Research

15 pages, 5085 KiB

Open AccessArticle

Integration of In Silico, In Vitro and In Situ Tools for the Preformulation and Characterization of a Novel Cardio-Neuroprotective Compound during the Early Stages of Drug Development

by Claudia Miranda, Alejandro Ruiz-Picazo, Paula Pomares, Isabel Gonzalez-Alvarez, Marival Bermejo, Marta Gonzalez-Alvarez, Alex Avdeef and Miguel-Ángel Cabrera-Pérez

Pharmaceutics 2022, 14(1), 182; https://doi.org/10.3390/pharmaceutics14010182 - 13 Jan 2022

Cited by 1 | Viewed by 1681

Abstract

The main aim of this work is the biopharmaceutical characterization of a new hybrid benzodiazepine-dihydropyridine derivative, JM-20, derived with potent anti-ischemic and neuroprotective effects. In this study, the pKa and the pH-solubility profile were experimentally determined. Additionally, effective intestinal permeability was [...] Read more.

The main aim of this work is the biopharmaceutical characterization of a new hybrid benzodiazepine-dihydropyridine derivative, JM-20, derived with potent anti-ischemic and neuroprotective effects. In this study, the pKa and the pH-solubility profile were experimentally determined. Additionally, effective intestinal permeability was measured using three in vitro epithelial cell lines (MDCK, MDCK-MDR1 and Caco-2) and an in situ closed-loop intestinal perfusion technique. The results indicate that JM-20 is more soluble at acidic pH (9.18 ± 0.16); however, the Dose number (Do) was greater than 1, suggesting that it is a low-solubility compound. The permeability values obtained with in vitro cell lines as well as with the in situ perfusion method show that JM-20 is a highly permeable compound (Caco-2 value 3.8 × 10⁻⁵). The presence of an absorption carrier-mediated transport mechanism was also demonstrated, as well as the efflux effect of P-glycoprotein on the permeability values. Finally, JM-20 was provisionally classified as class 2 according to the biopharmaceutical classification system (BCS) due to its high intestinal permeability and low solubility. The potential good oral absorption of this compound could be limited by its solubility. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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15 pages, 3161 KiB

Open AccessArticle

In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in Rats

by Sandy Van Hemelryck, Rani Wens, Hannelore van Poppel, Milou Luijks, Koosha Shahidi, Marcin Marczak, Ariane Kahnt, René Holm, Erik Mannaert and Peter Langguth

Pharmaceutics 2021, 13(8), 1231; https://doi.org/10.3390/pharmaceutics13081231 - 10 Aug 2021

Cited by 3 | Viewed by 2222

Abstract

This study evaluated in vitro and in vivo drug release of bedaquiline from in situ forming gels (ISGs) containing 200 mg eq./g bedaquiline fumarate salt prepared with four different grades of poly(d,l-lactide) (PDLLA) or poly(d,l-lactide-co-glycolide) [...] Read more.

This study evaluated in vitro and in vivo drug release of bedaquiline from in situ forming gels (ISGs) containing 200 mg eq./g bedaquiline fumarate salt prepared with four different grades of poly(d,l-lactide) (PDLLA) or poly(d,l-lactide-co-glycolide) (PLGA) with a lactide/glycolide ratio of 50/50 or 75/25 and acid (A) or ester (E) end-capping in N-methyl-2-pyrrolidone at a polymer/solvent ratio of 20/80% (w/w). Mean in vitro drug release in 0.05 M phosphate buffer pH 7.4 with 1% (w/v) sodium lauryl sulphate was 37.3, 47.1, 53.3, and 62.3% within 28 days for ISGs containing PLGA5050A, PDLLA, PLGA7525A, and PLGA7525E, respectively. The data suggested that drug release was primarily controlled by precipitated drug redissolving, rather than polymer erosion. In vivo pharmacokinetic profiles after subcutaneous injections in rats were comparable for all ISGs (mean half-lives (t_1/2) ranged from 1411 to 1695 h) and indicated a sustained drug release when compared to a solution of bedaquiline fumarate salt in polyethylene glycol 400/water 50/50% (v/v) (mean t_1/2 of 895 h). In conclusion, PLGA or PDLLA-based ISGs have shown potential for parenteral sustained delivery of bedaquiline, suggesting further preclinical and clinical studies. From a formulation point of view, this case example highlights the importance of the interplay between drug solubility in biological media and dissolution of drug precipitates, which, in addition to the incorporation of diffusion controlling polymers, governs the release of the active drug. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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18 pages, 4329 KiB

Open AccessArticle

Mechanistic PBPK Modelling to Predict the Advantage of the Salt Form of a Drug When Dosed with Acid Reducing Agents

by Siri Kalyan Chirumamilla, Venkatesh Teja Banala, Masoud Jamei and David B. Turner

Pharmaceutics 2021, 13(8), 1169; https://doi.org/10.3390/pharmaceutics13081169 - 29 Jul 2021

Cited by 14 | Viewed by 2939

Abstract

Acid reducing agents (ARAs) reduce the dissolution rate of weakly basic drugs in the stomach potentially leading to lower bioavailability. Formulating the API as a rapidly dissolving salt is one strategy employed to reduce the impact of ARAs on dissolution of such drugs. [...] Read more.

Acid reducing agents (ARAs) reduce the dissolution rate of weakly basic drugs in the stomach potentially leading to lower bioavailability. Formulating the API as a rapidly dissolving salt is one strategy employed to reduce the impact of ARAs on dissolution of such drugs. In the present work, a model drug was selected with an immediate release formulation of the free base dosed in both the absence and presence of the ARA famotidine. In the latter case, bioavailability is restricted and several salt formulations were investigated. To simulate these drug products a mechanistic physiologically based pharmacokinetic (PBPK) model was built using the Simcyp Simulator, which illustrates the advantage of formulating an API as a salt compared to the free base form. The simulations use a mechanistic salt model utilising knowledge of the solubility product which was applied to predict the salt advantage. The developed PBPK model exemplifies that it can be critical to account for the surface pH and solubility when modelling the dissolution of low pKa bases and their salts in the gastric environment. In particular, the mechanistic salt model can be used to aid in screening and salt form selection where the aim is to mitigate effects of ARAs. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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17 pages, 32519 KiB

Open AccessArticle

Bioequivalence of Oral Drug Products in the Healthy and Special Populations: Assessment and Prediction Using a Newly Developed In Vitro System “BE Checker”

by Takato Masada, Toshihide Takagi, Keiko Minami, Makoto Kataoka, Ken-ichi Izutsu, Kazuki Matsui and Shinji Yamashita

Pharmaceutics 2021, 13(8), 1136; https://doi.org/10.3390/pharmaceutics13081136 - 26 Jul 2021

Cited by 6 | Viewed by 2459

Abstract

In order to assess and predict the bioequivalence (BE) of oral drug products, a new in vitro system “BE checker” was developed, which reproduced the environmental changes in the gastrointestinal (GI) tract by changing the pH, composition, and volume of the medium in [...] Read more.

In order to assess and predict the bioequivalence (BE) of oral drug products, a new in vitro system “BE checker” was developed, which reproduced the environmental changes in the gastrointestinal (GI) tract by changing the pH, composition, and volume of the medium in a single chamber. The dissolution and membrane permeation profiles of drugs from marketed products were observed in the BE checker under various conditions reflecting the inter-patient variations of the GI physiology. As variable factors, initial gastric pH, gastric emptying time, and GI agitation strength were varied in vitro. Dipyridamole, a basic drug, showed rapid and supersaturated dissolution when the paddle speed in the donor chamber was 200 rpm, which corresponds to the high agitation strength in the stomach. In contrast, supersaturated dissolution disappeared, and the permeated amount decreased under the conditions with a slow paddle speed (100 and 50 rpm) and short gastric emptying time (10 min). In those conditions, disintegration of the formulation was delayed, and the subsequent dissolution of dipyridamole was not completed before the fluid pH was changed to neutral. Similar results were obtained when the initial gastric pH was increased to 3.0, 5.0, and 6.5. To investigate that those factors also affect the BE of oral drug products, dissolution and permeation of naftopidil from its ordinary and orally disintegrating (OD) tablets were observed in the BE checker. Both products showed the similar dissolution profiles when the paddle speed and gastric emptying time were set to 100 rpm and 10 or 20 min, respectively. However, at a low paddle speed (50 rpm), the dissolution of naftopidil from ordinary tablets was slower than that from the OD tablets, and the permeation profiles became dissimilar. These results indicated the possibility of the bioinequivalence of some oral formulations in special patients whose GI physiologies are different from those in the healthy subjects. The BE checker can be a highly capable in vitro tool to assess the BE of oral drug products in various populations. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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20 pages, 2473 KiB

Open AccessArticle

Application of Artificial Neural Networks to Predict the Intrinsic Solubility of Drug-Like Molecules

by Elena M. Tosca, Roberta Bartolucci and Paolo Magni

Pharmaceutics 2021, 13(7), 1101; https://doi.org/10.3390/pharmaceutics13071101 - 20 Jul 2021

Cited by 13 | Viewed by 2793

Abstract

Machine learning (ML) approaches are receiving increasing attention from pharmaceutical companies and regulatory agencies, given their ability to mine knowledge from available data. In drug discovery, for example, they are employed in quantitative structure–property relationship (QSPR) models to predict biological properties from the [...] Read more.

Machine learning (ML) approaches are receiving increasing attention from pharmaceutical companies and regulatory agencies, given their ability to mine knowledge from available data. In drug discovery, for example, they are employed in quantitative structure–property relationship (QSPR) models to predict biological properties from the chemical structure of a drug molecule. In this paper, following the Second Solubility Challenge (SC-2), a QSPR model based on artificial neural networks (ANNs) was built to predict the intrinsic solubility (logS₀) of the 100-compound low-variance tight set and the 32-compound high-variance loose set provided by SC-2 as test datasets. First, a training dataset of 270 drug-like molecules with logS₀ value experimentally determined was gathered from the literature. Then, a standard three-layer feed-forward neural network was defined by using 10 ChemGPS physico-chemical descriptors as input features. The developed ANN showed adequate predictive performances on both of the SC-2 test datasets. Benefits and limitations of ML approaches have been highlighted and discussed, starting from this case-study. The main findings confirmed that ML approaches are an attractive and promising tool to predict logS₀; however, many aspects, such as data quality, molecular descriptor computation and selection, and assessment of applicability domain, are crucial but often neglected, and should be carefully considered to improve predictions based on ML. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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19 pages, 5980 KiB

Open AccessArticle

One and Two-Step In Vitro-In Vivo Correlations Based on USP IV Dynamic Dissolution Applied to Four Sodium Montelukast Products

by Mercedes Prieto-Escolar, Juan J. Torrado, Covadonga Álvarez, Alejandro Ruiz-Picazo, Marta Simón-Vázquez, Carlos Govantes, Jesús Frias, Alfredo García-Arieta, Isabel Gonzalez-Alvarez and Marival Bermejo

Pharmaceutics 2021, 13(5), 690; https://doi.org/10.3390/pharmaceutics13050690 - 11 May 2021

Cited by 4 | Viewed by 2865

Abstract

Montelukast is a weak acid drug characterized by its low solubility in the range of pH 1.2 to 4.5, which may lead to dissolution-limited absorption. The aim of this paper is to develop an in vivo predictive dissolution method for montelukast and to [...] Read more.

Montelukast is a weak acid drug characterized by its low solubility in the range of pH 1.2 to 4.5, which may lead to dissolution-limited absorption. The aim of this paper is to develop an in vivo predictive dissolution method for montelukast and to check its performance by establishing a level-A in vitro-in vivo correlation (IVIVC). During the development of a generic film-coated tablet formulation, two clinical trials were done with three different experimental formulations to achieve a similar formulation to the reference one. A dissolution test procedure with a flow-through cell (USP IV) was used to predict the in vivo absorption behavior. The method proposed is based on a flow rate of 5 mL/min and changes of pH mediums from 1.2 to 4.5 and then to 6.8 with standard pharmacopoeia buffers. In order to improve the dissolution of montelukast, sodium dodecyl sulfate was added to the 4.5 and 6.8 pH mediums. Dissolution profiles in from the new method were used to develop a level-A IVIVC. One-step level-A IVIVC was developed from dissolution profiles and fractions absorbed obtained by the Loo–Riegelman method. Time scaling with Levy’s plot was necessary to achieve a linear IVIVC. One-step differential equation-based IVIVC was also developed with a time-scaling function. The developed method showed similar results to a previously proposed biopredictive method for montelukast, and the added value showed the ability to discriminate among different release rates in vitro, matching the in vivo clinical bioequivalence results. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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14 pages, 4033 KiB

Open AccessArticle

Effects of Magnesium, Calcium, and Aluminum Chelation on Fluoroquinolone Absorption Rate and Bioavailability: A Computational Study

by Daniel M. Walden, Maksim Khotimchenko, Hypatia Hou, Kaushik Chakravarty and Jyotika Varshney

Pharmaceutics 2021, 13(5), 594; https://doi.org/10.3390/pharmaceutics13050594 - 21 Apr 2021

Cited by 18 | Viewed by 5555

Abstract

Fluoroquinolones (FQs) are a widespread class of broad-spectrum antibiotics prescribed as a first line of defense, and, in some cases, as the only treatment against bacterial infection. However, when administered orally, reduced absorption and bioavailability can occur due to chelation in the gastrointestinal [...] Read more.

Fluoroquinolones (FQs) are a widespread class of broad-spectrum antibiotics prescribed as a first line of defense, and, in some cases, as the only treatment against bacterial infection. However, when administered orally, reduced absorption and bioavailability can occur due to chelation in the gastrointestinal tract (GIT) with multivalent metal cations acquired from diet, coadministered compounds (sucralfate, didanosine), or drug formulation. Predicting the extent to which this interaction reduces in vivo antibiotic absorption and systemic exposure remains desirable yet challenging. In this study, we focus on quinolone interactions with magnesium, calcium and aluminum as found in dietary supplements, antacids (Maalox) orally administered therapies (sucralfate, didanosine). The effect of FQ–metal complexation on absorption rate was investigated through a combined molecular and pharmacokinetic (PK) modeling study. Quantum mechanical calculations elucidated FQ–metal binding energies, which were leveraged to predict the magnitude of reduced bioavailability via a quantitative structure–property relationship (QSPR). This work will help inform clinical FQ formulation design, alert to possible dietary effects, and shed light on drug–drug interactions resulting from coadministration at an earlier stage in the drug development pipeline. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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17 pages, 291 KiB

Open AccessArticle

ICH Guideline for Biopharmaceutics Classification System-Based Biowaiver (M9): Toward Harmonization in Latin American Countries

by Claudia Miranda, Alexis Aceituno, Mirna Fernández, Gustavo Mendes, Yanina Rodríguez, Verónica Llauró and Miguel Ángel Cabrera-Pérez

Pharmaceutics 2021, 13(3), 363; https://doi.org/10.3390/pharmaceutics13030363 - 10 Mar 2021

Cited by 2 | Viewed by 2836

Abstract

The biopharmaceutical classification system (BCS) is a very important tool to replace the traditional in vivo bioequivalence studies with in vitro dissolution assays during multisource product development. This paper compares the most recent harmonized guideline for biowaivers based on the biopharmaceutics classification system [...] Read more.

The biopharmaceutical classification system (BCS) is a very important tool to replace the traditional in vivo bioequivalence studies with in vitro dissolution assays during multisource product development. This paper compares the most recent harmonized guideline for biowaivers based on the biopharmaceutics classification system and the BCS regulatory guidelines in Latin America and analyzes the current BCS regulatory requirements and the perspective of the harmonization in the region to develop safe and effective multisource products. Differences and similarities between the official and publicly available BCS guidelines of several Latin American regulatory authorities and the new ICH harmonization guideline were identified and compared. Only Chile, Brazil, Colombia, and Argentina have a more comprehensive BCS guideline, which includes solubility, permeability, and dissolution requirements. Although their regulatory documents have many similarities with the ICH guidelines, there are still major differences in their interpretation and application. This situation is an obstacle to the successful development of safe and effective multisource products in the Latin American region, not only to improve their access to patients at a reasonable cost, but also to develop BCS biowaiver studies that fulfill the quality standards of regulators in developed and emerging markets. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

22 pages, 3186 KiB

Open AccessArticle

Shared IVIVR for Five Commercial Enabling Formulations Using the BiPHa+ Biphasic Dissolution Assay

by Alexander Denninger, Ulrich Westedt and Karl G. Wagner

Pharmaceutics 2021, 13(2), 285; https://doi.org/10.3390/pharmaceutics13020285 - 22 Feb 2021

Cited by 8 | Viewed by 2553

Abstract

The present study intended to confirm the in vivo relevance of the BiPHa+ biphasic dissolution assay using a single set of assay parameters. Herein, we evaluated five commercial drug products formulated by various enabling formulation principles under fasted conditions using the BiPHa+ assay. [...] Read more.

The present study intended to confirm the in vivo relevance of the BiPHa+ biphasic dissolution assay using a single set of assay parameters. Herein, we evaluated five commercial drug products formulated by various enabling formulation principles under fasted conditions using the BiPHa+ assay. The in vitro partitioning profiles in the organic phase were compared with human pharmacokinetic data obtained from literature. In the first part, a meaningful in vitro dose of the formulations was assessed by determining the maximum drug concentration in the artificial absorption sink during dissolution (organic 1-decanol layer, C_dec,max). Then, the maximum concentration of the partitioned drug in the organic layer was correlated with the in vivo fraction absorbed, which was derived from published human pharmacokinetic data. Fraction absorbed represents the percentage, which is absorbed from the intestine without considering first pass. It was found that the maximum drug concentration in the organic phase obtained from an in vitro dose of ten milligrams, which is equivalent to 15–25 µmol of the respective drug, led to the highest congruency with the fraction absorbed in vivo. In the second part, the in vivo relevance of the BiPHa+ dissolution data was verified by establishing a shared in vitro/in vivo relationship including all formulations. Based on the in vitro kinetics of the BiPHa+ experiments human in vivo plasma profiles were predicted using convolutional modelling approach. Subsequently, the calculated pharmacokinetic profiles were compared with in vivo performance of the studied drug products to assess the predictive power of the BiPHa+ assay. The BiPHa+ assay demonstrated biorelevance for the investigated in vitro partitioning profiles using a single set of assay parameters, which was verified based on human pharmacokinetic data of the five drug products. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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26 pages, 8822 KiB

Open AccessArticle

In Vitro–In Vivo Correlation (IVIVC) Population Modeling for the In Silico Bioequivalence of a Long-Acting Release Formulation of Progesterone

by Elena M. Tosca, Maurizio Rocchetti, Elena Pérez, Conchi Nieto, Paolo Bettica, Jaime Moscoso del Prado, Paolo Magni and Giuseppe De Nicolao

Pharmaceutics 2021, 13(2), 255; https://doi.org/10.3390/pharmaceutics13020255 - 12 Feb 2021

Cited by 7 | Viewed by 2765

Abstract

Health authorities carefully evaluate any change in the batch manufacturing process of a drug before and after regulatory approval. In the absence of an adequate in vitro–in vivo correlation (Level A IVIVC), an in vivo bioequivalence (BE) study is frequently required, increasing the [...] Read more.

Health authorities carefully evaluate any change in the batch manufacturing process of a drug before and after regulatory approval. In the absence of an adequate in vitro–in vivo correlation (Level A IVIVC), an in vivo bioequivalence (BE) study is frequently required, increasing the cost and time of drug development. This study focused on developing a Level A IVIVC for progesterone vaginal rings (PVRs), a dosage form designed for the continuous delivery in vivo. The pharmacokinetics (PK) of four batches of rings charged with 125, 375, 750 and 1500 mg of progesterone and characterized by different in vitro release rates were evaluated in two clinical studies. In vivo serum concentrations and in vitro release profiles were used to develop a population IVIVC progesterone ring (P-ring) model through a direct differential-equation-based method and a nonlinear-mixed-effect approach. The in vivo release,

R_{vivo} (t)

, was predicted from the in vitro profile through a nonlinear relationship.

R_{vivo} (t)

was used as the input of a compartmental PK model describing the in vivo serum concentration dynamics of progesterone. The proposed IVIVC P-ring model was able to correctly predict the in vivo concentration–time profiles of progesterone starting from the in vitro PVR release profiles. Its internal and external predictability was carefully evaluated considering the FDA acceptance criteria for IVIVC assessment of extended-release oral drugs. Obtained results justified the use of the in vitro release testing in lieu of clinical studies for the BE assessment of any new PVRs batches. Finally, the possible use of the developed population IVIVC model as a simulator of virtual BE trials was explored through a case study. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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13 pages, 3155 KiB

Open AccessArticle

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

by Johannes Andreas Blechar, Jozef Al-Gousous, Christoph Wilhelmy, Annika Marielina Postina, Marcus Getto and Peter Langguth

Pharmaceutics 2020, 12(12), 1197; https://doi.org/10.3390/pharmaceutics12121197 - 10 Dec 2020

Cited by 4 | Viewed by 3266

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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23 pages, 4089 KiB

Open AccessArticle

Clinical Pharmacokinetic Evaluation of Optimized Liquisolid Tablets as a Potential Therapy for Male Sexual Dysfunction

by Fayez O. Alotaibi, Nabil A. Alhakamy, Abdelsattar M. Omar and Khalid M. El-Say

Pharmaceutics 2020, 12(12), 1187; https://doi.org/10.3390/pharmaceutics12121187 - 07 Dec 2020

Cited by 3 | Viewed by 2587

Abstract

The study aimed at developing a liquisolid tablet (LST) containing tadalafil (TDL) and dapoxetine (DPX) with improved bioavailability as a potential therapy for male sexual dysfunction. A mixture of nonvolatile solvents, namely PEG 200 and Labrasol®, was utilized to prepare LSTs that were [...] Read more.

The study aimed at developing a liquisolid tablet (LST) containing tadalafil (TDL) and dapoxetine (DPX) with improved bioavailability as a potential therapy for male sexual dysfunction. A mixture of nonvolatile solvents, namely PEG 200 and Labrasol®, was utilized to prepare LSTs that were assessed for their quality characteristics. The Box–Behnken design (BBD) was employed to statistically explore the effect of the formulation factors on the quality attributes of LSTs. Furthermore, an in vivo pharmacokinetic study was carried out for the optimized LST in comparison with the marketed tablets on healthy human volunteers. The optimized LST revealed acceptable quality limits with enhanced dissolution for both APIs. The pharmacokinetic parameters after oral administration of the optimized LST indicated that the Cmax of TDL in LSTs was 122.61 ng/mL within 2h compared to the marketed tablets, which reached 91.72 ng/mL after 3 h, indicating the faster onset of action. The AUC was improved for TDL in LST (4484.953 vs. 2994.611 ng/mL∙h in the marketed tablet) and DPX in LST (919.633 vs. 794.699 ng/mL∙h in the marketed tablet). This enhancement in bioavailability potentially minimizes the associated side effects and improves the treatment of male sexual dysfunction, particularly for diabetic patients. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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20 pages, 4527 KiB

Open AccessArticle

Dynamic Colon Model (DCM): A Cine-MRI Informed Biorelevant In Vitro Model of the Human Proximal Large Intestine Characterized by Positron Imaging Techniques

by Konstantinos Stamatopoulos, Sharad Karandikar, Mark Goldstein, Connor O’Farrell, Luca Marciani, Sarah Sulaiman, Caroline L. Hoad, Mark J. H. Simmons and Hannah K. Batchelor

Pharmaceutics 2020, 12(7), 659; https://doi.org/10.3390/pharmaceutics12070659 - 13 Jul 2020

Cited by 13 | Viewed by 3787

Abstract

This work used in vivo MRI images of human colon wall motion to inform a biorelevant Dynamic Colon Model (DCM) to understand the interplay of wall motion, volume, viscosity, fluid, and particle motion within the colon lumen. Hydrodynamics and particle motion within the [...] Read more.

This work used in vivo MRI images of human colon wall motion to inform a biorelevant Dynamic Colon Model (DCM) to understand the interplay of wall motion, volume, viscosity, fluid, and particle motion within the colon lumen. Hydrodynamics and particle motion within the DCM were characterized using Positron Emission Tomography (PET) and Positron Emission Particle Tracking (PEPT), respectively. In vitro PET images showed that fluid of higher viscosity follows the wall motion with poor mixing, whereas good mixing was observed for a low viscosity fluid. PEPT data showed particle displacements comparable to the in vivo data. Increasing fluid viscosity favors the net forward propulsion of the tracked particles. The use of a floating particle demonstrated shorter residence times and greater velocities on the liquid surface, suggesting a surface wave that was moving faster than the bulk liquid. The DCM can provide an understanding of flow motion and behavior of particles with different buoyancy, which in turn may improve the design of drug formulations, whereby fragments of the dosage form and/or drug particles are suspended in the proximal colon. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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21 pages, 2959 KiB

Open AccessArticle

Candesartan Cilexetil In Vitro–In Vivo Correlation: Predictive Dissolution as a Development Tool

by Andrés Figueroa-Campos, Bárbara Sánchez-Dengra, Virginia Merino, Arik Dahan, Isabel González-Álvarez, Alfredo García-Arieta, Marta González-Álvarez and Marival Bermejo

Pharmaceutics 2020, 12(7), 633; https://doi.org/10.3390/pharmaceutics12070633 - 06 Jul 2020

Cited by 17 | Viewed by 3684

Abstract

The main objective of this investigation was to develop an in vitro–in vivo correlation (IVIVC) for immediate release candesartan cilexetil formulations by designing an in vitro dissolution test to be used as development tool. The IVIVC could be used to reduce failures in [...] Read more.

The main objective of this investigation was to develop an in vitro–in vivo correlation (IVIVC) for immediate release candesartan cilexetil formulations by designing an in vitro dissolution test to be used as development tool. The IVIVC could be used to reduce failures in future bioequivalence studies. Data from two bioequivalence studies were scaled and combined to obtain the dataset for the IVIVC. Two-step and one-step approaches were used to develop the IVIVC. Experimental solubility and permeability data confirmed candesartan cilexetil. Biopharmaceutic Classification System (BCS) class II candesartan average plasma profiles were deconvoluted by the Loo-Riegelman method to obtain the oral fractions absorbed. Fractions dissolved were obtained in several conditions in USP II and IV apparatus and the results were compared calculating the f₂ similarity factor. Levy plot was constructed to estimate the time scaling factor and to make both processes, dissolution and absorption, superimposable. The in vitro dissolution experiment that reflected more accurately the in vivo behavior of the products of candesartan cilexetil employed the USP IV apparatus and a three-step pH buffer change, from 1.2 to 4.5 and 6.8, with 0.2% of Tween 20. This new model was able to predict the in vivo differences in dissolution and it could be used as a risk-analysis tool for formulation selection in future bioequivalence trials. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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21 pages, 3305 KiB

Open AccessArticle

In Vivo Predictive Dissolution (IPD) for Carbamazepine Formulations: Additional Evidence Regarding a Biopredictive Dissolution Medium

by Marival Bermejo, Jessica Meulman, Marcelo Gomes Davanço, Patricia de Oliveira Carvalho, Isabel Gonzalez-Alvarez and Daniel Rossi Campos

Pharmaceutics 2020, 12(6), 558; https://doi.org/10.3390/pharmaceutics12060558 - 17 Jun 2020

Cited by 7 | Viewed by 3392

Abstract

The aim of the present study was to bring additional evidence regarding a biopredictive dissolution medium containing 1% sodium lauryl sulphate (SLS) to predict the in vivo behavior of carbamazepine (CBZ) products. Twelve healthy volunteers took one immediate release (IR) dose of either [...] Read more.

The aim of the present study was to bring additional evidence regarding a biopredictive dissolution medium containing 1% sodium lauryl sulphate (SLS) to predict the in vivo behavior of carbamazepine (CBZ) products. Twelve healthy volunteers took one immediate release (IR) dose of either test and reference formulations in a bioequivalence study (BE). Dissolution profiles were carried-out using the medium. Level A in vitro–in vivo correlations (IVIVC) were established using both one-step and two-step approaches as well as exploring the time-scaling approach to account for the differences in dissolution rate in vitro versus in vivo. A detailed step by step calculation was provided to clearly illustrate all the procedures. The results show additional evidence that the medium containing 1% SLS can be classified as a universal biopredictive dissolution tool, and that both of the approaches used to develop the IVIVC (one and two-steps) provide good in vivo predictability. Therefore, this biopredictive medium could be a highly relevant tool in Latin-American countries to ensure and check the quality of their CBZ marketed products for which BE studies were not requested by their regulatory health authorities. Full article

(This article belongs to the Special Issue In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications)

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In Vivo Predictive Dissolution (iPD): Experimental and Mathematical Approaches and Regulatory Applications

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