Tablet for treating insomnia and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a tablet for treating insomnia and a preparation method thereof. The invention discloses a medicine YZG-331 tablet for treating insomnia as shown in a formula I and a preparation method of the medicine YZG-331 tablet. The invention particularly discloses a prescription composition and a preparation process flow of the medicine YZG-331 tablet. # imgabs0 #

Description

Technical Field

[0001] The 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 medicines. Background Art

[0002] Sleep is an important physiological process regulated by the brain. It can promote the development of brain function, allow the body to rest, restore physical strength, stop brain thinking activities, restore brain power, and consolidate memory. It plays a vital role in the development of the human brain, physical and mental health, and the maintenance of cognitive function. Insomnia is a disease characterized by frequent and persistent difficulty falling asleep and / or difficulty maintaining sleep, which leads to decreased sleep satisfaction. According to epidemiological surveys, about 29% of people in the world currently have insomnia to varying degrees. The "2021 Sports and Sleep White Paper" shows that 300 million people in China have sleep disorders. Insomnia seriously affects the quality of work and life. Patients with long-term insomnia will not only aggravate diseases such as hypertension, coronary heart disease, and diabetes, but also increase the risk of related diseases. China is currently in a stage where the aging degree is intensifying and the number of elderly people is continuously rising. With the increase in the number of elderly people, the number of people with sleep disorders is also expanding; at the same time, as the pace of life continues to accelerate, work pressure and life pressure are also increasing, which is more likely to induce sleep disorders [1,2]. These current situations have increased the clinical demand for sedative hypnotics.

[0003] Ideal sedative hypnotic drugs in clinical practice should be easy to use, quickly induce sleep, have no effect on physiological sleep structure, be eliminated quickly, have no residual effect the next day, have no effect on memory function, have no respiratory depression, have few drug interactions, and have 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 drug withdrawal rebound to varying degrees. Even though the development of sedative 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 hypnotic drugs in my country.

[0004] The diversity of natural product structures and biological activities and their biological adaptability are the source of modern small molecule drug development. The research on active ingredients in traditional Chinese herbal medicines and folk medicinal biological resources has received much attention. Gastrodia elata (Gastrodiaelata Bl.) is a perennial herbaceous plant of the genus Gastrodia in the orchid family. Its dried tubers are used as medicine and are a traditional precious Chinese medicine in my country. It is mainly used to treat a variety of neurological diseases such as convulsions, insomnia, headaches and vertigo. It can also strengthen the body, improve memory and promote blood circulation [4,5]. Domestic and foreign scholars have conducted a lot of research on the chemical components of Gastrodia elata extracts. The reported chemical components are mainly p-hydroxybenzyl derivatives and compounds with p-hydroxybenzyl as substituents [6-10]. The results of pharmacological activity studies have shown that p-hydroxybenzyl derivatives and gastrodin have a variety of 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 does not show sedative and hypnotic effects at higher doses under the same conditions [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 medicines such as Gastrodia elata, which is mainly based on water decoction, we conducted research on the water extract of Gastrodia elata, from which a series of p-hydroxybenzyl alcohol phenols, p-hydroxybenzyl alcohol glycosides and citrate benzyl ester glycosides have been isolated and identified [13-22], and a trace component N 6 -(p-Hydroxybenzyl)-adenosine (NHBA), with a yield of about 4 parts per 100,000, has a very significant sedative effect. When administered intraperitoneally, its sedative effect is more than 1,000 times that of gastrodin and other ingredients [23,24]. Given the low oral bioavailability of NHBA (the effective dose of oral administration differs by more than 200 times from that of intraperitoneal injection), we confirmed that NHBA is the key active ingredient of the sedative and hypnotic effect of Gastrodia elata, and further conducted repeated synthesis and drug efficacy, preliminary drug metabolism and toxicity tests and other drugability evaluations, and finally obtained the sedative and hypnotic candidate drug YZG-331, and conducted a series of studies on N containing YZG-331 and its analogs. 6 -Adenosine derivatives and N 6-Substituted purine derivatives, their preparation methods, pharmaceutical compositions and uses have been patented [25-28] and have been granted patents in China and the United States respectively. According to the "Guidelines for Estimating the Maximum Recommended Starting Dose of Drugs for the First Clinical Trial in Healthy Adult Volunteers" issued by NMPA, based on the no-observed-adult-effect-dose (NOAEL) of animal toxicology tests, the human equivalent dose (HED) was derived to obtain the maximum recommended starting dose (MRSD) = 11.2 mg. Considering the convenience of clinical operation, the MRSD dose in the clinical trial was finally selected as 10 mg. According to the characteristics of YZG-331, the clinical dosage is small and has a certain degree of hygroscopicity, which affects the clinical application of the drug. Considering the characteristics of oral preparations, it is more suitable for tablets.

[0006] References:

[0007] 1. Chinese Sleep Research Society. Chinese Guidelines for the Diagnosis and Treatment of Insomnia[J]. Chinese Medical Journal, 2017, 97(24):1844-1856.

[0008] 2. Zhang Xi. Modern Sleep Medicine[M]. Beijing: People's Military Medical Publishing House, 2007:155.

[0009] 3. Zhang Binjia, Qiu Ziliang, Zhang Jie. A brief history of the development of sleep drugs[J]. World Journal of Sleep Medicine, 2020, 7:1169.

[0010] 4. Jiangsu University School of Medicine. Chinese Medicine Dictionary [M]. Shanghai: Shanghai Science and Technology Press, 1977: 315.

[0011] 5. State Administration of Traditional Chinese Medicine, Chinese Materia Medica Editorial Committee. Chinese Materia Medica[M]. Shanghai: Shanghai Science and Technology Press, 1999:716.

[0012] 6.Zhan HD; Zhou HY; Sui YPThe rhizome of Gastrodia elata Blume–anethnopharmacological review[J].J.Ethnopharmacol,2016,189:361.

[0013] 7.Wang ZW; Li Y.; Liu DH; et al.Chemical constituents from therhizomes of Gastrodia elata f.glauca and their potential neuroprotectiveeffects[J].Phytochem.Lett.2018;24:167.

[0014] 8.Wang ZW; Li Y.; Liu DH; et al.Four new phenolic constituents from the rhizomes of Gastrodia elata Blume[J].Nat.Prod.Res.2019,33:1140.

[0015] 9.Chen SY; Geng CA; Ma YB; et al. Melatonin receptors agonisticactivities of phenols from Gastrodia elata[J].Nat.Prod.Bioprospect,2019,9:297.

[0016] 10.Chen SY; Geng CA; Ma YB; et al.Polybenzyls from Gastrodiaelata,their agonistic effects on melatonin receptors and structure-activityrelationships[J].Bioorg.Med.Chem.; 2019,27:3299.

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

[0018] 12. Huang Junhua; Wang Guilian. Comparison of the pharmacological effects of the gastrodin-free part and gastrodin of Tianma injection[J]. Journal of 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 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 water extract of Gastrodia elata[J]. Chinese 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.

[0024] 18.Guo Q.; Wang Y.; Lin S.; etal.4-Hydroxybenzyl-substituted amino acidderivatives from Gastrodia elata[J].Acta Pharm.Sin.B 2015,5:350.

[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.

[0028] 22.Wang Y.; Zhang M.; Zhou

[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 problem 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 candidate drug YZG-331 or a pharmaceutically acceptable salt thereof.

[0038] The 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 active pharmaceutical ingredient in 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. The preferred weight ratio of the filler in the tablet is 65% to 85%, and the more preferred dosage range is 75% to 85%.

[0040] The adhesive of the present invention is preferably povidone K30, and the amount of the adhesive used is in the range of 3% to 6%, preferably in the range of 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%, and the preferred dosage is 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, 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 usage range is 0.45% to 0.65%.

[0043] The film coating premix of the present invention is one or more of titanium dioxide, soybean lecithin, talcum powder, and polyvinyl alcohol, and more preferably the premix component is a mixture of titanium dioxide, soybean lecithin, talcum powder, 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 dosage range 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 in that it is 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 tablets in the preparation of drugs for preventing or treating insomnia.

[0051] Beneficial technical effects

[0052] YZG-331 tablets are original candidate drugs for psychotropics that have not been marketed in China or abroad. Its raw material 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 obvious inhibitory and inductive effects on liver enzymes, good safety, no respiratory depression, no physical dependence and mental dependence potential, etc. In addition, the target of action is different from the most commonly used clinical zolpidem tartrate and diazepam, and it is expected that YZG-331 tablets may reduce the common adverse reactions of clinical insomnia treatment drugs such as withdrawal rebound, tolerance and dependence addiction. 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 can further illustrate the present invention, but do not 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%, which are all within the commonly used dosage range of oral solid preparations. The tablet core prescription composition preliminarily confirms prescription 5.

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

[0060] Taking into account that the raw materials have a certain degree of hygroscopicity, it is designed to coat the surface of the tablets with a layer of ordinary moisture-proof film coating 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 meets the requirements, and the coating does not affect 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 unit dose of YZG-331 tablets

[0067]

[0068] Note 1: 50% ethanol solution is the solvent of 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] According to the prescription composition of this product, wet granulation tableting and film coating process 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] ②Mixing: Pass the API and excipients through a 60-mesh sieve respectively, then put them into a wet granulator, start stirring at 100 rpm, and mix for 10 minutes.

[0075] ③Preparing soft materials: Turn on the stirring speed of 125rpm and the cutting speed of 360rpm, add the prescribed amount of adhesive / wetting agent at a uniform speed, and continue granulation 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, put them in a drying oven, adjust the temperature of the drying oven to 60℃, and dry them. Turn them over manually every 30 minutes. The drying end point is when the granules lose weight ≤ 5%. When the granules lose weight at the drying end point, stop drying, take them out and let them cool naturally.

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

[0079] ⑦Total mixing: According to the dry granule yield, calculate the amount of magnesium stearate in proportion, add it to the dry granules, and shake it up and down manually 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 start-up: Turn on the instrument, set the inlet air temperature to 45°C, the inlet air to 1000 rpm, the exhaust air 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 at a speed of 6r / min and start preheating.

[0084] 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 0.23-0.25MPa, open the spray gun, spray, adjust the spray volume to 3-5mL / min, the pot speed to 10-15r / min, and start coating. During the coating process, monitor the coating condition in real time.

[0085] Drying: After the spraying is completed, adjust the inlet air temperature to 40℃, reduce the pot speed by 5-7r / min, and the inlet air 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 drug YZG-331 tablet, characterized in that: The tablet is composed of the following weight percentages: the active ingredient is YZG-331 or its pharmaceutically acceptable salt as shown in Formula 1, 5% to 15%, a filler, 65% to 85%, a binder, 3% to 6%, a disintegrant, 1.5% to 2.5%, a lubricant, 0.4% to 1.0%, a coating agent, 3.0% to 8.0%, and an appropriate amount of a wetting agent.

2. The pharmaceutical YZG-331 tablet according to claim 1, characterized in that: The filler is one or more of lactose, microcrystalline cellulose, corn starch and mannitol.

3. The pharmaceutical YZG-331 tablet according to claim 1, characterized in that: The adhesive is povidone K30; the disintegrant is crospovidone; the lubricant is one or a mixture of more than one of magnesium stearate, calcium stearate, talcum powder and stearic acid; and the wetting agent is 30% to 70% ethanol aqueous solution.

4. The pharmaceutical YZG-331 tablet according to claim 1, characterized in that: The film coating premix is ​​one or more of titanium dioxide, soybean lecithin, talcum powder and polyvinyl alcohol.

5. A method for preparing the YZG-331 tablet according to any one of claims 1 to 4, characterized in that: The drug YZG-331 tablet is prepared by a powder direct tableting method, comprising the following steps: Weigh YZG-331 or its pharmaceutically acceptable salt, filler, binder, and disintegrant; Mix evenly by adding equal amounts gradually; Add appropriate amount of binder solution for wet granulation, dry and size the particles, then add wetting agent and lubricant, mix well and press into tablets.

6. Coating: Use of the YZG-331 tablet according to any one of claims 1 to 4 in the preparation of a drug for preventing or treating insomnia.

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