NOVEL PROTEASE FORMULATION BASED ON CROSSLINKED CRYSTALS

描述（由申请人提供）：设计稳定有效的蛋白质制剂用于药物治疗一直是生物技术和制药公司的主要关注点。 在I期研究中，我们开发了一种稳定的活性蛋白酶制剂，即TheraCLEC-蛋白酶，用于治疗慢性胰腺炎中的慢性腹痛，并沿着TheraCLEC-脂肪酶和淀粉酶，用于治疗囊性纤维化和慢性胰腺炎中胰腺功能不全引起的吸收不良。 TheraCLEC-蛋白酶表现出优于市售胰酶产品的产品特性上级。TheraCLEC-蛋白酶对酪蛋白表现出非常高的活性水平，并且在低pH下对肠道中存在的各种蛋白酶表现出稳定性。此外，在初步研究中，TheraCLEC-蛋白酶未显示任何毒性。基于II期研究的这些结果，我们将制备一种用于治疗慢性胰腺炎腹痛的药物产品原型，并与TheraCLEC-脂肪酶一起沿着用于治疗囊性纤维化和慢性胰腺炎患者的胰腺功能不全、阿佐托品和脂肪酸。作为第一步，我们将用第一阶段开发的方法结晶和交联蛋白酶。随后，我们将TheraCLEC-蛋白酶与TheraCLEC-脂肪酶和淀粉酶混合，用于最终制剂或单独使用，这取决于疾病和治疗类型。将检测最终制剂在胰管结扎犬中消化蛋白质和脂肪的有效性。使用放射性标记的TheraCLEC-蛋白酶，我们将跟踪缺乏吸收进入体循环。此外，我们还将在两个物种中测试喂食TheraCLEC-蛋白酶的亚急性、亚慢性和长期影响。如果成功，TheraCLEC蛋白酶原型将为腹痛提供有效的治疗。TheraCLEC-Protease将准备进入临床试验，并将与TheraCLECLipase一起沿着为慢性胰腺炎和囊性纤维化中的胰腺功能不全提供一种新型治疗方法。

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.