Single-dose kinetics of oral propranolol, metoprolol, atenolol, and sotalol: relation to lipophilicity

Nine healthy volunteers received single oral doses of the following four beta-adrenergic blocking agents: propranolol (160 mg), metoprolol (100 mg), atenolol (200 mg), and sotalol (320 mg). The kinetics of each drug were determined from multiple serum concentrations measured during 24-48 h after each dose, and in vitro lipid solubility determined using the liquid chromatographic (HPLC) retention index. Oral clearance for the four drugs ranged from 40.2 ml/min/kg for propranolol down to 2.1 for sotalol. Oral clearance was highly correlated (r = 0.99) with in vitro lipid solubility, with propranolol being the most lipophilic drug and sotalol the least. Thus lipophilicity is a physicochemical property of beta-adrenergic blockers that appears to influence their intrinsic clearance after oral dosage.     

Transdermal Delivery of Timolol and Atenolol Using Electroporation and Iontophoresis in Combination: A Mechanistic Approach

PURPOSE: The purpose of this work was to study the effect of electroporation on iontophoretic transport of two beta-blockers, timolol (lipophilic) and atenolol (hydrophilic), and to have a better understanding of the mechanism of combination. METHODS: The transdermal delivery of these beta-blockers through human stratum corneum was studied in three-compartment diffusion cells. The transport of mannitol was evaluated to assess the electroosmotic flow. RESULTS: The iontophoretic transport of timolol was decreased by electroporation because the high accumulation of the lipophilic cation timolol in the stratum corneum resulted in a decrease of electroosmosis. In contrast, electroosmosis was not affected by atenolol, and the iontophoretic transport of atenolol was increased by electroporation. CONCLUSIONS: Using two different beta-blockers, we showed that lipophilicity and positive charges affect the electrotransport of drugs. Understanding the effect of the physicochemical properties of the drug, as well as the electrical parameters, is thus essential for the optimization of transdermal drug delivery by a combination of electroporation and iontophoresis.     

Effect of lipophilicity on in vivo iontophoretic delivery. II. Beta-blockers.

The objective of this study was to investigate the relationship between drug lipophilicity and the transdermal absorption processes in the iontophoretic delivery in vivo. Anodal iontophoresis of beta-blockers as model drugs having different lipophilicity (atenolol, pindolol, metoprolol, acebutolol, oxprenolol and propranolol) was performed with rats (electrical current, 0.625 mA/cm2; application period, 90 min), and the drug concentrations in skin, cutaneous vein and systemic vein were determined. Increasing the lipophilicity of beta-blockers caused a greater absorption into the skin. Exceptionally, it was found that pindolol had high skin absorption, irrespective of its hydrophilic nature. Further, the drug transfer rate from skin to cutaneous vein (R(SC)) was evaluated from the arterio-venous plasma concentration difference of drug in the skin. Normalized R(SC) by skin concentration showed a negative correlation with the logarithm of n-octanol/buffer partition coefficient (Log P, pH 7.4), suggesting the partitioning between stratum corneum and viable epidermis was a primary process to determine the transfer properties of beta-blockers to local blood circulation. Pindolol exhibited both high skin absorption and high transfer from skin to cutaneous vein. These characteristics of pindolol could be explained by the chemical structure, molecular size and hydrophilicity. These findings for pindolol should be valuable for the optimal design of drug candidates for iontophoretic transdermal delivery.     

Beta-adrenoceptor blockers and the blood-brian barrier.

1 This study on 21 neurosurgical patients was set up to investigate the extent to which four chronically administered beta-adrenoceptor blockers, propranolol, oxprenolol, metoprolol and atenolol, cross and blood-brain barrier and enter the cerebrospinal fluid (CSF) and brain tissue. The concentration in the CSF of the three lipophilic beta-adrenoceptor blockers, propranolol, oxprenolol and metoprolol, approximated to the free drug concentration in the plasma, and was a poor predictor of brain concentration. These three lipophilic beta-adrenoceptor blockers appeared in brain tissue at concentrations 10-20 times greater than that of hydrophilic atenolol. The approximate brain/plasma ratio for propranolol was 26, for oxprenolol 50, for metoprolol 12 and for atenolol 0.2. 2 The low concentration of atenolol in brain tissue is possibly responsible for the low incidence of central nervous system-related side effects in patients on this agent compared to lipophilic beta-adrenoceptor blockers.     

Transdermal delivery of β-blockers

β-Adrenoceptor blocking drugs (β-blockers) are one of the most frequently used class of cardiovascular drugs that are mainly used in conventional dosage forms., which have their own limitations including hepatic first-pass metabolism, high incidence of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. Essentially, attempts have been made to develop novel drug delivery systems for β-blockers, including transdermal delivery systems, to circumvent the drawbacks of conventional drug delivery. However, so far none of the β-blocker drugs have been marketed as transdermal delivery systems. Nevertheless, there have been noteworthy research endeavours worldwide at the laboratory level to investigate the skin permeation and to develop transdermal formulations of β-blockers including: propranolol, metoprolol, atenolol, timolol, levobunolol, bupranolol, bopindolol, mepindolol, sotalol, labetolol, pindolol, acebutolol and oxprenolol. Innovative research exploiting penetration-enhancing strategies, such as iontophoresis, electroporation, microneedles and sonophoresis, holds promise for the successful use of these drugs as consumer-friendly transdermal dosage forms in clinical practice. This paper presents an overview of the transdermal research on this important class of drugs.     

Transdermal delivery of beta-blockers

Beta-adrenoceptor blocking drugs (beta-blockers) are one of the most frequently used class of cardiovascular drugs that are mainly used in conventional dosage forms., which have their own limitations including hepatic first-pass metabolism, high incidence of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. Essentially, attempts have been made to develop novel drug delivery systems for beta-blockers, including transdermal delivery systems, to circumvent the drawbacks of conventional drug delivery. However, so far none of the beta-blocker drugs have been marketed as transdermal delivery systems. Nevertheless, there have been noteworthy research endeavours worldwide at the laboratory level to investigate the skin permeation and to develop transdermal formulations of beta-blockers including: propranolol, metoprolol, atenolol, timolol, levobunolol, bupranolol, bopindolol, mepindolol, sotalol, labetolol, pindolol, acebutolol and oxprenolol. Innovative research exploiting penetration-enhancing strategies, such as iontophoresis, electroporation, microneedles and sonophoresis, holds promise for the successful use of these drugs as consumer-friendly transdermal dosage forms in clinical practice. This paper presents an overview of the transdermal research on this important class of drugs.     

Hydrophilic polymeric matrices for enhanced transdermal drug delivery

For many drugs with various chemical structures, delivery rates from the hydrophilic polyvinylpyrrolidone (PVP)-polyethylene oxide (PEO) based pressure sensitive adhesive (PSA) matrices of transdermal therapeutic systems (TTS) are higher compared to the hydrophobic TTS matrices. Delivery of propranolol, glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN) from the hydrophilic water soluble TTS matrix across human cadaver skin epidermis or skin-imitating polydimethylsiloxane-polycarbonate block copolymer Carbosil membrane in vitro is characterized by high rate values and zero-order drug delivery kinetics up to the point of 75–85% drug release from their initial contents in matrix. Both in vitro and in vivo drug delivery rates from the TTS hydrophilic diffusion matrix are controlled by the skin or membrane permeability and may be described by Fick's law. The contributions of various physicochemical determinants to the control of transdermal drug delivery kinetics are discussed. Pharmacokinetic and pharmacodynamic properties of hydrophilic TTS matrix with propranolol, GTN and ISDN are described.     

β-Adrenoceptor antagonists: studies on behaviour (delayed differentiation) in the monkey (Macaca mulatta)

1 Activity of six β-adrenoceptor antagonists was studied on behavioural activity (delayed differentiation) in the monkey (Macaca mulatta). The drugs, three relatively lipophilic antagonists (propranolol, oxprenolol and metoprolol), and three relatively hydrophilic antagonists (acebutolol, atenolol and sotalol), were given by intraperitoneal injection (5 to 30 mg/kg).

2 With atenolol (25 to 30 mg/kg), total response time was increased, but there was no effect on the number of correct responses. With acebutolol (25 to 30 mg/kg), the number of correct responses was reduced, but there was no effect on total response time. With metoprolol (25 to 30 mg/kg), there was an increase in total response time and a decrease in the number of correct responses, and correct responses were decreased 4 h after injection over the whole dose range (5 to 30 mg/kg).

3 Some animals failed to respond or complete the task with 30 mg/kg oxprenolol, 25 mg/kg sotalol and 20 mg/kg propranolol. With 25 mg/kg oxprenolol, the total response time was increased and the number of correct responses was decreased. With 5-20 mg/kg sotalol, total response time was increased, but there was no effect on the number of correct responses. With 15 mg/kg of (±)-propranolol and its isomers, there were increases in total response time and decreases in correct responses.

4 The studies suggest that lipophilic antagonists, such as propranolol, oxprenolol and metoprolol, are likely to have, at least, effects on the central nervous system, while hydrophilic antagonists may modify the peripheral nervous system. In the dose-ranges studied, propranolol had the greatest, and atenolol and acebutolol had the least effects. Atenolol and acebutolol may prove to be particularly useful in man when disturbances of the nervous system are to be avoided.

     

Transdermal Delivery of Naltrexol and Skin Permeability Lifetime after Microneedle Treatment in Hairless Guinea Pigs

Controlled-release delivery of 6-β-naltrexol (NTXOL), the major active metabolite of naltrexone, via a transdermal patch is desirable for treatment of alcoholism. Unfortunately, NTXOL does not diffuse across skin at a therapeutic rate. Therefore, the focus of this study was to evaluate microneedle (MN) skin permeation enhancement of NTXOL’s hydrochloride salt in hairless guinea pigs. Specifically, these studies were designed to determine the lifetime of MN-created aqueous pore pathways. MN pore lifetime was estimated by pharmacokinetic evaluation, transepidermal water loss (TEWL) and visualization of MN-treated skin pore diameters using light microscopy. A 3.6-fold enhancement in steady-state plasma concentration was observed in vivo with MN treated skin with NTXOL HCl, as compared to NTXOL base. TEWL measurements and microscopic evaluation of stained MN-treated guinea pig skin indicated the presence of pores, suggesting a feasible nonlipid bilayer pathway for enhanced transdermal delivery. Overall, MN-assisted transdermal delivery appears viable for at least 48 h after MN-application. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3072-3080, 2010     

Review of patents on microneedle applicators

Transdermal drug delivery offers certain advantages over conventional oral or parenteral administration. However, transdermal delivery is not available to many promising therapeutic agents, especially high molecular weight hydrophilic compounds. This is due to the excellent barrier property of the superficial skin layer, the stratum corneum (SC). Only drugs with very specific physicochemical properties (molecular weight < 500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Of the several active approaches used to enhance the transport of drugs through the SC, the use of microneedles (MNs) has recently been shown to be very promising and has attracted considerable attention by researchers from both industry and academia. MNs, when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. However, for effective performance of these MNs in drug delivery applications, irrespective of the type, material, height and density, it is imperative that they penetrate into the skin with the greatest possible accuracy and reproducibility. Due to the inherent elasticity and irregular surface topography of the skin, it remains a major challenge to the reproducibility of MN penetration. Therefore, in order to achieve uniform and reproducible MN penetration into skin, an external source of assistance could be very useful. Accordingly, this review deals with various innovative applicator designs developed by industry and research centres in the context of effective application of MN arrays for transdermal drug delivery, as disclosed in the recent patent literature.     

Enhancement of propranolol hydrochloride and diazepam skin absorption in vitro: effect of enhancer lipophilicity

The enhancement of model hydrophilic (propranolol hydrochloride) and lipophilic (diazepam) drug penetration across rat and hairless mouse skin in vitro has been studied. Preliminary experiments established that most n-alkanes having chain lengths of between 7 and 16 promote the flux of both drugs. For propranolol, enhancement varied parabolically with carbon number; for diazepam, heptane was ineffective and all others were essentially equipotent. Enhancement by n-nonane was then compared with that by n-nonanol. Propranolol flux was increased by both enhancers, whereas diazepam penetration was not affected by the less lipophilic alcohol. The enhancement of propranolol by n-nonane and n-nonanol was examined as a function of adjuvant concentration in the applied formulation. Maximum increases in maximum penetration rates of 6.5-fold (n-nonane) and 8.2-fold (n-nonanol) were determined. As expected, the enhancement was saturable, indicative of a maximally perturbed stratum corneum. Finally, the penetration enhancing abilities of six monoterpenes were assessed. The purely hydrocarbon analogues promoted both propranolol and diazepam transport to an extent similar to that of n-nonane. The terpenes with hydrogen-bonding ability, however, only enhanced propranolol flux (at a level comparable to n-nonanol). While the data reported do not directly reveal mechanistic information on percutaneous penetration enhancement, they do provide a starting point for the rational investigation of interrelationships between drug, enhancer, and skin. Such information is clearly essential for the optimization and exploitation of transdermal drug delivery.     

Lipophilicity, hydrophilicity, and the central nervous system side effects of beta blockers

One of the attributes of beta-adrenergic blocking agents that has distinguished these drugs from each other is degree of lipophilicity. While this feature may play a role in facilitating passage across the blood-brain barrier, it is essential to realize that crossing the barrier is not necessarily synonymous with the ability to cause central nervous system (CNS) effects. Several studies have found some degree of CNS side effects, particularly tiredness and fatigue, with atenolol, a hydrophilic beta blocker. Pindolol, a moderately lipophilic beta blocker, has been reported to cause greater disturbances on electroencephalogram (EEG) than propranolol, the most highly lipophilic beta blocker. The investigational agent bevantolol exhibits a moderate degree of lipophilicity and a low frequency of CNS side effects. Drug-induced increases in plasma catecholamine levels, the possible saturation of CNS receptor sites at relatively low drug levels, and the specific structural details of beta-blocker molecules have been suggested as possible contributory factors in determining the degree of CNS effects.     

Drug adsorption in human skin: a streaming potential study

The objective of this study was to investigate the drug adsorption process in human skin using in vitro streaming potential measurements. Streaming potential is an electrokinetic phenomenon, which reflects both the charge density and the pore size of a membrane. Thus, the adsorption of charged solutes on the pore walls can be detected as a change of streaming potential, viz., as a change in the slope deltaE/deltaP. In these streaming potential measurements, hydrophilic nadolol and luteinizing hormone-releasing hormone, and lipophilic propranolol and Nafarelin were used as model drugs. As could be expected, the hydrophilic drugs did not change the slope. The more lipophilic propranolol and Nafarelin, instead, changed the slope. Propranolol changed the slope gradually from negative to positive when the concentration was increased from 1 to 10 mM. With Nafarelin, a straight line with a slope of about 0 was obtained at pH 7.3 and an ascending curve at pH 4.2. These results indicate that the negative charges on the pore walls of human skin are blocked by adsorption of the lipophilic cations. The adsorption of lipophilic cations in the skin alters the permselectivity of the skin, which, in turn, may lead to the inhibition of electroosmotic flow across the skin during iontophoresis and to the shut down of transdermal drug permeation of higher molecular weight drugs.     

Enhancement of propranolol hydrochloride and diazepam skin absorption in vitro. II: Drug, vehicle, and enhancer penetration kinetics.

The fluxes of representative hydrophilic (propranolol hydrochloride) and lipophilic (diazepam or indomethacin) drugs, administered as ethanolic solutions containing putative penetration enhancers (n-nonane, 1-nonanol, and 1-decanol), were measured across hairless mouse skin in vitro. Propranolol transport was augmented significantly by the presence of 4% (v/v) alkane or alkanol in the vehicle; diazepam and indomethacin, on the other hand, were enhanced only by n-nonane. Experiments with saturated solutions of the drugs as the donor phase revealed that the actions of the enhancers were taking place in the skin and were not a result of an alteration of solute thermodynamic activity in the vehicle. In separate runs, the impact of n-nonane and 1-nonanol on the percutaneous penetration of ethanol was determined. Temporal effects identical to those on the flux of propranolol were observed. A further measurement revealed that the penetration of 1-decanol, when administered as a 4% (v/v) solution in ethanol, followed a profile similar to that of the solvent (which, in turn, was comparable with that of the independently assessed propranolol hydrochloride). Thus, considerable linkage exists between the transport of a hydrophilic drug and the major vehicle component in the presence of n-nonane and 1-nonanol. The lipophilic drugs, conversely, were promoted only by n-nonane and only after most of the ethanol had been absorbed. The results show that an apparent synergy of transport between a putative enhancer and a cosolvent may not always lead to augmented drug flux. Study of the transport of all key formulation components is recommended, therefore, to optimize vehicles for transdermal drug delivery.     

Pharmacokinetics of β-adrenoceptor blockers in obese and normal volunteers

Aims Obesity can modify the pharmacokinetics of lipophilic drugs. As β-adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic β-adrenoceptor blockers in obese and control subjects. Methods Nine obese (157±24% of ideal body weight (IBW) mean±s.d.) and nine non-obese healthy volunteers (98±10% IBW), aged 32±9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic β-adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of β-adrenoceptor blockers were assessed. Results The pharmacokinetic data for the three drugs were qualitatively similar. There was a trend towards a greater total distribution volume (V_ss ) in obese patients than in controls. However, V_ss expressed per kg body weight was slightly smaller in obese patients. The relationship between V_ss and lipophilicity of five β-adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The V_ss of the five drugs was positively and well-correlated (r²=0.90; P<0.01) with their distribution coefficient at pH 7.4 (log D^7.4 ), but not with their partition coefficients. The linear regression coefficients for lean and obese subjects were very similar. Conclusions Lipophilic β-adrenoceptor blockers seem to diffuse less into adipose than into lean tissues. All electrical forms of the drugs (i.e. cations, neutral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects.Their tissue distribution in obese patients could be restricted by the sum of hydrophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.     

Comparative pharmacokinetics of propranolol and atenolol in primary hyperlipidemia

The study was aimed to examine the effects of different types of hyperlipidemia on the pharmacokinetics of lipophilic propranolol and hydrophilic atenolol. Thirty subjects were divided into four study groups: normolipemics, hypercholesterolemics, hypertriglyceridemics, and patients with mixed form of hyperlipidemia. The drugs were administered orally at a single dose of 80 mg for propranolol and 100 mg for atenolol, using a cross-over study design. Pharmacokinetic parameters of the drugs were calculated using a noncompartmental open model. The results of the present study demonstrated a possible influence of dyslipidemia on pharmacokinetics of both the lipophilic and hydrophilic drugs. As for the lipophilic drug propranolol, a significant decrease in elimination rate constant was found (from 0.24 +/- 0.08 h(-1) to 0.16 +/- 0.04 h(-1), p < 0.03) in comparison to normolipemic subjects. In the case of the hydrophilic atenolol, the most marked alterations were also seen in subjects with mixed form of hyperlipidemia, especially significantly lower values of area under the concentration-time curve (8950.8 +/- 2060.5 ng/ml x h and 6715.4 +/- 1813.8 ng/ml x h, p < 0.05) as well as higher elimination rate constant (0.08 +/- 0.03 h(-1) and 0.13 +/- 0.05 h(-1), p < 0.05) in comparison with the controls, respectively. Total body clearance per kg of body weight of propranolol as well as atenolol was not influenced by dyslipidemias. The results of the study indicate that lipid metabolism disturbances might to some extent influence the pharmacokinetics of propranolol and atenolol, with the most significant alterations seen in the patients with mixed form of hyperlipidemia.     

Inhibition of synaptosomal [3H]noradrenaline uptake by beta-adrenoceptor blocking drugs: influence of lipophilicity

Ten beta-adrenoceptor blocking drugs varying in lipophilicity and beta-adrenoceptor blocking potency were examined for inhibitory effects on synaptosomal [3H]noradrenaline uptake. All compounds produced a concentration-dependent inhibition of noradrenaline uptake, but were at least one order of magnitude less potent than desmethylimipramine and cocaine. The order of potency was pronethalol greater than propranolol greater than betaxolol greater than alprenolol greater than oxprenolol greater than practolol greater than metoprolol greater than acebutolol greater than sotalol greater than atenolol, with IC50 values ranging from 4.0 X 10(-6) to 2.2 X 10(-3) M. Uptake inhibition was unrelated to beta-adrenoceptor blocking potency, but was highly correlated with drug lipophilicity. (+)-Propranolol was an effective uptake inhibitor, as was the local anaesthetic procaine. Kinetic analysis of uptake inhibition by propranolol, oxprenolol, metoprolol and procaine revealed a mixed inhibition for all four agents examined. It is suggested that this effect of beta-adrenoceptor blockers may be mediated, at least in part, by an action on membrane phospholipids associated with the noradrenaline carrier protein, and that noradrenaline uptake inhibition may underlie certain central side-effects observed with some drugs in this group.     

Stability of atenolol, acebutolol and propranolol in acidic environment depending on its diversified polarity

The main objective of this research was to investigate the relationship between the polarity of atenolol, acebutolol, and propranolol described by logP and kinetic and thermodynamic parameters characterizing their degradation process in acidic solution. Hydrolysis was carried out in hydrochloric acid at molal concentrations of 0.1 mol/L, 0.5 mol/L, and 1 mol/L for 2 hr at 40 degrees C, 60 degrees C, and 90 degrees C. Chromatographic-densitometric method was used for the determination of drugs under investigation. The identification of degradation products was carried out by using 1H NMR. The degradation processes that occurred in drugs under investigation are described with kinetic parameters (k, t0.1, and t0.5) and energy of activation (Ea). It has been found that the stability of drugs increases toward lipophilic propranolol in the assumed experimental model. The rate constants k decrease, contrary to t0.1, t0.5, and Ea, which vary comparably to logP, thus increasing from the most hydrophilic atenolol, through acebutolol, of lower polarity, to the most lipophilic propranolol. This study demonstrated that the stability of chosen beta-adrenergic blocking agents increases with their lipophilicity.     

Pharmacokinetics of propranolol and atenolol in patients after partial gastric resection: a comparative study

Objective: Partial gastric resection alters the anatomy and secretory activity of the gastrointestinal tract. It might be expected that the consequences of such changes should affect the pharmacokinetics, especially concerning the absorption of orally administered drugs. Propranolol and atenolol, as representatives of lipophilic and hydrophilic β-adrenoreceptor antagonists, have been studied in order to define their pharmacokinetic characteristics in patients after partial gastrectomy. Methods: The study was carried out in 29 patients after gastric resection with Billroth I (B1) anastomosis and in 18 healthy volunteers as controls. Pharmacokinetics of propranolol and atenolol was investigated after a single oral dose of 80 mg and 100 mg, respectively, following a cross-over schedule. Blood samples were collected ten times during the 24 h after the drug administration. Pharmacokinetic parameters of propranolol and atenolol were calculated using a one-compartment open model with first-order absorption. Results: The average blood plasma concentrations of propranolol in gastrectomised patients were lower than those in controls, reaching significance between 1.5 h and 6.0 h of the observation period. Pharmacokinetic parameters of propranolol were different in subjects submitted to surgery compared with healthy persons. We observed a significant decrease in the area under the concentration–time curve (32%) and the peak plasma concentration (20%), and an increase in half-life (25%). Mean plasma concentrations and pharmacokinetic parameters of atenolol in patients following partial gastric resection were not significantly different from those in the controls. No relationship between time interval following partial gastrectomy and pharmacokinetic parameters of the investigated drugs was noted. Conclusion: Partial gastrectomy with B₁ anastomosis affects the pharmacokinetics of propranolol (lipophilic drug) but not atenolol (hydrophilic drug). Received: 17 May 1999 / Accepted in revised form: 7 January 2000     

Evaluation of Transdermal Drug Permeation as Modulated by Lipoderm and Pluronic Lecithin Organogel

The transdermal delivery of 2 fluorescent probes with similar molecular weight but different lipophilicity, into and through the skin from 2 commercially available transdermal bases, pluronic lecithin organogel, and Lipoderm^® has been evaluated. First, in vitro penetration of fluorescein sodium and fluorescein (free acid) through porcine skin was evaluated. Retention and depth distribution profiles in skin were obtained by tape stripping and then followed by optical sectioning using multiphoton microscopy. The results showed that Lipoderm^® led to an enhanced penetration of the hydrophilic compound, fluorescein sodium. For the lipophilic compound fluorescein (free acid), Lipoderm^® performed similar to pluronic lecithin organogel base, where minimal drug was detected in either receptor phase. The skin retention and depth distribution results also showed that the hydrophilic fluorescein sodium had high skin retention with Lipoderm^®, whereas fluorescein (free acid) had very low penetration and retention with increasing skin depth. Moreover, optical sectioning by multiphoton microscopy revealed an uneven distribution of probes across the skin in the x-y plane for both transdermal bases. This work showed that a hydrophilic compound has significantly increased skin penetration and retention when formulated with Lipoderm^®, and the skin retention of the probe was the main determinant of its skin flux.