Within the past few decades, the number of patients on organ transplant waiting lists has increased dramatically while the number of available organs has remained constant (1). This shortage has led to a reduction in the acceptable criteria for organ transplants ("marginal" donor) and a higher risk for organ rejection. Coupled with the rise in incidence of autoimmune diseases, safer and more effective immunosuppressant medication is needed. Immunosuppressants are used to modulate and in some cases inhibit the cascade of reactions leading to an immune response. Classification of immunosuppressants is based on their mechanism of action, and each class has its own set of formulation challenges. Researchers have used several strategies to improve formulation design of these drugs to overcome some of these formulation challenges. Nanoparticle engineering [Nanocrystals®, solution based dispersion by supercritical fluids (SEDS), and emulsification techniques] is one example of formulation design that can overcome formulation challenges such as poor aqueous solubility. Choice of excipients and different routes of administration of the drug can also improve bioavailability of immunosuppressants hindered by p-glycoprotein (PGP)
efflux and cytochrome P450 (CYP 3A) metabolism. Changing the route of administration of these drugs can improve targeting and absorption of the drugs (e.g. inhalation administration for lung transplantation), leading to improved therapeutic outcomes. Novel approaches to formulation design of immunosuppressant drugs have lead to enhanced therapeutic outcomes of these drugs for various disease states. While immunosuppressants are primarily used to treat solid organ (liver, kidney, heart, and lung) and tissue (bone marrow) transplant rejection, other disorders such as multiple sclerosis, psoriasis, ulcerative colitis, and asthma are all being aggressively treated with immunosuppressant drugs. Advanced design of drug delivery systems for delivering immunosuppressants shows promise in treating these disease states along with other autoimmune diseases. Immunosuppressant drugs are classified into one of four categories based on their mechanism of action in the body and the type of immunosuppressive effect that is observed in vivo. The categories of immunosuppressants are: glucocorticoids, immunophilin binders, cytostatics, and other immunosuppressant drugs (including monoclonal antibodies, interferons, and other proteins) (2). For the purposes of this review, novel formulations of "small" molecule drugs, including glucocorti-coids, immunophilin binders, and cytostatics, will be discussed.
Over a period of time, doses of the drug can be reduced in transplant patients as the chance of transplant rejection decreases, but most transplant patients must maintain administration of immunosuppressants for life. Therapeutic drug monitoring of blood drug concentrations typically accompanies long-term immunosuppressant therapy due to intrapatient variability of drug absorption. Normalizing the bioavailability of these medications and acquiring more stable blood levels has been the goal of formulation scientists. Frequently, patients are administered combinations of different types of immunosuppressants in order to modulate all components of the immune response cascade.
Using novel drug delivery systems, immunosuppressant drugs can show increased efficacy in vivo. Various strategies have been used to develop drug delivery systems of immunosuppressants with enhanced therapeutic outcomes. Reducing primary particle size of the drug has shown increased absorption with various different types of immunosuppressants. Nanocrystal wet-milling technology has shown promise in delivery of the poorly water soluble crystalline drugs (3), including immunosuppres-sants (4). Various types of immunosuppressant-loaded microparticles and nanoparticles have been produced, showing promising therapeutic results in vivo. Solid lipid nanoparticles (5, 6), biodegradable encapsulating nano-particles (7), and diffusion controlled release nanoparticles (8) have shown enhanced modes of delivery for various routes of administration. Overall, this chapter summarizes advanced formulation designs of immunosuppres-sants resulting in enhanced therapeutic outcomes of these drugs with improved targeting and delivery.
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