spray, adjust the spray volume to 3-5 mL / min, the pot speed to 10-15 r / min, and start coating. During the coating process, monitor the coating status in real time.

[0085] Drying: After the spraying is completed, adjust the air inlet temperature to 40℃, reduce the pot speed by 5-7r / min, and the air inlet to 1000 rpm. When the tablet bed temperature drops to 40℃, stop drying.

[0086] ⑩ Packaging: Use oral solid pharmaceutical high-density polyethylene bottles, 60 tablets per bottle, manually count the tablets, bottle, seal, and label.

Claims

1. A YZG-331 tablet formulation, characterized in that: The weight percentage composition of the tablet is as follows: the active ingredient is YZG-331 as shown in Formula 1: 7.7%, lactose monohydrate: 34.6%, microcrystalline cellulose: 34.6%, corn starch: 15.9%, povidone K30: 4.6%, crospovidone: 2.0%, magnesium stearate: 0.5%, 50% w / w ethanol qs, 2. A drug YZG-331 tablet, characterized in that, The weight percentage composition of the tablet is as follows: the active ingredient is YZG-331 as shown in Formula 1: 7.7%, lactose monohydrate: 34.6%, microcrystalline cellulose 101: 34.6%, corn starch: 15.9%, povidone K30: 4.6%, crospovidone: 2.0%, magnesium stearate: 0.5%, coating agent composed of titanium dioxide, soybean lecithin, talc, polyvinyl alcohol: 4.9%, 50% w / w ethanol is appropriate and removed during the process, 3. A method for preparing the YZG-331 tablet according to claim 2, characterized in that: The pharmaceutical YZG-331 tablets are prepared by the following method, which comprises the following steps: Weigh YZG-331, a filler selected from lactose monohydrate, microcrystalline cellulose 101, and corn starch, a binder selected from povidone K30, and a disintegrant selected from crospovidone; Mix evenly by adding equal amounts gradually; Add an appropriate amount of binder solution for wet granulation, dry, and shape the granules, then add a wetting agent selected from 50% w / w ethanol and a lubricant selected from magnesium stearate, mix well, and then press into tablets; Coating.

4. Use of the YZG-331 tablet formulation according to claim 1 or the YZG-331 tablet according to claim 2 in the preparation of a drug for preventing or treating insomnia.

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