Introduction to Topic
Liposomal drugs are complex in terms of their composition and the complexity of composition also results in the difficulty in the development of the generic versions. The first successful liposomal drug is Doxilreg;, approved by FDA in 1995, whose original patent was expired in 2009. However, the generic version of Doxilreg; was not introduced until 2013 in a priority review in response to the shortage of Doxilreg; (1). The delayed introduction of generics into the market illustrates the fact that the quality control and assurance as well as the regulation system of liposomal formulations and their generics are not well-established (2). So, in this study, a liposomal drug AmBisomereg; and its generics will be used to develop analytical methodologies to characterize composition, physicochemical properties, toxicity and efficacy in vitro.
Literature Review
Liposomal drugs are within a class of drugs called Non-Biological Complex Drugs (NBCDs). One way to define NBCDs is lsquo;a non-biological complex drug is a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure but consists of different (closely related and often nanoparticulate) structures that canrsquo;t be isolated and fully quantitated, characterized, and/or described by physicochemical analytical meansrsquo; (3). Based on the definition, a conclusion can be safely drawn that liposomal drugs are much more complicated than small molecule drugs. The complexity of NBCDs makes it difficult to assure consistency of products and to develop follow-on versions.
In this project, AmBisomereg; is the model drug. AmBisomereg; is a sterile, non-pyrogenic lyophilized product for intravenous infusion. The active pharmaceutical ingredient is amphotericin B (Amp B). Amp B is a broad-spectrum polyene antifungal agent effective against many fungi species, especially Candida spp. (4, 5), which are of great concern according to the World Health Organization(6, 7). Amp B is listed as one of the essential medicines and is also used in the leishmaniasis treatment (8). It binds to ergosterol, a critical component in fungal cell membrane, and creates transmembrane channels that disrupt membrane integrity, causing cellular components leakage and cell death (4). However, Amp B also has a binding affinity to cholesterol, which is present in mammal cell membranes (9). The side effects include hypokalemia, nephrotoxicity, and hypomagnesemia (10), so that the application of Amp B in clinical setting is limited.
AmBisomereg; is a liposomal formulation of Amp B and was introduced by FDA in 1997 (11), with a pronounced improvement in Amp B safety profile. According to FDArsquo;s orange book, there is no patent protecting AmBisomereg; currently (12), but no follow-on version has been approved by FDA up to date. But there are generics of AmBisomereg; marketed in other countries and regions, such as such as Phosomereg; (Cipla), Amphonexreg; (Bharat Serums and Vaccines Limited), and AmBiLreg; (Taiwan Liposome Co.). One of the facts that resulting in the lack of AmBisomereg; generics is that AmBisomereg; is a liposomal formulation whose evaluation and regulation system has not been well-established. As FDA requires in its regulatory science research report of nanotechnology, for many generic nano-products, equivalence in physicochemical properties must be demonstrated, which in many cases is challenging because of the inherent complexity of the formulation (13, 14).
The overall objective of this project is to develop analytical methodologies that are capable of detecting similarities and differences in performance between innovator and generic liposomal products, typically, between AmBisomereg; and its generics. This could help to guide the development of the follow-on versions of AmBisomereg; in US and potentially help to establish a comprehensive regulation system of liposome generics.
Research Questions and Hypothesis
Research question: Are the generic versions marketed in other countries and regions the same as the innovator drug AmBisomereg;?
Null hypothesis: Generic versions are the same as the innovator AmBisomereg; even though they are produced by different manufactures and companies.
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