Effect of pH on in vitro permeation of ondansetron hydrochloride across porcine buccal mucosa

The influence of drug concentration, pH in donor chamber, and 1-octanol/buffer partition coefficient on transbuccal permeation of ondansetron hydrochloride (pKa, 7.4) across porcine buccal mucosa was studied by using an in-line Franz type diffusion cell at 37 degrees C. The pH was adjusted to several values and the solubility of the drug in different pH was measured. Solubility of ondansetron hydrochloride decreases with increasing pH. The permeability of the drug was evaluated at different donor pH and drug concentrations. Permeability of un-ionized (Pu) and ionized (Pi) species of drug was calculated by fitting the data to a mathematical model. The steady state flux increased linearly with the donor concentration (r2 = 0.9843) at pH 7.4. The permeability coefficient and the partition coefficient of the drug increased with increasing pH. The values of Pu and Pi were 4.86 x 10(-6) cm/sec and 7.18 x 10(-7) (c)m/sec, respectively. The observed permeability coefficients and the permeability coefficients calculated from the mathematical model at various pH showed good linearity (r2 = 0.9799). The total permeability coefficient increased with increasing the fraction of un-ionized form of the drug. The drug permeated through buccal mucosa by a passive diffusion process. The non-ionized species of drug penetrated well through buccal mucosa and the permeation was a function of pH. Transbuccal delivery is a potential route for the administration of ondansetron hydrochloride.     

Stability of intravenous nitroglycerin solutions

The stability of intravenous nitroglycerin solutions prepared from either sublingual tablets or a 10% nitroglycerin-lactose adsorbate (powder) was examined under various conditions. Nitroglycerin concentration was measured by high-pressure liquid chromatography. Nitroglycerin stock solutions (0.8-1.0 mg/ml) prepared from tablets or powder in either 0.9% saline were stored upright in refrigerated multidose vials for 6 months without a significant decrease in concentration. Storage of the solutions at room temperature resulted in a 20% loss after 3 months. Intravenous nitroglycerin solutions (0.2 mg/ml) prepared from tablets or powder in 0.9% saline or 5% dextrose in water were stored in glass intravenous bottles at temperatures between 6 and 38 degrees for 24 hr with a maximum loss of 18%. Stability was not affected by light. Solutions in contact with rubber stoppers, plastic intravenous bags, or plastic administration sets exhibited decreased nitroglycerin concentration characteristic of sorption. Nitroglycerin concentrations decreased to a greater extent when the administration sets were equipped with plastic burets. Brief contact of nitroglycerin solutions with a plastic syringe did not result in decreased concentration. The stability of intravenous nitroglycerin solutions packaged in glass was not dependent on light, the vehicle, or the source of nitroglycerin. Contact with rubber or plastic surfaces should be minimized.     

The availability of nitroglycerin from parenteral solutions

The availability of nitroglycerin from solutions infused from Viaflex plastic infusion bags or glass infusion bottles through Buretrol plastic giving sets has been examined. Each of the individual components of the infusion bag/giving set system (i.e. infusion bag, burette and infusion tubing) sorbed nitroglycerin to a significant extent. It was found that the extent and rate of nitroglycerin disappearance from solutions stored in each of the components were in the rank order: tubing > burette > infusion bag. The disappearance kinetics of nitroglycerin from solutions stored in each component was more accurately described by a ‘diffusion’ model than by the ‘two compartment kinetic’ model reported previously. The dimensions of the components and the volume of solution used were determinants of the rate and extent of nitroglycerin disappearance. In simulated infusions of nitroglycerin through plastic infusion bag (or glass bottle)/giving set system the flow rate of solution through the plastic infusion tubing affected the concentration of nitroglycerin in the effluent and the extent of sorption by the components of the infusion delivery system. The loss of nitroglycerin in these studies could be accounted for solely by the sorption of nitroglycerin by the plastic components of the infusion bag/giving set system.     

Stability of nitroglycerin injection determined by gas chromatography.

The stability of nitroglycerin injection was studied over an eight-week period. Gas-liquid chromatographic assay and thin-layer chromatography were used to study the stability in relation to sorption by rubber and plastic (Viaflex), light and the effect of two diluents (5% dextrose in water and 0.9% sodium chloride for injection). More nitroglycerin was lost from vials with rubber closures, and the loss occurred at a faster rate when compared with nitroglycerin packaged in ampuls. There was no difference in the loss of nitroglycerin from injection packaged in ampuls when stored in the light or in the dark, or in the loss of nitroglycerin from two diluents, 5% dextrose in water and 0.9% sodium chloride for injection, packaged in glass bottles. A 70.4% greater loss of nitroglycerin occurred from Viaflex bags than from glass bottles. Loss of nitroglycerin in this study may have been characterized by reversible first-order kinetics.     

Diffusion modeling of percutaneous absorption kinetics: 3. Variable diffusion and partition coefficients, consequences for stratum corneum depth profiles and desorption kinetics

Stratum corneum (SC) desorption experiments have yielded higher calculated steady-state fluxes than those obtained by epidermal penetration studies. A possible explanation of this result is a variable diffusion or partition coefficient across the SC. We therefore developed the diffusion model for percutaneous penetration and desorption to study the effects of either a variable diffusion coefficient or variable partition coefficient in the SC over the diffusion path length. Steady-state flux, lag time, and mean desorption time were obtained from Laplace domain solutions. Numerical inversion of the Laplace domain solutions was used for simulations of solute concentration-distance and amount penetrated (desorbed)-time profiles. Diffusion and partition coefficients heterogeneity were examined using six different models. The effect of heterogeneity on predicted flux from desorption studies was compared with that obtained in permeation studies. Partition coefficient heterogeneity had a more profound effect on predicted fluxes than diffusion coefficient heterogeneity. Concentration-distance profiles show even larger dependence on heterogeneity, which is consistent with experimental tape-stripping data reported for clobetasol propionate and other solutes. The clobetasol propionate tape-stripping data were most consistent with the partition coefficient decreasing exponentially for half the SC and then becoming a constant for the remaining SC.     

Ethanol: water mutually enhanced transdermal therapeutic system II: skin permeation of ethanol and nitroglycerin

An optimal concentration range of aqueous ethanol produces 5-10-fold increases in nitroglycerin flux across skin and ethanol skin permeation that are far greater than reported previously. For aqueous ethanol solutions saturated with nitroglycerin with an ethanol volume fraction less than or equal to 0.7, the flux of nitroglycerin across skin is linear with the ethanol flux and is traced to a linear solubility relationship and a constant diffusion coefficient.     

Gas-liquid chromatographic determination and pharmacological studies of six clinically-used local anesthetics.

A gas-liquid chromatographic method was developed for the simultaneous assay of six local anesthetics, including amethocaine, bupivacaine, etidocaine, lignocaine, mepivacaine and prilocaine, in biological samples. These drugs and internal standard (clomipramine) in basified samples were extracted into 5 ml n-hexane, and the extract was analyzed by a temperature programming method (the column temperature was kept at 210 degrees C for 5 min, then raised to 280 degrees C at the rate of 10 degrees C/min) using a 3% W/W SP 2250 glass column (2 m x 2 mm i.d.) connected to a nitrogen sensitive detector. The injector and detector temperature were maintained at 300 degrees C. The pKa values, partition coefficients (K) and buccal absorptions of six local anesthetics were determined. The results showed that the onset of action and duration could be shown to be dependent on the pKa values and partition coefficients, respectively. A relatively good positive correlation (r = 0.991) was observed between the percentage of buccal absorption at pH 7.4 and the logarithms of K in n-hexane-S?rensen buffer system, and hence the more lipid soluble the local anesthetic, the greater the buccal absorption. The buccal absorption test supplemented by the n-hexane-buffer partition coefficient could be used as indicators for the ability of the anesthetics to penetrate biological barriers. The lipid penetration of the drugs, and thus their pharmacological action, is also influenced by the pKa values of the anesthetics.     

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.     

Drug release from diffusion pellets coated with the aqueous ethyl cellulose dispersion Aquacoat ECD-30 and 20% dibutyl sebacate as plasticizer: partition mechanism and pore diffusion.

The release of the hydrophilic etofylline and the lipophilic propyphenazone (octanol/water partition coefficient PC = 0.35 and 119, respectively) from diffusion pellets coated with the aqueous ethyl cellulose dispersion Aquacoat ECD-30 and 20% dibutyl sebacate (DBS) as plasticizer is investigated as a function of pH. The relatively slow release is not constant, due to the broad distribution of different release rates within the pellet population and the non-linearity of the release of each diffusion pellet itself. The release proceeds according to a partition mechanism at a pH < 6. The partition mechanism is not influenced by the osmotic pressure difference between the release medium and the saturated solution within the diffusion pellets. The diffusion coefficients of different drugs in the plasticized coating are in the range 1 to 5 x 10(-8) cm2/s. At a of pH > 6 an additional hydrophilic pathway without partition exists if the diffusion pellets did not have any contact with an acidic medium. This is due to the strongly increased water uptake of more than 20% by the coatings as a consequence of the dissociation of carboxyl groups in the ethyl cellulose.     

Dynamics of clomethiazole edisylate interaction with plastic infusion systems

The dynamics of the interaction of clomethiazole edisylate (1) with polyvinyl chloride and cellulose propionate, the main plastics used in the manufacture of infusion bags and sets, was examined. An experimental system in which the plastic was either open or closed to the environment was used to determine the relative contribution of the sorption and permeation processes to loss from solutions of clomethiazole edisylate (I) in contact with the plastic infusion systems. Sorption by the plastic infusion materials accounted for most of the drug loss, while permeation into the external environment accounted for the remainder. The sorption and permeation into and through polyvinyl chloride was temperature dependent. The diffusion coefficient and permeation rate constant both increased with temperature, while the polyvinyl chloride-water partition coefficients were independent of temperature. The activation energy for the diffusion in polyvinyl chloride was 13.5 kcal/mol. The permeability of the infusion bag plastic and the evaporation across an unstirred air boundary layer adjacent to the external surface of the plastic both appeared to contribute to the overall diffusional resistance encountered in the permeation process. The plastic-water partition coefficients are independent of initial concentration, suggesting that the concentration-dependent loss of the drug from solutions stored in plastic infusion bags and burets is a result of the greater diffusivity of the drug in the plastic at the higher initial concentrations. Plasticization of the polymers by the drug is indicated by the increase in the diffusivity of the drug in polyvinyl chloride and cellulose propionate, the increase in the rate and extent of sorption of a radiolabeled marker (diazepam) by the plastic, and the decreased stiffness of polyvinyl chloride exposed to higher concentrations of the drug.     

In vitro and in situ absorption of etamsylate. Part 2: In vitro and in situ properties.

The oil to water partition behaviour, the diffusion across artificial lipid barriers and the in situ gastro-intestinal absorption of the haemostatic etamsylate were studied. Very small partition coefficients were obtained (0.015-0.13) which are independent on the pH (range 1 to 6) and the nature of the organic phase (n-hexane, n-octanol, ethylacetate). Using the Sartorius membrane stimulator small diffusion constants were calculated both at phase I pH 6.0 (kd = 7.82.10(-3)cm.min-1) and especially at phase I pH 1.2 (kd = 4.7.10(-6) cm x min-1). The in situ absorption experiments on male Wistar rats showed very poor gastric absorption, but considerable intestinal absorption rate (absorption rate constant ka = 0.39 +/- 0.19 h-1, absorption half life t1/2(ka) = 1.94 +/- 0.60 h). The ion-pair diffusion across the intestinal wall seems to be the main reason responsible for the fast intestinal absorption. The obtained results are consistent to the literature data concerning etamsylate pharmacokinetics in vivo.     

The single-pass perfused rabbit ear as a model for studying percutaneous absorption of clonazepam. I. General characteristics.

A single-pass perfused rabbit ear was employed as the model for studying percutaneous absorption of clonazepam in an open perfusion system. Clonazepam at 1.5% concentration (w/w) was suspended in a gel containing 1% (w/w) neutralized Carbopol 934 vehicled by a 50% water solution of propylene glycol and applied to the skin, in a thermostatically controlled chamber, after 10 min pretreatment with a lauryl alcohol enhancer. At 32 degrees C, the amount of clonazepam which diffused into the effluent after a 3 h lag phase was constant for 3 h and the flux averaged 0.486 mcg/h/cm2, whereas at 25 degrees C, the flux averaged 0.424 mcg/h/cm2. The amount of drug diffusing into the effluent was a function of the contact surface area and was independent of the rate of perfusion up to values of 1 ml/min. The apparent diffusion coefficient, Ds, and the partition coefficient, KM, were 2.75/10(6)/cm/h and 5.21, respectively.     

Kinetics and thermodynamics of chloroquine and hydroxychloroquine transport across the human erythrocyte membrane

Chloroquine (CQ) and hydroxychloroquine (HCQ) have almost identical molecular volumes but showed very different permeability characteristics. The permeability coefficient for the unionised species of CQ (2.0 cm/sec at 25 degrees) was about fifty times that of HCQ (0.039 cm/sec at 25 degrees), but the apparent activation energy for transport (85 kJ/mol for CQ, 81 kJ/mol for HCQ) was almost identical for the two drugs. The partition coefficient of CQ into various organic solvents was much higher than for HCQ, but the different permeability behaviour cannot be quantitatively explained by partitioning behaviour into hexane or octanol, two solvents commonly used to mimic the membrane interior. A comparison of permeability and partitioning characteristics suggests that the barrier phase for these drugs within the membrane can be modelled by a mixed solvent of 5% octanol in hexane. The results suggest that interactions with hydrogen bonding groups within the membrane are important in the membrane transport of these drugs, and that the membrane does not behave functionally as a simple hydrocarbon barrier.     

Rapid adsorpiwe loss of nitroglycerin from aqueous solution to plastic

In short time periods the loss of nitroglycerin from normal saline solutions to plastic polyvinylchloride tubing is treated as an adsorption process. The rate of adsorption is rapid and can be quantified as an apparent first-order process. The half-life of the loss at 21°C is 2.8 min. Temperature dependence of the rate constant gives a non-linear Arrhenius dependence between 6.5 and 21°C. Equilibrium amounts of nitroglycerin adsorbed at several constant bulk concentrations and 3 temperatures show a Type III adsorption behavior. At reduced concentrations of 0.1—0.8, the data conform to a Polanyi adsorption potential theory treatment. The amount of niitroglycerin adsorbed increases as temperature increases. This unusual behavior may be explained by analogy to systems where similar anomalies have been reported. The theoretical approaches presented, here for a practical case provide a basis for studying systems involving general adsorptive phenomena.     

Supersaturation: enhancement of skin penetration and permeation of a lipophilic drug

Purpose. To increase the dermal delivery of a lipophilic model compound (LAP), and to deduce the underlying mechanism of enhanced absorption. Methods. Penetration of LAP from mixtures of up to four degrees of saturation into the stratum corneum was evaluated using a tape-stripping method; epidermal permeation of the drug was measured in Franz diffusion cells. The relative diffusion and stratum corneum-vehicle partition coefficients of LAP were determined by fitting the results to the appropriate solutions to Fick's second law of diffusion. Results. Both the skin permeation rate and the amount of LAP in the stratum corneum increased linearly with increasing degree of saturation. The apparent diffusivity and its partition coefficient deduced from the penetration experiments were independent of the degree of saturation of the drug in the applied formulation, and consistent with corresponding parameters derived from the permeation experiments. Conclusions. Supersaturation can increase the skin penetration and permeation of lipophilic drugs. The diffusion and partition parameters deduced for LAP indicate that supersaturation acts exclusively via increased thermodynamic activity without apparent effect on the barrier function of the skin per se.     

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.     

Physico-chemical determinants of dermal drug delivery: effects of the number and substitution pattern of polar groups.

The aim of this study was to investigate the effect of number and substitution pattern of -OH groups of a set of phenols on the in vitro permeation of heat-separated human epidermis. The diffusion was calculated from Log(D/x)=logk(p)-0.59logK(oct)+0.024 (D, diffusion coefficient; x, pathlength; k(p), permeability coefficient (cm/h); and K(oct), octanol-water partition coefficient). The main factors reducing D were the dipolar and hydrogen bonding capabilities of the permeants quantified as their Hansen partial solubility parameters delta(p) and delta(h). These parameters are significantly reduced by the degree of symmetry of the molecule, so that phloroglucinol (1,3,5-benzenetriol), with three -OH groups, diffuses more rapidly that phenol. When symmetry is absent, as in 1,2,4-benzenetriol, the number of -OH groups results in very slow diffusion. D/x (cm/h) was related to the combined solubility parameter delta(a) defined as radical(delta(p)(2)+delta(h)(2)) by: (D/x)=0.0024-0.000065delta(a) (n=7, R(2)=0.70, P=0.012).