Simulated intestinal fluid

Figure 5. Enzymatic degradation of H214/03 in simulated intestinal fluid. S(t)/S(0) is the fraction of remaining peptide at time t. The compositions of the samples are listed in Table HI.

Highly insoluble molecules are in part transported in the GIT by partitioning into the mixed micelles injected into the lumen from the biliary duct in the duodenum (Fig. 2.3). Mixed micelles consist of a 4 1 mixture of bile salts and phospholipids (Fig. 7.13). In contrast, at the point of absorption in the BBB, highly insoluble molecules are transported by serum proteins. This distinction is expected to be important in in vitro assay modeling. The use of simulated intestinal fluids is appealing. 

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. 

Here, APsuv is the absorption potential measured from the distribution in small unilamellar vesicles (SUV) at pH 6.8, the solubility was measured at pH 6.8 in simulated intestinal fluid, V is the volume of intestinal fluid, and dose is a mean single oral dose. Liposome partitioning is only partly correlated with octanol/water distribution. 

FaSSIF Fasted state simulating intestinal fluid... 

The two media typically used include Simulated Gastric Fluid (pH 1-pH 3) and Simulated Intestinal Fluid (pH 6-pH 7). The drug substance under investigation is introduced, and its uptake in the diffusion cell ( absorption ) is governed by its hydrophilic-lipophilic balance (HLB). The absorption model proposed by Strieker (26) in the early 1970s therefore effectively took into consideration (in an experimental sense) all aspects considered by the theory of the BCS, which was introduced more than 20 years later. 

Ingels F, Deferme S, Destexhe E, Oth M, Van den Mooter G, Augustijns P. Simulated intestinal fluid as transport medium... 

In an attempt to increase the biorelevance of the Ussing chambers technique even further, the use of simulated intestinal fluids (FaSSIF and FeSSIF) as transport media was recently evaluated [105], However, the potential difference collapsed to zero after 120 min when exposed to FaSSIF solution and permeability for mannitol was increased twofold. Electron micrographs revealed erosion of the villi tips and substantial denudation of the microvilli after exposure of the ileal tissue to FaSSIF and FeSSIF [105],... 

Ingels F, Beck B, Oth M, Augustijns P (2004) Effect of simulated intestinal fluid on drug permeability estimation across Caco-2 monolayers. Int J Pharm 274 221-232. 

Patel N, Forbes B, Eskola S, Murray J (2006) Use of simulated intestinal fluids with Caco-2 cells and rat ileum. Drug Dev Ind Pharm 32 151-161. 

Lomstein Pedersen B, Brondstedt H, Lennernas H, Norring Christensen F, Mullertz A, Gjelstrup Kristensen H (2000) Dissolution of Hydrocortisone in human and simulated intestinal fluids. Pharm. Res. 17 183-189. 

Dissolution testing is carried out in United States Pharmacopeia (USP) Apparatus I (100 rpm) or Apparatus II (50 rpm) utilizing 900 ml of the following dissolution media (1) 0.1 N HC1 or simulated gastric fluid USP without enzymes (2) a pH 4.5 buffer and (3) a pH 6.8 buffer or simulated intestinal fluid USP without enzymes. When 85% of the labeled amount of... 

All chemicals were used as received. PDADMAC and PAMPS were obtained from Aldrich Chemical Co. (Milwaukee, WI). Diclofenac sodium, sodium sulfathiazole, labetalol HCl, propranolol HCl, verapamil HCl, and diltiazem HCl were purchased from Sigma Chemical (St. Louis, MO). Dextrose USP was obtained from Amend Co. (Irvinton, NJ). Water was distilled and deionized using a Nanopure purihcation system (Fischer Scientihc, Fair Lawn, NJ). Simulated intestinal fluid was prepared using a O.OIM phosphate buffer (sodium phosphate monobasic and potassium phosphate dibasic) at pH 7 and 5.5 with different amounts of NaCl to vary the ionic strength. Simulated gastric fluid (pH 1.5) was prepared with concentrated HCl with different amounts of NaCl to vary the ionic strength. 

Simulated intestinal fluid is associated more with dissolution rate determination than solubility measurements. Sometimes when a compound has particularly low solubility the dissolution is studied in simulated fluids. The intent is to try and produce an increased dissolution rate. If there is an increased rate it would be due to an interaction between the compound and the dissolution fluid. Sometimes this... 

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... 

The applicability of PBPK models can be described in the context of the BDDCS classification [24]. PBPK models are very predictive for class 1 and class 2 compounds. However for poorly soluble compounds, the use of aqueous solubility is shown to be inadequate for reliable prediction of oral absorption in physiologically based models [7]. In such cases, it is recommended to use solubility measured in simulated intestinal fluids (FeSSIF, FaSSIF). Such data proved to be very relevant to simulate the oral absorption of BCS 2 (low solubility, high permeability) compounds [25]. 

The release tests were performed using the USP dissolution method (apparatus I) and utilized 1000 ml of pH 1.2 simulated gastric fluid (USP XXI) or pH 6.8 simulated intestinal fluid (USP XXI) without enzymes, equilibrated to 37°C and stirred with the basket rotating at 50 or 150 rev/ min. Drug concentrations were assayed by UV spectrophotometry at 255 nm. The experiments were continued until 100% dissolution was achieved. The release data were analysed to zero order, calculating the slope and intercept of the line. Each data point is the average of six individual determinations. In all cases the standard deviation was less than 9%. 

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