川芎嗪的猪口腔粘膜透过特性

目的:确定川芎嗪(TMP)在猪口腔粘膜的主要渗透途径并用体外方法研究药物浓度、供给池pH和TMP油水分配系数对药物透过性的影响.方法:采用在线流通扩散池法进行透过实验,并用Scientist~((R))软件对数据进行处理.结果:稳态流量随药物浓度呈线性增大;透过系数和油水分配系数均随pH的增大而增大,且经细胞内的透过系数 9.05 ×10~(-6)cm·s~(-1)远远大于经细胞间的透过系数 2.99 ×10~(-7)cm·s~(-1).结论:药物经猪口腔粘膜吸收是一个被动扩散过程;药物转运的主要通道为细胞内途径.     

盐酸丁螺环酮对动物口腔粘膜的渗透性及其机理

目的　研究盐酸丁螺环酮对动物口腔粘膜的渗透性及渗透机理。方法　采用离体动物口腔粘膜的体外渗透试验方法,比较盐酸丁螺环酮对家兔、豚鼠、猪、羊和牛的口腔粘膜渗透性,考察药物浓度及溶液pH值的影响。结果　盐酸丁螺环酮对家兔口腔粘膜的渗透性最大,渗透速率随溶液pH值升高而增大,与药物浓度成正比。结论盐酸丁螺环酮通过口腔粘膜转运的方式为被动扩散,转运途径为穿过细胞途径     

Transbuccal Delivery of Acyclovir: I. In Vitro Determination of Routes of Buccal Transport

Purpose. To determine the major routes of buccal transport of acyclovir and to examine the effects of pH and permeation enhancer on drug permeation. Methods. Permeation of acyclovir across porcine buccal mucosa was studied by using side-by-side flow through diffusion cells at 37°C. The permeability of acyclovir was determined at pH range of 3.3 to 8.8. Permeability of different ionic species was calculated by fitting the permeation data to a mathematical model. Acyclovir was quantified using HPLC. Results. Higher steady state fluxes were observed at pH 3.3 and 8.8. The partition coefficient (1-octanol/buffer) and the solubility of acyclovir showed the same pH dependent profile as that of drug permeation. In the presence of sodium glycocholate (NaGC) (2–100 mM), the permeability of acyclovir across buccal mucosa was increased 2 to 9 times. This enhancement was independent of pH and reached a plateau above the critical micelle concentration of NaGC. The permeabilities of anionic, cationic, and zwitterionic species were 3.83 × 10^–5, 4.33 × 10^–5, and 6.24 × 10^–6cm/sec, respectively. Conclusions. The in vitropermeability of acyclovir across porcine buccal mucosa and the octanol-water partitioning of the drug were pH dependent. A model of the paracellular permeation of the anionic, cationic, and zwitterionic forms of acyclovir is consistent with these data. The paracellular route was the primary route of buccal transport of acyclovir, and the enhancement of transbuccal transport of acyclovir by sodium glycocholate (NaGC) appeared to operate via this paracellular route.     

Ex Vivo Correlation of the Permeability of Metoprolol Across Human and Porcine Buccal Mucosa

The pH partition theory proposes a correlation between fraction of unionized drug substance and permeability. The aim of this study was to compare the permeability of metoprolol and mannitol in ex vivo human and porcine buccal mucosa models at varying pH to validate whether the porcine permeability model is predictive for human buccal absorption. Human (n = 9-10) and porcine (n=6-7) buccal mucosa were mounted in a modified Ussing chamber, and the kinetics of metoprolol and mannitol transport was assessed for a period of 5.5 h with the pH values of donor medium set at 7.4, 8.5, and 9.0. In addition, hematoxylin-eosin and Alcian blue-van Gieson were used as tissue stains to evaluate the histology and the presence of acidic polysaccharides (e.g., mucins), respectively. The permeability of metoprolol was decreased in human buccal mucosa by almost twofold when compared with porcine buccal mucosa with a positive correlation (r² = 0.96) between the permeability assessed in porcine and human buccal mucosa. There was no change in the degree of either epithelial swelling or desquamation when treating with the pH 9.0 donor medium for 5.5 h. These data suggest that buccal mucosa from pigs can be used to predict human buccal absorption.     

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.     

An investigation of the chick chorioallantoic membrane as an alternative model to various biological tissues for permeation studies

Objectives The chick chorioallantoic membrane (CAM) was explored as a biological membrane for use in the study of drug permeation with a Franz diffusion cell. Methods The CAM was removed from fertilized chicken eggs of embryo age 9–18 days. The permeation profiles of nicotine through the fresh CAM were first obtained with a Franz diffusion cell. The permeation profiles of nicotine through frozen CAM, snake skin, pig skin, pig retina and pig buccal mucosa were also determined and compared with those of the fresh CAM. Key findings The permeability coefficient of the CAM varied with its age. The CAM at embryo age 13 was the most robust, showing the lowest standard error in permeability. It was thus chosen for comparative studies with snake skin, pig skin, retina and buccal mucosa. The CAM was found to be most similar to the buccal mucosa in terms of permeation profile and permeability coefficient values. Frozen CAM was also found to have a higher permeability coefficient than fresh CAM. The enhanced permeability was attributed to freezing, which affected the integrity of the CAM structure. Conclusions From the findings, CAM shows potential as an alternative to the pig buccal mucosa as an in‐vitro buccal model. The robustness of the CAM for drug permeation studies is affected by its age.     

Characterization of captopril sublingual permeation: determination of preferred routes and mechanisms.

Although sublingual captopril has been used clinically to treat hypertensive emergencies, a mechanistic understanding of sublingual permeation will facilitate the optimization of drug delivery. A correlation of sublingual steady-state flux with donor captopril concentration in a porcine model showed the absence of saturability and suggested a passive diffusion permeation mechanism. A simultaneous evaluation of permeability and partition coefficient demonstrated that the paracellular route is the predominant pathway for sublingual permeation. The enhancement factors of specific ion permeabilities in the presence of tight junction perturbants indicated that although the paracellular pathway is preferred by the ionized species of captopril, the lipophilic transcellular pathway is preferred by the neutral, un-ionized species.     

pH-dependent functional activity of P-glycoprotein in limiting intestinal absorption of protic drugs: kinetic analysis of quinidine efflux in situ

The purpose of this investigation is to evaluate the quantitative contribution of pH-dependent passive permeability on the functional activity of P-glycoprotein (P-gp) in limiting intestinal absorption of weakly basic drugs, in order to include this effect in prediction models. pH-dependent octanol/buffer partition coefficient, artificial membrane permeability and in situ rat intestinal permeability of quinidine were determined in the physiological pH range of gastrointestinal tract. In situ permeability, as a function of luminal pH, was also determined in the presence of P-gp inhibitor, verapamil (500 microM). Octanol/buffer partition coefficient, transport across artificial membrane, and rat in situ permeability showed high pH-dependency. Absorption quotient (AQ), calculated from in situ permeability to express the functional activity of P-gp, declined with increase in luminal pH or increase in luminal quinidine concentration because of the increased passive permeability or saturation of P-gp. AQ was 0.57 +/- 0.02 and 0.41 +/- 0.05, while passive permeability was 0.32 +/- 0.01 x 10(-4) cm/sec and 0.43 +/- 0.02 x 10(-4) cm/sec, in jejunum and ileum, respectively, at pH 7.4. Further, apparent Michaelis-Menten constants (K(M), J(P-gp,max)) for the quinidine efflux in jejunum indicated that efflux activity was more at luminal pH 4.5 over pH 7.4. K(M) values for jejunum quinidine efflux at pH 4.5 and pH 7.4 were determined to be 77.63 +/- 10.90 and 22.86 +/- 5.22 microM, with J(P-gp,max) values of 1.47 +/- 0.08 and 0.62 +/- 0.04 nM/cm2/sec, respectively. AQ vs passive permeability showed significant relationship indicating dependency of P-gp-mediated efflux on pH-dependent passive permeability, which is dictated by ionization status for a protic or ampholytic drug. In conclusion, an orally administered drug is absorbed from various segments of intestine, which inherit difference in luminal pH, transcellular permeability and P-gp expression. In situ data suggests that pH-dependency and regional variability in passive permeability of protic substrates significantly influence their P-gp-mediated efflux and may have implications on predictions of the in vivo drug absorption.     

Permeation of several drugs through keratinized epithelial-free membrane of hamster cheek pouch

The hamster cheek pouch mucosa was selected as a substitute for the human buccal mucosa in an in vitro permeation study. Considering that a keratinized layer is not present in the human buccal mucosa, keratinized epithelial-free hamster cheek pouch (KEF-membrane) was prepared by chemical splitting. To confirm the usefulness of the KEF-membrane, a permeation study was conducted using several drugs with different lipophilicities. The permeability coefficient of hydrophilic drugs through the KEF-membrane (Pkef) was significantly greater than that through a viable KEF-membrane (Pkef-viable), which was estimated by using the permeability coefficient of the viable full-thickness membrane and that of the keratinized layer. On the other hand, the Pkef values of lipophilic drugs were comparable with the Pkef-viable values. Furthermore, the ratio of these P values (Pkef/Pkef-viable) decreased with increasing lipophilicity of drugs. These findings indicate that the KEF-membrane may be useful for buccal permeation studies of lipophilic drugs.     

Buccal permeation of buspirone: mechanistic studies on transport pathways

The transport of buspirone across porcine buccal mucosa in vitro was investigated to elucidate the mechanisms of transport and permeation enhancement. The apparent permeability increased with an increase in pH to a lesser degree than the dependence of the partition coefficient. Whereas the lipophilic or apparent transcellular pathway was found to be the dominant buccal transport route for buspirone, ionized species contributed significantly to transport at acidic pH. At neutral pH, bile salts did not increase the flux of the lipophilic species of buspirone, and in contrast to its effect on stratum corneum, aqueous propylene glycol alone did enhance the flux of buspirone across buccal mucosa in vitro. The use of an enhancer combination containing 5% oleic acid, 40% propylene glycol in buffer resulted in the greatest flux, and this was consistent with the effect of this combined enhancer on the flux of lipophilic drugs across stratum corneum and the dominance of the transcellular pathway for buspirone at neutral pH.     

Development of a mucoadhesive and permeation enhancing buccal delivery system for PACAP (pituitary adenylate cyclase-activating polypeptide)

The buccal mucosa providing direct entry into the systemic circulation appears to be a potential site for the delivery of PACAP (pituitary adenylate cyclase-activating polypeptide), a new therapeutic agent in the treatment of type 2 diabetes. In order to reach a sufficient buccal bioavailability a drug delivery system with strong permeation enhancing and mucoadhesive properties is needed. In this study the enhancing effect of a strongly mucoadhesive chitosan-thioglycolic acid (TGA) conjugate in combination with reduced glutathione (GSH) on the permeation of PACAP across the buccal mucosa was investigated. The apparent permeability coefficient (P(app)) of PACAP in buffer only was (5.7 +/- 3.1) x 10(-8), while in the presence of chitosan-TGA conjugate (1%) a P(app) of (20.0 +/- 3.4) x 10(-8) was achieved. The combination of chitosan-TGA (1%) with GSH (2%) led to an improvement of the P(app) up to (57.3 +/- 31.7) x 10(-8). Release studies of PACAP demonstrated that a controlled release can be provided from tablets consisting of chitosan-TGA at a pH of 5, whereas more than twice as much was released from chitosan-TGA tablets pH 4. According to the combination of permeation enhancing properties, controlled drug release and the mucoadhesive character, chitosan-TGA conjugates represent a promising tool for the buccal administration of PACAP.     

Enhanced<Emphasis Type="Italic">ex vivo</Emphasis> buccal transport of propranolol: Evaluation of phospholipids as permeation enhancers

The aim of the present study was to evaluate the effects of two phospholipid permeation enhancers, lysophosphatidylcholine (LPC) and didecanoylphosphatidylcholine (DDPC), along with a fusidic acid derivative, sodium taurodihydrofusidate (STDHF) and ethanol (EtOH) on the buccal transport of propranolol hydrochloride (PPL) using an ex vivo buccal diffusion model. The permeation rate of [3H]PPL as measured by steady-state fluxes increased with increasing EtOH concentration. A significant flux enhancement (P<0.05) was achieved by EtOH at 20 and 30 %v/v concentrations. At a 0.5 %w/v permeation enhancer concentration, the buccal permeation of [3H]PPL was significantly enhanced by all the enhancers studied (i.e., LPC, DDPC and STDHF) compared to the control (phosphate-buffered saline pH 7.4, PBS). LPC and DDPC displayed a greater degree of permeation enhancement compared with STDHF and EtOH-PBS mixtures with an enhancement ratio of 3.2 and 2.9 for LPC and DDPC, respectively compared with 2.0 and 1.5 for STDHF and EtOH:PBS 30:70 %v/v mixture, respectively. There was no significant difference between LPC and DDPC for the flux values and apparent permeability coefficients of [3H]PPL. These results suggest that phospholipids are suitable as permeation enhancers for the buccal delivery of drugs.     

Buccal permeation of [D-Ala(2), D-Leu(5)]enkephalin from liquid crystalline phases of glyceryl monooleate

The ex vivo buccal permeability of a [D-Ala(2), D-Leu(5)]enkephalin (DADLE) and glyceryl monooleate (GMO) was examined from the cubic and lamellar liquid crystalline phases of GMO and aqueous phosphate-buffered saline (pH 7.4, PBS) solution across excised porcine buccal mucosa mounted in a Franz cell. GMO was released in vitro from the liquid crystalline phases indicating the erosion of the liquid crystal matrices. GMO released from the liquid crystalline matrices permeated the porcine buccal mucosa with fluxes of 0.10+/-0.03 and 0.07+/-0.00%/cm(2) per h for the cubic and lamellar phases, respectively. The flux of DADLE (1.21+/-0.32 and 1. 15+/-0.11%/cm(2) per h for the cubic and lamellar phases, respectively) from the liquid crystalline phases was significantly enhanced by the GMO compared with PBS solution (0.43+/-0.08%/cm(2) per h) during the initial permeation phase (t<3 h). Our results suggest that the cubic and lamellar liquid crystalline phases can be considered as promising buccal drug carriers for peptide drugs as well as acting as permeation enhancers.     

Transbuccal permeation of a nucleoside analog, dideoxycytidine: effects of menthol as a permeation enhancer

The use of a safe and effective permeation enhancer is paramount to the success of a buccal drug delivery system intended for systemic drug absorption. The enhancing effects of menthol (dissolved in an aqueous buffer in the absence of co-enhancers) on buccal permeation of a model hydrophilic nucleoside analog, dideoxycytidine (ddC), were investigated. In vitro transbuccal permeation of ddC was examined using freshly obtained porcine buccal mucosa. The experiments were carried out in side-bi-side flow through diffusion cells. Permeation enhancement studies were performed with varying concentrations of l-menthol dissolved in Krebs buffer solutions containing ddC. Partition coefficient experiments were carried out to probe into the mechanism of permeation enhancing properties of l-menthol and DSC studies were conducted to determine if there is a eutectic formation between ddC and l-menthol at various concentrations. Permeation of ddC increased significantly (P<0.05) in the presence of l-menthol independent of the concentration of the terpene. The apparent 1-octanol/buffer partition coefficient (log K(p)) of ddC was significantly (P<0.05) increased in presence of l-menthol and was also independent of the enhancer concentration. However, the tissue/buffer partition coefficient (log K'(p)) data showed a concentration dependent increase of log K'(p) in presence of l-menthol. Since log K'(p) is a measure of drug binding to the tissue in addition to drug partitioning, binding of ddC to the buccal tissue may provide an explanation for the concentration dependent increase in these values.     

Carbopol 934-Sodium Alginate-Gelatin Mucoadhesive Ondansetron Tablets for Buccal Delivery: Effect of pH Modifiers

The present work aims at developing mucoahesive tablets of ondansetron hydrochloride using bioadhesive polymers like carbopol-934, sodium alginate and gelatin. Tablets prepared by direct compression using different polymer with varying ratio were evaluated for hardness, friability, uniformity of weight, disintegration time, microenvironmental pH, bioadhesion and in vitro release. Hardness, friability disintegration time and drug release were found within pharmacopoeial limit. Microenvironmental pH decreased whereas bioadhesive strength, water uptake, and in vitro release increased with increase in carbopol-934. Increasing sodium alginate and gelatin increased the microenviromental pH and decreased bioadhesive strength, water uptake and in vitro release. With a view to investigate the modulation of drug release from formulation by addition of pH modifiers viz. citric acid and sodium bicarbonate, the tablets with carbopol-934 (2.0), sodium alginate (0.5) and gelatin (6.5) were used and the effect of pH modifiers on microenvironmental pH, bioadhesion, water uptake, in vitro permeation and in vitro release was studied. Microenvironmental pH, bioadhesive strength, water uptake, in vitro release and permeation decreased with increasing concentration of citric acid whereas microenvironmental pH, water uptake and release were enhanced and bioadhesive strength was lowered with increase in sodium bicarbonate. Present study demonstrates carbopol-934, sodium alginate, gelatin polymer system with added pH modifier can be successfully formulated for buccal delivery of ondansetron with desired release profile.     

Effect of surfactants and pH on naltrexone (NTX) permeation across buccal mucosa

The objective of this pre-formulation study was to systematically investigate the effects of two surfactants (Brij 58(?) and Tween 80(?)) and change in solution pH on in vitro permeation of naltrexone HCl (NTX-HCl) across tissue engineered human buccal mucosa. For the study, 10mg/ml solutions of Tween 80(?) (0.1 and 1%, w/v) and Brij 58(?) (1%, w/v) were prepared in standard artificial saliva buffer solution (pH 6.8). For studying pH effects, solution pH was adjusted to either 7.5 or 8.2. As controls, three concentrations of NTX-HCl (2.5, 10 and 25mg/ml) were prepared. Using NTX standard solution (10mg/ml; pH 6.8), the permeation was observed between in vitro human and ex vivo porcine mucosa. It was observed that Brij 58(?) increased the permeation rates of NTX significantly. The flux of 10mg/ml solution (pH 6.8) increased from 1.9 ± 0.6 (× 10(2)) to 13.9 ± 2.2 (× 10(2))μg/(cm(2)h) (approximately 6-fold) in presence of 1% Brij 58(?). Increasing pH of NTX-HCl solution was found to increase the drug flux from 1.9 ± 0.6 (× 10(2)) (pH 6.8) to 3.0 ± 0.6 (× 10(2)) (pH 7.4) and 8.0 ± 3.5 (× 10(2)) (pH 8.2)μg/(cm(2)h), respectively. Histological analyses exhibited no tissue damage due to exposure of buccal tissue to Brij 58(?). The mean permeability coefficients (K(p)) for 2.5, 10 and 25mg/ml solutions of NTX-HCl (pH 6.8) were 5.0 (× 10(-2)), 1.8 (× 10(-2)) and 3.2 (× 10(-2))cm/h, respectively, consistent with data from published literature sources. Increase of NTX flux observed with 1% Brij 58(?) solution may be due to the effects of ATP. Increase in flux and the shortening of lag time observed by increasing in solution pH confirmed earlier finding that distribution coefficient (logD) of NTX is significantly affected by small increments in pH value and therefore plays an important role in NTX permeation by allowing faster diffusion across tissue engineered human buccal tissue.     

Physicochemical characterization and evaluation of buccal adhesive patches containing propranolol hydrochloride

Buccal adhesive patches containing 20 mg of propranolol hydrochloride were prepared using solvent casting method. Chitosan was used as a natural bioadhesive polymer. Patches were prepared at different ratios of PVP K-30 and evaluated for various physicochemical characteristics such as weight variation, drug content uniformity, folding endurance, surface pH, ex-vivo mucoadhesive strength, ex-vivo residence time, in vitro drug release and in vitro buccal permeation study. Patches exhibited sustained release over a period of 7 hours. The mechanism of drug release was found to be Non-Fickian diffusion. Addition of PVP K-30 generally enhanced the releasing rate. The ex-vivo mucoadhesive strength was performed using sheep buccal mucosa on modified physical balance. Optimized patches (batch F4) showed satisfactory bioadhesive strength (9.6 degrees 2.0 gram) and ex vivo residence time (272 degrees 0.25 minutes). Swelling index was proportional to PVP K-30. The surface pH of all batches was within satisfactory limit (7.0+/-1.5) and hence patches would not cause irritation in the buccal cavity. Good correlation was observed between in vitro drug release and in vitro drug permeation with correlation coefficient of 0.9364. Stability of optimized patches was performed in natural human saliva showed that both drug and dosage forms were stable in human saliva.     

pH值对马来酸噻吗洛尔角膜透过性的影响

目的　研究pH值对马来酸噻吗洛尔(TM)角膜透过性的影响,为其处方设计提供理论依据。方法　测定TM的表观油水分配系数(DC_app)。用体外扩散实验考察各种pH值条件下离体兔眼角膜对TM的透过性。结果　由DC_app求得TM的分配系数和pKa分别为63.63和9.17。在生理介质中,TM的表观透过系数为1.43×10^-5cm·s^-1。随着pH值由6.65升高至9.20 ,TM透过角膜的滞后时间缩短到1/20 ,累积透过量增加1.3倍。计算得到游离型噻吗洛尔的角膜透过系数为解离型的3.3倍。结论　噻吗洛尔主要以分子状态经细胞内途径透过角膜,且角膜上皮是其扩散的主要屏障。     

Mechanism of transcorneal permeation of pilocarpine

The mechanism of transcorneal permeation of pilocarpine has been investigated in relation to the physicochemical properties of the permeating species and its interaction with the membrane biophase. In vitro corneal transport experiments suggested the transport of un-ionized as well as ionized pilocarpine species across the corneal membrane. However, the permeability of the ionized pilocarpine species was 4.818 x 10(-6) cm s-1, a value only one-half of that obtained for the un-ionized pilocarpine species (9.744 x 10(-6) cm s-1). Further evidence of ion transport across the cornea was obtained by examining the transport of the quaternized pilocarpine compound (i.e., pilocarpinium methyl iodide). The quaternized compound had a corneal permeability of 4.66 x 10(-6) cm s-1, similar to that obtained for the ionized pilocarpine species. The lipoidal epithelial layer of the corneal membrane appears to be the predominant barrier to the transport of polar species. Therefore, the transport of pilocarpinium cations across the lipoidal epithelium might have occurred as tightly bound ion pairs with dihydrogen phosphate and/or nitrate counter ions. Excellent linear correlation has been obtained between pilocarpine corneal permeability and the 1-octanol-water partition coefficient as a function of the state of ionization of pilocarpine. The ratio of un-ionized to ionized drug permeability across the cornea is expected to be much higher for drugs with higher 1-octanol-water partition coefficients.     

A membrane model of the human oral mucosa as derived from buccal absorption performance and physicochemical properties of the β-blocking drugs atenolol and propranolol

The buccal absorption characteristics and physicochemical properties of the β-adrenoceptor blocking agents propranolol and atenolol have been investigated to evaluate their permeation properties across biological lipid membranes. The dissociation constants, solubilities of free base, and n-heptane partition coefficients show that propranolol in its unionized form is much more lipophilic than atenolol, both drugs being bases with a similar pKa. Buccal absorption was studied under conditions of varying drug concentration, contact time, and pH, and controlled through the use of a non-absorbable marker. The absorption findings are in general agreement with the pH-partition theory. A new compartmental diffusional model that includes membrane storage and a hypothetical ‘aqueous pH-buffering surface system’ allowed a more exhaustive interpretation to be made. A method for the estimation of the intrinsic pH and buffer capacity of the postulated surface system from drug pH-absorption data and partition coefficients alone is described. With human oral mucosa the intrinsic pH was near 6·7, and the buffering capacity of the system (expressed as the ratio ΔpH/ΔpH eff) about 2·86. The method was validated using published absorption data from the rat small intestine. Absorption of unionized drug through pores is shown to be negligible in the buccal absorption situation. The time course of absorption suggests membrane storage of lipophilic compounds; the in vivo partition coefficient of unionized propranolol relative to the mucous membrane could be calculated for the peusdo-steady state of absorption, i.e. the partition equilibrium between mouth content and membrane, to be approximately 776; this value is of the same order as the in vitro partition coefficient for the erythrocyte/plasma system. The lipid biophase of the buccal membrane is estimated semiquantitatively to be of intermediate polarity (? = 3–4).