Cyclodextrin supramolecular systems for oral antiretroviral drug delivery

The global pandemic of Human Immunodeficiency Virus (HIV) is responsible for the death of more than 39 million people. Currently, about 37 million people are infected with an estimated rate of 2.1 million new cases and 1.2 million HIV related deaths per annum. Over the past three decades, Antiretroviral Therapy (ART) has significantly improved HIV prognosis and health related quality of life. However, HIV still remains a significant public health and socio-economic concern due to the inability to cure or completely eradicate both long-lived latently infected cells and replication competent provirus from anatomical and lymphatic reservoirs. This has necessitated lifelong pharmacotherapy in order to keep the viral loads below detection and prevent progression of the infection to full blown Acquired Immune Deficiency Syndrome (AIDS). Presently, antiretroviral (ARVs) drugs used in the management of HIV are administered orally due to the volume and ambulatory nature of the lifelong therapeutic interventions. However, poor oral bioavailability, inadequate biodistribution and adverse side effects of many ARVs continue to preclude optimal therapeutic outcomes. In recent years, there has been an increased interest in the development of ARV delivery systems specifically tailored to improve HIV's therapeutic outcomes. Within this context, cyclodextrins (CyD) based drug delivery systems offer several possibilities for constructing an ARV drug delivery system with enhanced bioavailability, biodistribution and therapeutic performance. The traditional role of cyclodextrins (CyDs) in the pharmaceutical industry has been to enhance the aqueous solubility, physicochemical and physiological stability, the deliverability and therapeutic performance, and reduce the adverse side effects of several active pharmaceutical ingredients (APIs). Also, CyDs have been reported to modulate cytochrome P450 (CYP450) metabolism and p-glycoprotein (P-gp) efflux transport for enhanced drug pharmacokinetic profiles. Thus, this study was designed to explore the utility of CyD supramolecular systems in the development of an oral ARV delivery system with enhanced pharmacokinetic properties. Lopinavir (LPV), a potent inhibitor of HIV-1 protease and a Class 4 Biopharmaceutical Classification System (BSC) drug with poor oral bioavailability was chosen as our model drug. LPV's poor bioavailability is a combined effect of low aqueous solubility, P-gp efflux transport/low gastric permeability and CYP450 3A metabolism. Presently, LPV is clinically available as a co-formulation with suboptimal doses of ritonavir (RTV) which enhances oral bioavailability by inhibiting LPV's metabolism. The adverse side effects associated with RTV has made necessary the development of a RTV free LPV formulation. Also, paediatric formulations of LPV (even with RTV) is fraught with problems such as the presence of high quantities of ethanol and propylene glycol in the commercially available oral solution. Therefore, an in silico method was developed an validated experimentally (using ibuprofen as model drug) to study the host-guest molecular interaction between LPV and CyD, and to predict the best CyD molecule for developing a CyD based LPV delivery system. The predicted derivative of (2-hydroxyl)propyl-gamma-cyclodextrin (HP-γ-CyD) with a high degree of substitution (DS) that is, HP17-γ-CyD, was synthesized and evaluated comparatively with parent γ-CyD and commercially available HP-γ-CyD. The applicability of supercritical assisted spray drying (SASD), a non-toxic and cheap method for enhancing CyD complex formation was also evaluated. Then, polymer CyD (pCyD) sub-microcarriers were synthesized, loaded with LPV and evaluated for its ability to modulate drug release and enhance antiviral activity. The results suggests the application of in silico methodologies is a feasible approach for the rational and/or deductive development of CyD based drug delivery systems. The predicted HP17-γ-CyD facilitated a higher LPV amorphization and solubilization relative to the parent γ-CyD and commercially available HP-γ-CyD. Also, the application of SASD technique for preparing LPV-CyD complexes enhanced drug solubilization and complexation. With regards to the sub-microcarrier, results indicate the successful synthesis of a water soluble p(CyD) based on (2-hydroxyl)propyl-beta-cyclodextrin (HP-β-CyD) and methyl-beta-cyclodextrin (M-β-CyD) as monomers, and pyromellitic dianhydride as crosslinker. The physicochemical analysis of the LPV loaded pCyD revealed the successful preparation of sub-micron sized particles with good encapsulation efficiencies, a pCyD mediated amorphization of LPV and a significant increase in LPV solubilization and release. In vitro cytotoxicity of the pCyD and their LPV formulations revealed good safety profiles in Caco-2 and Sup-T1 cell lines. Results obtained from the in vitro antiviral assays revealed a dose independent HIV-1 inhibition by the synthesized pCyD and a CyD monomer dependent synergistic antiviral activity in their formulations. Overall, the study contributed to a better understanding of in silico methodologies as predictive tools for CyD selection in drug development. It was possible to completely avoid the tedious and time/resource consuming traditional approach of selecting CyD by calculating association constants from phase solubility studies or isothermal titration calorimetry. The application of SASD for drug-CyD complexation seems an interesting alternative to conventional spray drying and other methods of CyD solid complex formation. Also, considering the potential for drug dose reduction without a compromise on antiretroviral activity, the synthesized pCyDs represent a promising approach for formulating new alternatives to clinically available antiretroviral drugs. In conclusion, all the results obtained in this experimental work showed the interest of CyDs as promising vehicles for the development of ARV drug delivery systems with enhanced pharmacokinetic profiles