scholarly journals A Mechanistic Physiologically-Based Biopharmaceutics Modeling (PBBM) Approach to Assess the In Vivo Performance of an Orally Administered Drug Product: From IVIVC to IVIVP

Pharmaceutics ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 74 ◽  
Author(s):  
Marival Bermejo ◽  
Bart Hens ◽  
Joseph Dickens ◽  
Deanna Mudie ◽  
Paulo Paixão ◽  
...  
Keyword(s):  
Oral Absorption ◽  
Drug Product ◽  
Continuous Optimization ◽  
In Vitro Dissolution ◽  
Oral Drug ◽  
Dissolution Testing ◽  
Bicarbonate Buffer ◽  
Physiologically Based

The application of in silico modeling to predict the in vivo outcome of an oral drug product is gaining a lot of interest. Fully relying on these models as a surrogate tool requires continuous optimization and validation. To do so, intraluminal and systemic data are desirable to judge the predicted outcomes. The aim of this study was to predict the systemic concentrations of ibuprofen after oral administration of an 800 mg immediate-release (IR) tablet to healthy subjects in fasted-state conditions. A mechanistic oral absorption model coupled with a two-compartmental pharmacokinetic (PK) model was built in Phoenix WinNonlinWinNonlin® software and in the GastroPlus™ simulator. It should be noted that all simulations were performed in an ideal framework as we were in possession of a plethora of in vivo data (e.g., motility, pH, luminal and systemic concentrations) in order to evaluate and optimize these models. All this work refers to the fact that important, yet crucial, gastrointestinal (GI) variables should be integrated into biopredictive dissolution testing (low buffer capacity media, considering phosphate versus bicarbonate buffer, hydrodynamics) to account for a valuable input for physiologically-based pharmacokinetic (PBPK) platform programs. While simulations can be performed and mechanistic insights can be gained from such simulations from current software, we need to move from correlations to predictions (IVIVC → IVIVP) and, moreover, we need to further determine the dynamics of the GI variables controlling the dosage form transit, disintegration, dissolution, absorption and metabolism along the human GI tract. Establishing the link between biopredictive in vitro dissolution testing and mechanistic oral absorption modeling (i.e., physiologically-based biopharmaceutics modeling (PBBM)) creates an opportunity to potentially request biowaivers in the near future for orally administered drug products, regardless of its classification according to the Biopharmaceutics Classification System (BCS).

A physiologically based biopharmaceutical analysis of zolpidem

2021 ◽  
Author(s):  
◽  
Rafael Leal Monteiro Paraiso
Keyword(s):  
Drug Development ◽  
Drug Absorption ◽  
Oral Absorption ◽  
Food Effect ◽  
Simulation Software ◽  
Oral Drug ◽  
Oral Drug Absorption ◽  
Physiologically Based

Computational oral absorption models, in particular PBBM models, provide a powerful tool for researchers and pharmaceutical scientists in drug discovery and formulation development, as they mimic and can describe the physiologically processes relevant to the oral absorption. PBBM models provide in vivo context to in vitro data experiments and allow for a dynamic understanding of in vivo drug disposition that is not typically provided by data from standard in vitro assays. Investigations using these models permit informed decision-making, especially regarding to formulation strategies in drug development. PBBM models, but can also be used to investigate and provide insight into mechanisms responsible for complex phenomena such as food effect in drug absorption. Although there are obviously still some gaps regarding the in silico construction of the gastrointestinal environment, ongoing research in the area of oral drug absorption (e.g. the UNGAP, AGE-POP and InPharma projects) will increase knowledge and enable improvement of these models. PBBM can nowadays provide an alternative approach to the development of in vitro–in vivo correlations. The case studies presented in this thesis demonstrate how PBBM can address a mechanistic understanding of the negative food effect and be used to set clinically relevant dissolution specification for zolpidem immediate release tablets. In both cases, we demonstrated the importance of integrating drug properties with physiological variables to mechanistically understand and observe the impact of these parameters on oral drug absorption. Various complex physiological processes are initiated upon food consumption, which can enhance or reduce a drug’s dissolution, solubility, and permeability and thus lead to changes in drug absorption. With improvements in modeling and simulation software and design of in vitro studies, PBBM modeling of food effects may eventually serve as a surrogate for clinical food effect studies for new doses and formulations or drugs. Furthermore, the application of these models may be even more critical in case of compounds where execution of clinical studies in healthy volunteers would be difficult (e.g., oncology drugs). In the fourth chapter we have demonstrated the establishment of the link between biopredictive in vitro dissolution testing (QC or biorelevant method) PBBM coupled with PD modeling opens the opportunity to set truly clinically relevant specifications for drug release. This approach can be extended to other drugs regardless of its classification according to the BCS. With the increased adoption of PBBM, we expect that best practices in development and verification of these models will be established that can eventually inform a regulatory guidance. Therefore, the application of Physiologically Based Biopharmaceutical Modelling is an area with great potential to streamline late-stage drug development and impact on regulatory approval procedures. Freie Schlagwörter / Tags

scholarly journals Deciphering nifedipine in vivo delivery from modified release dosage forms: Identification of food effect

2015 ◽  
Vol 65 (4) ◽  
pp. 427-441 ◽  
Author(s):  
Marija Ilić ◽  
Ivan Kovačević ◽  
Jelena Parojčić
Keyword(s):  
In Silico ◽  
Food Effect ◽  
Drug Product ◽  
Dosage Forms ◽  
In Vitro Dissolution ◽  
Dissolution Testing ◽  
Modified Release ◽  
In Vivo Delivery

Abstract With the increased reliance on in vitro dissolution testing as an indicator of in vivo drug behavior and the trend towards the in silico modeling of dosage form performance, the need for bioperformance dissolution methodology development has been enhanced. Determination of the in vivo drug delivery profile is essential for the bioperformance dissolution test development and in vitro/in vivo correlation modeling, as well as the understanding of absorption mechanisms. The aim of this study was to compare different methods in terms of their usefulness and applicability in deciphering in vivo delivery of nifedipine administered in modified release dosage forms. A detailed survey of publications on nifedipine pharmacokinetics was done and used to identify the magnitude of food effect. In vitro dissolution testing was performed under various experimental conditions. Obtained results indicate the potential for using the developed in silico model coupled with discriminative in vitro dissolution data for identification of the in vivo drug product behavior

scholarly journals A STELLA simulation model for in vitro dissolution testing of respirable size particles

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Basanth Babu Eedara ◽  
Ian G. Tucker ◽  
Shyamal C. Das
Keyword(s):  
Simulation Model ◽  
In Vitro Dissolution ◽  
Membrane Thickness ◽  
Dissolution Testing ◽  
Custom Made ◽  
Quality Control Tool ◽  
Modeling Software ◽  
Fast Dissolution

AbstractIn vitro dissolution testing is a useful quality control tool to discriminate the formulations and to approximate the in vivo drug release profiles. A dissolution apparatus has been custom-made for dissolution testing of dry powder formulations in a small volume of stationary medium (25 μL spread over 4.91 cm2 area i.e. ~50 μm thick). To understand the system and predict the key parameters which influence the dissolution of respirable size particles, a simulation model was constructed using STELLA modeling software. Using this model, the permeation (dissolution followed by diffusion through the membrane) of two anti-tubercular drugs of differing solubilities, moxifloxacin (17.68 ± 0.85 mg mL−1) and ethionamide (0.46 ± 0.02 mg mL−1), from the respirable size particles and their diffusion from a solution were simulated. The simulated permeation profiles of moxifloxacin from solution and respirable size particles were similar, indicating fast dissolution of the particles. However, the simulated permeation profile of ethionamide from respirable size particles showed slower permeation compared to the solution indicating the slow dissolution of the respirable size particles of ethionamide. The sensitivity analysis suggested that increased mucus volume and membrane thickness decreased the permeation of drug. While this model was useful in predicting and distinguishing the dissolution behaviours of respirable size moxifloxacin and ethionamide, further improvement could be made using appropriate initial parameter values obtained by experiments.

INVESTIGATION OF SOLUBILITY ENHANCEMENT OF PRASUGREL HYDROCHLORIDE: NANOSUSPENSIONS AND CYCLODEXTRIN INCLUSION COMPLEXES

INDIAN DRUGS ◽  
2014 ◽  
Vol 51 (02) ◽  
pp. 29-38
Author(s):  
R. K Devara ◽  
◽  
P. Reddipogu ◽  
S Kumar ◽  
B. Rambabu ◽  
...  
Keyword(s):  
Dissolution Rate ◽  
Inclusion Complexes ◽  
Oral Bioavailability ◽  
Oral Absorption ◽  
In Vitro Dissolution ◽  
Precipitation Method ◽  
Formulation Development ◽  
Pure Drug

The objective of this study was to investigate nanosuspensions, hydroxypropyl-β-cyclodextrin (HPβCD) complexes and SLS powders for enhancing the solubility and dissolution rate of Prasugrel HCl (PHCl) so as to reduce the fluctuations in its oral bioavailability. PHCl nanosuspensions were prepared using evaporative precipitation method. HPβCD inclusion complexes of PHCl were prepared using physical mixture, co-evaporation and kneading methods. Powders of the pure drug with different SLS amounts were prepared. The formulations were characterized using techniques such as powder x-ray diffractometry, scanning electron microscopy, in vitro dissolution and in vivo absorption in rats. To further aid in the betterment of development of nevirapine nanosuspension, in vitro in vivo correlation (IVIVC) was established using deconvolution technique. Nanosuspensions and HPβCD inclusion complexes of PHCl were successfully prepared. The dissolution rate and oral absorption of PHCl in the form of nanosuspensions was significantly higher than that of HPβCD complexes, SLS powders as well as pure drug. All the techniques investigated in this study can be used to enhance dissolution rate and oral absorption of prasugrel HCl and thus can reduce the fluctuations in its oral bioavailability. Nanosuspensions demonstrated to be better and superior technique when compared to other techniques investigated in enhancing oral bioavailability of PHCl. IVIVC that could aid in further formulation development of PHCl nanosuspension was successfully developed using a deconvolution approach.

Enhancement of in vitro dissolution and in vivo performance/oral absorption of FEB-poloxamer-TPGS solid dispersion

2018 ◽  
Vol 46 ◽  
pp. 408-415 ◽  
Author(s):  
Xiaoxia Sheng ◽  
Jingjing Tang ◽  
Jiayin Bao ◽  
Xiangjun Shi ◽  
Weike Su
Keyword(s):  
Solid Dispersion ◽  
Oral Absorption ◽  
In Vitro Dissolution

scholarly journals Formulation, In Vitro and In Vivo Evaluation of Gefitinib Solid Dispersions Prepared Using Different Techniques

Processes ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 1210
Author(s):  
Sultan Alshehri ◽  
Abdullah Alanazi ◽  
Ehab M. Elzayat ◽  
Mohammad A. Altamimi ◽  
Syed S. Imam ◽  
...  
Keyword(s):  
Oral Absorption ◽  
Solid Dispersions ◽  
Water Soluble ◽  
In Vitro Dissolution ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
In Vivo Evaluation ◽  
Significant Release

Gefitinib (Gef) is a poorly water-soluble antitumor drug, which shows poor absorption/bioavailability after oral administration. Therefore, this study was carried out to develop Gef solid dispersions (SDs) using different carriers and different techniques in order to enhance its dissolution and oral absorption/bioavailability. Various SD formulations of Gef were established using fusion and microwave methods utilizing Soluplus, Kollidone VA64, and polyethylene glycol 4000 (PEG 4000) as the carriers. Developed SDs of Gef were characterized physicochemically and evaluated for in vitro dissolution and in vivo pharmacokinetic studies. The physicochemical evaluation revealed the formation of Gef SDs using fusion and microwave methods. In vitro dissolution studies indicated significant release of Gef from all SDs compared to the pure Gef. Optimized SD of Gef (S2-MW) presented significant release of Gef (82.10%) compared with pure Gef (21.23%). The optimized Gef SD (S2) was subjected to in vivo pharmacokinetic evaluation in comparison with pure Gef in rats. The results indicated significant enhancement in various pharmacokinetic parameters of Gef from an optimized SD S2 compared to the pure Gef. In addition, Gef-SD S2 resulted in remarkable improvement in bioavailability compared to the pure Gef. Overall, this study suggested that the prepared Gef-SD by microwave method showed marked enhancement in dissolution and bioavailability.

scholarly journals Toward Mechanistic Design of Surrogate Buffers for Dissolution Testing of pH-Dependent Drug Delivery Systems

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1197
Author(s):  
Johannes Andreas Blechar ◽  
Jozef Al-Gousous ◽  
Christoph Wilhelmy ◽  
Annika Marielina Postina ◽  
Marcus Getto ◽  
...  
Keyword(s):  
Ionic Strength ◽  
Polymeric Materials ◽  
Rapid Screening ◽  
In Vitro Dissolution ◽  
Routine Practice ◽  
Transport Modelling ◽  
Bicarbonate Buffer ◽  
Enteric Polymer

The in vivo dissolution of enteric-coated (EC) products is often overestimated by compendial in vitro dissolution experiments. It is of great interest to mimic the in vivo conditions as closely as possible in vitro in order to predict the in vivo behavior of EC dosage forms. The reason behind this is the overly high buffering capacity of the common compendial buffers compared to the intestinal bicarbonate buffer. However, a bicarbonate-based buffer is technically difficult to handle due to the need for continuous sparging of the media with CO2 to maintain the desired buffer pH. Therefore, bicarbonate buffers are not commonly used in routine practice and a non-volatile alternative is of interest. A mathematical mass transport modelling approach was previously found to enable accurate calculation of surrogate buffer molarities for small molecule compounds; however, the additional complexity of polymeric materials makes this difficult to achieve for an enteric coat. In this work, an approach was developed allowing relatively rapid screening of potential surrogate buffers for enteric coating. It was found that the effective buffering pKa of bicarbonate at the surface of a dissolving enteric polymer tended to be around 5.5, becoming higher when the dissolving enteric polymer formed a gel of greater firmness/viscosity and vice versa. Using succinate (pKa 5.2 under physiological ionic strength) and/or citrate (pKa 5.7 under physiological ionic strength) at conjugate base molarities corresponding to bicarbonate molarities in the intestinal segments of interest as an initial “guess” can minimize the number of experimental iterations necessary to design an appropriate surrogate.

scholarly journals Formulation of Lipid-Based Tableted Spray-Congealed Microparticles for Sustained Release of Vildagliptin: In Vitro and In Vivo Studies

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2158
Author(s):  
Khaled H. Al Zahabi ◽  
Hind Ben tkhayat ◽  
Ehab Abu-Basha ◽  
Al Sayed Sallam ◽  
Husam M. Younes
Keyword(s):  
Sustained Release ◽  
Oral Drug Delivery ◽  
Immediate Release ◽  
In Vitro Dissolution ◽  
Oral Drug ◽  
Once Daily ◽  
Significant Difference ◽  
In Vivo Pharmacokinetics

Spray-congealing (SPC) technology was utilized to prepare lipid-based microparticles (MP) capable of sustaining the release of Vildagliptin (VG) for use as a once-daily treatment for type 2 diabetes mellitus. VG microparticles were prepared using Compritol® and Gelucire®50/13 as lipid carriers in the presence of various amounts of Carbomer 934 NF. The lipid carriers were heated to 10 °C above their melting points, and VG was dispersed in the lipid melt and sprayed through the heated two-fluid nozzle of the spray congealer to prepare the VG-loaded MP (VGMP). The microparticles produced were then compressed into tablets and characterized for their morphological and physicochemical characteristics, content analysis, in vitro dissolution, and in vivo bioavailability studies in mixed-breed dogs. The VGMP were spherical with a yield of 76% of the total amount. VG was found to be in its semicrystalline form, with a drug content of 11.11% per tablet and a percentage drug recovery reaching 98.8%. The in vitro dissolution studies showed that VG was released from the tableted particles in a sustained-release fashion for up to 24 h compared with the immediate-release marketed tablets from which VG was completely released within 30 min. The in vivo pharmacokinetics studies reported a Cmax, Tmax, T1/2, and MRT of 118 ng/mL, 3.4 h, 5.27 h, and 9.8 h, respectively, for the SPC formulations, showing a significant difference (p < 0.05)) from the pk parameters of the immediate-release marketed drug (147 ng/mL, 1 h, 2.16 h, and 2.8 h, respectively). The area under the peak (AUC) of both the reference and tested formulations was comparable to indicate similar bioavailabilities. The in vitro–in vivo correlation (IVIVC) studies using multiple level C correlations showed a linear correlation between in vivo pharmacokinetics and dissolution parameters. In conclusion, SPC was successfully utilized to prepare a once-daily sustained-release VG oral drug delivery system.

scholarly journals In Vivo Predictive Dissolution Testing of Montelukast Sodium Formulations Administered with Drinks and Soft Foods to Infants

2020 ◽  
Vol 21 (7) ◽  
Author(s):  
J. Martir ◽  
T. Flanagan ◽  
J. Mann ◽  
N. Fotaki
Keyword(s):  
Drug Product ◽  
Drug Dissolution ◽  
Simulated Gastric Fluid ◽  
Dissolution Testing ◽  
Fed State ◽  
Fasted State ◽  
Direct Administration ◽  
The Impact

Abstract In vitro dissolution testing conditions that reflect and predict in vivo drug product performance are advantageous, especially for the development of paediatric medicines, as clinical testing in this population is hindered by ethical and technical considerations. The aim of this study was to develop an in vivo predictive dissolution test in order to investigate the impact of medicine co-administration with soft food and drinks on the dissolution performance of a poorly soluble compound. Relevant in vitro dissolution conditions simulating the in vivo gastrointestinal environment of infants were used to establish in vitro-in vivo relationships with corresponding in vivo data. Dissolution studies of montelukast formulations were conducted with mini-paddle apparatus on a two-stage approach: infant fasted-state simulated gastric fluid (Pi-FaSSGF; for 1 h) followed by either infant fasted-state or infant fed-state simulated intestinal fluid (FaSSIF-V2 or Pi-FeSSIF, respectively; for 3 h). The dosing scenarios tested reflected in vivo paediatric administration practices: (i.) direct administration of formulation; (ii.) formulation co-administered with vehicles (formula, milk or applesauce). Drug dissolution was significantly affected by co-administration of the formulation with vehicles compared with after direct administration of the formulation. Montelukast dissolution from the granules was significantly higher under fed-state simulated intestinal conditions in comparison with the fasted state and was predictive of the in vivo performance when the granules are co-administered with milk. This study supports the potential utility of the in vitro biorelevant dissolution approach proposed to predict in vivo formulation performance after co-administration with vehicles, in the paediatric population.

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