An Electrically Modulated Drug Delivery Device: I

A controlled drug delivery device based on the principle of electrophoresis is described. A model system using propranolol HC1 and PHEMA films was used to demonstrate how control over the release of a model drug may be achieved using low constant electric currents. It was found that a linear relationship existed between electric current and drug delivery rate. Additionally, two main effects of applying an electric current during the lag period of delivery from the system were identified. First, the drug delivery rate was less when a current was applied before the lag period had expired, and second, the voltage–time profiles were found to be significantly different. The model shows the feasibility of using an electrophoretically controlled drug delivery device to provide truly controllable and predictable release rates.     

Preliminary report of the effects of propranolol HCl on the discomfiture caused by niacin.

Subjective discomfort caused by nausea and hot, pruritic skin has been described in patients after ingestion of therapeutic dosages of niacin is shown by this study to be alleviated by propranolol HC1. A dosage of 2 mg, I.V., given incrementally, in a clinical trial of six patients is described. The peripheral vasodilator effects of niacin were attenuated in some subjects but not in others. However, all subjects reported relief of unpleasant symptoms. Serial vital signs were taken and no significant changes were found. It is postulated that propranolol HC1 exerts a calmative effect at the CNS level. In a series that utilized doses of 40 and 80 mg of propranolol HC1 taken orally 30 min prior to the ingestion of 500 or 1000 mg of niacin, a progressive increase in the onset of the niacin flush was observed. It is proposed that as the available plasma level of propranolol HC1 falls, the ratio of niacin to propranolol HC1 increases, exceeding the threshold at which the flush occurs. Both these studies suggest that further work is indicated to establish the possible therapeutic efficacy of propranolol HC1.     

Spectral and polarographic determination of eprosartan. Kinetic studies of the oxidation of eprosartan using a platinum electrode

Two simple and sensitive methods are presented for the determination of eprosartan in pharmaceutical preparations. The first method, spectrophotometry, was based on the oxidation of this drug by ammonium cerium (IV) nitrate in the presence of perchloric acid with subsequent measurement of the absorbance at 326 nm; this principle was adopted to develop a kinetic method for the determination of eprosartan in dosage forms. The second method, differential pulse polarography, was based on measuring the peak height at -1300 mV, corresponding to the reduction of the drug in Britton-Robinson buffer (pH 3). The proposed methods proved to be accurate and precise and can be applied for the routine analysis of this drug in commercial dosage forms, without interference from the excipients. The work was extended to study the electrochemical oxidation of eprosartan at different electrolysis currents (10-40 mA). The electrochemical decomposition products were characterized by UV/visible spectroscopy; the decomposition rates follow first order reactions and increase with raising the current. The degradation was found to be faster in basic than acidic medium. The thermodynamics for electrochemical decomposition were also evaluated at different pH values.     

Evaluation of Drug-Containing Polymer Films Prepared from Aqueous Latexes

Polymeric films containing salicylic acid or propranolol HC1 were prepared by casting and drying a drug-containing, aqueous colloidal polymer dispersion (Eudragit NE 30D) as an alternative to films cast from organic polymer solutions. The drug was either dissolved (salicylic acid) or dissolved/ dispersed (propranolol HC1) in the polymeric matrix. Incompatibilities (flocculation or coagulation) between salts of basic drugs and two ethylcellulose latexes were overcome by substituting the anionic surfactants with a nonionic surfactant (Pluronic P103). The drug release was studied as a function of drug loading, film thickness, amount of hydrophilic additive (hydroxypropyl methylcellulose), and storage humidity. The release of propranolol HC1 (monolithic dispersion) was a combination of diffusion through the polymer and pores or channels; the extent of each release mechanism depended on the drug loading. On DSC thermograms, melting transitions were obtained with monolithic dispersions but not with monolithic solutions. The heat of fusion was linearly correlated to the amount of drug in the films. The amount of drug remaining in the film after the dissolution study was not detectable and corresponded to the drug dissolved in the polymer. The drug release increased with increased drug loading and increased amount of hydroxypropyl methylcellulose but was independent of film thickness and relatively insensitive to different storage humidities.     

Anionic Gels as Vehicles for Electrically-Modulated Drug Delivery. I. Solvent and Drug Transport Phenomena

Purpose. The purpose of this study was to elucidate the in vitro behavior of anionic gels as formulation matrices for electrically-modulated drug delivery. Agarose and combinations of agarose with other anionic polymers (carbomer 934P; xanthan gum) were selected and tested to evaluate their potential for drug delivery. Methods. Electrical current was applied by an automatic crossover power supply to minimize the current fluctuation. Hydrocortisone was selected as the model drug in order to minimize electrostatic interference with drug transport. Syneresis and drug migration were evaluated as a function of current application time and the intensity of electrical current. Results. The data show that electrical current strength and gellant content can affect both the syneresis and drug migration. A linear correlation was found between hydrocortisone loss and mass loss via the exudate. Moreover, in agarose-carbomer 934P gel systems, cumulative gel mass loss is a linear function of time at low intensities of electrical current (e.g., 0.5 mA and 1 mA). However, hydrocortisone distribution, after electrical application, is relatively asymmetric in those agarose-carbomer 934P gels (and in agarose-xanthan gum gels) in contrast to gel matrices containing only agarose. Conclusions. In this study, the use of carbomer 934P in conjunction with agarose enables the formulator to achieve zero-order release with electrical application. Increased anisotropicity of a gel system due to the application of electrical current could alter the effectiveness of a drug delivery system.     

Performance of baboons under a repeated acquisition procedure during chronic oral exposure to atenolol and propranolol

Repeated acquisition behavioral performances of normotensive and renovascular hypertensive baboons were tested before, during, and following chronic oral dosing with the-adrenergic antagonists atenolol HC1 (2.6 mg/kg/day PO), andd,l propranolol HC1 (6.8 mg/kg twice daily PO) in separate studies. Each study administered active drug for 21 consecutive days preceded and followed by 14-day baseline and recovery periods, respectively. Animals pressed five keys in sequence for food reinforcement during daily experimental sessions which consisted of alternating acquisition (new sequence learning) and performance (previously learned) task components. Atenolol increased response latencies during acquisition in comparison to performance components, and during early portions of sessions. Propranolol also increased response latencies during acquisition components in early periods of sessions, but fewer dependent measures were affected, and the magnitude of increases in response latencies was smaller (12%±5 SEM) as compared with atenolol (47%±13). Test doses of phencyclidine HC1 (PCP) increased latencies to the same degree as atenolol. PCP markedly reduced accuracy, while atenolol or propranolol did not. Blood pressures remained stable under atenolol, and decreased by approximately 10–15 mmHg under propranolol. No differences between renovascular hypertensive and normotensive baboons were found as a function of drug conditions. Drug effects were not dependent on plasma propranolol concentration.     

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.     

Drug release and permeation studies of nanosuspensions based on solidified reverse micellar solutions (SRMS)

Solidified reverse micellar solutions (SRMS), i.e. mixtures of lecithin and triglycerides, offer high solubilisation capacities for different types of drugs in contrast to simple triglyceride systems [Friedrich, I., Müller-Goymann, C.C., 2003. Characterisation of SRMS and production development of SRMS-based nanosuspensions. Eur. J. Pharm. Biopharm. 56, 111-119]. Nanosuspensions based on SRMS were prepared by homogenisation close to the melting point of the SRMS matrix. In a first step the SRMS matrices of 1:1 (w/w) ratios of lecithin and triglycerides were loaded with 17beta-estradiol-hemihydrate (EST), hydrocortisone (HC) or pilocarpine base (PB), respectively, and subsequently ground in liquid nitrogen to minimise drug diffusion later on. The powder was then dispersed in a polysorbate 80 solution using high pressure homogenisation. The drug loading capacities of the nanosuspensions were very high in the case of poorly water-soluble EST (99% of total 0.1%, w/w, EST) and HC (97% of total 0.5%, w/w, HC) but not sufficient with the more hydrophilic PB (37-40% of total 1.0%, w/w, PB). These findings suggest SRMS-based nanosuspensions to be promising aqueous drug carrier systems for poorly soluble drugs like EST and HC. Furthermore, in vitro drug permeation from the different drug-loaded nanosuspensions was performed across human cornea construct (HCC) as an organotypical cell culture model. PB permeation did not differ from the nanosuspension and an aqueous solution whereas the permeation coefficients of HC-loaded nanosuspensions were reduced in comparison to aqueous and oily solutions of HC. However, the permeated amount was higher from the nanosuspensions due to a much lower HC concentration in the solution than that in the nanosuspension (solution 0.02%, w/w, versus nanosuspension 0.5%, w/w). The high drug load of the nanoparticles provides prolonged HC release. Permeated amounts of EST were reduced in comparison to HC and only detectable with an ELISA technique. The EST release from nanosuspensions and different EST-loaded systems revealed a prolonged EST release from the nanoparticulate systems in contrast to a faster release of an oily solution of an equal EST concentration. With regard to an aqueous EST suspension of similar concentration which represents a depot system the release rate from the nanosuspensions revealed the same order of magnitude which points again to a prolonged release potential of the nanosuspensions.     

Drug release kinetics from polymeric films containing propranolol hydrochloride for transdermal use

Polymeric films containing propranolol hydrochloride (PPN) were formulated and evaluated with a view to select a suitable formulation for the development of transdermal drug delivery systems. Films containing different ratios of ethyl cellulose (EC), poly(vinylpyrrolidone) (PVP), and PPN were prepared by mercury substrate method. In vitro drug release and skin permeation studies were conducted using paddle over disk and modified Franz diffusion cell, respectively. The drug release profiles from the polymeric film indicated that the drug content in the film decreased at an apparent first-order rate, whereas the quantity of drug release was proportional to the square root of time. The release rate of PPN increased linearly with increasing drug concentration and PVP fraction in the film, but was found to be independent of film thickness. The increase in release rate may be due to leaching of hydrophilic fraction of the film former, which resulted in the formation of pores. It was also observed that the release of drug from the films followed the diffusion-controlled model at low drug concentration. A burst effect was observed initially, however, at high drug loading level, which may be due to rapid dissolution of the surface drug followed by the diffusion of the drug through the polymer network in the film. The in vitro skin permeation profiles displayed increased flux values with increase of initial drug concentration in the film, and also with the PVP content. From this study, it is concluded that the films composed of EC/PVP/PPN, 9:1:3, 8:2:2, and 8:2:3, should be selected for the development of transdermal drug delivery systems using a suitable adhesive layer and backing membrane for potential therapeutic applications.     

Transdermal Delivery of Isoproterenol HC1: An Investigation of Stability,Solubility, Partition Coefficient,and Vehicle Effects

Effects of solubility, partition coefficient, and selected adjuvants (propylene glycol and Azone) on percutaneous penetration of isoproterenol HC1 have been investigated using human cadaver skin. Isoproterenol was found to be stable (<1% decomposition) for 24 hr at 22 ± 0.5°C in the pH range 1 to 7 in the following solvents: water, normal saline, propylene glycol and a series of propylene glycol–water mixtures (10, 20, 40, and 60%; v/v); however, decomposition was significant beyond pH 8. In normal saline, the rate of decomposition increased significantly with an increase in temperature to 37°C. The solubility of isoproterenol HC1 decreased and its skin/vehicle partition coefficient increased with increasing proportions of propylene glycol in the vehicle, while the product of the solubility and partition coefficient appeared to plateau at 20% propylene glycol in water. Optimal penetration enhancing effects of Azone were seen when incorporated at a concentration of 1% (v/v) in the 20% (v/v) propylene glycol–water blend and, more significantly, when skin was pretreated with pure Azone for 60 min prior to application of the drug formulation.     

Adaptational responses to prolonged beta-adrenoceptor blockade in adult rabbits.

1 A method for measuring propranolol concentrations in plasma has been modified to permit estimations to be made on small volumes. The method has been used to correlate blockade of heart rate increases in response to intravenous isoprenaline, in both young and adult rabbits, with plasma concentrations of propranolol after subcutaneous injections of 2 or 4 mg/kg. It has been found that the relation between beta-adrenoceptor blockade and plasma concentrations is the same in rabbits as that determined by previous workers in man. 2 Adult Dutch dwarf rabbits were treated for 9 weeks twice daily subcutaneously with 2 mg/kg propranolol, or 10 mg/kg practolol, or with saline. 3 The treatment caused no change in heart weight in relation to body weight or in the water content of the hearts, in contrast to effects previously observed in young rabbits. 4 As in the young rabbits, treatment did cause a prolongation of action potential duration, as measured with intracellular electrodes in hearts of animals killed 24 h after the last dose of drug. 5 In another series of experiments, with a similar regime of treatment for 6 weeks, a significant reduction of diastolic blood pressure was observed in the propranolol group. 6 During the course of treatment and at the end, there was no change in the heart-rate increases observed in response to intravenous isoprenaline administered not less than 15 h after the previous dose of beta-blockers. Thus no functional alteration in sensitivity ot beta-adrenoceptor stimulation was apparent.     

Effect of polymers on dissolution from drug suspensions.

The effect of three viscosity grades of methylcellulose on the dissolution-dialysis rate of nitrofurantoin suspensions was investigated using a cell designed to provide a large surface area for dialysis. Apparent dialytic rate constants of drug dispersions and solutions were measured in 0.1 N HC1 and in pH 7.4 buffer. Samples containing methylcellulose had lower rates of dialysis, with the lowest rate being observed for samples in which the polymer was used as the suspending agent. The reduced rate of dialysis of the drug suspension containing methylcellulose is thought to be due to complexation of the drug in solution with the polymer as well as formation of microscopic regions of high viscosity surrounding the undissolved drug particles leading to a reduction in the dissolution rate of the drug. An empirical relationship was obtained to enable the estimation of the effective drug concentration in the dissolution chamber for drug dispersions. The method is based on utilizing dialysis rate data of drug solutions. This relationship could be used for comparing suspension formulations in terms of the amount of drug available for dialysis.     

Organic solvent-free polymeric microspheres prepared from aqueous colloidal polymer dispersions by a w/o-emulsion technique

Polymeric microspheres were prepared from water-insoluble polymers by a novel technique without the use of organic solvents. Aqueous colloidal polymer dispersions (latexes or pseudolatexes) were emulsified into a heated external oil phase to form a w/o emulsion. The colloidal polymer particles fused (coalesced) into homogeneous polymeric microspheres at temperatures above the minimum film formation temperature upon removal of water. The formation of the microspheres was affected by the glass transition temperature of the polymer, the type of oil and surfactant, the heating temperature and time, and the addition of plasticizers. Plasticizers had to be added to colloidal dispersions with high minimum film formation temperatures. The resulting microspheres were spherical with a smooth surface and non-agglomerated. The particle size could be varied between 5 and 250 μm. Water-soluble compounds such as propranolol HC1 could be entrapped with drug loadings up to 40% within the microspheres by dissolving the drug in the aqueous polymer dispersion prior to the emulsification step. The drug release was sustained over a 6-h period with microspheres prepared with the acrylic pseudolatex, Eudragit RS 30D.     

The effect of propranolol on sympathetic nerve stimulation in isolated vasa deferentia.

(+/-)-Propranolol hydrochloride (0.5 mg kg(-1) twice daily, subcutaneously, for 3 days or approximately 2.4 mg kg(-1) daily, orally, for 21 days) failed to produce ptosis or to affect responses to transmural stimulation of isolated vasa deferentia removed from treated mice. In guinea-pig isolated vasa deferentia responses to transmural stimulation through parallel electrodes were reduced by propranolol (1 to 20 mug ml(-1); blockade was concentration dependent, fast to equilibrium (45 min), easily reversed by washing but not reversed by (+)-amphetamine sulphate (0.2 mug ml(-1). At lower concentrations (0.04 and 0.2 mug ml(-1), propranolol marginally potentiated responses to transmural stimulation. In contrast, guanethidine (0.2 mug ml(-1)) produced a slow onset blockade which was completely reversed by (+)-amphetamine. The response to electrical stimulation through concentric ring electrodes was reduced by low concentrations of propranolol but this effect is ascribed to the known local anaesthetic actions of propranolol and no evidence of true adrenergic neuron blockade was found.     

The effect of acebutolol and propranolol on the hypoglycaemic action of glibenclamide.

1 The effect of acebutolol, a relatively selective beta-adrenoceptor blocking drug and propranolol, a non-selective one, on the hypoglycaemic action of glibenclamide after an oral glucose load has been investigated in a group of maturity-onset diabetic patients. 2 Glibenclamide significantly reduced the blood glucose levels and both acebutolol and propranolol, at therapeutic doses, were found to modify this action significantly. 3 The effect of acebutolol was slightly less than that of propranolol. The difference was not statistically significant. 4 The modes of action of sulphonylureas are reviewed and it is suggested that beta-adrenoceptor blockers may modify their effect on insulin release. This appears to be a drug interaction rather than an effect of beta-adrenoceptor blockade on glucose tolerance.     

The study of organic nitrates, part IV. Chemical and pharmacological study of N-(1-methylethyl)-3-(1-naphthalenyloxy)-2-nitroxypropylamine--potential NO donor

The reaction of N-(1-methylethyl)-3-(1-naphthalenyloxy)-2-nitroxypropylamine (nitrate analogue of propranolol) with hydrochloride of ethyl ester of L-cysteine at pH 7.7, temp. 37 degrees C was studied. The course of the reaction was monitored by HPLC method. It was found that at these conditions the substrates react and the main product of the decomposition of the nitrate of propranolol analogue is propranolol, nitrate and nitrite ions. The reaction has been described qualitatively and quantitatively. The influence of nitrate analogue of propranolol and propranolol alone on arterial blood pressure and heart rate in normotensive and hypertensive rats (SHR) was also studied. It has been found that both compounds exert a similar effect.     

Degradation Rate Observations as a Function of Drug Load in Solid-State Drug Products

Degradation rates of solid-state drug products generally increase as the drug load decreases. A model for quantifying this effect based on surface area ratios is proposed here. This model relates the degradation rate to an estimate of the proportion of drug substance in contact with the excipient, and that the drug substance in contact with excipients degrades more quickly. Degradation data from previously published case studies and from 5 new case studies were found to be consistent with our proposed model; our model performed better than similar previously published models. It was also found that the relationship between degradation rate and drug load is largely independent of the temperature and humidity conditions, suggesting that drug load solely affects the pre-exponential factor of the Arrhenius equation and does not significantly affect the activation energy of the degradation process. A second method for calculating the proportion of the drug substance surface in contact with the excipient surface is presented in the Supplementary Material. Fundamentally, the 2 methods are very similar and provide almost identical fits to the experimental data.     

The Development of A Stable,Coated Pellet Formulation of a Water-Sensitive Drug,a Case Study: Development of a Stable Core Formulation

A development program has been carried out to provide a stable extrusion/spheronisation pellet formulation for a highly water-soluble drug, sitagliptin, which undergoes a change in physical form on processing and is subject to hydrolytic decomposition. A conventional extrusion/spheronization formulation resulted in significant degradation of the drug. The inclusion of glyceryl monostearate into the formulation was found to reduce the water levels required to such a level that there was no significant degradation of the drug during processing to form pellets. The use of a ram extruder to screen formulations with small quantities minimizes the need for the drug in the formulation-screening process, and the results from this method of extrusion were found to be translatable to the use of a screen extruder, which allowed scale-up of the process.     

Transdermal iontophoretic delivery and degradation of vasopressin across human cadaver skin

Transdermal iontophoretic transport and degradation of a peptide, vasopressin, across human cadaver skin, was investigated. Modified Valia-Chien cells were supplied with 0.5 mA/cm² current density via silver/silver chloride electrodes from a Scepter® power supply. Vasopressin (0.25 mg/ml) spiked with [^3Hvasopressin was transported across skin with anode in donor. Samples were analyzed by HPLC using a radio-chromatography detector. Degradation of vasopressin in contact with intact skin and in skin homogenates was also studied. Greater degradation was observed in receptor where the peptide was in contact with the dermal side of the skin. The cumulative amounts of intact vasopressin permeated during 8 h of iontophoretic transport was 15.37 (±5.31; n = 3) μg/cm², which corresponds to only about 1% permeation. Of the total radioactivity permeated, only about 40% was intact vasopressin by 12 h. Several degradation peaks could be seen in the chromatogram. No intact vasopressin was found to permeate under passive conditions. The enzymatic activity of cadaver skin is likely to be less than that expected in an in vivo drug delivery situation. Therefore, delivery to patients would be even less than that predicted by this study.     

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.