卵泡刺激素缓释制剂的制备及药效学研究

发布时间：2018-05-03 02:25

本文选题：卵泡刺激素 + 透明质酸　；参考：《华侨大学》2017年硕士论文

【摘要】：对于辅助生殖技术(Assisted reproductive technology,ART),如体外受精(In vitro fertilization,IVF)和胞浆内精子注射(Intracytoplasmic sperminjection,ICSI),卵泡刺激激素(Folliclestimulating Hormone,FSH)的注射是实现超数排卵的必要步骤。目前临床上常用的FSH制剂,存在半衰期短、需多次注射、患者依从性差等局限性,因此,FSH缓释制剂的研究意义重大。缓释制剂因其使用便利,疗效佳,患者依从性好,安全性高而被人们广泛接受,其中基于生物降解和生物溶蚀系统的FSH缓释制剂是新型FSH制剂的主要研究方向。目前国内外新型FSH制剂的研究主要集中在基于重组基因技术生产长效FSH的制剂,忽略了基于高分子化学等理论进行FSH缓释制剂的研制。其实,FSH缓释制剂的研究前景也十分广阔,其理论和应用研究在不孕不育的临床治疗和畜牧业的发展方面意义深远!透明质酸(Hyaluronan,HA)的衍生物透明质酸钠已成为临床上常用的药物缓释载体。本实验首先以透明质酸钠为辅料,将FSH荷载于透明质酸凝胶,得到FSH缓释制剂。并且基于卵巢增重法进行了FSH缓释凝胶的体内生物活性检测,并对透明质酸钠的使用浓度进行初步筛选;随后研究了FSH缓释凝胶对卵巢增重大鼠的卵巢和子宫发育的影响;然后基于超数排卵用昆明小鼠进行了药效学研究。最后,为探究未成熟卵巢增重小鼠的卵巢发育机制及超数排卵对于小鼠卵巢发育、卵泡成熟的影响,本实验还研究了卵巢发育过程中相关生长因子(表皮生长因子和胰岛素样生长因子I)和促性腺激素(卵泡刺激素和促黄体生成素)的受体的表达变化,以探究FSH缓释凝胶对于卵巢和卵泡发育成熟的作用机制。上述研究表明,以透明质酸为基质制备得到的FSH缓释凝胶,体内生物活性高,单次注射即可达到市售FSH三次注射的卵巢增重效果。且其超数排卵效果显著优于市售超排药物的作用和自然排卵。实验证明HA浓度为5mg/mL,FSH剂量为5IU的FSH缓释凝胶对于昆明小鼠的超数排卵效果为最佳。相关机制的研究,为阐明FSH的作用机理,及其药理作用和医药研究奠定了基础。综上所述,本研究为制备成本低,药效好,低副作用的FSH缓释制剂提供了新的思路。
[Abstract]:The injection of assisted reproductive technology, such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), Follicl estimation of Hormoneated FSHs, is a necessary step for the realization of superovulation. At present, the commonly used FSH preparations have some limitations, such as short half-life, multiple injections, poor compliance of patients and so on, so the study of FSH sustained-release preparations is of great significance. Sustained-release preparations are widely accepted for their convenience, efficacy, compliance and safety. Among them, FSH sustained-release preparation based on biodegradation and biodissolution system is the main research direction of new FSH preparations. At present, the research of new FSH preparations at home and abroad is mainly focused on the production of long-acting FSH based on recombinant gene technology, ignoring the development of FSH sustained-release preparations based on the theory of macromolecule chemistry. In fact, the research prospect of FSH sustained-release preparation is also very broad, its theory and application research in the clinical treatment of infertility and the development of animal husbandry far-reaching significance! Sodium hyaluronate, a derivative of Hyaluronan HA, has become a commonly used drug delivery carrier. In this experiment, sodium hyaluronate was used as excipient and FSH was loaded on hyaluronic acid gel to obtain FSH sustained-release preparation. The biological activity of FSH sustained-release gel was determined based on the method of ovarian weight gain, and the concentration of sodium hyaluronate was preliminarily screened, and the effects of FSH sustained-release gel on ovary and uterus development of ovarian weight increasing rats were studied. Then the pharmacodynamics of Kunming mice was studied based on superovulation. Finally, in order to explore the mechanism of ovarian development and the effect of superovulation on ovarian development and follicular maturation in immature ovarian weight gain mice, In this study, we also studied the changes of receptor expression of related growth factors (epidermal growth factor and insulin-like growth factor I) and gonadotropin (follicle stimulating hormone and luteinizing hormone) during ovarian development. To explore the mechanism of FSH sustained-release gel on ovarian and follicular development and maturation. The results showed that the FSH sustained-release gel prepared from hyaluronic acid had high bioactivity in vivo and could gain ovarian weight with three injections of FSH on the market. The effect of superovulation was better than that of superovulation drugs and natural ovulation. The results showed that FSH sustained-release gel with a concentration of 5 mg / mL FSH of 5IU had the best effect on the superovulation of Kunming mice. The study of the related mechanism laid a foundation for elucidating the action mechanism, pharmacological action and pharmaceutical research of FSH. In conclusion, this study provides a new idea for the preparation of FSH sustained-release preparations with low cost, good efficacy and low side effects.
【学位授予单位】：华侨大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943;R965

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