Influence of ß2- and ß3-adrenoceptor agonists on contractile activity of the porcine myometrium in the luteal phase and the first days of pregnancy.

This study analysed the relaxant properties of salbutamol (ß2-adrenoceptors agonist) and BRL 37344 (ß3-adrenoceptors agonist) regarding the contractility of porcine myometrium on days 10-14 of the oestrous cycle (cyclic group; n = 10) and on days 3-5 of pregnancy (early pregnant group; n = 6). The activity of myometrial strips (tension, frequency and amplitude) was recorded under isometric conditions using force transducers. The contractility was assessed further following the administration of increasing concentrations of the agonists (10-9-10-4 M), both with and without ß-adrenoceptor antagonists (butaxamine - a selective ß2- adrenoceptor antagonist, propranolol- a non-selective ß1- and ß2-adrenoceptor antagonist and bupranolol - a non-selective ß1-, ß2- and ß3-adrenoceptor antagonist) at a concentration of 10-4 M. Although neither salbutamol nor BRL 37344 caused changes in the tension, at the highest concentrations they decreased the frequency and amplitude of contractions. These changes were more evident after salbutamol treatment and in the early pregnant group. Antagonists given alone did not cause changes in the parameters examined but changed some activity of the agonists. Butoxamine reduced the decrease in frequency and amplitude induced by salbutamol and produced a decrease in the tension after BRL 37344 treatment in the early pregnant group. Propranolol reduced the decrease in frequency and amplitude induced by salbutamol in both examined groups and did not cause significant changes in BRL 37344 activity. The administration of bupranolol before salbutamol treatment caused an increase in the tension and reduced the decrease in the frequency in the cyclic group. Moreover, bupranolol eliminated a decrease in frequency and induced an increase in amplitude caused by BRL 37344 in both groups and these changes were more evident in the early pregnant group. The data indicates that both ß2- and ß3-adenoreceptors are involved in the regulation of the contractility in both groups, but the changes after agonists and antagonists treatment are more evident in the early pregnant myometrium.

Polymer based solutions of bupranolol hydrochloride for intranasal systemic delivery.

The present study was aimed at developing intranasal polymer based solutions as alternative route for systemic delivery of Bupranolol hydrochloride (BPH). It is a potent ß-blocker drug which upon oral administration undergoes extremely high hepatic first-pass metabolism (>90% in humans). The polymeric solutions were prepared using varying concentrations of polymers like sodium alginate, chitosan, sodium carboxymethylcellulose, methylcellulose (MC), polyvinyl alcohol, carbopol, hydroxypropyl MC, and hydroxypropyl cellulose. The prepared formulations were evaluated in terms of pH of the solution, angular viscosity, drug content, gel strength, gelation temperature, in vitro drug release, in vivo pharmacodynamic studies, histopathological, and stability studies. Except MC based solutions, a biphasic pattern of drug release was obtained in all other cases. Nasal administration of selected batches of polymeric solutions were found to be nontoxic and were able to improve drug bioavailability when compared to oral, nasal, and intravenous solution administrations of BPH.

Cardiovascular effects of transdermally delivered bupranolol in rabbits: effect of chemical penetration enhancers.

Bupranolol is a promising candidate for transdermal drug delivery system (TDDS) development. The effect of permeation enhancers on the in vivo delivery and beta-blocking effect of reservoir type TDDS was studied in comparison with intravenous BPL in rabbits. The beta-blocking effect was quantified by measuring the inhibition of isoprenaline induced tachycardia in rabbits after BPL administration via transdermal and intravenous routes. The reservoir type TDDS containing a hydroxypropyl cellulose gel and polyethylene membrane was used as a control device. In comparison, the TDDS containing skin penetration enhancers, either 2-pyrrolidone or partially methylated beta cyclodextrin (PMbetaCD) were evaluated. The control device (no enhancer) produced about 52% inhibition of isoprenaline induced tachycardia at 2 h and the effect continued over 24 h application period, however, the devices with 2-pyrolidone or PMbetaCD produced about 85% inhibition of isoprenaline induced tachycardia at 3 h and the same effect continued over 24 h application period. Likewise, the AUC of these devices were significantly higher than that of control device. The intravenous bupranolol showed rapid decline in the pharmacodynamic effect with time indicating its rapid elimination. The in vivo delivery of bupranolol (as estimated by a mass balance study) from the devices made with pyrolidone or PMbetaCD was 3-fold higher than that of control. The results of this study strongly suggest that the penetration enhancers in the TDDS increased the in vivo delivery of BPL, thereby increased the beta-blocking activity of BPL by 50-60% higher than control, enabling the reduction of the TDDS patch size, accordingly.

Effect of penetration enhancers on the transdermal delivery of bupranolol through rat skin.

Bupranolol (BPL) is a suitable drug candidate for transdermal drug delivery system development based on its favorable physicochemical and pharmacokinetic properties. The effect of different penetration enhancers on the permeation of BPL across rat skin was studied using side-by-side diffusion cells. 2-Pyrrolidone (PY), 1-methyl-2-pyrrolidone (MPY), and propylene glycol (PG) at various concentrations were used as penetration enhancers along with 0.4% w/v aqueous suspension of BPL. Menthol at different concentrations in isopropanol-water (6:4) mixture also was used as an enhancer wherein BPL at 0.4% w/v was completely solubilized. Skin pretreatment studies were carried out with all the above enhancers to understand their role in the penetration enhancement effect. PY and MPY at 5% w/v concentrations increased the permeation of BPL by 3.8- and 2.4-fold, respectively, versus control (p < .01). PG at 10% and 30 w/v concentrations increased the flux of BPL by 2.5- and 5.0-fold, respectively, versus control (p < .001). Menthol at 2% w/v concentration increased the flux of BPL by 3.8-fold (p < .01) and further increase in menthol concentration significantly decreased the flux of BPL. Overall, pyrrolidones and menthol at low concentrations (5% w/v or less) and PG at 30% w/v concentration were effective as penetration enhancers for BPL.

Effect of penetration enhancers on the release and skin permeation of bupranolol from reservoir-type transdermal delivery systems.

A reservoir-type transdermal delivery system (TDS) of bupranolol (BPL) was designed and evaluated for different formulation variables like gel reservoirs (made with anionic and nonionic polymers), rate controlling membranes and penetration enhancers on the drug release and in vitro skin permeation kinetics of the devices. Keshary-Chien type diffusion cells and pH 7.4 phosphate buffered saline (PBS) were used for drug release studies and excised rat skin was used as a barrier for permeation experiments. The release rate of BPL from nonionic polymer gel reservoirs [hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC)] was much higher than anionic polymer gel reservoirs [carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (Na CMC) and sodium alginate)]. Among different rate controlling membranes, Cotran-polyethylene microporous membrane demonstrated highest release rate for BPL than all other membranes. An optimized TDS formulation with HPC gel and Cotran-polyethylene microporous membrane was used to study the effect of penetration enhancers on the release and skin permeation rate of BPL from the TDS. Permeation rates of the devices containing 5% (w/v) pyrrolidone (PY) or 1-methyl-2-pyrrolidone (MPY) were about 3- and 1.5-fold higher than control (no enhancer, P<0.01) indicating PY to be better penetration enhancer for BPL than MPY. The permeation rates of devices containing partially methylated beta-cyclodextrin (PMbetaCD) and PMbetaCD-BPL complex were about 2.5- and 1.4-fold higher than control (P<0.01). Inclusion of 10 and 30% w/v propylene glycol (PG) in the devices increased the permeation rate by 1.4- and 1.8-fold higher than control (P<0.05). In conclusion, reservoir-type TDS of BPL was developed and penetration enhancers increased the skin permeation of BPL at 4-5 times higher levels than the desired target delivery rate.

Effect of cyclodextrins on the complexation and transdermal delivery of bupranolol through rat skin.

Bupranolol (BPL) is a potent beta-blocking agent, the extensive first-pass metabolism (>90%) and rapid elimination half-life (1.5-2.0 h) of this drug make it well suited to be developed as a transdermal delivery system (TDS). Hydroxypropyl betaCD (HPbetaCD) and partially methylated betaCD (PMbetaCD) were used as penetration enhancers for BPL. The formation of inclusion complex of BPL with these cyclodextrins (CDs) was characterized in solution and solid states by phase solubility, X-ray diffractometry and differential scanning calorimetry (DSC) analyses. The effect of CDs on the permeation enhancement of BPL through rat skin was studied using side-by-side diffusion cells and pH 7.4 phosphate-buffered saline (PBS). CDs were employed at different concentrations with 0.4% (w/v) BPL as well as with excess quantity of BPL (1.0%, w/v) that CDs could not complex all the BPL and the drug was in the form of an aqueous suspension. The permeation of BPL from its aqueous suspension (0.4%, w/v) significantly increased when CDs were used at low concentrations (up to 2 and 5%, w/v concentration for HPbetaCD and PMbetaCD, respectively) (P < 0.01). At higher CD concentrations, the permeation of BPL decreased; and both CDs at 10% (w/w), showed similar flux values to that of control (no enhancer, P > 0.05). The permeation of BPL from its 1.0% (w/v) aqueous suspension increased with increase in concentration of CD up to 10% (w/v) for HPbetaCD and PMbetaCD. At 10% (w/v) concentration of HPbetaCD and PMbetaCD, the flux of BPL from its 1.0% aqueous suspension increased 3.8- and 4.6-fold (P < 0.01 and P < 0.001, respectively). The permeation data of skin pretreatment with CDs indicate that HPbetaCD had no effect on the skin, whereas PMbetaCD significantly reduced the skin barrier for BPL, as shown by 1.7-fold increase in the flux by PMbetaCD pretreatment (P < 0.001). Overall, both HPbetaCD and PMbetaCD were found to be suitable for improving the solubility and penetration enhancement of BPL.

Synthesis and evaluation of radiolabeled antagonists for imaging of beta-adrenoceptors in the brain with PET.

Five potent, lipophilic beta-adrenoceptor antagonists (carvedilol, pindolol, toliprolol and fluorinated analogs of bupranolol and penbutolol) were labeled with either carbon-11 or fluorine-18 and evaluated for cerebral beta-adrenoceptor imaging in experimental animals. The standard radioligand for autoradiography of beta-adrenoceptors, [125I]-iodocyanopindolol, was also included in this survey. All compounds showed either very low uptake in rat brain or a regional distribution that was not related to beta-adrenoceptors, whereas some ligands did display specific binding in heart and lungs. Apparently, the criteria of a high affinity and a moderately high lipophilicity were insufficient to predict the suitability of beta-adrenergic antagonists for visualization of beta-adrenoceptors in the central nervous system.

Transdermal absorption of bupranolol in rabbit skin in vitro and in vivo.

This study was designed to clarify the percutaneous penetration of bupranolol (BP), a beta-adrenoceptor antagonist, through rabbit skin and to compare the in vitro penetration with the in vivo absorption. BP penetrated across the skin slowly in the absence of enhancers in vitro. Isopropyl myristate and N-methyl-2-pyrrolidone enhanced the in vitro penetration, with a 3.6 times higher flux compared with that without enhancers. However, in the in vivo percutaneous absorption, the maximal penetration was obtained with the formulation added dlimonene, with a 3.0 times higher area under the concentration-time curve (AUC) than that for the formulation without enhancers. The plasma levels of BP determined, however, were extremely lower than the theoretical plasma steady-state concentrations predicted. The plasma levels of BP after application of these formulations were maintained in the range of 7-22 ng/ml for 30 h, of which concentrations were above the therapeutically effective concentration (1.5-4 ng/ml). Therefore, the transdermal systems will offer an efficient drug delivery system for the treatment of angina pectoris and tachycardia.

Pharmacodynamic effects of transdermal bupranolol and timolol in vivo: comparison of microemulsions and matrix patches as vehicle.

Transdermal administration of drugs possesses several advantages in therapy, but is limited by generally poor penetration through the skin. The aim of this study was to assess whether in vivo transdermal absorption could be enhanced by using microemulsions (ME) as vehicles. Water uptake from the occluded skin changes the water-free microemulsion base (MEB) into a ME. The increasing content of water decreases the solubility of apolar drugs. This leads to in situ formation of a super-saturated ME that possesses a particularly high absorption rate due to the enhanced diffusion pressure of the drug. A saturated solution of the model drugs bupranolol (B) and timolol (T) in a water-free microemulsion base was applied to an clipped area of the dorsal skin of rabbits with an occlusive patch. Evaluations were made in comparison to matrix patches (M) containing 1.2 mg/cm2 B or 2.0 mg/cm2 T. The beta-blocker dose applied was 2.0 mg/kg body weight throughout the study. The measured parameter of the pharmacodynamic effect was the maximal heart rate (HR) after an i.v. bolus injection of a standard dose of isoproterenol. Observations were made in different intervals over a 10-h time period after application of the patches. The response to isoproterenol was calculated as beta-blocker effect. Faster increasing effects and higher maxima for both drugs was found after application in MEB compared to M. After administration of B and T in MEB the effects were found to be identical, with a maximum (85-90%) after 2 h. Application in M showed B to be less effective (34%, 10h no plateau) than T (74%, 10h). Therefore microemulsions represent an improved vehicle for transdermal administration of test drugs.