Date of Award
Master of Science in Pharmaceutical Sciences
Biomedical and Pharmaceutical Sciences
Samantha A. Meenach
The human immunodeficiency virus (HIV) impacts up to 37 million people globally. Although not fatal on its own, HIV can develop into acquired immunodeficiency disease (AIDS), in which a person’s immune system becomes compromised. To date, there is no cure for HIV, although many treatment options are available. Despite their effectiveness, these treatments are commonly plagued by their inherent complexity. Factors such as doing regimen, pill burden, and undesirable side effects all contribute to variability in patient compliance, particularly in pediatric populations. Currently, there is no anti-HIV drug product readily available for pediatrics, despite close to 1.8 million children living with HIV. This is partially due to a diverse patient population (ranging from birth till adolescence age) with specific needs for various dosage forms and dosing unit size. In addition, taste preferences and toxicity of excipients and may differ in children compared to adults.
In the present study, we aimed to develop a pediatric-friendly formulation for anti-HIV therapeutics. Two protease inhibitors, lopinavir (LPV) and ritonavir (RTV) (commercially available as Kaletra®), were chosen as model drugs. Kaletra® is a fixed-dose combination (FDC) of LPV and RTV (4/1, w/w) in either a tablet or an oral solution form. However, neither of these dosage forms is suitable for children. The tablet is large, and therefore can be difficult to swallow for young children, especially for children under four years who generally cannot swallow tablets. In addition, the excipients used in the tablet formulation have been shown to induce adverse events in a pediatric population. On the other hand, the oral solution contains upwards of 40% ethanol and is not suitable for children. Both of these drugs exhibit very bitter taste profiles, which children are very sensitive to. In addition, both LPV and RTV, are inherently poorly water-soluble and suffer from low bioavailability. In order to develop a pediatric-friendly formulation for FDC of LPV and RTV, it is critical to improve dissolution and palatability of the therapeutics using safe excipient(s).
Cyclodextrins (CD) are cyclic oligosaccharides that can form water-soluble complexes with hydrophobic drugs, and potentially enhance solubility and mask taste of the therapeutics. In this study, two CD derivatives, 2-hydroxoypropyl-β-CD (HP-β-CD) and 2-HP-γ-CD were investigated. Phase solubility, isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR) and molecular modelling studies were conducted to determine interactions between them and the two anti-HIV drugs, LPV and RTV. The results showed that complexes can be formed between drug and CD and the optimal complexion ratio of drug/CD is 1:1. The results from each study showed that RTV is capable of forming more stable complexes than LPV, with both types of CD. Stability constant values calculated via phase solubility studies indicated that β-CD formed more stable complexes with the drugs than γ-CD. However, a different trend was obtained from the NMR and molecular modelling studies, which showed that γ-CD formed more stable complexes. This suggested that non-inclusion complex formation was favored, which NMR and modelling are less sensitive to detecting, over traditional inclusion complex formation. These studies also showed that the specific interactions that occurred between LPV and CD, and RTV and CD, such as hydrogen bonding and hydrophobic interactions, were different, as each drug has a fundamentally unique molecular structure.
Following this interaction analysis, formulation optimization of drug:CD complexes was conducted. The prepared drug:CD complexes were spray dried to obtain a final dry powder formulation. Solid state characterization of the spray-dried complexes was performed to determine physicochemical characteristics such as thermal profile, crystallinity, and morphology. Results showed that the spray-dried complexes did not exhibit a melting temperature, and were comprised of drug in an amorphous state, based on differential scanning calorimetry (DSC), X-ray diffraction (XRD) and polarized light microscopy (PLM) data. In addition, scanning electron microscopy (SEM) images showed that the spray-dried complexes exhibited a corrugated, raisin-like morphology. In vitro dissolution studies showed that RTV in an amorphous state exhibits a faster release profile than crystalline RTV. Spray-dried HP-β-CD/RTV complexes showed the most favorable dissolution profile, as 100% RTV was released in 45 minutes. Unexpectedly, converting LPV from crystalline to amorphous via spray-drying resulted in lower dissolution rate and extent. In addition, spray-dried CD/LPV complexes did not exhibit favorable dissolution characteristics, compared to the physical mixture of LPV, polymer, and CD.
Overall, interactions between both drugs and both CDs were characterized, and CD/drug complexes were successfully prepared. Further studies will be conducted to assess taste masking effect and in vivo bioavailability of the prepared drug/CD complexes. In addition, other strategies such as freeze drying and kneading will be investigated in the future to further optimize a suitable formulation with improved dissolution characteristics for LPV.
Ivone, Ryan, "DEVELOPMENT OF PEDIATRIC ANTI-HIV FORMULATIONS WITH IMPROVED DISSOLUTION CHARACTERISTICS" (2019). Open Access Master's Theses. Paper 1465.