Studies Of S-Nitrosocaptopril Monohydrate In Preparations

S-nitrosapopril monohydrate（Cap-NO·H2O）is a novel and stable compound based on the S-nitrosapopril（Cap-NO）structure.It effectively overcomes the instability and greatly promotes Cap-NO to be a potential new drug.Cap-NO·H2O is not only a nitric oxide（NO）donor but also an angiotensin-converting enzyme inhibitor（ACEI）.Hence,Cap-NO·H2O has great potential for the study and possible treatment of numerous diseases which may bring broad social and economic benefitsChapter one:A more detailed information of Cap-NO was reviewed in terms of chemical synthesis,pharmacology,pharmacodynamics,preparation,pharmacokinetics,and toxicology.Then the research works were presented in order to fill the gaps of Cap-NO·H2O tablets and dry powder inhalers in the treatment of pulmonary arterial hypertension（PAH）and coronavirus disease 2019（COVID-19）respectively.1.Pharmacodynamics and pharmaceutics of Cap-NO·H₂O for PAHChapter two:Active Pharmaceutical Ingredient（API）storage stability is an essential prerequisite for Pharmacology and pharmaceutics studies.Thus,Plackett-Burman method was performed to figure out the significant factors influencing Cap-NO·H2O storage stability.The path of steepest ascent was used to approach the optimal region of the above-mentioned factors,followed by the application of response surface methodology to identify the optimal storage conditions.The result suggests that 2 g Cap-NO·H2O individually packed turned out to be stable for more than 6 months,under the condition at 97%nitrogen filling,1.2 g Deoxygenant,and-10°C.Chapter three:Pharmacodynamic of API was systematically investigated on the monocrotaline（MCT）-induced rat model for the first time.The best efficacy was seen at 50 mg/k/d dose of Cap-NO·H2O after a 14-day treatment.Compared with those in the model group,the mean pulmonary arterial pressure（m PAP）and right ventricular systolic pressure（RVSP）of the treatment group were decreased by 20.71%and22.27%,respectively.Cardiac function indexes were significantly improved.Specifically,the tricuspid annular plane systolic excursion was restored to levels nearly equivalent to those observed in healthy controls.Right heart infusion was improved by 159.46%compared with the control group,meanwhile,the rat survival rate was improved by 66.25%.Histopathology revealed that Cap-NO·H2O could prevent or delay the process of pulmonary vascular fibrosis and cause no significant toxicity to the liver and kidney in PAH rats.In addition,the effect of tablet excipients on pharmacodynamic was required for further examination,and the results showed that excipients have no significant effect on API through variable control experiments.2.Pharmaceutics Study of Cap-NO·H₂O for COVID-19Chapter four:As an NO donor,Cap-NO·H2O can alleviate acute respiratory distress syndrome（ARDS）.Meanwhile,as ACEI,Cap-NO·H2O can compete with severe acute respiratory syndrome coronavirus-2（SARS Co V-2）for ACE2 target.We speculated that Cap-NO·H2O wrapped by Poly（Lactic-Co-Glycolic Acid）（PLGA）for pulmonary administration,which may be effective for COVID-19.Taguchi’s L9orthogonal experimental was design for multi factors and multi responses for nine formulations.The main response was set as the cumulative release rate in 24 h.Through a series of experiments,for a polyvinyl alcohol concentration of 1 w%,a PLGA:Cap-NO·H2O weight ratio of 3:1,an oil:water weight ratio of 20:1 and a stirring speed of 8500 rpm,were found to be optimal for PLGA-Cap NO formulation preparation.Under optimized conditions,PLGA-Cap NO was obtained in particle size of 183.2nm,an encapsulation rate of 67.84%,a potential of-1.77 V and a cumulative release rate of 68.08%.PLGA-Cap-NO-NP dry powder inhaler could be further obtained with an angle of repose of 24.33°,a bulk density of 284.24 mg/ml and an MMAD of 3.88μm by adding leucine（10%）as a support agent.Such size of the PLGA-Cap-NO-NP enables them to reach the deep lung from the bronchus via slow breathing.Chapter five:When pilot-scale production of Cap-NO·H2O dry powder inhaler drying was carried out,the process was found instability and incontinuity.Hence,Cap-NO·H2O dry powder inhaler drying control process was developed by applying the state-space model to a continuous drying tunnel.According to the law of energy conservation,the state-space model is established,and a simplified model can be obtained for further decoupled control of the model.The Cap-NO·H2O-related parameters obtained in the previous sections were taken into the model and the simulated drying process was run in MATLAB software.The results showed that the obtained multi-input and multi-output process control system behaved stably and could realize customized automatic process control of the drying air pressure and temperature.Also taking into account the production economy benefit issue,the partial parameters of this state-space function are replaced and a further closed-loop pole configuration is performed.This model can also be applied to the in-process control of drying sterilization of vials that loaded Cap-NO·H2O powders.