ChemInform Abstract: Computational Oral Absorption Simulation for Low-Solubility Compounds.

ChemInform ◽  
2010 ◽  
Vol 41 (8) ◽  
Author(s):  
Kiyohiko Sugano
Keyword(s):  
Oral Absorption ◽  
Low Solubility

Modeling the influence of cyclodextrins on oral absorption of low solubility drugs: II. Experimental validation

2010 ◽  
Vol 105 (2) ◽  
pp. 421-430 ◽  
Author(s):  
Ece Dilber Gamsiz ◽  
Lee Miller ◽  
Avinash G. Thombre ◽  
Imran Ahmed ◽  
Rebecca Lyn Carrier
Keyword(s):  
Experimental Validation ◽  
Oral Absorption ◽  
Low Solubility ◽  
Low Solubility Drugs

scholarly journals Prediction of Oral Absorption of Low-Solubility Drugs by Using Rat Simulated Gastrointestinal Fluids: The Importance of Regional Differences in Membrane Permeability and Solubility

2014 ◽  
Vol 17 (1) ◽  
pp. 106 ◽  
Author(s):  
Yusuke Tanaka ◽  
Toshiyuki Baba ◽  
Koji Tagawa ◽  
Ryoichi Waki ◽  
Shunji Nagata
Keyword(s):  
Oral Administration ◽  
Regional Differences ◽  
Oral Absorption ◽  
Aqueous Solubility ◽  
Oral Drug ◽  
Novel Approach ◽  
Low Solubility ◽  
Low Solubility Drugs ◽  
Saturated Solubility

Purpose. This study aimed to develop a novel approach for predicting the oral absorption of low-solubility drugs by considering regional differences in solubility and permeability within the gastrointestinal (GI) tract. Methods. Simulated GI fluids were prepared to reflect rat in vivo bile acid and phospholipid concentrations in the upper and lower small intestine. The saturated solubility and permeability of griseofulvin (GF) and albendazole (AZ), a drug with low aqueous solubility, were measured using these simulated fluids, and fraction absorbed (Fa) at time t after oral administration was calculated. Results. The saturated solubility of GF and AZ, a drug with low aqueous solubility, differed considerably between the simulated GI fluids. Large regional differences in drugs concentration were also observed following oral administration in vivo. The predicted Fa values using solubility and permeability data of the simulated GI fluid were found to correspond closely to the in vivo data. Conclusion. These results indicated the importance of evaluating regional differences in drug solubility and permeability in order to predict oral absorption of low-solubility drugs accurately. The new methodology developed in the present study could be useful for new oral drug development. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals BCS Class IV Oral Drugs and Absorption Windows: Regional-Dependent Intestinal Permeability of Furosemide

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1175
Author(s):  
Milica Markovic ◽  
Moran Zur ◽  
Inna Ragatsky ◽  
Sandra Cvijić ◽  
Arik Dahan
Keyword(s):  
Intestinal Permeability ◽  
In Silico ◽  
Oral Absorption ◽  
Critical Role ◽  
Oral Drugs ◽  
Absorption Window ◽  
Low Solubility ◽  
Class Iv

Biopharmaceutical classification system (BCS) class IV drugs (low-solubility low-permeability) are generally poor drug candidates, yet, ~5% of oral drugs on the market belong to this class. While solubility is often predictable, intestinal permeability is rather complicated and highly dependent on many biochemical/physiological parameters. In this work, we investigated the solubility/permeability of BCS class IV drug, furosemide, considering the complexity of the entire small intestine (SI). Furosemide solubility, physicochemical properties, and intestinal permeability were thoroughly investigated in-vitro and in-vivo throughout the SI. In addition, advanced in-silico simulations (GastroPlus®) were used to elucidate furosemide regional-dependent absorption pattern. Metoprolol was used as the low/high permeability class boundary. Furosemide was found to be a low-solubility compound. Log D of furosemide at the three pH values 6.5, 7.0, and 7.5 (representing the conditions throughout the SI) showed a downward trend. Similarly, segmental-dependent in-vivo intestinal permeability was revealed; as the intestinal region becomes progressively distal, and the pH gradually increases, the permeability of furosemide significantly decreased. The opposite trend was evident for metoprolol. Theoretical physicochemical analysis based on ionization, pKa, and partitioning predicted the same trend and confirmed the experimental results. Computational simulations clearly showed the effect of furosemide’s regional-dependent permeability on its absorption, as well as the critical role of the drug’s absorption window on the overall bioavailability. The data reveals the absorption window of furosemide in the proximal SI, allowing adequate absorption and consequent effect, despite its class IV characteristics. Nevertheless, this absorption window so early on in the SI rules out the suitability of controlled-release furosemide formulations, as confirmed by the in-silico results. The potential link between segmental-dependent intestinal permeability and adequate oral absorption of BCS Class IV drugs may aid to develop challenging drugs as successful oral products.

Prediction Characteristics of Oral Absorption Simulation Software Evaluated Using Structurally Diverse Low-Solubility Drugs

2020 ◽  
Vol 109 (3) ◽  
pp. 1403-1416 ◽  
Author(s):  
Naoya Matsumura ◽  
Shun Hayashi ◽  
Yoshiyuki Akiyama ◽  
Asami Ono ◽  
Satoko Funaki ◽  
...  
Keyword(s):  
Oral Absorption ◽  
Simulation Software ◽  
Low Solubility ◽  
Low Solubility Drugs

Modeling the influence of cyclodextrins on oral absorption of low-solubility drugs: I. Model development

2010 ◽  
Vol 105 (2) ◽  
pp. 409-420 ◽  
Author(s):  
Ece Dilber Gamsiz ◽  
Lee Miller ◽  
Avinash G. Thombre ◽  
Imran Ahmed ◽  
Rebecca Lyn Carrier
Keyword(s):  
Oral Absorption ◽  
Model Development ◽  
Low Solubility ◽  
Low Solubility Drugs

scholarly journals CONTROLE DE QUALIDADE DE CÁPSULAS MANIPULADAS CONTENDO ATORVASTATINA CÁLCICA

2020 ◽  
Vol 12 (2) ◽  
pp. 59-69
Author(s):  
Diego da Silva Ribeiro ◽  
Nayra Mendes da Silva ◽  
Ana Julia Pereira Santinho Gomes
Keyword(s):  
Oral Absorption ◽  
Content Uniformity ◽  
Dissolution Profile ◽  
High Permeability ◽  
Pharmaceutical Dosage Forms ◽  
Atorvastatin Calcium ◽  
Pharmaceutical Ingredients ◽  
Continuous Use ◽  
Low Solubility

Atorvastatin calcium (ATC) is one of the most used drugs in the treatment of dyslipidemia. The compounding of capsules containing ATC has often been requested as it is an exceptionaldispensing drug (continuous use and high cost). ATC presents low solubility and high permeability, therefore, pharmaceutical ingredients are capable of interfering with its solubility. The aim of this work was to evaluate the quality of ATC capsules prepared incompoundingpharmacies in Divinópolis,Brazil.Fourier Transform Infrared spectroscopy (FTIR) was used to identify the ATC. Tests for weight determination (WD), content uniformity (CU) and dissolution were also carried out. The FTIRconfirmed the authenticity of ATC. All batches were approved in relation to the WD, however only 67% were approved in relation to the CU, although all have been approved for acceptance value.It was also observed that 1/3 of the products did not display the specified dissolution rate. This is due to the excipient composition impacting on a significantly slower dissolution profile compared to the others. It was noted that the choice of a specific excipient for ATC together with an appropriate encapsulation procedure play key roles in ensuring the quality of an exceptional dispensing drug, whose dissolution behaviorcan influence oral absorption. In conclusion, the importance of monitoring the compounding process was demonstrated, expanding the relevance of the constant evaluation of the quality of pharmaceutical dosage forms, bringing to light the difficulties of the compounding sector, as well as the effectiveness of the approval criteria employed to date.

scholarly journals 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

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 182
Author(s):  
Claudia Miranda ◽  
Alejandro Ruiz-Picazo ◽  
Paula Pomares ◽  
Isabel Gonzalez-Alvarez ◽  
Marival Bermejo ◽  
...  
Keyword(s):  
Cell Lines ◽  
Intestinal Permeability ◽  
Oral Absorption ◽  
Neuroprotective Effects ◽  
In Situ Perfusion ◽  
In Vitro Cell Lines ◽  
Low Solubility

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.

scholarly journals In Situ Absorption in Rat Intestinal Tract of Solid Dispersion of Annonaceous Acetogenins

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Yun-Jie Dang ◽  
Han-Zhou Feng ◽  
Limei Zhang ◽  
Chun-Hui Hu ◽  
Chun-Yan Zhu
Keyword(s):  
Solid Dispersion ◽  
Intestinal Tract ◽  
Oral Absorption ◽  
Biological Properties ◽  
Annonaceous Acetogenins ◽  
Peg 4000 ◽  
Simplex Lattice ◽  
In Situ Absorption ◽  
Low Solubility

Isolated fromAnnona squamosa L, Annonaceous acetogenins (ACGs) exhibit a broad range of biological properties yet absorbed badly due to the low solubility. Solid dispersion in polyethylene glycol 4000 (PEG 4000) has been developed to increase the solubility and oral absorption of ACGs. The formulation of ACGS-solid dispersion was optimized by a simplex lattice experiment design and carried out by a solvent-fusion method. We studied the absorption property of ACGs in rat’s intestine, which showed there was a good absorption and uptake percentages with solid dispersion. The study on uptake percentage in different regions of rat’s intestine attested that the duodenum had the best permeability, followed by jejunum, ileum, and colon in order with no significant differences. So the paper drew the conclusion that solid dispersion could improve the solubility and oral absorption of annonaceous acetogenins.

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