Development and Innovative Application of the Sleep-Inducing Traditional Chinese Medicine Ziziphi Spinosae Semen

Ziziphi Spinosae Semen, also known as sour jujube kernel or sour jujube pit, refers to the dried and mature seeds of the shrub plant Ziziphus jujuba belonging to the Rhamnaceae family. The process involves harvesting the ripe fruits of the sour jujube, removing the flesh and shell, retaining the mature seeds, and then naturally drying them to obtain Ziziphi Spinosae Semen. This traditional Chinese medicine has a long history of medicinal use, particularly as a sedative agent. Modern research has revealed that Ziziphi Spinosae Semen possesses various pharmacological effects, including tranquillizing the mind and calming the nerves, anti-inflammatory, antioxidant, antidepressive, immune-enhancing properties, as well as the ability to improve learning and memory capabilities.

Over 130 chemical components have been identified in Ziziphi Spinosae Semen, encompassing Ziziphi Spinosae Semen oil, flavonoids, saponins, alkaloids, vitamins, amino acids, polysaccharides, and trace elements. Among these, the primary utilized substances are Ziziphi Spinosae Semen flavonoids, saponins, polysaccharides, and oil. Notably, Ziziphi Spinosae Semen oil, saponins, and flavonoids are widely recognized for their sedative and hypnotic effects. Specifically, the total saponins in Ziziphi Spinosae Semen exhibit stronger sedative and hypnotic properties than total flavonoids. Additionally, after roasting, the content of spinosin, Ziziphi Spinosae Semen saponin A, and B increases, thereby enhancing the sedative and hypnotic effects. The sedative and hypnotic mechanisms of Ziziphi Spinosae Semen primarily involve the gamma-aminobutyric acid (GABA) and serotonin (5-HT) systems, with polysaccharides not contributing to this effect.

Moreover, Ziziphi Spinosae Semen oil, saponins, and flavonoids also demonstrate the potential to improve learning and memory, making them valuable in the treatment of cognitive disorders such as Alzheimer's disease. Ziziphi Spinosae Semen oil, rich in 17 fatty acids predominantly comprising oleic acid and linoleic acid, exhibits antidepressant, antioxidant, hypolipidemic, and cardioprotective effects. The saponins possess anxiolytic, antidepressant, hypolipidemic, anti-atherosclerotic, and antioxidant properties. The flavonoids, on the other hand, exhibit antidepressant, anti-inflammatory, and antioxidant activities. Lastly, Ziziphi Spinosae Semen polysaccharides demonstrate multiple biological activities, including regulating intestinal flora, antioxidation, antitumor, hepatoprotective, hypoglycemic, and immunomodulatory effects.

As a traditional Chinese medicine that can be used both as medicine and food, Ziziphi Spinosae Semen boasts the primary advantages of mild efficacy and low side effects, with approximately 80% of its demand stemming from medicinal purposes. According to the Yaozhi Data website, a search for "Ziziphi Spinosae Semen" reveals 283 traditional Chinese medicine prescriptions, 160 proprietary Chinese medicine formulas, and 438 health food products containing this ingredient. Furthermore, it is also utilized in some food and cosmetic products.

Clinical Drug Application

Ziziphi Spinosae Semen is primarily used in clinical settings in the form of traditional Chinese medicine (TCM) prescriptions. There are numerous TCM prescriptions in which Ziziphi Spinosae Semen is incorporated as a decoction piece, each with varying effects, commonly including sedation, sleep promotion, and tranquillization. Currently, a significant number of proprietary Chinese medicines containing Ziziphi Spinosae Semen have been launched onto the market, such as Ziziphi Spinosae Semen syrup, Ziziphi Spinosae Semen mixture, Ziziphi Spinosae Semen oil dripping pills, Zaoren Anshen Liquid, Zaoren Anshen Granules, Tianwang Buxindan, Qiangxin Pill, Yangxin Ningshen Pill, and Renshen Guipi Pill. These medicines primarily function to nourish the heart and calm the spirit, improve sleep quality, and exhibit no significant toxic side effects or dependency, thus ensuring high safety in clinical use. For instance, Zaoren Anshen Granules are used to treat insomnia, forgetfulness, dizziness, and headaches caused by deficiency of heart and liver blood and neurasthenia, with its mechanism of improving sleep associated with 5-HT receptors and GABA-benzodiazepine receptors. Zaoren Anshen Capsules have demonstrated remarkable efficacy in treating senile insomnia with minimal side effects. Both Tianwang Buxindan and Compound Ziziphi Spinosae Semen Soft Capsules possess the effects of nourishing yin and blood, nourishing the heart, and calming the spirit, making them important proprietary Chinese medicines for the clinical treatment of neurasthenia. The Compound Ziziphi Spinosae Semen Capsules, formulated with Ziziphi Spinosae Semen, Polygonum multiflorum, black sesame, and black fungus, and the Ziziphi Spinosae Semen Compound Capsules, primarily composed of Ziziphi Spinosae Semen and Radix Polygalae, both have the effects of tranquillization and improving sleep quality. The Compound Ziziphi Spinosae Semen Paste, a prescription formulated by the Xiyuan Hospital of China Academy of Chinese Medical Sciences, serves to nourish yin and blood, tranquilize the mind, nourish the liver and spleen, and promote qi and blood circulation. Additionally, the Compound Gardenia Oil Soft Capsules, formulated with effective ingredients such as gardenia oil, Ziziphi Spinosae Semen oil, and Semen Platycladi oil, exhibit sedative and hypnotic effects, enhance the body's resistance, aid in weight loss and muscle gain, improve learning and memory in mice, and possess antioxidant properties, all while maintaining high clinical safety.

Furthermore, research on new drugs related to Ziziphi Spinosae Semen is gradually increasing, primarily focused on the development of new dosage forms using different active ingredients as raw materials to enhance efficacy and expand administration routes. For instance, a sustained-release, stable, and effective sleep-aid and anti-depressant drug in the form of a Ziziphi Spinosae Semen oil-based thermosensitive gel has been developed. Another example is the Ziziphi Spinosae Semen nasal thermosensitive gel formulation, primarily composed of Ziziphi Spinosae Semen saponins, which offers convenient administration through direct instillation into the nasal cavity. Upon absorption through the nasal mucosa, it enters the central nervous system to exert its therapeutic effects, thereby enhancing efficacy. Due to the good water solubility, poor lipid solubility, and low bioavailability of flavonoid C-glycosides in Ziziphi Spinosae Semen, research on new dosage forms for flavonoid administration primarily targets the development of flavonoid-based dripping pills, solid lipid nanoparticles, and spinosin phospholipid complex self-microemulsion formulations. These aim to improve the water and lipid solubility of the drug, enhancing its membrane permeability and bioavailability in the body while reducing side effects. Different active ingredients in Ziziphi Spinosae Semen can also be combined to increase efficacy and reduce dosage. For example, a combined capsule formulation prepared with Ziziphi Spinosae Semen alkaloids and flavonoids exhibits particularly significant anti-depressant and sedative-hypnotic effects.

Ziziphi Spinosae Semen, rich in various functional and nutritional components, has been widely used in health food products in China. It is often combined with other traditional Chinese medicines and developed into health supplements with functions such as improving sleep, enhancing immunity, assisting in blood pressure reduction, and combating fatigue, with those promoting better sleep being the most prevalent. For example, the Sanshengbao Demei Tablets, formulated with Ziziphi Spinosae Semen in combination with Polygala tenuifolia and Poria cocos, possess health benefits for improving sleep. The Red Date and Ziziphi Spinosae Semen Oral Liquid, prepared primarily from red dates and Ziziphi Spinosae Semen, enhances immunity. Hefei Antai Powder, containing extracts from Gastrodia elata, Apocynum venetum leaves, and Ziziphi Spinosae Semen, assists in blood pressure reduction and improving sleep. Ziziphi Spinosae Semen Oil Dripping Pills, made mainly from Ziziphi Spinosae Semen oil, have been proven safe for long-term consumption with no significant toxic or side effects, making them an excellent health supplement for lipid reduction. Additionally, Ziziphi Spinosae Semen can be utilized in the development of health products that improve learning and memory capabilities, as well as exhibit antioxidant properties.

Currently, there are relatively few health food products developed from the leaves and flesh of Ziziphi Spinosae Semen. However, the Zhenmeng Capsules, a health supplement primarily made from Ziziphi Spinosae Semen leaves, exhibit health benefits for improving sleep. Nevertheless, both the leaves and flesh of Ziziphi Spinosae Semen possess various health-promoting properties, indicating significant untapped potential for their application in health food products.

Moreover, due to its high safety profile, Ziziphi Spinosae Semen is also commonly used in food products, particularly in various beverages. For instance, a health-functional acidic vegetable protein beverage has been developed through mixed fermentation of Lactobacillus bulgaricus and Streptococcus thermophilus, using Ziziphi Spinosae Semen and sour milk as the main ingredients. Functional milk beverages with the auxiliary treatment of insomnia are produced by extracting the active ingredients from Ziziphi Spinosae Semen with purified water, then blending them with milk, followed by homogenization and sterilization. Furthermore, combining the extract of Ziziphi Spinosae Semen with traditional eight-treasure porridge ingredients such as millet, glutinous rice, and coicis semen, an eight-treasure porridge aiding in sleep improvement has been developed.

Ziziphi Spinosae Semen is highly favored by medical practitioners throughout history for its excellent effect in nourishing the heart and calming the mind. The well-known Ziziphi Spinosae Semen Decoction, which uses Ziziphi Spinosae Semen as the primary ingredient, is particularly effective in treating insomnia. Therefore, exploring the mechanism of action of the active ingredients in Ziziphi Spinosae Semen and innovating its applications will undoubtedly lead to a broader range of development and application prospects for Ziziphi Spinosae Semen in pharmaceuticals, foods, and health food products.

References:

[1] Gong Li, Xie Junbo, Lai Changjiangsheng, Zhang Yanqing, Cui Xusheng. Research Progress on the Comprehensive Utilization of Ziziphi Spinosae Semen and Its By-products. Chinese Journal of Experimental Traditional Medical Formulae, 2021, 27(03): 222-230.

[2] Han Peng, Li Ji, Hu Xiaoyang, Fu Qiang, Hu Xinying. Research Progress on the Chemical Constituents, Pharmacological Effects, and Clinical Applications of Ziziphi Spinosae Semen. Journal of Traditional Chinese Medicine, 2021, 49(02): 110-114.

[3] Sun Mingzhe, Zhang Shanshan, Yan Lin, Zheng Xiaojie, Li Xiaoyan. Research and Development Progress of Ziziphi Spinosae Semen Oil. Science and Technology of Cereals, Oils and Foods, 2020, 28(04): 119-125.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.