In silico model of drug permeability across sublingual mucosa.

The objective of this work was to develop an in silico model to predict the sublingual permeability of a drug based on physicochemical descriptors of a molecule. Fourteen model drugs with diverse physicochemical properties were selected for this study. Molecular volume, molecular weight, logP, logD (pH 6.8), pKa, total polar surface area, hydrogen bond acceptors and donors (HBD), number of rotatable bonds, solubility (pH 6.8), and melting point were used as molecular descriptors. Apparent permeability coefficients (Pe) of drugs across porcine sublingual mucosa were determined experimentally. Multiple linear regression (MLR) was used to develop the model with permeability as the response variable and various descriptors as the predictive variables. Q(2), the cross-validated correlation coefficient, was used to assess the prediction ability of the model. MLR analysis showed that HBD and logD were the significant descriptors (P<0.05, Q(2)=0.88) in the sublingual permeability model. The resulting model is expressed as the following equation:An excellent fit with R(2) of 0.93 was obtained between experimental and predicted permeabilities. The analysis of contributions of molecular descriptors to sublingual permeability revealed the molecular structure basis of permeation across sublingual mucosa. In conclusion, an in silico model was developed to predict sublingual permeability of drugs using known descriptors for evaluating the feasibility of sublingual drug delivery.

In silico prediction of drug permeability across buccal mucosa.

PURPOSE: To develop and validate a computational model capable of predicting buccal permeability based on various structural and physicochemical descriptors. METHODS: Apparent permeability coefficients (K(p)) of 15 different drugs across porcine buccal mucosa were determined. Multiple linear regression (MLR) and maximum likelihood estimations (MLE) were used to develop the model based on a training set of 15 drugs with permeability as the response variable and the various descriptors as the predictor variables. The final model was validated with an external data set consisting of permeability values obtained from the literature. RESULTS: Drug permeabilities ranged from 30 x 10(-6) (nimesulide) to 3.3 x 10(-9) cm/s (furosemide). Regression analysis showed that 95% of the variability in permeability data can be explained by a model that includes molecular volume, distribution coefficient at pH 6.8, number of hydrogen bond donors, and number of rotatable bonds. Smaller molecular size, high lipophilicity, lower hydrogen bond capability and greater flexibility were important for permeability. The buccal model was found to have a good predictive capability. CONCLUSION: A simple model was developed and validated for predicting the buccal drug permeability. This model will be useful in assessing the feasibility of drugs for transbuccal delivery.

HPLC detection of marker compounds during buccal permeation enhancement studies.

A simple, isocratic and sensitive high-performance liquid chromatographic (HPLC) method was developed and validated for the simultaneous analysis of marker compounds for the aqueous (atenolol) and lipoidal (lidocaine) pathways during permeation enhancement studies across the buccal mucosa. A reversed-phase C18 column with UV detection at 224 nm was used for chromatographic separation and analysis, respectively. The mobile phase contained a mixture of acetonitrile-methanol-monobasic potassium phosphate (pH 3.0; 50 mM) (7.5:7.5:85, v/v/v). The permeabilities of marker compounds were determined across porcine buccal mucosa, which was either untreated (control) or pre-treated with sodium glycodeoxycholate (GDC-Na; 10 mM). The calibration curve showed good linearity over the concentration range of 0.1-25 microg/mL. The intra- and inter-day accuracy and precision were also within acceptable limits. The application of this method was demonstrated by an increase in the permeation of atenolol after pre-treatment with GDC-Na while the permeation of lidocaine did not change significantly.

Effect of thermodynamic activities of the unionized and ionized species on drug flux across buccal mucosa.

The objective of this work was to delineate the contribution of thermodynamic activities of ionized and unionized species on buccal drug permeation. The flux and permeability of a model acidic (nimesulide) and basic (bupivacaine) drug were determined across porcine buccal mucosa at different pH conditions. Thermodynamic activities of ionized and unionized drug species were expressed as degree of saturation (DS) and also calculated using a modified Debye-Hückel equation. Flux of model drugs across buccal mucosa depended on pH and donor chamber concentration. For saturated solution, the DS or the relative activity of the unionized species remained constant (DS(unionized) = 1) under different pH conditions. The DS of ionized species (DS(ionized)), however, increased (nimesulide) or decreased (bupivacaine) with an increase in pH, resulting in either an increased (nimesulide) or decreased (bupivacaine) flux. On the contrary, at subsaturated drug concentrations in the donor chamber, a decrease in nimesulide flux was observed with an increase in pH due to a decrease in DS(unionized). In case of a subsaturated bupivacaine solution, DS(unionized) increased with pH, thereby increasing the flux. In conclusion, thermodynamic activities of both ionized and unionized species of a drug contribute to flux across the buccal mucosa. The ionized and unionized species contributed equally to total flux when 90% of the drug was ionized.

Transport of a novel anti-cancer agent, fenretinide across Caco-2 monolayers.

Fenretinide is a synthetic retinoid with chemotherapeutic activity against various malignancies. Upon oral administration to animals, fenretinide was found to be incompletely absorbed and excreted primarily in feces. The purpose of this study was to determine the possible reasons for poor oral absorption of fenretinide using Caco-2 cell monolayers. To achieve this purpose, a solid dispersion of fenretinide with Povidone K25 was used. The apparent permeability coefficient (P(app)) of fenretinide across Caco-2 monolayers in the presence of bovine serum albumin (BSA) in the receiver was determined. Apical to basolateral (AP-BL) and basolateral to apical (BL-AP) flux studies were performed to determine the role of an efflux mechanism. In the presence of 4% BSA in the receiver, the P(app) was found to be (8.8 +/- 0.5) x 10(-8) cm/sec. The AP-BL flux increased linearly with an increase in fenretinide concentration (125-640 microM) in the presence of 4% BSA in the receiver. Efflux and paracellular pathways played an insignificant role in the permeability of fenretinide. A significant amount of drug, approximately 13-15% of the initial amount accumulated in the cell membrane. The amount of fenretinide in the donor decreased by 16% over a 3 h period. However, only 0.12% of the initial amount was found in the receiver. Also, the P(app) increased with an increase in plasma protein concentration in the receiver. On the basis of these results, the poor permeability of fenretinide can be attributed to its accumulation in the lipophilic cell membrane and poor partitioning into the receiver medium.