Permeation studies

The permeability of the drug substance can be determined by different approaches such as pharmacokinetic studies in humans (fraction absorbed or mass balance studies) or intestinal permeability studies (in vivo intestinal perfusion studies in humans or suitable animal models or in vitro permeation studies using excised intestinal tissue or epithelial cell culture monolayers like CaCo-2 cell line). In order to avoid misclassification of a drug subject to efflux transporters such as P-glycoprotein, functional expression of such proteins should be investigated. Low- and high-permeability model... 

Reconstructed Human Epidermis Equivalents Because of the limited availability of human skin, reconstructed human epidermis equivalents are under investigation to serve as membranes in permeation experiments. A summary on these replacement tools has been recently published by Netzlaff et al. [92], First results of a German prevalidation study have shown the suitability of such bioengineered human epidermis equivalents in permeation studies [93],... 

The tape-stripping technique has been applied in vivo, as well as in vitro. The used in vitro incubation devices are the same as described for skin permeation studies. A specialized incubation device developed by Loth and coworkers, the Saarbriicken penetration model, allows investigation of skin penetration bypassing the normally occurring nonphysiological hydration of the dermis [64],... 

G. Lee and P. Parlicharla. An examination of excised skin tissues used for in vitro membrane permeation studies. Pharm. Res. 3 356-359 (1986). 

Artusi M, Santi P, Colombo P, Junginger HE (2003) Buccal delivery of thio-colchicoside In vitro and in vivo permeation studies. Int J Pharm 250 203-213... 

Ungphaiboon S, Maitani Y (2001) In vitro permeation studies of triamcinolone acetonide mouthwashes. Int J Pharm 220 111-117... 

Xiang J, Fang X, Li X (2002) Transbuccal delivery of 2/,3/-dideoxycytidine In vitro permeation study and histological investigation. Int J Pharm 231 57-66... 

Richter T, Keipert S (2004) In vitro permeation studies comparing bovine nasal mucosa, porcine cornea and artificial membrane androstenedione in microemulsions and their components. Eur J Pharm Biopharm 58 137-143. 

Ventura CA, Giannone I, Musumeci T, Pignatello R, Ragni L, Landolfi C, Milanese C, Paolino D, Puglisi G (2006) Physico-chemical characterization of disoxaril-dimethyl-beta-cyclodextrin inclusion complex and in vitro permeation studies. Eur J Med Chem 41 233-240. 

The Clonetics cell line from Cambrex Bio Science represents a cultured human corneal epithelial model (order no. CMS-2015 Cambrex Bio Science, Walkersville, MD). The culture model was generated by isolation of cells from normal human corneal tissues. The cells were then infected with an amphotropic recombinant retrovirus containing HPV-16 E6/E7 genes to extend the useful cell life span. The Clonetics cell model is a very recent entry into the immortalized corneal cell line field, but it has been proved to be useful for toxicity testing as well as in vitro drug permeation studies so far. Because of its very recent introduction, further examinations have to be undertaken to... 

Thus far, a wide array of useful cell culture models of the corneal epithelium has been established. Many of these cell culture models focus on toxicity testing and ocular irritation, but some cell layer models for drug permeation studies are also available. Indispensable for successful drug penetration testing is a cell layer that exhibits a tight epithelial barrier. This latter requirement of tight barrier properties disqualifies some of the models that were established as substitutes for the Draize test. At least two cell lines are available for pharmaceutical studies and some newer models may qualify as a useful tool, once they are characterized for their barrier properties. 

In another approach, Parnigotto and coworkers reconstructed corneal structures in vitro by using corneal stroma containing keratocytes to which corneal epithelial cells from bovine primary cultures were overlaid [73], However, this particular corneal model did not contain an endothelial layer. This model was histochemically characterized and the toxicity of different surfactants was tested using MTT methods. This stroma-epithelium model has been reported to show a cornea-like morphology, where a multilayered epithelial barrier composed of basal cells (of a cuboidal shape) and superficial cells (of a flattened shape) is noted. Furthermore, the formation of a basement membrane equivalent and expression of the 64-kDa keratin were reported, indicating the presence of differentiated epithelial cells. The toxicity data for various surfactants obtained with this model correlate well with those seen by the Draize test [73], However, this corneal equivalent was not further validated or used as a model for permeation studies. 

Reichl S, Muller-Goymann CC. The use of a porcine organotypic cornea construct for permeation studies from formulations containing befunolol hydrochloride. Int J Pharm 250 191-201 (2003). 

Burgalassi S, Monti D, Brignoccoli A, Fabiani O, Lenzi C, Pirone A, Chetoni P. Development of cultured rabbit corneal epithelium for drug permeation studies A comparison with excised rabbit cornea. J Ocul Pharmacol Ther 20 518-532 (2004). 

Reichl S, Bednarz J, Miiller-Goymann CC. Human corneal equivalent as cell culture model for in vitro drug permeation studies. Br J Ophthalmol 88 560-565 (2004). 

Tegtmeyer S, Papantoniou I, Miiller-Goymann CC. Reconstruction of an in vitro cornea and its use for drug permeation studies from different formulations containing pilocarpine hydrochloride. Eur J Pharm Biopharm 51 119-125 (2001). 

Meyer L, Bednarz J, Miiller-Goymann CC, Reichl S. Esterase activity of human organotypic cornea construct (HCC) as in vitro model for permeation studies. Ophthalmologe 102 971-980 (2005). 

Results of analogous permeation studies for the hydrophobic toluene molecule are shown in Fig. 20. Now the opposite selectivity pattern is observed i.e., toluene is preferentially transported in the R = -CieHjj membranes. This can be illustrated by defining the alternative selectivity coefficient aci6/0H (Table 3). As was the case for aoH/cia. the acie/on values increase with decreasing tubule diameter. In addition to toluene, acie/on values were determined for p-xylene and naphthalene in the i.d. = 1.9 nm membranes. The following acu/on values were obtained 2.8 for toluene, 6.2 for j9-xylene, and 16 for naphthalene. 

Zhang, L., Ma, C. and Mukerjee, S. 2003. Oxygen permeation studies on alternative proton exchange membranes designed for elevated temperature operation. Electrochimica Acta 48 1845-1859. 

Two-compartment glass permeation cells were used for solute permeation study as a function of temperature. Hydrocortisone was used as a model solute. The volume of each compartment was 6 cm and the area for the diffusion was 1.77 cm. Stirring was maintained at 600 rpm for all experiments via internal bar magnet. The donor compartment was filled with 2 wt% hydrocortisone aqueous solution (the hydrocortisone water solubility at 25°C is 280 pig/cm ) and the receptor compartment was filled with water. 

Based on the solution property of poly (DMAEMA-co-AAm) in response to temperature, the temperature dependence of equilibrium swelling of poly (DMAEMA-c6>-AAm) gel as a function of chemical composition was observed as shown in Figure 6. The transition temperature of copolymer gel between the shrunken and swollen state was shifted to the lower temperature with increases in AAm content in the gel network. This is attributed to the hydrogen bond in the copolymer gel network and its hydrophobic contribution to the LCST Copolymer II gel was selected as a model polymer network for permeation study because it showed the sharp swelling transition around 34°C. 

Interpenetrating polymer networks of PMAA/PNIPAAm were prepared. The material exhibited both pH and temperature sensitivities. The temperature sensitivity was verified by DSC studies. The permeation studies showed a significant size exclusion phenomenon of the IPNs. The influence of pH and temperature on the IPN permeability was investigated. A hypothetical mechanism was presented to explain the high permeability at high temperature and high pH. 

In vitro permeation studies employ a glass diffusion cell with the buccal tissue mounted between the two halves of the eell whieh may be filled with constantly stirred buffer solutions. The bueeal mueosa is exeised from the eanine, porcine, or rabbit eheek immediately after saerifiee. Permeation studies may provide meaningful results on the simultaneous proeesses of drug transport and metabolism in the tissue... 

Our studies on BLM system for separation of 7-ACA [23], cephalexin [24], CPC [26] using AHquat-336 as an anion exchange carrier revealed that pH gradient between the feed and stripping aqueous phases controlled the transport rate and separation efficiency. In some cases, uphill transport occurred with more than 90% recovery of cephalosporin molecules. BLM permeation study was also conducted for cephalothin, cefadroxil, cefazoHn, cefotaxim, cefaloridin, and 7-ACA for evaluation of initial flux. The initial permeation fluxes for various cephalosporins were well correlated with hydrophobicity [41] and the extraction equiHbrium constants. This seems to be in agreement with the idea that... 

---