Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: Case example nelfinavir

Shono, Yasushi; Jantratid, Ekarat; Dressman, Jennifer B.

doi:10.1016/j.ejpb.2011.04.005

Cited by 88 publications

(63 citation statements)

References 27 publications

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“…The latter approach predicted the dissolution process for formulations containing various excipients and complex matrices when in vitro and in vivo dissolution rate could be correlated (25,26). Precipitation in the intestinal lumen can occur for poorly water soluble basic drugs at low gastric pH in the stomach (1,22). With a meal, in vivo precipitation can be delayed due to a higher degree of supersaturation as the fed state pH is slightly lower and bile salt concentration is elevated (22).…”

Section: General Strategy For Human Food Effect Predictionsmentioning

confidence: 99%

“…Physiologically based models which integrate anatomical and physiological parameters of gastrointestinal tracts in preclinical species and humans, along with physicochemical drug product formulation properties, have been used to predict absorption and disposition (18)(19)(20)(21)(22)(23)(24)(30)(31)(32). These approaches have been applied during formulation development; yet their practical application in the prediction of human food effects has not been described extensively.…”

Section: General Strategy For Human Food Effect Predictionsmentioning

confidence: 99%

“…Now, the integration of in vitro, in silico, and in vivo data is greatly facilitated due to advances of physiologically based pharmacokinetic (PBPK) modeling tools, such as GastroPlus (18,19), Simcyp (20,21), and STELLA (22)(23)(24). Integration of in vitro dissolution/solubility data generated in biorelevant media (25,26) with in silico simulation tools (18,19,27,28) may complement or even substitute animal models for quantitative assessment of the food effects trends.…”

Section: Introductionmentioning

confidence: 99%

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Case Studies for Practical Food Effect Assessments across BCS/BDDCS Class Compounds using In Silico, In Vitro, and Preclinical In Vivo Data

Heimbach

Xia

Lin

et al. 2012

AAPS J

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Abstract. Practical food effect predictions and assessments were described using in silico, in vitro, and/or in vivo preclinical data to anticipate food effects and Biopharmaceutics Classification System (BCS)/ Biopharmaceutics Drug Disposition Classification System (BDDCS) class across drug development stages depending on available data: (1) limited in silico and in vitro data in early discovery; (2) preclinical in vivo pharmacokinetic, absorption, and metabolism data at candidate selection; and (3) physiologically based absorption modeling using biorelevant solubility and precipitation data to quantitatively predict human food effects, oral absorption, and pharmacokinetic profiles for early clinical studies. Early food effect predictions used calculated or measured physicochemical properties to establish a preliminary BCS/BDDCS class. A rat-based preclinical BCS/BDDCS classification used rat in vivo fraction absorbed and metabolism data. Biorelevant solubility and precipitation kinetic data were generated via animal pharmacokinetic studies using advanced compartmental absorption and transit (ACAT) models or in vitro methods. Predicted human plasma concentration-time profiles and the magnitude of the food effects were compared with observed clinical data for assessment of simulation accuracy. Simulations and analyses successfully identified potential food effects across BCS/BDDCS classes 1-4 compounds with an average fold error less than 1.6 in most cases. ACAT physiological absorption models accurately predicted positive food effects in human for poorly soluble bases after oral dosage forms. Integration of solubility, precipitation time, and metabolism data allowed confident identification of a compound's BCS/ BDDCS class, its likely food effects, along with prediction of human exposure profiles under fast and fed conditions.

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Section: General Strategy For Human Food Effect Predictionsmentioning

confidence: 99%

Section: General Strategy For Human Food Effect Predictionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Case Studies for Practical Food Effect Assessments across BCS/BDDCS Class Compounds using In Silico, In Vitro, and Preclinical In Vivo Data

Heimbach

Xia

Lin

et al. 2012

AAPS J

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“…For carvedilol, less precipitation is expected in the duodenum and fed-state intestinal fluid as apparent from the dissolution results of carvedilol in acetate buffer pH 4.5 and blank FeSSIF. Nonetheless, SIFsp and 0.05 M phosphate buffer (IntPh3) remain commonly used as compendial dissolution media (7,11,(38)(39)(40)(41)(42).…”

Section: Dissolution Studiesmentioning

confidence: 99%

pH-Dependent Solubility and Dissolution Behavior of Carvedilol—Case Example of a Weakly Basic BCS Class II Drug

et al. 2015

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Abstract. The objective of this study was to investigate the pH-dependent solubility and dissolution of weakly basic Biopharmaceutical Classification Systems (BCS) class II drugs, characterized by low solubility and high permeability, using carvedilol, a weak base with a pK a value of 7.8, as a model drug. A series of solubility and in vitro dissolution studies was carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH range of the GI from 1.2 to 7.8. The effect of ionic strength, buffer capacity, and buffer species of the dissolution media on the solubility and dissolution behavior of carvedilol was also investigated. The study revealed that carvedilol exhibited a typical weak base pH-dependent solubility profile with a high solubility at low pH (545.1-2591.4 μg/mL within the pH range 1.2-5.0) and low solubility at high pH (5.8-51.9 μg/mL within the pH range 6.5-7.8). The dissolution behavior of carvedilol was consistent with the solubility results, where carvedilol release was complete (95.8-98.2% released within 60 min) in media simulating the gastric fluid (pH 1.2-5.0) and relatively low (15.9-86.2% released within 240 min) in media simulating the intestinal fluid (pH 6.5-7.8). It was found that the buffer species of the dissolution media may influence the solubility and consequently the percentage of carvedilol released by forming carvedilol salts of varying solubilities. Carvedilol solubility and dissolution decreased with increasing ionic strength, while lowering the buffer capacity resulted in a decrease in carvedilol solubility and dissolution rate.

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“…Moreover, dissolution parameters should also consider pH at the site of absorption for the drugs showing pH-dependent solubility (42)(43)(44). Higher NT release into the pH 1.2 buffer in COAM form is particularly encouraging because dissolution is going to be a rate-limiting step particularly in the acidic pH of the stomach for immediate release formulations of NT (45,46). However, there was no major difference observed in the drug release of PM and COAM at a higher pH dissolution medium, precisely in phosphate buffer pH 6.8, at the end of 60 min (Fig.…”

Section: Discussionmentioning

confidence: 99%

Co-Amorphous Combination of Nateglinide-Metformin Hydrochloride for Dissolution Enhancement

Wairkar

Gaud

2015

AAPS PharmSciTech

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Abstract. The aim of the present work was to prepare a co-amorphous mixture (COAM) of Nateglinide and Metformin hydrochloride to enhance the dissolution rate of poorly soluble Nateglinide. Nateglinide (120 mg) and Metformin hydrochloride (500 mg) COAM, as a dose ratio, were prepared by ball-milling technique. COAMs were characterized for saturation solubility, amorphism and physicochemical interactions (X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR)), SEM, in vitro dissolution, and stability studies. Solubility studies revealed a sevenfold rise in solubility of Nateglinide from 0.061 to 0.423 mg/ml in dose ratio of COAM. Solid-state characterization of COAM suggested amorphization of Nateglinide after 6 h of ball milling. XRPD and DSC studies confirmed amorphism in Nateglinide, whereas FTIR elucidated hydrogen interactions (proton exchange between Nateglinide and Metformin hydrochloride). Interestingly, due to low energy of fusion, Nateglinide was completely amorphized and stabilized by Metformin hydrochloride. Consequently, in vitro drug release showed significant increase in dissolution of Nateglinide in COAM, irrespective of dissolution medium. However, little change was observed in the solubility and dissolution profile of Metformin hydrochloride, revealing small change in its crystallinity. Stability data indicated no traces of devitrification in XRPD of stability sample of COAM, and % drug release remained unaffected at accelerated storage conditions. Amorphism of Nateglinide, proton exchange with Metformin hydrochloride, and stabilization of its amorphous form have been noted in ball-milled COAM of NateglinideMetformin hydrochloride, revealing enhanced dissolution of Nateglinide. Thus, COAM of NateglinideMetformin hydrochloride system is a promising approach for combination therapy in diabetic patients.

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Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: Case example nelfinavir

Cited by 88 publications

References 27 publications

Case Studies for Practical Food Effect Assessments across BCS/BDDCS Class Compounds using In Silico, In Vitro, and Preclinical In Vivo Data

Case Studies for Practical Food Effect Assessments across BCS/BDDCS Class Compounds using In Silico, In Vitro, and Preclinical In Vivo Data

pH-Dependent Solubility and Dissolution Behavior of Carvedilol—Case Example of a Weakly Basic BCS Class II Drug

Co-Amorphous Combination of Nateglinide-Metformin Hydrochloride for Dissolution Enhancement

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