Oxprenolol-loaded bioadhesive microspheres: preparation and in vitro/in vivo characterization.

Biologically adhesive delivery systems offer important advantages over conventional drug-delivery systems. In this paper, microspheres intended as a sustained release carrier for oral or nasal administration have been prepared by associating a known bioadhesive polymer, poly(acrylic acid), in gelatin microspheres. A model drug oxprenolol hydrochloride was chosen. It was found that some of the formulation variables can influence the characteristics of the beads in a controlled manner. The internal structure of the microspheres studied by X-ray diffraction, thermal analysis and optical microscopy showed the absence of drug crystals in microspheres and a lowering in the glass transition temperature. The dynamic swelling of the beads obeyed the square root of time and a shift from the diffusional to the relaxational process dependent on the content of poly(acrylic acid) in gelatin microspheres was observed. As expected, drug release from gelatin/poly(acrylic acid) microspheres was influenced by the poly(acrylic acid) content in beads, by the particle size of microspheres and by the pH of the medium. The mechanism of release was analysed by applying the empirical exponential equation and by calculation of the approximate contribution of the diffusional and relaxational mechanisms to the anomalous release process by fitting the data to the coupled Fickian/Case II equation. In vitro and in vivo experiments in rats showed good adhesive characteristics of the gelatin/poly(acrylic acid) microspheres, which were greater if the poly(acrylic acid) content was greater. A significant retardation in gastric and intestinal emptying time of the beads was observed. This was also suggested by the bioavailability of the model drug after intragastric and intranasal administration of the microspheres. The pharmacokinetic parameters after microsphere administration were more appropriate to a slow release drug-delivery system. The work suggests the potential of this pharmaceutical delivery system as an alternative controlled-release dosage form, either for oral or nasal administration.

Iontophoretic in vivo transdermal delivery of beta-blockers in hairless rats and reduced skin irritation by liposomal formulation.

PURPOSE: To demonstrate the in vivo transdermal delivery and establish the comparative pharmacokinetics of five beta-blockers in hairless rat. METHODS: Intravenous dosing was initially done via jugular cannula. For iontophoretic delivery, current (0.1 mA/cm2) was applied for 2 h through a drug reservoir patch containing the beta-blocker (10 mg/ml). Blood samples were collected and analyzed by stereoselective HPLC assays. Any irritation resulting from patch application was quantified by a chromameter. Multilamellar liposomal formulation was prepared by the thin-film hydration method and converted to unilamellar liposomes by extrusion. RESULTS: With transdermal iontophoresis, therapeutically relevant amounts of propranolol (83.78 +/- 7.4 ng/ml) were delivered within an hour and lasted for up to 4 h. Cmax (185.1 +/- 56.8 ng/ml) was reached at hour 3. A significantly higher amount (p < 0.05) of sotalol HCl was delivered compared to other beta-blockers. There was no significant difference in the S/R ratio of AUC0-t for enantiomers after both intravenous and transdermal delivery. Skin irritation was significantly reduced (p < 0.05) when a liposomal formulation of the propranolol base was used rather than the base itself. CONCLUSIONS: The comparative pharmacokinetics of intravenous and transdermal iontophoretic delivery of five beta-blockers in hairless rats was established. It was shown that there is no stereoselective permeation.

Oxprenolol release from bioadhesive gelatin/poly(acrylic acid) microspheres.

Drug release from gelatin/poly(acrylic acid) oxprenolol-loaded microspheres has been evaluated using an in situ sink immersion method and a wetting method. The kinetics of drug release were analysed by applying the empirical exponential equation and by the calculation of the approximate contribution of the diffusional and relaxational mechanism to the anomalous release process by fitting the data to the coupled Fickian/Case II equation. The influence of glutaraldehyde cross-linking agent concentration, the poly(acrylic acid) content, the pH of the release medium and the particle size of the beads on the drug release kinetics were evaluated and discussed.

Dynamic swelling behaviour of gelatin/poly(acrylic acid) bioadhesive microspheres loaded with oxprenolol.

The dynamic swelling of gelatin/poly(acrylic acid) microspheres loaded with oxprenolol has been evaluated. The movement of two distinct and characteristic swelling boundaries was measured directly using an optical microscope. Swelling rate constants associated with the inner moving front and the outer swelling boundary were determined. A polynomial equation incorporating both Fickian diffusion and case II relaxational models was used to fit the kinetics of liquid uptake. The influence of the concentration of the cross-linking agent, the poly(acrylic acid) load, the pH of the swelling medium and the particle size of the microspheres, on the swelling kinetics, was evaluated and discussed.

Relationship between amount of beta-blockers permeating through the stratum corneum and skin irritation after application of beta-blocker adhesive patches to guinea pig skin.

We evaluated the relationship between the cumulative amounts of 5 kinds of beta-blockers (alprenolol, oxprenolol, timolol, acebutolol and atenolol) permeating through the stratum corneum and a* values obtained by measuring the formation of erythema, a skin irritation reaction, with a chromameter after transdermal application of adhesive patches containing 2 beta-blocker to the skin of guinea pigs. The cumulative amount of beta-blocker released from each adhesive patch to the skin increased with the increase in application time. The contents of alprenolol, oxprenolol and timolol in the stratum corneum and in the stripped skin increased markedly up to 4 h after application and thereafter were maintained at high levels up to 24 h. The contents of acebutolol and atenolol, on the other hand, increased up to 24 h, but these values were low. a* values of all adhesive patches 24 h after application were higher than those before application. The correlation coefficients between the cumulative amounts of alprenolol, oxprenolol, timolol, acebutolol or atenolol permeating through the stratum corneum and (delta a* -delta a*Placebo) values were 0.739, 0.717, 0.722, 0.551 and 0.633, respectively. The correlation coefficient calculated by averaging the cumulative amounts of 6 kinds of beta-blockers permeating through the stratum corneum [including propranolol which was reported previously (Kobayashi I., et al., Biol. Pharm. Bull., 19, 839-844 (1996))] was 0.731, higher than the correlation coefficient between contents of these beta-blockers in the stripped skin and (delta a* -delta a*Placebo) values (r = 0.552). This suggests that there was a high correlation between the cumulative amounts of beta-blockers permeating through the stratum corneum and (delta a* -delta a*Placebo) values.

Disposition of human drug preparations in the horse. V. Orally administered oxprenolol.

Urinary concentrations of the beta-antagonist oxprenolol and some of its major human metabolites were determined following oral administration of a dose of 160 mg to five fasted horses. Quantitation was performed by gas chromatography-mass spectrometry (GC-MS) in the selected ion mode (SIM) by monitoring ion m/z 466 of the heptafluorobutyric derivatives. As early as 2 h after dosage oxprenolol could be detected in hydrolysed urine and remained detectable up to 24 h. Maximum urinary concentrations and excretion rates were obtained between 2 and 12 h. After 12 h only 2.8% of the administered dose was excreted as conjugates of oxprenolol and major human metabolites including 4-OH-oxprenolol and 5-OH-oxprenolol. These metabolites were detectable up to 48 h.

[Chronology of regression of hypertensive ventricular hypertrophy during antihypertensive therapy with beta blockers]. / Cronologia della regressione dell'ipertrofia ventricolare ipertensiva durante terapia antipertensiva con betabloccanti.

To define the time course of regression of left ventricular hypertrophy (LVH) during antihypertensive therapy with beta-blocking agents, 73 hypertensive patients were serially studied by echocardiography during 12-months therapy with beta-blockers. Blood pressure decreased significantly after 1 month and further on after 12 months (from 164 +/- 18/110 +/- 9 to 139 +/- 14/94 +/- 7 mmHg, p < 0.001). Left ventricular (LV) end-diastolic dimension increased significantly after 1 month (from 51.2 +/- 3.9 to 52.2 +/- 4.7 mm, p < 0.01) and decreased after 12 months (50.4 +/- 4.0 mm, p < 0.05). Septal and posterior wall thickness decreased progressively after 1 month and 3 months, respectively. LV mass index decreased significantly after 3 months, and further on after 12 months (from 164 +/- 42 to 145 +/- 33 g/m2, p < 0.001). LV fractional shortening did not significantly change throughout the study. Thus, a reduction of hypertensive LVH occurred after 3 months of therapy with beta-blocking agents and went on during the subsequent months without impairment of LV systolic function.

Constant-rate drug release from novel anionic gel beads with transient composite structure.

A new anionic composite bead system with a transient membrane-matrix structure, capable of prolonged constant-rate drug release, has been developed from suspension-polymerized poly(methyl methacrylate-co-methacrylic acid) (PMMA/MAA). These composite beads have a thin PMMA/MAA surface layer and a core consisting of the sodium salt form of the polymer (PMMA/MANa). The high loading (> 20%) of a model drug (oxprenolol HCl) that is achievable in this system from a loading solution concentration as low as 0.5% suggests the formation of a drug-polymer complex in the form of an ionic salt in the core. The release of oxprenolol from such composite beads shows an initial burst effect followed by an extended constant-rate region before leveling off. Apparently, the surface PMMA/MAA layer functions as a transient rate-controlling membrane before it is completely ionized. Because the ionization process is slow, the rate-controlling characteristics of the surface layer and the resulting constant rate of drug release are both sustained for an extended period. The unique feature of the present system is not only its high drug loading capability, but also the transient nature of the rate-controlling surface layer, which is completely ionized towards the latter part of the drug release, thus avoiding prolonged tailing of drug release that is normally associated with permanent membrane-matrix systems.

The effect of oxprenolol dosage time on its pharmacokinetics and haemodynamic effects during exercise in man.

We have studied the effect of dosage time of oxprenolol (Trasicor) on its pharmacokinetics and pharmacodynamics in six healthy volunteers. The drug effects measured were heart rate and systolic blood pressure during exercise. Oxprenolol was taken orally at 08.00 h, 14.00 h, 20.00 h, and 02.00 h in randomized order, with 1 week between successive doses. There were differences in the pharmacokinetics of oxprenolol for the ratio between the apparent volume of distribution and systemic availability (P = 0.04) and for elimination half-life (P = 0.006). Both were lowest after administration at 14.00 h (163 (77) l and 1.2 (0.6) h; mean (SD)) and highest after administration at 02.00 h (229 (100) l, and 1.7 (0.6) h). The systolic blood pressure during exercise before oxprenolol did not vary with dosage time, but heart rate during exercise before intake was lowest before dosage time 08.00 h and highest before dosage time 20.00 h (P = 0.03). The time-course of heart rate during exercise after oxprenolol was described by a model that incorporated the factors drug concentration and spontaneous diurnal variation. EC50 and Emax did not vary between dosage times. The spontaneous diurnal variation in heart rate during exercise was unaffected by oxprenolol, leading to an apparently greater effect of oxprenolol during the night than during the day.

Effect of loading on swelling-controlled drug release from hydrophobic polyelectrolyte gel beads.

The effect of oxprenolol HCl loading on the kinetics of polymer swelling and drug release from suspension-polymerized poly(methyl methacrylate-co-methacrylic acid) (PMMA/MAA) beads has been studied in detail. Within the range of variables studied, the polymer swelling rate increases with buffer pH and concentration. And an ionization-controlled swelling mechanism (analogous to the relaxation-controlled mechanism) mechanism) seems to become more rate-limiting at higher buffer concentrations. At oxprenolol HCL loading levels below 17.8%, the drug release and associated dimensional changes (in pH 7.4) exhibit an extended quasi-linear region despite the inherent limitation of spherical geometry. At higher loading levels, the drug release becomes faster and first-order in nature. This is apparently a result of the transition from a dissolved to a dispersed system above a percolation threshold (15-18% loading in the present study). As a result of competition from processes such as the reduction of bead dimension due to drug release and the dimensional increase due to polymer swelling and osmotic contributions from the drug, the transient bead diameter increases monotonically during drug release at loading levels up to 25.6%, whereas upon further increasing the drug loading, the bead diameter goes through a maximum during the early drug release, which eventually increases again as a result of the slow but continuous increase in polymer swelling due to further ionization. In all cases, both the drug release and the dimensional changes approach completion as the penetrating ionization fronts meet at the center, indicating a true swelling-controlled behavior.

Hydrophobic anionic gel beads for swelling-controlled drug delivery.

Using oxprenolol HCl as a model drug, the effects of pH and buffer concentration on the swelling and drug release properties in cross-linked poly(methyl methacrylate-co-methacrylic acid) (PMMA/MAA) beads have been investigated. The kinetics of swelling of such hydrophobic anionic gel beads from the dehydrated state appear to be governed primarily by a diffusion-ionization process which becomes more ionization-controlled at higher buffer concentrations. Within the range of ionic compositions studied, the swelling rate increases and the initial swelling/ionization front penetration becomes increasingly linear in time with increasing pH or buffer concentration of the swelling medium. The corresponding swelling bead diameter appears to reach an equilibrium value as soon as the penetrating ionization fronts meet at the center, suggesting a swelling equilibrium in the ionized shell due to rapid mechanical readjustment in the gel phase. At oxprenolol loading levels up to 15%, both the transient drug release and swelling bead diameter exhibit extended quasi-linear regions despite the inherent limitation of decreasing surface area at the penetrating front in the spherical geometry. In addition, both the drug release and the dimensional changes reach completion when the penetrating ionization fronts meet at the center, suggesting a true swelling-controlled drug release behavior.

Relative bioavailability of oral sustained-release and regular-release oxprenolol tablets at steady-state.

The relative bioavailability of a test sustained-release (SR) oxprenolol tablet against an approved regular-release (RR) tablet has been investigated at steady-state. In a randomized two-way crossover study, one tablet of 160 mg SR oxprenolol once every 24 h and one tablet of 80 mg RR oxprenolol once every 12 h were given to 12 healthy volunteers for 5 days. Blood samples were collected from each subject just prior to each dose-administration on days 1 through 4, and at scheduled time points on day 5 and analysed for oxprenolol concentration using HPLC. The SR tablet resulted in 42 per cent reduction in mean peak drug levels (p = 0.0341) and a statistically non-significant 14 per cent increase in mean trough levels (p = 0.8357) than the RR tablet. However it required 160 per cent longer time to reach average steady-state concentrations (Css) on day 5 (1.38 h for SR versus 0.53 h for RR; p = 0.0205). The mean area under the plasma drug concentration-time curve at steady state (AUC96-120) with the SR tablet was approximately 18 per cent lower than that observed with the RR tablet, and the degree of fluctuation (DF) was reduced by 30 per cent (2.81 for SR versus 4.11 for RR; p = 0.0069). On average, a single dose of SR tablet and two doses of RR tablets maintained the drug levels above a constant Css of 204.6 ng ml-1 for 7.88 and 7.65 h, respectively (p = 0.3513).

Efficacy and tolerability of long term oxprenolol and chlorthalidone singly and in combination in hypertensive blacks.

Sixty two black patients who had confirmed but untreated hypertension participated in a double blind clinical trial of the efficacy and tolerability of slow-release oxprenolol in a daily dose of 160 mg initially and 320 mg subsequently versus chlorthalidone 50 mg daily. Thereafter, a combination of oxprenolol with chlorthalidone in an initial dose of 160 mg and 25 mg and a subsequent dose of 320 mg and 50 mg, respectively, was administered and the effects compared with those of the same drugs given singly. The trial lasted for 3 years, but each participant took active medication for 1 year. Oxprenolol as monotherapy had no effect on the blood pressure, irrespective of the dose. Chlorthalidone as monotherapy produced a significant fall in blood pressure (p less than 0.01). Combining the 2 drugs enhanced their blood pressure lowering effects (p less than 0.001). Oxprenolol as monotherapy and as part of combination therapy was well tolerated by all patients. Chlorthalidone as monotherapy was well tolerated by most patients while a fraction of the patients developed biochemical derangements. These results confirm the findings that a beta-blocker alone may be ineffective in lowering blood pressure in hypertensive blacks. The results also show that the efficacy and tolerability of a beta-blocker and a diuretic are enhanced by their combined administration. Finally, the results show that increasing the dose of a beta-blocker or a diuretic does not produce a further increase in its blood pressure lowering effect.

[A comparative study of the ocular hypotonic action of collyria with oxprenolol and timolol maleate]. / Studiu comparativ al actiunii hipotonizante oculare a colirurilor cu oxprenolol si maleat de timolol.

Comparison of the decrease in intraocular tension in a group of 25 patients show that the collyria of oxprenolol, 0.25%, led to an average decrease of 6.36 mmHg, whereas that of thymolol maleate, 0.25%, to a decrease of 8.76 mmHg. Both decreases were statistically significant versus the initial intraocular tension.

Use of tensiomin (captopril) in the antihypertensive treatment of haemodialysis patients.

The observations of a 16-week Tensiomin therapy of 10 hypertensive patients treated with hemodialysis have been discussed. The patients have been treated for about 5 years with hemodialysis, suffered from anuria and required besides systhematical ultrafiltration a combination antihypertensive therapy. Tensiomin was combined with Minipress, Trasicor, Depressan, Estulic and Corinfar by using three- or four-drug combinations. In the course of the administration of Tensiomin the doses of the other antihypertensive drugs could be decreased by 50% on average, while the blood pressure of the patients was normalized. By controlling the patients on weeks 1, 4, 12 and 16 of therapy toxic side-effects or notable pathological changes of the examined laboratory parameters (WBC, serum total protein, Na, K, Ca, P, bilirubin, blood sugar and SGOT values) were not seen. It has been concluded that Tensiomin is an effective drug in combination therapy applied for normalizing the hypertension of dialysed patients.

Zero-order release formulation of oxprenolol hydrochloride with swelling and erosion control.

Zero-order release of oxprenolol hydrochloride was obtained by controlling the swelling and erosion of the matrix. This formulation involves only mixing of drug, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (Na CMC) at the ratio of 1:0.4:1.6, respectively, and compressing the mixture directly into tablets. The in vitro release pattern from this optimized matrix tablet was reproducible. Accelerated stability studies revealed that the optimized formulation remains stable for an approximately 2-year shelf life. This sustained-release (SR) tablet was evaluated in dogs, and for comparison a conventional (CV) formulation was also given at the same dose level. Plasma oxprenolol levels were monitored by a sensitive and specific high-performance liquid chromatographic (HPLC) method. Significant differences in the pharmacokinetic parameters, i.e., lower Cmax, higher values of tmax, MRT, AUC, and plasma concentration at 24 hr, and nearly constant plasma levels over 12 hr, indicated that the SR matrix tablet is superior to the CV rapid-releasing formulation. The in vitro release parameters and in vivo pharmacokinetics correlated well.

Effects of chlorthalidone, oxprenolol, and their combination in hypertensive blacks: a randomized double-blind crossover study.

One hundred twenty black patients with mild to moderate essential hypertension participated in a double-blind placebo-controlled crossover study of the efficacy and tolerability of slow release oxprenolol versus chlorthalidone singly and in combination. Oxprenolol as monotherapy produced no effect on blood pressure as compared with placebo even after doubling the dose. Chlorthalidone as monotherapy produced a significant decrease in blood pressure (p less than 0.01). Combining oxprenolol with chlorthalidone yielded hypotensive effects in excess of those of either of the components given singly. Oxprenolol produced a significant decrease in plasma renin activity (PRA) whereas chlorthalidone produced a significant increase in PRA. These results indicate that a beta-blocking agent alone is ineffective in lowering blood pressure in hypertensive blacks, even when the dose is high. Oxprenolol may increase the hypotensive effect of chlorthalidone by counteracting the hypokalemic effect of the diuretic and by attenuating the diuretic-induced increase in plasma renin activity.

Relationship between the rate of appearance of oxprenolol in the systemic circulation and the location of an oxprenolol Oros 16/260 drug delivery system within the gastrointestinal tract as determined by scintigraphy.

1. The position in the gastrointestinal tract of an orally administered oxprenolol Oros drug delivery system labelled with technetium-99m DTPA was followed by gamma scintigraphy, and the corresponding plasma drug concentration-time profiles after oral and i.v. administration were used to relate pharmacokinetic and transit data. 2. Gastric emptying time (0.8 +/- 0.4 h, mean +/- s.d.), and the time to arrival in the colon (3.8 +/- 0.7 h) were reasonably consistent after administration of the Oros system to fasted subjects, as were the calculated small intestine transit times (3.0 +/- 0.7 h). As expected there were wide individual variations in colonic transit, so that recorded values for total transit ranged from 6 to 32 h (median, 24.7 h). 3. Absorption of oxprenolol occurred throughout the GI tract including the colon. Plasma drug concentration-time profiles and input functions (calculated by deconvolution) could be related to transit behaviour and in vitro release. Inflexions in the calculated rate of drug input when the Oros system was located in the colon corresponded with periods of stagnation at the hepatic and splenic flexures in two subjects and the ileocaecal junction in two others. The mechanism of these changes is unclear.

Relationships between verapamil plasma concentrations and its antihypertensive action.

Twenty-seven hypertensive outpatients were studied to evaluate the efficacy of verapamil after a single oral dose as well as following a short-term treatment and also in combination with oxprenolol. Blood pressure was significantly reduced (p 0.01) after verapamil monotherapy and the combined treatment. PR interval was lengthened from 30 min to 4 h during acute testing, and also after short-term treatment. QT was only prolonged after the verapamil monotherapy. Systolic time intervals (STIs) were not modified, except left ventricular ejection time (LVETc). Direct correlations were found among verapamil plasma concentrations and changes provoked on blood pressure and PR interval. The mean side effects found were disturbance of atrioventricular conduction in two patients without ulterior complications. The results suggest that verapamil monotherapy or in combination with oxprenolol could be useful in the treatment of essential hypertension.