Clinical development drug formulation

Because of its clinical importance and the expected benefits of the drug in liposomal form for cancer treatment, all three American "liposome enterprises" (i.e.. Liposome Technology Inc., Erbamont, LyphoMed/Vestar joint ventures, and the Liposome Company, Inc.) are developing a formulation of liposomal doxorubicin. Clinical studies already show promising results as far as the acute toxicity is concerned (less vomiting, nausea, and hair loss) (Gabizon et al., 1989 Treat et al., 1989),... 

The ex vivo methods lend themselves easily for the performance of mechanistic investigations. In order to optimize selection of drug candidates prior to further clinical development, it is important to decipher the contributive roles of permeation, metabolism, efflux, and toxicity. This will then make it possible to properly channel the optimization process, for instance, by permeation enhancement, mucoadhesion, modification of the physicochemical characteristics of the drug, or even change in the route of administration in case the drug and/or formulation turns out to be too toxic. Regarding permeability studies, it is possible not only to quantify passive diffusion but also to identify and characterize (compound)-specific carrier-mediated transport routes. These tools have been used to identify and characterize the relative contribution of... 

Formidable chemical obstacles stood in the way of clinical development of these agents derived from natural products, notably in formulation of very poorly soluble compounds for intravenous infusion and in manufacture of bulk drug. For a time, production of Taxol from the bark of the Pacific Yew tree aroused public controversy, which became a story of nature and politics in pursuit of an anti-cancer drug [22]. 

Formulation Development. The formulation is finalized based on the experience gained in the manufacture of clinical phase I and II trial materials. Scale-up of the manufacturing process will be completed to qualify the manufacturing capability of the facility. The primary stability study is initiated to assess the stability of the drug product. 

One of the inhibitors designed during the drug discovery process, 9-(3-pyridylmethy)-9-deazaguanine (BCX-34), was selected for initial clinical development. Current clinical trials utilize both topical and oral formulations of the drug. 

Antidepressants as analgesics are almost a closed book as far as preclinical and clinical development is concerned. TCAs are an old drug class, and because of the rather problematic side-effect profile, interest in developing new drugs from this class is small. BL-1834 (Bioglan Lab.) is an intranasal formulation of doxepine that is in clinical development (phase II) for the treatment of severe pain. In patents on novel monoamine reuptake inhibitors, pain is usually claimed as a possible indication, but depression and anxiety are mentioned as the primary indications in most cases, and we are not aware of novel... 

In conclusion, the recent increase in the number of water-insoluble drug candidates will doubtless enhance the importance of oral lipid-based formulations in the coming years. If a candidate has adequate solubility in the vehicles described in this chapter, lipid-based systems will usually provide an attractive approach for efLcient in-house development of clinical and commercial formulations. 

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