NOVEL PROTEASE FORMULATION BASED ON CROSSLINKED CRYSTALS

描述（由申请人提供）：设计稳定和有效的治疗用药物蛋白质配方一直是生物技术和制药公司的主要关注点。在I期资助中，我们开发了一种稳定的、活性的甜瓜曲霉蛋白酶制剂theraclece -蛋白酶，用于治疗慢性胰腺炎的慢性腹痛，并与theraclece -脂肪酶和淀粉酶一起用于治疗囊性纤维化和慢性胰腺炎中胰腺功能不全导致的吸收不良。theraclecl蛋白酶表现出优于市售胰酶产品的产品特性。theraclece蛋白酶对酪蛋白具有非常高的活性，并且在低pH下对肠道中存在的各种蛋白酶具有稳定性。此外，在初步研究中，theraclece蛋白酶没有显示出任何毒性。基于这些II期的结果，我们将准备一个用于治疗慢性胰腺炎腹痛的药物产品原型，并与theraclecl - lipase一起用于治疗囊性纤维化和慢性胰腺炎患者的胰腺功能不全、氮漏和脂肪漏。作为第一步，我们将使用I期开发的方法结晶和交联蛋白酶。随后，我们将根据疾病和治疗类型，将theraclece -蛋白酶与theraclece -脂肪酶和淀粉酶混合，用于最终配方或单独使用。最终的配方将被测试对胰管结扎的狗消化蛋白质和脂肪的功效。使用放射标记的theraclecc蛋白酶，我们将跟踪吸收不足进入体循环。此外，我们将在两个物种中测试喂食theraclecc -蛋白酶的亚急性、亚慢性和长期效应。如果成功，theraclecl蛋白酶原型将为腹痛提供有效的治疗方法。theraclecl - protease将准备进入临床试验，并将与TheraCLECLipase一起为慢性胰腺炎和囊性纤维化的胰腺功能不全提供新的治疗方法。

DESCRIPTION (provided by applicant): Design of stable and efficient formulation of proteins for therapeutic use as drugs has been a major focus of biotechnology and pharmaceutical companies. In the Phase I grant, we developed a stable, active formulation of protease from Aspergillus melleus, TheraCLEC-Protease, for use in the treatment of chronic abdominal pain in chronic pancreatitis and also along with TheraCLEC-Lipase and amylase for the treatment of malabsorption as a result of pancreatic insufficiency in cystic fibrosis and chronic pancreatitis. TheraCLEC-Protease exhibited product characteristics superior to commercially available pancreatic enzyme products. TheraCLEC-Protease exhibited a very high level of activity against casein and stability under low pH and towards various proteases present in the intestine. Moreover, in the preliminary investigations, the TheraCLEC-Protease did not show any toxicity. Based on these results in Phase II, we will prepare a drug product prototype for use in the treatment of abdominal pain in chronic pancreatitis and along with TheraCLEC-Lipase for use in the treatment of pancreatic insufficiency, azotorrhea and steatorrhea in cystic fibrosis and chronic pancreatitis patients. As a first step, we will crystallize and crosslink the protease with methods developed in Phase I Subsequently, we will mix TheraCLEC-Protease with TheraCLEC-Lipase and amylase for use in a final formulation or alone depending on the disease and type of treatment. The final formulation will be tested for efficacy in digesting proteins and fats in dogs with ligated pancreatic ducts. Using radiolabeled TheraCLEC-Protease, we will follow the lack of absorption into the systemic circulation. In addition, we will test the subacute, subchronic and long-term effects of feeding TheraCLEC-Protease in two species. If successful, a TheraCLEC-Protease prototype will provide an efficient treatment for abdominal pain. TheraCLEC-Protease will be ready to enter clinical trials, and will provide a novel treatment for pancreatic insufficiency in chronic pancreatitis and cystic fibrosis along with TheraCLECLipase.