Local anaesthetic drugs are usually administered as symptom relieving drug formulations for the treatment of pain in superficial skin extremities. The anaesthesia is delivered into skin tissues at the site of pain because of nociceptive receptors. Concerns that exist regarding local anaesthetic drug formulations are low drug encapsulation efficiency, polydispersity of colloidal formulations, chemical interactions of released local anaesthetic drug with skin proteins and bulk viscoelastic properties. Complimenting drug formulation characteristics are the desirable rates of controlled release of drug molecules from chosen formulations pertaining to favourable in vitro skin permeation kinetics are imperative pharmaceutics based research areas because skin percutaneous delivery has distinct barrier property restrictions for passive diffusion (PD) of active molecules. Lidocaine is currently the active anaesthetic molecule of choice in local anaesthesia by clinicians because of minimum toxicity and good potency. It is a low molecular weight drug comprising of electron donating and electron withdrawing functional groups with the capacity to interact by hydrogen bonding and electrostatic interactions with several drug formulation vehicles. In this work, a naturally occurring bi-polymeric formulation was achieved with lidocaine NaCMC:gelatine hydrogel. Lidocaine NaCMC:gelatine ratio of 1:2.3 was the most favourable formulation because of faster skin permeation kinetics. Lidocaine NaCMC:gelatine 1:2.7 provided the highest drug encapsulation efficiency. This resulted in high, sustained permeation rates after adaptation of the microneedle (MN) poke and patch technique, past the stratum corneum layer of skin for quick target delivery in attaining a maximum permeation flux of near 6.0 μg/cm2/h in the hypodermis layer. Mass balance of in vitro studies using an indirect approach to quantify lidocaine permeation showed significant lidocaine permeation in skin. Subsequent vertical and horizontal (depth averaged) in vitro studies using similar MN techniques resulted in crossing minimum therapeutic level across a 10 mm radius from the epicentre of the skin sample at major reduced lag times of minutes for vertical permeation and within 0.5 hours for horizontal permeation. Furthermore, the spreadability of lidocaine NaCMC:gelatine hydrogel shows favourability in the control of droplet spreading on MN treated skin.

Due to its larger surface area and ease of preparation, pig esophageal mucosa has emerged as a practical and viable alternative to buccal mucosa for studying permeability characteristics in vitro. However, the permeation results in biological membranes have shown high variability due to inter-specimen and intra-specimen variations. These biological variables can significantly influence the drug permeation across porcine esophageal mucosa. Therefore, this study aimed to investigate the viability associated with drug permeation by examining four to five porcine specimens (inter-specimen variations) and different regions of the esophageal mucosa within the same pig (intra-specimen variation). The analysis revealed that inter-specimen variation was more pronounced in the lipophilic model diffusant hydrocortisone, compared to the hydrophilic diffusant caffeine. Both model diffusants exhibited a linear increase in permeability from the upper esophageal sphincter (UES) to the lower esophageal sphincter (LES). Notably, the permeability of LES was 1.7-fold greater for caffeine and 2.5-fold greater for hydrocortisone compared to UES. The histological examination revealed that the epithelial thickness of UES was greater than the LES. Additionally, the lag time of both model diffusants decreased linearly from UES to LES. Based on these results, it could be concluded that intra-specimen variation is highly pronounced for hydrocortisone than caffeine. These findings contribute to the advancement of research in drug permeation studies, emphasizing the importance of carefully considering both inter-specimen variation and intra-specimen variation when utilizing porcine esophageal mucosa as an ex vivo model to human buccal mucosa.

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<p>Drug transport across the intestinal epithelium is roughly predicted from permeability values obtained from Caco-2 cell monolayers. This thesis examines the important role of <i>pH</i> and extracellular additives for increasing the reliability and predictivity of the <i>in vitro</i> screening system, Caco-2.</p><p>It was shown that the passive transport of ionizable compounds may be biased by a false efflux or uptake component, when applying a physiological <i>pH</i>-gradient across the membrane. <i>pH</i> also affected the amount of compound available at the transporter-binding site. Therefore, <i>pH</i> dependence should be considered in studies of such compounds and of drug-drug interactions involving efflux transporters. It was also shown that proton-dependent apical uptake or basolateral efflux should be studied both with and without a <i>pH</i> gradient over the whole monolayers. </p><p>The two extracellular additives, bovine serum albumin (BSA) and the solubilizing agent, Cremophor^® EL, also influenced Caco-2 permeabilities. BSA applied to the receiver side increases, and to the donor side decreases drug permeation according to the drug’s protein binding capacity. Thus, the absorptive transport for both passive and active compounds is favoured, giving a physiologically sound improvement of the Caco-2 cell model. Inclusion of BSA increased both the predictivity and quality of permeability studies, particularly of highly lipophilic, BCS class II compounds. Passive and active transport processes could also be distinguished after accounting for unbound concentrations. The overall effect of Cremophor^® EL on the permeability to a drug was compound-specific and probably dependent on micellar incorporation. Cremophor^® EL can therefore not be recommended. </p><p>Neither <i>pH</i> nor BSA affect the functionality of transporters such as P-glycoprotein. However, efflux ratios of ionizable or protein bound drugs are altered in the presence of a <i>pH</i>-gradient or BSA, indicating that an experimental system without protein or <i>pH</i> gradient can over- or underestimate active and passive efflux in drug transport.</p>

Drug transport across the intestinal epithelium is roughly predicted from permeability values obtained from Caco-2 cell monolayers. This thesis examines the important role of pH and extracellular additives for increasing the reliability and predictivity of the in vitro screening system, Caco-2. It was shown that the passive transport of ionizable compounds may be biased by a false efflux or uptake component, when applying a physiological pH-gradient across the membrane. pH also affected the amount of compound available at the transporter-binding site. Therefore, pH dependence should be considered in studies of such compounds and of drug-drug interactions involving efflux transporters. It was also shown that proton-dependent apical uptake or basolateral efflux should be studied both with and without a pH gradient over the whole monolayers. The two extracellular additives, bovine serum albumin (BSA) and the solubilizing agent, Cremophor® EL, also influenced Caco-2 permeabilities. BSA applied to the receiver side increases, and to the donor side decreases drug permeation according to the drug’s protein binding capacity. Thus, the absorptive transport for both passive and active compounds is favoured, giving a physiologically sound improvement of the Caco-2 cell model. Inclusion of BSA increased both the predictivity and quality of permeability studies, particularly of highly lipophilic, BCS class II compounds. Passive and active transport processes could also be distinguished after accounting for unbound concentrations. The overall effect of Cremophor® EL on the permeability to a drug was compound-specific and probably dependent on micellar incorporation. Cremophor® EL can therefore not be recommended. Neither pH nor BSA affect the functionality of transporters such as P-glycoprotein. However, efflux ratios of ionizable or protein bound drugs are altered in the presence of a pH-gradient or BSA, indicating that an experimental system without protein or pH gradient can over- or underestimate active and passive efflux in drug transport.