Kaolinite/cashew gum bionanocomposite for doxazosin incorporation and its release.

Incorporation of drugs in clay minerals has been widely proposed for the controlled-release or increased solubility of drugs. In this context, a bionanocomposite based on kaolinite and cashew gum (Kln/Gum) was synthesized and characterized by X-ray diffraction (XRD), thermal analysis (TG/DTA), and Fourier transform infrared spectroscopy (FTIR). The bionanocomposite was applied to the incorporation and further release of doxazosin mesylate (DB). The influence of solution pH (1-3), adsorbent dose (20-50 mg), initial drug concentration (20.0-70.0 mg L-1), contact time (15-300 min), and temperature (25, 35, and 45 °C) were systematically evaluated. Equilibrium was reached around 60 min, with a maximum adsorption capacity of 31.5 ± 2.0 mg g-1 at a pH of 3.0 and 25 °C. Hydrogen bonding contributed to DB incorporation on the Kln/Gum. In addition, DB maximum amounts of 16.80 ± 0.58 and 77.00 ± 2.46% were released at pH values of 1.2 and 7.4, respectively. These results indicated that the Kln/Gum bionanocomposite is an effective and promising material for the incorporation/release of drugs with similar structures to DB.

Chitosan-TPP nanoparticles stabilized by poloxamer for controlling the release and enhancing the bioavailability of doxazosin mesylate: in vitro, and in vivo evaluation.

Objective: Control the release and enhance the bioavailability of chitosan-doxazosin mesylate nanoparticles (DM-NPs). Significance: Improve DM bioavailability for the treatment of benign prostatic hyperplasia and hypertension. Methods: Plackett-Burman design was utilized to screen the variables affecting the quality of DM-NPs prepared by ionic gelation method. The investigated variables were initial drug load (X1), chitosan percentage (X2), tripolyphosphate sodium (TPP) percentage (X3), poloxamer percentage (X4), homogenization speed (X5), homogenization time (X6) and TPP addition rate (X7). The prepared DM-loaded NPs have been fully evaluated for particle size (Y1), Zeta potential (Y2), production yield (Y3), entrapment efficiency (Y4), loading capacity (Y5), initial burst (Y6), and cumulative drug release (Y7). Finally, DM pharmacokinetic has been investigated on healthy albino male rabbits by means of non-compartmental analysis. Results: The combination of variables showed variability of Y1, Y2, and Y3 equal to 122-710 nm, 3.49-23.63 mV, and 47.31-92.96%, respectively. While Y4 and Y5, reached 99.87%, and 8.53%, respectively. The prepared NPs revealed that X2, X3, and X4 are the variables that play the important role in controlling the release behavior of DM from the NPs. The in vivo pharmacokinetic results indicated the enhancement in bioavailability of DM by 7 folds compared to drug suspension and the mean residence time prolonged to 23.72 h compared to 4.7 h of drug suspension. Conclusion: The study proved that controlling the release of DM from NPs enhance its bioavailability and improve the compliance of patients with hypertension or benign prostatic hyperplasia.

An efficient spectrofluorimetric method adopts doxazosin, terazosin and alfuzosin coupling with orthophthalaldehyde: Application in human plasma.

A new, selective and sensitive spectrofluorimetric method was designed for the quantitation of doxazosin (DOX), terazosin (TER) and alfuzosin (ALF) in their dosage forms and human plasma. The method adopts efficient derivatization of the studied drugs with ortho-phthalaldehyde (OPA), in the presence of 2-mercaptoethanol in borate buffer (pH9.7) to generate a highly fluorescent isoindole derivatives, which can strongly enhance the fluorescence intensities of the studied drugs, allowing their sensitive determination at 430nm after excitation at 337nm. The fluorescence-concentration plots were rectilinear over the ranges (10.0-400.0) ng/mL. Detection and quantification limits were found to be (0.52-3.88) and (1.59-11.76) ng/mL, respectively. The proposed method was validated according to ICH guidelines, and successfully applied for the determination of pharmaceutical preparations of the studied drugs. Moreover, the high sensitivity of the proposed method permits its successful application to the analysis of the studied drugs in spiked human plasma with % recovery (96.12±1.34-100.66±0.57, n=3). A proposal for the reaction mechanism was presented.

Design and synthesis of small molecule agonists of EphA2 receptor.

Ligand-independent activation of EphA2 receptor kinase promotes cancer metastasis and invasion. Activating EphA2 receptor tyrosine kinase with small molecule agonist is a novel strategy to treat EphA2 overexpressing cancer. In this study, we performed a lead optimization of a small molecule Doxazosin that was identified as an EphA2 receptor agonist. 33 new analogs were developed and evaluated; a structure-activity relationship was summarized based on the EphA2 activation of these derivatives. Two new derivative compounds 24 and 27 showed much improved activity compared to Doxazosin. Compound 24 possesses a bulky amide moiety, and compound 27 has a dimeric structure that is very different to the parental compound. Compound 27 with a twelve-carbon linker of the dimer activated the kinase and induced receptor internalization and cell death with the best potency. Another dimer with a six-carbon linker has significantly reduced potency compared to the dimer with a longer linker, suggesting that the length of the linker is critical for the activity of the dimeric agonist. To explore the receptor binding characteristics of the new molecules, we applied a docking study to examine how the small molecule binds to the EphA2 receptor. The results reveal that compounds 24 and 27 form more hydrogen bonds to EphA2 than Doxazosin, suggesting that they may have higher binding affinity to the receptor.

Identification of anti-cancer potential of doxazocin: Loading into chitosan based biodegradable hydrogels for on-site delivery to treat cervical cancer.

In this study, an effective, biocompatible and biodegradable co-polymer comprising of chitosan (CS) and polyvinyl alcohol (PVA) hydrogels, chemically crosslinked and impregnated with doxazocin, is reported. The chemical structural properties of the hydrogels were evaluated by Fourier Transform Infrared spectroscopy (FTIR) and physical properties were analysed by scanning electron microscopy (SEM). The swelling behaviour is an important parameter for drug release mechanism and was investigated to find out the solution absorption capacity of the synthesized hydrogels. MTT assay revealed that doxazocin loaded hydrogels significantly hindered the cell viability. Flow cytometry analysis was performed to analyse the effect of 8CLH and 4CLH on regulation of cell cycle. Moreover, in vivo anti-cancer potential of synthesized hydrogels was assessed by CAM Assay. Results displayed that 8CLH with 1mg/ml of doxazocin had prominently decreased the angiogenesis and significantly increased the number of cells in G1 phase of cell cycle. These results declared that 8CLH will be a good addition among hydrogels used for treatment of cancer by onsite delivery of drug.

Release mechanism of doxazosin from carrageenan matrix tablets: Effect of ionic strength and addition of sodium dodecyl sulphate.

The polyelectrolyte matrix tablets loaded with an oppositely charged drug exhibit complex drug-release mechanisms. In this study, the release mechanism of a cationic drug doxazosin mesylate (DM) from matrix tablets based on an anionic polyelectrolyte λ-carrageenan (λ-CARR) is investigated. The drug release rates from λ-CARR matrices are correlated with binding results based on potentiometric measurements using the DM ion-sensitive membrane electrode and with molecular characteristics of the DM-λ-CARR-complex particles through hydrodynamic size measurements. Experiments are performed in solutions with different ionic strength and with the addition of an anionic surfactant sodium dodecyl sulphate (SDS). It is demonstrated that in addition to swelling and erosion of tablets, the release rates depend strongly on cooperative interactions between DM and λ-CARR. Addition of SDS at concentrations below its critical micelle concentration (CMC) slows down the DM release through hydrophobic binding of SDS to the DM-λ-CARR complex. On the contrary, at concentrations above the CMC SDS pulls DM from the complex by forming mixed micelles with it and thus accelerates the release. Results involving SDS show that the concentration of surfactants that are naturally present in gastrointestinal environment may have a great impact on the drug release process.

Analysis of Aged Human Serum Albumin Affinity for Doxazosin.

Structural changes of human serum albumin (HSA) caused by old age and coexisting diseases result in differences in the binding of doxazosin (DOX). DOX is a postsynaptic α1- adrenoreceptor antagonist used for treatment of hypertension and benign prostatic hyperplasia. In elderly people suffering from various renal or hepatic diseases the significant portion of N-form of human serum albumin (normal) is converted to A-form (aged). The differences in binding of doxazosin to N- and Aform of albumin are an important factor, which may determines therapeutic dosage and toxicity of the test drug. To indicate these differences, the technique of fluorescence spectroscopy was used. The association constant (Ka) obtained from fluorescence quenching demonstrated that doxazosin has higher affinity for AHSA than for HSA. In order to describe the cooperativity in binding process, the values of the Hill's coefficient has been analysed. For DOX-HSA system (λex 295 nm) Hill's coefficient is close to 1 and it indicates that there is a single class of binding sites. For DOX-HSA (λex 275 nm) and DOX-AHSA (λex 275 nm and λex 295 nm) systems we observed positive cooperativity (nH>1). A greater red shift of fluorescence emission maximum of AHSA than HSA in the presence of DOX was observed. This suggests that the binding of DOX to AHSA was accompanied by a stronger increase in polarity around the fluorophores in comparison to HSA. The binding interaction between DOX and HSA has been also studied by molecular docking simulation.

Targeting the Eph-ephrin System with Protein-Protein Interaction (PPI) Inhibitors.

Eph-ephrin system is emerging as a new potential target in several diseases including cancer, diabetes, neurodegenerative diseases and inflammation. In the last decade, several efforts have been made to develop small molecule antagonists of Eph receptors. Both natural and synthetic compounds were discovered with (poly) phenol and steroidal derivatives on one side and the α1 agonist doxazosin, 2,5-dimethylpyrrol- 1-yl-benzoic acids and amino acid conjugates of lithocholic acid on the other. In the present paper we critically present available data for these compounds and discuss their potential usefulness as pharmacological tools or as candidates for a lead-optimization program.

Enantioselective pharmacokinetics of doxazosin and pharmacokinetic interaction between the isomers in rats.

In this study, the stereoselective pharmacokinetics of doxazosin enantiomers and their pharmacokinetic interaction were studied in rats. Enantiomer concentrations in plasma were measured using chiral high-pressure liquid chromatography (HPLC) with fluorescence detection after oral or intravenous administration of (-)-(R)-doxazosin 3.0 mg/kg, (+)-(S)-doxazosin 3.0 mg/kg, and rac-doxazosin 6.0 mg/kg. AUC values of (+)-(S)-doxazosin were always larger than those of (-)-(R)-doxazosin, regardless of oral or intravenous administration. The maximum plasma concentration (Cmax ) value of (-)-(R)-doxazosin after oral administration was significantly higher when given alone (110.5 ± 46.4 ng/mL) versus in racemate (53.2 ± 19.7 ng/mL), whereas the Cmax value of (+)-(S)-doxazosin did not change significantly. The area under the curve (AUC) and Cmax values for (+)-(S)-doxazosin after intravenous administration were significantly lower, and its Cl value significantly higher, when given alone versus in racemate. We speculate that (-)-(R)-doxazosin increases (+)-(S)-doxazosin exposure probably by inhibiting the elimination of (+)-(S)-doxazosin, and the enantiomers may be competitively absorbed from the gastrointestinal tract. In conclusion, doxazosin pharmacokinetics are substantially stereospecific and enantiomer-enantiomer interaction occurs after rac-administration.

Pulse release of doxazosin from hydroxyethylcellulose compression coated tablet: mechanistic and in vivo study.

Chronotherapeutically programmed hydroxyethylcellulose (HEC) based compression coated doxazosin tablets were prepared and the influence of disintegrants croscarmellose sodium, L-hydroxypropylcellulose (L-HPC), gellan gum on drug release and in vivo performance were investigated. Infrared spectroscopy and differential scanning calorimetric studies did not indicate any excipient incompatibility in the tablets. The disintegrants induced a continuous water influx resulting in a rapid expansion of the membrane. The subsequent formation of fractures into the coats leads to a fast drug release after an initial lag time. Release rates indicated that croscarmellose sodium and L-HPC were directly proportional to their concentration in the formulations. In vitro optimized croscarmellose sodium-HEC matrix showed significantly faster (p < 0.05) drug release (t90% = 46 min) after an initial lag of 243 min. Disintegrant-HEC blended matrices were found significantly superior (p < 0.05) in terms of in vitro release and bioavailability in comparison to plain HEC matrices. Drug release kinetics followed modified power law and Weibull model (r > 0.99). The mechanism involved in release was anomalous transport and super case II transport with matrix swelling. The pulsatile tablets showed no changes either in physicochemical appearance, drug content or in dissolution pattern during its accelerated stability studies.

Doxazosin selectively potentiates contraction to serotonin via 5-HT2A receptors in longitudinal muscle strips of the rabbit gastric body.

The aims of this study were to examine the effects of doxazosin on contractile responses to 5-hydroxytryptamine (5-HT), carbachol, and histamine, and to compare them with those of prazosin, alfuzosin, and terazosin, and then characterize a pharmacological profile of the 5-HT-induced contractile response using preparations of isolated longitudinal muscle strips from the rabbit gastric body. The results from these preparations showed that the contraction response to 5-HT, but not to carbachol or histamine, was found to be dose-dependently potentiated by doxazosin and its enantiomers. The specific potentiation effect on 5-HT was not observed in the preparations that were treated with prazosin, terazosin, or alfuzosin. The contractile response to 5-HT and its potentiation by doxazosin were not affected by treatment with phenoxybenzamine. However, 5-HT-induced contraction was competitively antagonized by nefazodone (with pA2 value of 8.64 ± 0.17), and was almost completely inhibited by treatment with indomethacin. In conclusion, doxazosin, but not prazosin, alfuzosin, or terazosin, selectively potentiates 5-HT-induced contraction in the rabbit gastric body strips via an α1-adrenoceptor-independent mechanism, without chiral recognition of its enantiomers. Additionally, the contraction to 5-HT was found to be mediated via 5-HT(2) receptors, and was similar to PGs synthesis in the preparations.

Stereoselective binding of doxazosin enantiomers to plasma proteins from rats, dogs and humans in vitro.

AIM: (±)Doxazosin is a long-lasting inhibitor of α1-adrenoceptors that is widely used to treat benign prostatic hyperplasia and lower urinary tract symptoms. In this study we investigated the stereoselective binding of doxazosin enantiomers to the plasma proteins of rats, dogs and humans in vitro. METHODS: Human, dog and rat plasma were prepared. Equilibrium dialysis was used to determine the plasma protein binding of each enantiomer in vitro. Chiral HPLC with fluorescence detection was used to measure the drug concentrations on each side of the dialysis membrane bag. RESULTS: Both the enantiomers were highly bound to the plasma proteins of rats, dogs and humans [(-)doxazosin: 89.4%-94.3%; (+)doxazosin: 90.9%-95.4%]. (+)Doxazosin exhibited significantly higher protein binding capacities than (-)doxazosin in all the three species, and the difference in the bound concentration (Cb) between the two enantiomers was enhanced as their concentrations were increased. Although the percentage of the plasma protein binding in the dog plasma was significantly lower than that in the human plasma at 400 and 800 ng/mL, the corrected percentage of plasma protein binding was dog>human>rat. CONCLUSION: (-)Doxazosin and (+)doxazosin show stereoselective plasma protein binding with a significant species difference among rats, dogs and humans.

Quantitation of in vitro α-1 adrenergic receptor antagonist binding capacity to biologic melanin using tandem mass spectrometry.

PURPOSE: The purpose of this study was to develop methods to allow evaluation of the binding characteristics for a series of α-1 antagonists to biologically-derived melanin. METHODS: Fresh bovine globes were used to obtain iridal and choroid/retinal pigment epithelial (CRPE) derived melanin. Binding characteristics of chloroquine, tamsulosin and doxazosin were then evaluated in vitro using tandem mass spectroscopy. RESULTS: Tandem mass spectrometry-based assays were developed for three α-1 antagonists that provided linear assay ranges which spanned (minimally) 0.01-10 µg/mL, while exhibiting excellent inter-assay precision and accuracy. When applied to the evaluation of binding characteristics for iridal melanin, mean chloroquine and tamsulosin fractions were found to be 41.9 ± 14.2 pmoles mg(-1) and 25.34 ± 6.186 pmoles mg(-1), respectively. Mean iridal doxazosin binding was found to be 6.36 ± 2.19 pmoles mg(-1). Interestingly, mean levels of tamsulosin, but not doxazosin found bound to choroid/CRPE derived melanin approached that of chloroquine (27.91 µg/mL, 25.68 µg/mL and 5.94 µg/mL for chloroquine, tamsulosin and doxazosin, respectively). One way ANOVA for binding affinity for chloroquine, tamsulosin and doxazosin was statistically significant for both iridal and CRPE-derived melanin (p = 0.0012 and 0.0023), respectively. A Bonferroni post-hoc analysis demonstrated a statistically significant difference in the amount of binding between tamsulosin, doxazosin and chloroquine to iridal but not CRPE derived melanin (p < 0.05). CONCLUSIONS: Tamsulosin appears to demonstrate melanin binding affinity which approaches chloroquine and exceeds doxazosin for both iridal and CRPE-derived bovine melanin.

[Determination of doxazosin enantiomers in rat plasma and investigation of their chiral inversion].

The study is to establish an HPLC method using fluorescence detector for the determination of doxazosin enantiomers and investigate their chiral inversion in vitro and in vivo. Ultron ES-OVM was taken as the chiral chromatographic column, and the column temperature was 30 degrees C. Isocratic elution using a mobile phase of phosphate buffer-acetonitrile (85 : 15, v/v) at a flow rate of 0.8 mL x min(-1) was done. The fluorescence detection was set at lambda(Ex) = 255 nm and lambda(Em) = 385 nm. Prazosin was used as the internal standard. (-) Doxazosin or (+) doxazosin added into rat plasma in vitro was determined after incubating in 37 degrees C water bath for 2, 5 and 10 days. (-) Doxazosin or (+) doxazosin was administered orally to the rats for one months. Plasma samples were taken at 8 h after the last administration. A good linear relationship was achieved when the concentration of doxazosin enantiomers was within the range of 4 - 2 000 ng x mL(-1). The average recovery for (-) doxazosin was 99.5% with RSD 3.6%, and for (+) doxazosin was 99.3% with RSD 4.3%. Chiral inversion was observed neither in vitro nor in vivo studies. The method is selective, accurate and reproducible, which is suitable for the detection of doxazosin enantiomers in rat plasma. The in vitro and in vivo studies indicate that chiral inversion occurs uneasily between (-) doxazosin and (+) doxazosin in the rat.

Preparation and evaluation of sustained-release doxazosin mesylate pellets.

Doxazosin mesylate (DXM) sustained release pellets were prepared by an extrusion-spheronization and fluid-bed coating technique. The core pellets containing DXM were prepared by extrusion-spheronization technique, and coated by a fluid-bed coater to control the release of DXM. The factors affecting to properties of pellets, such as diluent content, type and coating level of coating agents and plasticizers were studied in the present study. Polymethacrylate derivatives (Eudragit® RS PO and RL PO) were used for coating agents, and polyethylene glycol 6000 (PEG 6000), triethyl citrate (TEC) and castor oil were as plasticizers. To evaluate the properties of prepared pellets, the size of prepared pellets was investigated by sieve analysis technique and the morphology of pellets was evaluated by scanning electron microscopy. Through the dissolution test, factors that have an effect on the dissolution of the drug were evaluated. As the content ratio of microcrystalline cellulose (MCC) had increased, the dissolution was proportionally sustained. Eudragit® RS PO had more marked sustaining effect on the dissolution rate than Eudragit® RL PO, and the effect was more pronounced with the increased coating level. PEG 6000 was an appropriate plasticizer for DXM pellets, and increasing the content of PEG 6000, was also slightly decreasing the dissolution rate.

In vitro vs. canine data for assessing early exposure of doxazosin base and its mesylate salt.

In this study, we evaluated the usefulness of biorelevant in vitro data and of canine data in forecasting early exposure after the administration of two phases of a BCS Class II compound, i.e., doxazosin base (DB) and its mesylate salt (DM). DB, DM, and doxazosin hydrochloride (DH) were prepared and characterized. In vitro data were collected in various media, including human aspirates. Solubilities of DB and DM in human gastric fluid were forecasted by data in fasted state simulating gastric fluid containing physiological components (FaSSGF-V2) but not by data in HCl(pH 1.8). Unlike data in FaSSGF-V2, dissolution of DB and DM tablets in HCl(pH 1.6) is rapid. Dissolution of DB tablet in FaSSGF-V2 is incomplete and conversion to DH seems to occur. Differences between DB and DM in dissolution in the small intestine are overestimated in the absence of physiological solubilizers. Using the in vitro data and previously described modeling procedures, the cumulative doxazosin profile in plasma was simulated and the 0-2h profile was used for evaluating early exposure. Individual cumulative doxazosin profiles in plasma, after single DM tablet administrations to 24 adults, were constructed from corresponding actual plasma profiles. Compared with in vitro DM data in pure aqueous buffers, DM data in biorelevant media led to better prediction of early exposure. Based on intersubject variability in early exposure after DM administration and simulated profiles, the administered phase, DB or DM, does not have a significant impact on early exposure. Partial AUCs were used for evaluating early exposure after DB and DM administration in 4 dogs. Early exposure was significantly higher after administration of DM to dogs. Dogs are not appropriate for evaluating differences in early exposure after DB and DM administrations.

Relaxant and contractile responses of detrusor muscle strips obtained from bladder outlet-obstructed rats treated with doxazosin enantiomers.

(-)Doxazosin, one of (±)doxazosin enantiomers, was speculated to have a pharmacological enantioselectivity between the cardiovascular system and the urinary system by comparison with (+)doxazosin. Therefore, to evaluate the potential benefits of (-)doxazosin in the treatment of benign prostate hyperplasia, we compared the effects of the 3 agents, using rat mesenteric artery preparations and obstructed bladder strips. Concentration-response curves for carbachol (contractile response) and isoprenaline (relaxant response) in detrusor muscle strips of the bladder outlet obstruction (BOO) rats were shifted to the left, with significant increases in the Emax values, and significant decreases in the EC50 values by comparison with the sham-operated rats (P < 0.05, n = 10). The enhanced responses in detrusor muscle strips of the BOO rats treated with (±)doxazosin and its enantiomers at 3 mg·(kg body mass)(-1)·day(-1) for 2 weeks returned to normal levels, and the 3 agents inhibited the enhanced responses to carbachol and isoprenaline to the same extent. On the other hand, the 3 agents uncompetitively inhibited the vasoconstrictive response curves for NA in the rat isolated mesenteric artery, and the pKB value of (-)doxazosin at vascular α1-adrenoceptors was significantly smaller (P < 0.05, n = 6) than that of (+)doxazosin or (±)doxazosin. In conclusion, although (-)doxazosin inhibits vascular functional α1-adrenoceptors more weakly than (+)doxazosin, both agents equally ameliorate the enhanced responses in detrusor muscle of BOO rats, suggesting that the chiral carbon atom in the molecular structure of doxazosin does not affect its beneficial effects in the bladder smooth muscle of BOO rats.

Doxazosin-carrageenan interactions: a novel approach for studying drug-polymer interactions and relation to controlled drug release.

When a cationic drug like doxazosin mesylate (DM) is incorporated into matrix tablets made of anionic polyelectrolytes carrageenans (CARRs) of different types (κ-, ι-, λ-CARR), DM-CARR interactions have a strong impact on drug release. To investigate these interactions, special DM ion-selective membrane electrode was made and applied for construction of binding isotherms. Isotherms were treated by the Zimm-Bragg theory and cooperative binding model. It was demonstrated that binding of doxazosin cations, DH(+), to CARRs is cooperative. It starts at very low drug concentrations with strong electrostatic interactions followed by aggregation of DH(+) ions. Hydrophobic interactions between bound DH(+) substantially contribute to the extent of binding. The strength of interactions increases with increasing negative charge of CARRs. At saturation, the number of DM molecules bound per repeat unit depends on the charge and steric distribution of binding sites on CARRs. Drug release rates of DM from CARR matrices were in accordance with the cooperativity binding constants: the weakest binding resulted in the fastest release. However it was proven that prolonged drug release is possible only by several processes running simultaneously, i.e., by swelling and erosion of CARR matrices on one side and electrostatic interactions and cooperativity effects on the other.

pH-independent sustained release matrix tablet containing doxazosin mesylate: effect of citric acid.

The aim of this study was to develop a pH-independent sustained release matrix tablets of doxazosin mesylate. The matrix tablets were prepared by direct compression technique using polyethylene oxide, sodium alginate and citric acid as a pH modifier. Formulations were evaluated for an in vitro drug release study, erosion study, and the microenvironmental pH was studied using the pH indicator methyl red. For formulations without citric acid, the extent and rate of drug release in simulated gastric fluid were much higher than those in simulated intestinal fluid. By adding the citric acid, the drug release rate in simulated intestinal fluid was increased, and microenvironmental pH values within the tablets were maintained at low pH during drug release. Furthermore, drug release from the matrix tablet containing 20% w/w citric acid was comparable to that from a commercial product, Cardura® XL, and a pH-independent release could be achieved. Therefore, the incorporation of citric acid as a pH modifier to Polyethylene oxide-sodium alginate matrix tablets effectively produced pH-independent doxazosin mesylate release profiles.

Matrix tablets based on carrageenans with dual controlled release of doxazosin mesylate.

The use of polymeric polyelectrolytes as matrix-forming agents is far from optimally or fully understood. Polyelectrolyte carrageenan (CARR) matrices loaded with oppositely charged active substance doxazosin mesylate (DM) were investigated according to their water-uptake/erosion properties, in situ complexation ability of CARR with DM, and the possibility to achieve dual drug release control. Interactions between different CARR types (ι-, κ-, and λ-) and DM were confirmed by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and zeta potential measurements. Combination of water-uptake/erosion with in situ complexation prolonged DM release from CARR matrices for more than 24 h. The rate order of drug release was in accordance with the number of ester sulfate moieties per disaccharide unit of CARRs (κ (1)>ι (2)>λ (3)). The higher the charge on the CARR backbone, the higher the number of interactions with DM and the slower the drug release. Low pH, more vigorous hydrodynamics, and higher ionic strength resulted in faster drug release. Based on zeta potential measurements of DM and CARRs, proposed influence of counterion condensation and its effect on screening polyelectrolyte-drug interactions was confirmed to lower in situ DM-CARR complexation. Dual drug release control from polyelectrolyte matrices by water-uptake/erosion and in situ complexation offers many new approaches for designing controlled-release systems.