Research

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15 pages, 3062 KiB

Open AccessArticle

In Vitro–In Vivo Correlations Based on In Vitro Dissolution of Parent Drug Diltiazem and Pharmacokinetics of Its Metabolite

by Constantin Mircioiu, Valentina Anuta, Ion Mircioiu, Adrian Nicolescu and Nikoletta Fotaki

Pharmaceutics 2019, 11(7), 344; https://doi.org/10.3390/pharmaceutics11070344 - 16 Jul 2019

Cited by 14 | Viewed by 4654

Abstract

In this study a novel type of in vitro–in vivo correlation (IVIVC) is proposed: The correlation of the in vitro parent drug dissolution data with the in vivo pharmacokinetic data of drug’s metabolite after the oral administration of the parent drug. The pharmacokinetic [...] Read more.

In this study a novel type of in vitro–in vivo correlation (IVIVC) is proposed: The correlation of the in vitro parent drug dissolution data with the in vivo pharmacokinetic data of drug’s metabolite after the oral administration of the parent drug. The pharmacokinetic data for the parent drug diltiazem (DTZ) and its desacetyl diltiazem metabolite (DTZM) were obtained from an in vivo study performed in 19 healthy volunteers. The pharmacokinetics of the parent drug and its metabolite followed a pseudomono-compartmental model and deconvolution of the DTZ or DTZM plasma concentration profiles was performed with a Wagner–Nelson-type equation. The calculated in vivo absorption fractions were correlated with the in vitro DTZ dissolution data obtained with USP 2 apparatus. A linear IVIVC was obtained for both DTZ and DTZM, with a better correlation observed for the case of the metabolite. This type of correlation of the in vitro data of the parent compound with the in vivo data of the metabolite could be useful for the development of drugs with active metabolites and prodrugs. Full article

(This article belongs to the Special Issue Gastrointestinal Variables and Drug Absorption: Experimental, Computational and In Vitro Predictive Approaches)

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12 pages, 1506 KiB

Open AccessArticle

In Silico Prediction of Plasma Concentrations of Fluconazole Capsules with Different Dissolution Profiles and Bioequivalence Study Using Population Simulation

by Marcelo Dutra Duque, Daniela Amaral Silva, Michele Georges Issa, Valentina Porta, Raimar Löbenberg and Humberto Gomes Ferraz

Pharmaceutics 2019, 11(5), 215; https://doi.org/10.3390/pharmaceutics11050215 - 05 May 2019

Cited by 15 | Viewed by 5532

Abstract

A biowaiver is accepted by the Brazilian Health Surveillance Agency (ANVISA) for immediate-release solid oral products containing Biopharmaceutics Classification System (BCS) class I drugs showing rapid drug dissolution. This study aimed to simulate plasma concentrations of fluconazole capsules with different dissolution profiles and [...] Read more.

A biowaiver is accepted by the Brazilian Health Surveillance Agency (ANVISA) for immediate-release solid oral products containing Biopharmaceutics Classification System (BCS) class I drugs showing rapid drug dissolution. This study aimed to simulate plasma concentrations of fluconazole capsules with different dissolution profiles and run population simulation to evaluate their bioequivalence. The dissolution profiles of two batches of the reference product Zoltec^® 150 mg capsules, A1 and A2, and two batches of other products (B1 and B2; C1 and C2), as well as plasma concentration–time data of the reference product from the literature, were used for the simulations. Although products C1 and C2 had drug dissolutions < 85% in 30 min at 0.1 M HCl, simulation results demonstrated that these products would show the same in vivo performance as products A1, A2, B1, and B2. Population simulation results of the ln-transformed 90% confidence interval for the ratio of C_max and AUC_0–t values for all products were within the 80–125% interval, showing to be bioequivalent. Thus, even though the in vitro dissolution behavior of products C1 and C2 was not equivalent to a rapid dissolution profile, the computer simulations proved to be an important tool to show the possibility of bioequivalence for these products. Full article

(This article belongs to the Special Issue Gastrointestinal Variables and Drug Absorption: Experimental, Computational and In Vitro Predictive Approaches)

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15 pages, 2956 KiB

Open AccessArticle

An In Vitro Study of the Influence of Curcuma longa Extracts on the Microbiota Modulation Process, In Patients with Hypertension

by Emanuel Vamanu, Florentina Gatea, Ionela Sârbu and Diana Pelinescu

Pharmaceutics 2019, 11(4), 191; https://doi.org/10.3390/pharmaceutics11040191 - 18 Apr 2019

Cited by 30 | Viewed by 4088

Abstract

The multiple causes of cardiovascular diseases signify a major incidence and developmental risk of this pathology. One of the processes accountable for this pathologic development is the instauration of dysbiosis and its connection with an inflammatory process. Low antioxidant colonic protection encourages the [...] Read more.

The multiple causes of cardiovascular diseases signify a major incidence and developmental risk of this pathology. One of the processes accountable for this pathologic development is the instauration of dysbiosis and its connection with an inflammatory process. Low antioxidant colonic protection encourages the progression of inflammation, with cardiovascular dysfunctions being a secondary consequence of the dysbiosis. Curcumin is one of the bioactive compounds displaying promising results for the reduction of an inflammatory process. The present study aims at demonstrating the capacity of three extracts drawn from Curcuma (C.) longa through an in vitro simulation process, for microbiota modulation in patients with hypertension. The acidic pH in the extraction process determined a high curcumin content in the extracts. The major phenolic compound identified was curcumin III, 622 ± 6.88 µg/mL for the ethanol/water/acetic acid extract. Low EC50 values were associated (0.2 µg/mL for DPPH scavenging activity) with the presence of curcumin isomers. A metabolic pattern became evident because the relationship between the short-chain fatty acids acted as a clinical biomarker. The curcumin present stimulated the formation of butyric and propionic acids. Microbiota activity control included a high degree of curcumin degradation and biotransformation in the other phenolic compounds. This developmental process was supported by the progression in the enterobacteria with a corresponding escalation in the pH level. The metabolomic pattern demonstrated a performance similar to the administration of dietary fibre, with the positive effects being dose-dependent. Full article

(This article belongs to the Special Issue Gastrointestinal Variables and Drug Absorption: Experimental, Computational and In Vitro Predictive Approaches)

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22 pages, 4700 KiB

Open AccessArticle

Gellan Gum/Laponite Beads for the Modified Release of Drugs: Experimental and Modeling Study of Gastrointestinal Release

by Alessandra Adrover, Patrizia Paolicelli, Stefania Petralito, Laura Di Muzio, Jordan Trilli, Stefania Cesa, Ingunn Tho and Maria Antonietta Casadei

Pharmaceutics 2019, 11(4), 187; https://doi.org/10.3390/pharmaceutics11040187 - 17 Apr 2019

Cited by 28 | Viewed by 3725

Abstract

In this study, gellan gum (GG), a natural polysaccharide, was used to fabricate spherical porous beads suitable as sustained drug delivery systems for oral administration. GG was cross-linked with calcium ions to prepare polymeric beads. Rheological studies and preliminary experiments of beads preparation [...] Read more.

In this study, gellan gum (GG), a natural polysaccharide, was used to fabricate spherical porous beads suitable as sustained drug delivery systems for oral administration. GG was cross-linked with calcium ions to prepare polymeric beads. Rheological studies and preliminary experiments of beads preparation allowed to identify the GG and the CaCl₂ concentrations suitable for obtaining stable and spherical particles. GG beads were formed, through ionotropic gelation technique, with and without the presence of the synthetic clay laponite. The resultant beads were analyzed for dimensions (before and after freeze-drying), morphological aspects and ability to swell in different media miming biological fluids, namely SGF (Simulated Gastric Fluid, HCl 0.1 M) and SIF (Simulated Intestinal Fluid, phosphate buffer, 0.044 M, pH 7.4). The swelling degree was lower in SGF than in SIF and further reduced in the presence of laponite. The GG and GG-layered silicate composite beads were loaded with two model drugs having different molecular weight, namely theophylline and cyanocobalamin (vitamin B12) and subjected to in-vitro release studies in SGF and SIF. The presence of laponite in the bead formulation increased the drug entrapment efficiency and slowed-down the release kinetics of both drugs in the gastric environment. A moving-boundary swelling model with “diffuse” glassy-rubbery interface was proposed in order to describe the swelling behavior of porous freeze-dried beads. Consistently with the swelling model adopted, two moving-boundary drug release models were developed to interpret release data from highly porous beads of different drugs: drug molecules, e.g., theophylline, that exhibit a typical Fickian behavior of release curves and drugs, such as vitamin B12, whose release curves are affected by the physical/chemical interaction of the drug with the polymer/clay complex. Theoretical results support the experimental observations, thus confirming that laponite may be an effective additive for fabricating sustained drug delivery systems. Full article

(This article belongs to the Special Issue Gastrointestinal Variables and Drug Absorption: Experimental, Computational and In Vitro Predictive Approaches)

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14 pages, 2255 KiB

Open AccessArticle

Development of a New Ex Vivo Lipolysis-Absorption Model for Nanoemulsions

by Lu Xiao, Ying Liu and Tao Yi

Pharmaceutics 2019, 11(4), 164; https://doi.org/10.3390/pharmaceutics11040164 - 04 Apr 2019

Cited by 4 | Viewed by 2813

Abstract

The use of lipid-based formulations (LBFs) in improving the absorption of poorly water-soluble drugs has now well established. Because the in vivo evaluation of LBFs is labor-intensive, in vitro or ex vivo approaches could provide advantages. In this study, a new ex vivo [...] Read more.

The use of lipid-based formulations (LBFs) in improving the absorption of poorly water-soluble drugs has now well established. Because the in vivo evaluation of LBFs is labor-intensive, in vitro or ex vivo approaches could provide advantages. In this study, a new ex vivo lipolysis-absorption model (evLAM) composed of an intestinal digestion system and an intestinal tissue system was developed to evaluate and predict the in vivo absorption performances of LBFs. Model factors, including the pH of the system and concentrations of d-glucose and pancreatic lipase, were investigated and optimized by a Box-Behnken design. To evaluate this new model, a lipid formulation of indomethacin, which was chosen based on preliminary studies of pseudo-ternary phase diagrams, emulsion droplets, and solubility, was further investigated by an in vivo pharmacokinetic study of rats, the everted gut sac model, and the evLAM, respectively. The absorption percentages obtained from the evLAM were much more similar to the data of rats in vivo than those from the everted gut sac model, showing a preferable in vitro-in vivo correlation (r = 0.9772). Compared with the conventional in vitro and in vivo methods, the evLAM, which allowed precise insights into the in vivo absorption characteristics without much time or a complicated process, could be a better tool for assessing LBFs of poorly water-soluble drugs. Full article

(This article belongs to the Special Issue Gastrointestinal Variables and Drug Absorption: Experimental, Computational and In Vitro Predictive Approaches)

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23 pages, 1194 KiB

Open AccessArticle

Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption

by Yvonne E. Arnold, Julien Thorens, Stéphane Bernard and Yogeshvar N. Kalia

Pharmaceutics 2019, 11(3), 139; https://doi.org/10.3390/pharmaceutics11030139 - 21 Mar 2019

Cited by 28 | Viewed by 7302

Abstract

Drug absorption across viable porcine intestines was investigated using an Ussing chamber system. The apparent permeability coefficients, P_app,pig, were compared to the permeability coefficients determined in humans in vivo, P_eff,human. Eleven drugs from the different Biopharmaceutical Classification System (BCS) [...] Read more.

Drug absorption across viable porcine intestines was investigated using an Ussing chamber system. The apparent permeability coefficients, P_app,pig, were compared to the permeability coefficients determined in humans in vivo, P_eff,human. Eleven drugs from the different Biopharmaceutical Classification System (BCS) categories absorbed by passive diffusion with published P_eff,human values were used to test the system. The initial experiments measured P_app,pig for each drug after application in a Krebs–Bicarbonate Ringer (KBR) buffer and in biorelevant media FaSSIF V2 and FeSSIF V2, mimicking fasted and fed states. Strong sigmoidal correlations were observed between P_eff,human and P_app,pig. Differences in the segmental P_app,pig of antipyrine, cimetidine and metoprolol confirmed the discrimination between drug uptake in the duodenum, jejunum and ileum (and colon); the results were in good agreement with human data in vivo. The presence of the P-gp inhibitor verapamil significantly increased P_app,pig across the ileum of the P-gp substrates cimetidine and ranitidine (p < 0.05). Clotrimazole, a potent CYP3A4 inhibitor, significantly increased P_app,pig of the CYP3A4 substrates midazolam, verapamil and tamoxifen and significantly decreased the formation of their main metabolites. In conclusion, the results showed that this is a robust technique to predict passive drug permeability under fasted and fed states, to identify regional differences in drug permeability and to demonstrate the activity of P-gp and CYP3A4. Full article

(This article belongs to the Special Issue Gastrointestinal Variables and Drug Absorption: Experimental, Computational and In Vitro Predictive Approaches)

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18 pages, 4357 KiB

Open AccessArticle

Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses

by Marival Bermejo, Gislaine Kuminek, Jozef Al-Gousous, Alejandro Ruiz-Picazo, Yasuhiro Tsume, Alfredo Garcia-Arieta, Isabel González-Alvarez, Bart Hens, Deanna Mudie, Gregory E. Amidon, Nair Rodriguez-Hornedo and Gordon L. Amidon

Pharmaceutics 2019, 11(3), 122; https://doi.org/10.3390/pharmaceutics11030122 - 15 Mar 2019

Cited by 17 | Viewed by 5388

Abstract

The present work aimed to explain the differences in oral performance in fasted humans who were categorized into groups based on the three different drug product formulations of dexketoprofen trometamol (DKT) salt—Using a combination of in vitro techniques and pharmacokinetic analysis. The non-bioequivalence [...] Read more.

The present work aimed to explain the differences in oral performance in fasted humans who were categorized into groups based on the three different drug product formulations of dexketoprofen trometamol (DKT) salt—Using a combination of in vitro techniques and pharmacokinetic analysis. The non-bioequivalence (non-BE) tablet group achieved higher plasma C_max and area under the curve (AUC) than the reference and BE tablets groups, with only one difference in tablet composition, which was the presence of calcium monohydrogen phosphate, an alkalinizing excipient, in the tablet core of the non-BE formulation. Concentration profiles determined using a gastrointestinal simulator (GIS) apparatus designed with 0.01 N hydrochloric acid and 34 mM sodium chloride as the gastric medium and fasted state simulated intestinal fluids (FaSSIF-v1) as the intestinal medium showed a faster rate and a higher extent of dissolution of the non-BE product compared to the BE and reference products. These in vitro profiles mirrored the fraction doses absorbed in vivo obtained from deconvoluted plasma concentration–time profiles. However, when sodium chloride was not included in the gastric medium and phosphate buffer without bile salts and phospholipids were used as the intestinal medium, the three products exhibited nearly identical concentration profiles. Microscopic examination of DKT salt dissolution in the gastric medium containing sodium chloride identified that when calcium phosphate was present, the DKT dissolved without conversion to the less soluble free acid, which was consistent with the higher drug exposure of the non-BE formulation. In the absence of calcium phosphate, however, dexketoprofen trometamol salt dissolution began with a nano-phase formation that grew to a liquid–liquid phase separation (LLPS) and formed the less soluble free acid crystals. This phenomenon was dependent on the salt/excipient concentrations and the presence of free acid crystals in the salt phase. This work demonstrated the importance of excipients and purity of salt phase on the evolution and rate of salt disproportionation pathways. Moreover, the presented data clearly showed the usefulness of the GIS apparatus as a discriminating tool that could highlight the differences in formulation behavior when utilizing physiologically-relevant media and experimental conditions in combination with microscopy imaging. Full article

(This article belongs to the Special Issue Gastrointestinal Variables and Drug Absorption: Experimental, Computational and In Vitro Predictive Approaches)

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14 pages, 1869 KiB

Open AccessArticle

Regional Absorption of Fimasartan in the Gastrointestinal Tract by an Improved In Situ Absorption Method in Rats

by Tae Hwan Kim, Soo Heui Paik, Yong Ha Chi, Jürgen B. Bulitta, Da Young Lee, Jun Young Lim, Seung Eun Chung, Chang Ho Song, Hyeon Myeong Jeong, Soyoung Shin and Beom Soo Shin

Pharmaceutics 2018, 10(4), 174; https://doi.org/10.3390/pharmaceutics10040174 - 03 Oct 2018

Cited by 5 | Viewed by 3456

Abstract

The aim of the present study was to assess the regional absorption of fimasartan by an improved in situ absorption method in comparison with the conventional in situ single-pass perfusion method in rats. After each gastrointestinal segment of interest was identified, fimasartan was [...] Read more.

The aim of the present study was to assess the regional absorption of fimasartan by an improved in situ absorption method in comparison with the conventional in situ single-pass perfusion method in rats. After each gastrointestinal segment of interest was identified, fimasartan was injected into the starting point of each segment and the unabsorbed fimasartan was discharged from the end point of the segment. Blood samples were collected from the jugular vein to evaluate the systemic absorption of the drug. The relative fraction absorbed (F_abs,relative) values in the specific gastrointestinal region calculated based on the area under the curve (AUC) values obtained after the injection of fimasartan into the gastrointestinal segment were 8.2% ± 3.2%, 23.0% ± 12.1%, 49.7% ± 11.5%, and 19.1% ± 11.9% for the stomach, duodenum, small intestine, and large intestine, respectively, which were comparable with those determined by the conventional in situ single-pass perfusion. By applying the fraction of the dose available at each gastrointestinal segment following the oral administration, the actual fraction absorbed (F′_abs) values at each gastrointestinal segment were estimated at 10.9% for the stomach, 27.1% for the duodenum, 40.7% for the small intestine, and 5.4% for the large intestine, which added up to the gastrointestinal bioavailability (F_X·F_G) of 84.1%. The present method holds great promise to assess the regional absorption of a drug and aid to design new drug formulations. Full article

(This article belongs to the Special Issue Gastrointestinal Variables and Drug Absorption: Experimental, Computational and In Vitro Predictive Approaches)

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Review

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18 pages, 1374 KiB

Open AccessReview

Intestinal Permeability and Drug Absorption: Predictive Experimental, Computational and In Vivo Approaches

by David Dahlgren and Hans Lennernäs

Pharmaceutics 2019, 11(8), 411; https://doi.org/10.3390/pharmaceutics11080411 - 13 Aug 2019

Cited by 135 | Viewed by 10995

Abstract

The main objective of this review is to discuss recent advancements in the overall investigation and in vivo prediction of drug absorption. The intestinal permeability of an orally administered drug (given the value P_eff) has been widely used to determine the [...] Read more.

The main objective of this review is to discuss recent advancements in the overall investigation and in vivo prediction of drug absorption. The intestinal permeability of an orally administered drug (given the value P_eff) has been widely used to determine the rate and extent of the drug’s intestinal absorption (F_abs) in humans. Preclinical gastrointestinal (GI) absorption models are currently in demand for the pharmaceutical development of novel dosage forms and new drug products. However, there is a strong need to improve our understanding of the interplay between pharmaceutical, biopharmaceutical, biochemical, and physiological factors when predicting F_abs and bioavailability. Currently, our knowledge of GI secretion, GI motility, and regional intestinal permeability, in both healthy subjects and patients with GI diseases, is limited by the relative inaccessibility of some intestinal segments of the human GI tract. In particular, our understanding of the complex and highly dynamic physiology of the region from the mid-jejunum to the sigmoid colon could be significantly improved. One approach to the assessment of intestinal permeability is to use animal models that allow these intestinal regions to be investigated in detail and then to compare the results with those from simple human permeability models such as cell cultures. Investigation of intestinal drug permeation processes is a crucial biopharmaceutical step in the development of oral pharmaceutical products. The determination of the intestinal P_eff for a specific drug is dependent on the technique, model, and conditions applied, and is influenced by multiple interactions between the drug molecule and the biological membranes. Full article

(This article belongs to the Special Issue Gastrointestinal Variables and Drug Absorption: Experimental, Computational and In Vitro Predictive Approaches)

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19 pages, 2448 KiB

Open AccessReview

MRI of the Colon in the Pharmaceutical Field: The Future before us

by Sarah Sulaiman and Luca Marciani

Pharmaceutics 2019, 11(4), 146; https://doi.org/10.3390/pharmaceutics11040146 - 27 Mar 2019

Cited by 13 | Viewed by 8393

Abstract

Oral solid drug formulation is the most common route for administration and it is vital to increase knowledge of the gastrointestinal physiological environment to understand dissolution and absorption processes and to develop reliable biorelevant in vitro tools. In particular, colon targeted drug formulations [...] Read more.

Oral solid drug formulation is the most common route for administration and it is vital to increase knowledge of the gastrointestinal physiological environment to understand dissolution and absorption processes and to develop reliable biorelevant in vitro tools. In particular, colon targeted drug formulations have raised the attention of pharmaceutical scientists because of the great potential of colonic drug delivery. However, the distal bowel is still a relatively understudied part of the gastrointestinal tract. Recently, magnetic resonance imaging (MRI) has been gaining an emerging role in studying the colon. This article provides a comprehensive; contemporary review of the literature on luminal MRI of the colonic environment of the last 15 years with specific focus on colon physiological dimensions; motility; chyme and fluids; transit and luminal flow. The work reviewed provides novel physiological insight that will have a profound impact on our understanding of the colonic environment for drug delivery and absorption and will ultimately help to raise the in vitro/in vivo relevance of computer simulations and bench models. Full article

(This article belongs to the Special Issue Gastrointestinal Variables and Drug Absorption: Experimental, Computational and In Vitro Predictive Approaches)

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24 pages, 715 KiB

Open AccessReview

In Vitro Methods to Study Colon Release: State of the Art and An Outlook on New Strategies for Better In-Vitro Biorelevant Release Media

by Marie Wahlgren, Magdalena Axenstrand, Åsa Håkansson, Ali Marefati and Betty Lomstein Pedersen

Pharmaceutics 2019, 11(2), 95; https://doi.org/10.3390/pharmaceutics11020095 - 22 Feb 2019

Cited by 37 | Viewed by 7684

Abstract

The primary focus of this review is a discussion regarding in vitro media for colon release, but we also give a brief overview of colon delivery and the colon microbiota as a baseline for this discussion. The large intestine is colonized by a [...] Read more.

The primary focus of this review is a discussion regarding in vitro media for colon release, but we also give a brief overview of colon delivery and the colon microbiota as a baseline for this discussion. The large intestine is colonized by a vast number of bacteria, approximately 10¹² per gram of intestinal content. The microbial community in the colon is complex and there is still much that is unknown about its composition and the activity of the microbiome. However, it is evident that this complex microbiota will affect the release from oral formulations targeting the colon. This includes the release of active drug substances, food supplements, and live microorganisms, such as probiotic bacteria and bacteria used for microbiota transplantations. Currently, there are no standardized colon release media, but researchers employ in vitro models representing the colon ranging from reasonable simple systems with adjusted pH with or without key enzymes to the use of fecal samples. In this review, we present the pros and cons for different existing in vitro models. Furthermore, we summarize the current knowledge of the colonic microbiota composition which is of importance to the fermentation capacity of carbohydrates and suggest a strategy to choose bacteria for a new more standardized in vitro dissolution medium for the colon. Full article

(This article belongs to the Special Issue Gastrointestinal Variables and Drug Absorption: Experimental, Computational and In Vitro Predictive Approaches)

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