Assessing Supersaturation and Its Impact on In Vivo Bioavailability of a Low-Solubility Compound ABT-072 With a Dual pH, Two-Phase Dissolution Method (original) (raw)
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Journal of Pharmaceutical Innovation, 2019
Purpose Delaying precipitation of weakly basic drugs in supersaturated state following their transition from the acidic gastric environment to the near-neutral proximal small intestinal fluid is emerging as a promising tactic for achieving higher transitional solubility and improving bioavailability of such drugs. The aim of this study was to assess the effect of supersaturation on drug dissolution and permeation in vitro, and to evaluate the in vitro-in vivo correlation of the supersaturation effect for the poorly soluble basic drug ketoconazole. Method We monitored dissolution of drugs in simulated gastric fluid followed by drug dissolution in simulated intestinal fluid and simultaneous permeation across Caco-2 cell monolayers using the IDAS2 experimental procedure. The pH shift from pH 1.6 to pH 6.5 (mimicking in vivo gastric to intestinal transition) was used to induce transient in vitro supersaturation of the tested weakly basic poorly soluble drugs. Polymeric precipitation inhibitor, hydroxypropyl methylcellulose acetate succinate (HPMCAS), was added to dissolution medium in order to increase the amplitude and duration of the pH-driven supersaturation of the weakly basic drug ketoconazole in the in vitro IDAS2 setting. The effect of HPMCAS on oral bioavailability of ketoconazole was demonstrated in the rat pharmacokinetic model. Results Drug supersaturation induced by pH shift was assessed in vitro by comparing drug dissolution and permeation under the 2-stage (pH shift from gastric pH 1.6 to intestinal pH 6.5) conditions vs. 1-stage (constant intestinal pH 6.5) conditions. Compared to the 1-stage conditions, 2-stage procedure increased in vitro dissolution AUC (area under the concentration-time curve) of the weakly basic drugs dipyridamole, ketoconazole, and itraconazole by 393%, 161%, and 71%, respectively, accompanied by corresponding 543%, 264%, and 46% increase in in vitro permeation. In contrast, the BCS 2 acidic drug warfarin exhibited 9% decrease in dissolution under 2-stage conditions, which was associated with a 21% decrease in permeation. None of the tested BCS 1 drugs (minoxidil and metoprolol) exhibited supersaturation after the gastric to intestinal pH shift; consistent with the absence of supersaturation, and the permeation of these drugs was not affected by the transition from simulated gastric to simulated intestinal environments. The polymeric precipitation inhibitor, HPMCAS, increased the in vitro dissolution and permeation AUC values of ketoconazole by 187% and 119%, respectively, and ketoconazole plasma AUC 0-24h and C max by 54% and 49% following oral administration in rats. Conclusion This study has shown that the novel in vitro dissolution-absorption methodology simulating the in vivo gastrointestinal environments that influence drug release and absorption of orally administered drugs constitutes a sensitive and physiologically relevant approach for investigating the potential utility of formulation excipients for exploiting supersaturation as a means to improve systemic drug absorption.
The AAPS journal, 2015
Poorly soluble drugs are increasingly formulated into supersaturating drug delivery systems which may precipitate during oral delivery. The link between in vitro drug concentration profiles and oral bioavailability is under intense investigation. The objective of the present work was to develop closed-form analytical solutions that relate in vitro concentration profiles to the amount of drug absorbed using several alternate assumptions and only six parameters. Three parameters define the key features of the in vitro drug concentration-time profile. An additional three parameters focus on physiological parameters. Absorption models were developed based on alternate assumptions; the drug concentration in the intestinal fluid: (1) peaks at the same time and concentration as in vitro, (2) peaks at the same time as in vitro, or (3) reaches the same peak concentration as in vitro. The three assumptions provide very different calculated values of bioavailability. Using Case 2 assumptions, ...
Molecular Pharmaceutics, 2019
The characterization of intestinal dissolution of poorly soluble drugs represents a key task 31 during development of both new drug candidates and drug products. The bicarbonate buffer is 32 considered as the most biorelevant buffer for simulating intestinal conditions. However, due to 33 its complex nature, being the volatility of CO 2 , it has only been rarely used in the past. The aim 34 of this study was to investigate the effect of a biorelevant bicarbonate buffer on intestinal 35 supersaturation and precipitation of poorly soluble drugs using a GI transfer model. Therefore, 36 results of ketoconazole, pazopanib, and lapatinib transfer model experiments using 37 FaSSIF bicarbonate were compared to results obtained using standard FaSSIF phosphate. Additionally, 38 the effect of HPMCAS as precipitation inhibitor was investigated in both buffer systems and 39 compared to rat PK studies with and without co-administration of HPMCAS as precipitation 40 inhibitor. While HPMCAS was found to be an effective precipitation inhibitor for all drugs in 41 FaSSIF phosphate , the effect in FaSSIF bicarbonate was much less pronounced. The PK studies 42 revealed that HPMCAS did not increase the exposure of any of the model compounds 43 significantly, indicating that the transfer model employing bicarbonate-buffered FaSSIF has a 44 better predictive power compared to the model using phosphate-buffered FaSSIF. Hence, the 45 application of a bicarbonate buffer in a transfer model setup represents a promising approach 46 to increase the predictive power of this in vitro tool and to contribute to the development of 47 drug substances and drug products in a more biorelevant way.
Dissolution Media Development for In-vitro Bioequivalence Studies of Abacavir Sulphate
2011
The present investigation is aimed to develop the stability indicating dissolution media for determination of abacavir sulphate in pharmaceutical dosage forms during bioequivalence studies for first time. The stability of abacavir sulphate was tested in various dissolution media, ie. 0.1M HCl, pH 1.2 KCl-HCl buffer and pH 5.8, 6.2, 6.6, 7.0, 7.4 and 7.8 phosphate buffers separately. The stability was tested at room temperature and 37 o C for 48 hrs. The samples were scanned for stability and the optimized samples were selected for further study. Stability studies of the drug in various media at room temperature and 37 o C indicated that it was stable in 0.1M HCl and pH 5.8 buffer in the UV region for a period of 48 hr. The λmax were found to be 297.6 for 0.1M HCl and 286.3 nm for pH 5.8 phosphate buffer with observed low coefficient of variation of <8.71%. Standard graphs were constructed in the above two media and linearity of the graphs were found to be in the range of 0.5-40 µg/ml for 0.1M HCl and 0.2-40 µg/ml for pH 5.8 phosphate buffer. The methods were validated and found to be precise, accurate and robust. These methods can be used for routine assay of abacavir sulphate in various dosage forms. In-vitro dissolution testing indicated that the drug was stable and drug release was found to be uniform for all dosage forms tested. It is concluded that the two optimized media could be used as dissolution media as simulated gastric and intestinal fluids to study the dissolution profiles of abacavir sulphate in bioequivalence studies.
Journal of Pharmaceutical Sciences, 2016
The generation of drug supersaturation close to the absorptive site is an important mechanism of how several formulation technologies enhance oral absorption and bioavailability. Lipid-based formulations belong to the supersaturating drug delivery systems although this is not the only mechanism of how drug absorption is promoted in vivo. Different methods to determine drug supersaturation and precipitation from lipid-based formulations are described in the literature. Experimental in vitro setups vary according to their complexity and proximity to the in vivo conditions and, therefore, some tests are used for early formulation screening, while others better qualify for a later stage of development. The present commentary discusses this rapidly evolving field of in vitro testing with a special focus on the advancements in analytical techniques and new approaches of mechanistic modeling. The importance of considering a drug absorption sink is particularly emphasized. This commentary should help formulators in the pharmaceutical industry as well as in academia to make informed decisions on how to conduct in vitro tests for lipid-based delivery systems and to decide on the implications of experimental results.
Molecular Pharmaceutics, 2022
Understanding the supersaturation and precipitation behavior of poorly water-soluble compounds in vivo and the impact on oral absorption is critical to design consistently performing products with optimized bioavailability. Weakly basic compounds are of particular importance in this context since they have an inherent tendency to undergo supersaturation in vivo upon exit from the stomach and entry into the small intestine because of their pH-dependent solubility. To understand and probe potential in vivo variability of supersaturating systems, rigorous understanding of compound physical properties and phase behavior landscape is essential. Herein, we extensively characterize the solution phase behavior of a model, poorly soluble and weakly basic compound, posaconazole. Phase boundaries for crystal-solution and amorphous-solution were established as a function of pH, allowing possible phase transformations, namely, crystallization or liquid–liquid phase separation, to be mapped for different initial doses and fluid volumes. Endogenous surfactants including sodium taurocholate, lecithin, glycerol monooleate, and sodium oleate in biorelevant media significantly extended the phase boundaries due to solubilization, to an extent that was dependent on the concentration of the surface-active agents. The nucleation induction time of posaconazole was much shorter in biorelevant media in comparison to the corresponding buffer solution, with two distinct regions observed in all media that could be attributed to a change in the nucleation mechanism at high and low supersaturation. The presence of undissolved nanocrystals accelerated the desupersaturation. This work enhances our understanding of biorelevant factors impacting precipitation kinetics, which might affect absorption in vivo. It is expected that findings from this study with posaconazole could be broadly applicable to other weakly basic compounds, after taking into consideration differences in pKa, solubility, and molecular structure.
Molecules
At present, the majority of APIs synthesized today remain challenging tasks for formulation development. Many technologies are being utilized or explored for enhancing solubility, such as chemical modification, novel drug delivery systems (microemulsions, nanoparticles, liposomes, etc.), salt formation, and many more. One promising avenue attaining attention presently is supersaturated drug delivery systems. When exposed to gastrointestinal fluids, drug concentration exceeds equilibrium solubility and a supersaturation state is maintained long enough to be absorbed, enhancing bioavailability. In this review, the latest developments in supersaturated drug delivery systems are addressed in depth.
International Journal of Applied Pharmaceutics
Objective: This study aimed to prepare and evaluate oral disintegrating tablets (ODTs) of Daclatasvir dihydrochloride (DCV) using different co-processed excipients to enhance drug dissolution and improve oral bioavailability for the treatment of hepatitis C infection. Methods: Ten Daclatasvir-ODTs formulae were prepared using co-processed excipients via direct compression. The prepared formulae were evaluated according to taste masking, weight variation, thickness, friability, hardness, drug content, and wetting time. In vitro disintegration time, in vivo disintegration time, and in vitro dissolution tests were also evaluated and taken as parameters for the selection of the best formula. The selected best formula was subjected to an in vivo study on volunteers and compared to a marketed product. Results: All DCV-ODTs had acceptable physical properties in accordance with pharmacopeial standards. DCV-ODTs prepared with Pharmaburst® (F10) recorded the shortest wetting time (14±0.08s), ...