Solubility Profiling of HIV Protease Inhibitors in Human Intestinal Fluids

Wuyts, Benjamin; Brouwers, Joachim; Mols, Raf; Tack, Jan; Annaert, Pieter; Augustijns, Patrick

doi:10.1002/jps.23698

Cited by 27 publications

(15 citation statements)

References 34 publications

(51 reference statements)

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“…S app values for 86 drugs in FaSSIF (3 mM taurocholate, 0.75 mM lecithin in PhB pH6.5 [ 11 ]) were extracted from in-house databases [ 8 , 16 , 17 , 29 ] and literature sources [ 30 – 38 ] (Table I ). To reduce experimental variability in the dataset the main part of the compounds was obtained from our in-house databases in which solubility measurements taking use of shake-flask or the μDISS Profiler are reported.…”

Section: Methodsmentioning

confidence: 99%

Computational Prediction of Drug Solubility in Fasted Simulated and Aspirated Human Intestinal Fluid

et al. 2014

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PurposeTo develop predictive models of apparent solubility (Sapp) of lipophilic drugs in fasted state simulated intestinal fluid (FaSSIF) and aspirated human intestinal fluid (HIF).MethodsMeasured Sapp values in FaSSIF, HIF and phosphate buffer pH 6.5 (PhBpH6.5) for 86 lipophilic drugs were compiled and divided into training (Tr) and test (Te) sets. Projection to latent structure (PLS) models were developed through variable selection of calculated molecular descriptors. Experimentally determined properties were included to investigate their contribution to the predictions.ResultsModest relationships between Sapp in PhBpH6.5 and FaSSIF (R2 = 0.61) or HIF (R2 = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R2 = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R2 = 0.69 and RMSEte of 0.77; HIF, R2 = 0.84 and RMSEte of 0.81). Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R2 = 0.76 and RMSETe of 0.65; HIF, R2 = 0.86 and RMSETe of 0.69), whereas no improvement was seen when melting point (Tm) or logDpH 6.5 were included in the models.ConclusionComputational models were developed, that reliably predicted Sapp of lipophilic compounds in intestinal fluid, from molecular structures alone. If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.

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Section: Methodsmentioning

confidence: 99%

Computational Prediction of Drug Solubility in Fasted Simulated and Aspirated Human Intestinal Fluid

et al. 2014

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“…Some chemical and physical properties of RTV and ATV including molecular weight (MW), pKa, log P, melting onset (T m ) and to melting enthalpy (∆H (kJ/mol)). [25] ND: Not determined RTV ATV Drug MW (g/mol) pKa log P Ionization behavior T m (K) ∆H (kJ/mol) T g (K) The maximum achievable supersaturation level of each drug following dissolution of a combination amorphous formulation under non-sink conditions was studied and rationalized based on our understanding of the LLPS phenomenon. Combining these drugs negatively influenced the maximum achievable supersaturation level for each drug, which in turn was shown to reduce the membrane transport rate across Caco-2 cells.…”

Section: Scheme 2 Schematic Drawing Of Energy and Solubility Relatiomentioning

confidence: 99%

Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations

Alhalaweh

Bergström

Taylor

2016

Journal of Controlled Release

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Herein, the thermodynamic properties of solutions evolving from the non-sink dissolution of amorphous solid dispersions (ASDs) containing two or more drugs have been evaluated, focusing on the maximum achievable supersaturation and tendency of the system to undergo liquid-liquid phase separation (LLPS). Ritonavir (RTV) and atazanavir (ATV) were co-formulated with polyvinylpyrrolidone to produce ASDs with different molar ratios of each drug, and the dissolution profile of each drug was studied under non-sink conditions. The phase behavior of the supersaturated solutions generated by ASD dissolution was compared to that of supersaturated solutions generated by antisolvent addition. Dissolution of an ASD containing RTV, ATV and lopinavir (LPV) was also investigated. A thermodynamic model was used to predict the maximum achievable supersaturation for ASDs containing two and three drugs. In addition, a transport study with Caco-2 cells was conducted to evaluate the impact of co-addition of drugs on membrane transport. It was found that the formulation containing a 1:1 molar ratio of RTV and ATV achieved only 50% of the supersaturation attained by dissolution of the single drug systems. The maximum achievable concentration of ATV decreased linearly as the mole fraction of ATV in the formulation decreased and a similar trend was observed for RTV. For the dispersion containing a 1:1:1 molar ratio of RTV, ATV and LPV, the maximum concentration of each drug was only one third of that achieved for the single drug formulations. The decrease in the achievable supersaturation was well-predicted by the thermodynamic model for both the binary and ternary drug combinations. These observations can be explained by a decrease in the concentration at which the drugs undergo LLPS in the presence of other miscible drugs, thereby reducing the maximum achievable supersaturation of each drug. The reduced free drug concentration was reflected by a decreased flux across Caco-2 cells for the drug combinations compared to drug alone. This study sheds light on the complex dissolution and solution phase behavior of multicomponent amorphous dosage forms, in particular those containing poorly water soluble drugs, which may undergo supersaturation in vivo.

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“…The first challenge of orally administered drugs is absorption through the gut wall. Because many ARVs, particularly protease inhibitors, are poorly water-soluble, incomplete dissolution in the gut lumen decreases transfer across the intestine wall [51]. Consequently, a large fraction of the ingested compound never reaches systemic circulation, which is often the main factor for a low plasma bioavailability [52].…”

Section: Bioavailability and Pharmacokineticsmentioning

confidence: 99%

The Potential of Long-Acting, Tissue-Targeted Synthetic Nanotherapy for Delivery of Antiviral Therapy Against HIV Infection

Andersen

Tolstrup

2020

Viruses

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Oral administration of a combination of two or three antiretroviral drugs (cART) has transformed HIV from a life-threatening disease to a manageable infection. However, as the discontinuation of therapy leads to virus rebound in plasma within weeks, it is evident that, despite daily pill intake, the treatment is unable to clear the infection from the body. Furthermore, as cART drugs exhibit a much lower concentration in key HIV residual tissues, such as the brain and lymph nodes, there is a rationale for the development of drugs with enhanced tissue penetration. In addition, the treatment, with combinations of multiple different antiviral drugs that display different pharmacokinetic profiles, requires a strict dosing regimen to avoid the emergence of drug-resistant viral strains. An intriguing opportunity lies within the development of long-acting, synthetic scaffolds for delivering cART. These scaffolds can be designed with the goal to reduce the frequency of dosing and furthermore, hold the possibility of potential targeting to key HIV residual sites. Moreover, the synthesis of combinations of therapy as one molecule could unify the pharmacokinetic profiles of different antiviral drugs, thereby eliminating the consequences of sub-therapeutic concentrations. This review discusses the recent progress in the development of long-acting and tissue-targeted therapies against HIV for the delivery of direct antivirals, and examines how such developments fit in the context of exploring HIV cure strategies.

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Solubility Profiling of HIV Protease Inhibitors in Human Intestinal Fluids

Cited by 27 publications

References 34 publications

Computational Prediction of Drug Solubility in Fasted Simulated and Aspirated Human Intestinal Fluid

Computational Prediction of Drug Solubility in Fasted Simulated and Aspirated Human Intestinal Fluid

Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations

The Potential of Long-Acting, Tissue-Targeted Synthetic Nanotherapy for Delivery of Antiviral Therapy Against HIV Infection

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