Permeability assessment for solid oral drug formulations based on Caco-2 monolayer in combination with a flow through dissolution cell

Motz, Stephan A.; Schaefer, Ulrich F.; Balbach, Stefan; Eichinger, Thomas; Lehr, Claus‐Michael

doi:10.1016/j.ejpb.2006.10.015

Cited by 48 publications

(21 citation statements)

References 35 publications

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“…For example, integration of the flow-through cell apparatus with MRI system has been proposed for discriminative evaluation of controlled-release dosage forms with similar dissolution profiles by investigating physical changes in the dosage form that can aid tablet formulation and can be used as a potential Process Analytical Technology tool (12,13). Furthermore, the flowthrough cell system can be used to detect the influences of dosage forms on permeation processes by connection to cell-culture-based permeability assessment (14).…”

Section: Combination With Other Systemsmentioning

confidence: 99%

Flow-Through Cell Apparatus (USP Apparatus 4): Operation and Features

Fotaki¹

2011

Dissolution Technol.

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Section: Combination With Other Systemsmentioning

confidence: 99%

Flow-Through Cell Apparatus (USP Apparatus 4): Operation and Features

Fotaki¹

2011

Dissolution Technol.

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“…In addition to drug dissolution, permeability component was also included by some researchers in their in vitro system, which proved to be useful to study food effect (12,18,19). Use of animal models, has been the common practice for estimation of the potential food effect in humans (6,15,20).…”

Section: Introductionmentioning

confidence: 99%

From Bench to Humans: Formulation Development of a Poorly Water Soluble Drug to Mitigate Food Effect

et al. 2014

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Abstract. This study presents a formulation approach that was shown to mitigate the dramatic food effect observed for a BCS Class II drug. In vitro (dissolution), in vivo (dog), and in silico (GastroPlus®) models were developed to understand the food effect and design strategies to mitigate it. The results showed that such models can be used successfully to mimic the clinically observed food effect. GastroPlus® modeling showed that food effect was primarily due to the extensive solubilization of the drug into the dietary lipid content of the meal. Several formulations were screened for dissolution rate using the biorelevant dissolution tests. Surfactant type and binder amount were found to play a significant role in the dissolution rate of the tablet prototypes that were manufactured using a high-shear wet granulation process. The performance of the lead prototypes (exhibiting best in vitro dissolution performance) was tested in dogs and human subjects. A new formulation approach, where vitamin E TPGS was included in the tablet formulation, was found to mitigate the food effect in humans.KEY WORDS: bioavailability; food effect; in vivo in vitro models; vitamin E TPGS; wet granulation.

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“…The difference in dissolution among the P2, P4 and P1, P3 formulations is significant at P=0.95 confidence level. A slight 36 decrease in dissolution could have a negative impact on bioavailability that is why it is proposed to increase the content of the disintegrant within the formulation when Cremophor ELP is used. …”

Section: Evaluation Of Xrpd and Dissolution Resultsmentioning

confidence: 99%

Pharmaceutical development of co-crystals

Venczel

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EARLY DRUG FORMULATION -FORMULATION POSSIBILITIES OF List of tables AIMSThe aims of this thesis are former has ten times higher solubility than the drug itself. However high aqueous solubility of co-crystal forms can lead to rapid convervation and hinter performance [20] that is why one of the main role of formulation experts is to work in a strong collaboration with chemical and analytical experts to protect physical integrity of co-crystals during the formulation work. Designing of co-crystalsCo-crystals are supramolecular homo-(I and III) or heterosynthons (II and IV) presented on is not suitable to reach the sink condition for active pharmaceutical ingredients, which are practically insoluble in aqueous solutions. In contrast to the past, when the majority of research compounds had a relatively small molecular weight and acceptable solubility, the Three active pharmaceutical ingredients were evaluated and compared. These are: SAR1 as a weak base, its di-HCl salt and its co-crystal with fumaric acid. All API study batches were manufactured in laboratory scale from 10 g to 30 g. Resynthesis batch of the fumaric acid cocrystal was manufactured in 0.7 kg scale. Active pharmaceutical ingredient in the area of flow-through dissolutionAn origin molecule of Sanofi coded as a "C" model material was used for FaSSIF (fasted state simulated intestinal fluid) and FeSSIF (fed state simulated intestinal fluid) dissolution study.The same "C" model API and its sevaral salt forms were applied to show the benefits of flow through dissolution during salt selection studies. BuffersBuffer solutions were prepared according to the USP and Ph. Eur. recommendations 39, 40. Pharmaceutical excipientsCremophor ELP was ordered from BASF. Cremophor ELP, a purifed grade of Cremophor EL was specially developed for sensitive active ingredients, as the higher purity was found to improve their stability 41. Tween 80, lactic acid, citric acid, Span 85, PEG 200, sodium hydroxide were purchased from Merck while Eudragit L100-55 was ordered from Evonic.Some pharmaceutical excipients such as mannitol, sulfobuthyl  cyclodextrin, vitamin E TPGS, PVP K25, sodium docusate, Miglyol 812 N, sodium dodecyl sulfate, methyl cellulose, HPMC, crospovidone, microcrystalline cellulose, magnesium stearate and colloidal silica anhydrous were ordered from the internal warehouse of Sanofi. METHODS Chemical manufacturing SAR1 as a fumaric acid co-crystalThe reactor was charged with acetone (12 L), SAR1 base Form III (592 g, 1.29 mol) and fumaric acid (600 g, 5.16 mol). The slurry was stirred at room temperature for 24 hours, the crystals were filtered off, washed with water (1 L) and ethanol (1 L), and dried in a vacuum at 80°C for five hours. Yield: 723 g (94.0%) pale yellow powder [42]. The purity of the product was: 98.9% (HPLC). SAR1 as a dihydrochloride saltSAR1 (29 g) was added to methanol (1370 ml) under nitrogen. The suspension of API was stirred in Ultra-Turrax system for 30 minutes at room temperature. The concentrated hydrochloric acid (8.03 ml, 2....

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Permeability assessment for solid oral drug formulations based on Caco-2 monolayer in combination with a flow through dissolution cell

Cited by 48 publications

References 35 publications

Flow-Through Cell Apparatus (USP Apparatus 4): Operation and Features

Flow-Through Cell Apparatus (USP Apparatus 4): Operation and Features

From Bench to Humans: Formulation Development of a Poorly Water Soluble Drug to Mitigate Food Effect

Pharmaceutical development of co-crystals

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