Fed state simulated intestinal fluid

In this project, compound A from a potential lead series was a neutral compound of MW 314 with low aqueous solubility (Systemic clearance, volume and AUC following a 0.5mg/kg intravenous dose to rats were well predicted (within twofold) from scaled microsomal clearance and in silica prediction of pKa, logP and unbound fraction in plasma. Figure 10.3a shows the predicted oral profile compared to the observed data from two rats dosed orally at 2mg/kg. The additional inputs for the oral prediction were the Caco-2 permeability and measured human fed-state simulated intestinal fluid (FeSSIF, 92(tg/mL). The oral pharmacokinetic parameters Tmax. Cmax. AUC and bioavailability were well predicted. Simulation of higher doses of compound A predicted absorption-limited... 

Figure 6.20 Plot of qo vs. 1/0, for the experimental data of Table 6.1 classified in Class II. The curves denote 90% absorption for two particle sizes (from left to right 10 and 25 pm) assigning Pe// = 2 x lCP2cmmin 1, which corresponds [170] to the mean, Papp = 1.68 x 10 5cms 1 of the Caco-2 permeability values of the data [90]. Drugs located above the curves are fully absorbed (Fa > 0.90) Class II drugs. Key (solubility values in) (A) buffer, pH 5.0 (B) fed state simulated intestinal fluid, pH 5.0.

Table 3 Typical fed state simulated intestinal fluids medium...

The study was performed with a Class 1 member in the form of tablets. Changes in pH have no effects while changes in agitation intensity for USP apparatus II and IV have shown clear influences on the tablet erosion and subsequently on its release. Finally to simulate the fasted and fed state in vivo, fasted state stimulated intestinal fluid(Fassif) and fed state simulated intestinal fluid(Fessif) media were used. None of the USP traditional apparatus show a clear relationship with the in vivo results, especially in the fed conditions. In vitro data obtained by the ADS in the fasted state were consistent with those in vivo, as well as in the fed state after a slight time adjustment allowed in the FDA notes of guidance. A Level A of IVIVC was easily established with a good correlation coefficient in the fasted and fed states, respectively. The main results are presented in Fig. 13. 

Table 2. Composition of fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) (Galia et al., 1998, Vertzoni et al., 2004).

Useful for predicting food effects during formulation development of poorly soluble drugs and for IV/IV correlation. Suggested media are fasted state simulated Intestinal fluid and fed state simulated intestinal fluid Last resort for insoluble drugs. Not recommended... 

Dimethylfoim amide Dimethylacetamide Propylene glycol Dimethyl sulfoxide Simulated gastric fluid Fasted state simulated intestinal fluid Fed state simulated intestinal fluid F[uman intestinal fluid Not applicable UV spectroscopy... 

The BCS scheme can be made more useful by incorporating a further improved basis of physicochemical profiling. For example, the role of pH in permeability measurements could be better defined. The use of simulated intestinal fluids for solubility measurements could be better promoted. The effects of fed/fasted states on absorption could be better address, in methods that have optimum clinical relevance. 

Literature describing simulated media for the fasted stomach and small intestine are available. In the fed state, the simulation of the fed stomach seems to be problematic because the composition is highly dependent on the associated meal. Therefore only a few publications of fed state gastric media are available. With regard to media simulating intestinal fluids in the fed state, several attempts have been made to develop suitable media, both with and without the addition of lipolysis product. 

Lipophilic drugs, being either weak acids, weak bases or non-ionized compounds, are dissolved in the lipid fraction of the food when the macroscopic structure of the food is broken down into microscopic particles during the formation of chyme. Consequently, lipophilic molecules are predissolved in triglyceride droplets when they enter the small intestine. For these compounds, it is especially relevant to include lipolysis products in the biorelevant media simulating the intestinal fluids. Sunesen et al. (2005) could only obtain fVTVC in the fed state for a non-ionized compound (danazol), when including lipolysis products in the media. 

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