The Development Of Ambroxol Hydrochloride Solution For Inhalation

Objective:Ambroxol hydrochloride is a mucolytic agent commonly used in clinic,and it is reported that its efficiency can be greatly improved by aerosol inhalation therapy.However,due to the shortage of OIDPs in China,ambroxol hydrochloride injection is often used as by oral inhalation,and the risk of adverse reactions is increased When used off-label.Therefore,the objective of this study is to develop a generic product of ambroxol hydrochloride solution for inhalation using Mucosolvan^?（2 m L:15 mg）from Boehringer Ingelheim as the reference product according the guideline for study on pharmaceuticals and human bioequivalence for inhalation drug product.Methods:Firstly,the analytical procedures for the assay,related substances,and the aerodynamic particle size distribution as well as delivery dose of ambroxol hydrochlo-ride solution for inhalation was established.And then the physicochemical properties and stability both for API and the reference product were studied and compared.The formulation for the reference product and the key parameters for the nebulizer were reversely engineered.Both the formulation and manufacture process for the generic product were designed and optimized by single factor method,and one batch of product at full commercial scale has been produced.The in vitro bioequivalence was studied by collecting the data of UDC and APSD of 10 vials/batch both for the test and the reference product.The results were statistically analyzed and judged according to the guideline from EMA,in which the maximum allowable in vitro difference of±15%is required for in vitro bioequivalence.The solution for inhalation and the reference product was on parallel placed on long term,middle and accelerated conditions for stability study.Results:A formulation consisting of ambroxol hydrochloride 15.00 mg,citric acid2.00 mg,Na₂HPO₄3.00 mg,Na Cl 14.70 mg and H₂O 2 m L has been finalized.The manufac-ture process for the solution has been developed and some critical steps were identified and the space of parameters for the in-process control were defined.The solution should be protected by nitrogen during the whole process,the temperature of water for injection was set at 80℃,the optimal pH should between 3.5 to 5.5.The solution was then filtered through a 0.22μm filter membrane of PES and filled into a brown ampoule at a volume of 2m L,and then sterilized at 121℃for 15 min.It is recommend that the solution is delivered by using the nebulizer made by German Berry.Data of UDC and APSD from the generic product were all within the range of±15%compared with those from the reference product.Furthermore,the results of stability study for 6 months at all three conditions indicated a similar trends and small change for both two products,fulfilling the criteria of non-inferiority test in comparison with the reference product.Conclusion:Based on the results obtained,it is showed that the formulation qualitative-ly and Quantitatively similar with that of the reference product,the process parameters have a good consistency and reproducibility,the quality of product is well controlled,fulfilling the requirement of comer-cial production.A conclusion of in vitro bioequi-valence can be drawn since both the data of UDC and APSD were comparable with each other for the test and reference product.