Development and microbiological evaluation of chitosan and chitosan-alginate microspheres for vaginal administration of metronidazole.

Metronidazole is the drug of choice in the treatment of bacterial vaginosis, but the oral therapy can induce several collateral effects. Aim of this work was the development of a vaginal multiparticulate system, loaded with metronidazole, able to improve its residence time allowing a complete drug release. Several kinds of MS were prepared using chitosan dissolved in different organic acids or alginate coated with chitosan. FTIR and DSC analyses were performed to study the interactions between the drug and the polymers, while MS morphology was investigated with optical and electron microscopy. All the formulations were characterized in terms of drug entrapment efficiency, mucoadhesion, swelling capacity and drug release behavior, demonstrating the best results for alginate MS coated with chitosan. The formulations evidenced a complete and rapid release of drug, compared with the commercial form: Zidoval®.The best formulations assayed for antibacterial activity confirmed the suitability of this new formulation for the vaginal treatment of local diseases.

Characterization and microbiological evaluation of chitosan-alginate microspheres for cefixime vaginal administration.

Chitosan-alginate microspheres (MS) were developed for cefixime vaginal administration, to overcome problems associated with its oral administration. The effect of increasing drug-loading amount, by keeping the chitosan-alginate content constant, was investigated. Mucoadhesion studies indicated that all formulations assured in situ permanence longer than 2 h. Entrapment efficiency increased with drug loading concentration in the starting solution, reaching a plateau at 30 mg/mL indicative of the achievement of an optimal drug-to-polymer ratio. MS swelling properties increased with the entrapped drug amount, and, interestingly, water-uptake reached its maximum value at the same drug loading concentration of 30 mg/mL. The relationship found between MS water-uptake and drug release rate confirmed MS prepared with 30 mg/mL cefixime as the best formulation. Microbiological studies showed a relation between cefixime release rate from MS and Escherichia coli viability reduction, definitely indicating the selected MS formulation as the best for an effective local treatment of urogenital infections.

Comparison of liposomal and NLC (nanostructured lipid carrier) formulations for improving the transdermal delivery of oxaprozin: Effect of cyclodextrin complexation.

The combined strategy of drug-cyclodextrin (CD) complexation and complex loading into nanocarriers (deformable liposomes or nanostructured lipid carriers (NLC)), was exploited to develop effective topical formulations for oxaprozin transdermal administration. Oxaprozin was loaded as ternary complex with randomly-methylated-ßCD and arginine, selected as the best system in improving drug solubility. The colloidal dispersions, characterized for particle size, zeta-potential and entrapment efficiency, were investigated for drug permeation properties in comparison with a plain drug aqueous suspension, a ternary complex aqueous solution and a plain drug liposomal or NLC dispersion. Experiments with artificial membranes showed that the joined use of CD and both liposomes or NLC enabled a marked increase of the drug permeability (16 and 8 times, respectively) and was significantly more effective (P<0.05) than the drug as ternary complex (3.2 times increase), and the corresponding liposomal or NLC dispersion of plain drug (5.6 and 4.3 times increase, respectively). Experiments with excised human skin confirmed the significantly (P<0.05) better performance of deformable liposomes than NLC in promoting drug permeation; moreover, they evidenced a more marked permeability increase compared to the plain drug (24 and 12 fold, respectively), attributed to a possible enhancer effect of the nanocarriers components and/or of the randomly-methylated-ßCD.

Polymeric mucoadhesive tablets for topical or systemic buccal delivery of clonazepam: Effect of cyclodextrin complexation.

Two kinds of mucoadhesive buccal tablets of clonazepam (CLZ) were developed to provide, a prolonged local or systemic delivery respectively. Tablets prepared by direct compression of combinations of different polymers were tested for swelling, erosion and residence time properties. Carbopol 971P/hydroxypropylmethylcellulose and Poloxamer/chitosan mixtures were the best and were selected for drug loading. The effect of CLZ complexation with different cyclodextrins was investigated. Randomly-methylated-ßCD (RAMEßCD) was the most effective, allowing 100% drug released increase from local-delivery buccal tablets. Kollicoat was the best among the tested backing-layers, assuring a unidirectional release from systemic-delivery buccal tablets (<0.8% drug released in simulated saliva after 24h). In vitro permeation studies from coated-tablets showed that CLZ loading as RAMEßCD-coground enabled a 5-times increase in drug flux and permeability. Therefore, complexation with RAMEßCD was a successful strategy to improve the CLZ performance from buccal tablets for both local or systemic action.

Development of solid lipid nanoparticles as carriers for improving oral bioavailability of glibenclamide.

A solid lipid nanoparticle (SLN) formulation was developed with the aim of improving the oral bioavailability and the therapeutic effectiveness of glibenclamide (GLI), a poorly water-soluble drug used in the treatment of type 2 diabetes. The SLN was prepared using different lipid components (Precirol® and Compritol®) and preparation procedures. Precirol-based SLN, obtained with the emulsion of solvent evaporation technique gave the best results and was selected for drug loading. Addition of lecithin to the SLN core or PEG coating was effective in increasing the nanoparticles stability in simulated gastric solution. Both such formulations were stable after one month storage at 5±3°C, exhibited the absence of in vitro cytotoxicity, and presented a similar in vitro prolonged-release, reaching 100% release after 24h. The lecithin-containing GLI-loaded SLN formulation, selected for in vivo studies in virtue of its higher EE% than the PEG-coated formulation (70.3% vs 19.6%), showed a significantly stronger hypoglycemic effect with respect to the drug alone, in terms of both shorter onset time and longer duration of the effect. These positive results indicated that the proposed SLN approach was successful in improving GLI oral bioavailability, confirming its potential as an effective delivery system for a suitable therapy of diabetes.

Combined use of bile acids and aminoacids to improve permeation properties of acyclovir.

The aim of this work was to develop a topical formulation with improved permeation properties of acyclovir. Ursodeoxycholic (UDC) and dehydrocholic (DHC) acids were tested as potential enhancers, alone or in combination with different aminoacids. Equimolar binary and ternary systems of acyclovir with cholic acids and basic, hydrophilic or hydrophobic aminoacids were prepared by co-grinding in a high vibrational micromill. Differential scanning calorimetry (DSC) was used to characterize the solid state of these systems, while their permeation properties were evaluated in vitro through a lipophilic artificial membrane. UDC was more than 2 times more effective than DHC in improving drug AUC and permeation rate. As for the ternary systems drug-UDC-aminoacid, only the combined use of l-lysine with UDC acid produced an evident synergistic effect in enhancing drug permeation properties, enabling an almost 3 and 8 times AUC increase compared to the binary UDC system or the pure drug, respectively. The best systems were selected for the development of topical cream formulations, adequately characterized and tested for in vitro drug permeation properties and stability on storage. The better performance revealed by acyclovir-UDC-l-lysine was mainly attributed to the formation of a more permeable activated system induced by the multicomponent co-grinding process.

Comparative evaluation of polymeric and waxy microspheres for combined colon delivery of ascorbic acid and ketoprofen.

The goal of this work was to combine the ketoprofen anti-inflammatory effect with the ascorbic acid antioxidant properties for a more efficient treatment of colonic pathologies. With this aim, microspheres (MS) based on both waxy materials (ceresine, Precirol(®) and Compritol(®)) or hydrophilic biopolymers (pectine, alginate and chitosan) loaded with the two drugs were developed, physicochemically characterized and compared in terms of entrapment efficiency, in vitro release profiles, potential toxicity and drug permeation properties across the Caco-2 cell line. Waxy MS revealed an high encapsulation efficiency of ketoprofen but a not detectable entrapment of ascorbic acid, while polymeric MS showed a good entrapment efficiency of both drugs. All MS need a gastro-resistant coating, to avoid any premature release of the drugs. Ketoprofen release rate from polymeric matrices was clearly higher than from the waxy ones. In contrast, the ASC release rate was higher, due to its high hydro-solubility. Cytotoxicity studies revealed the safety of all the formulations. Transport studies showed that the ketoprofen apparent permeability increased, when formulated with the different MS. In conclusion, only polymeric MS enabled an efficient double encapsulation of both the hydrophilic and lipophilic drugs, and, in addition, presented higher drug release rate and stronger enhancer properties.

Influence of cross-linking agent type and chitosan content on the performance of pectinate-chitosan beads aimed for colon-specific drug delivery.

Pectinate-chitosan-beads aimed for colon theophylline delivery have been developed. The effect of zinc or calcium ions as cross-linking agent, and of chitosan concentration on the properties and colon-targeting performance of beads was investigated. Beads were characterized for morphology, entrapment efficiency and mucoadhesion properties. Zn-pectinate-chitosan beads formed a stronger gel network than the Ca-containing ones, enabling a greater entrapment efficiency, which further increased with chitosan content, probably due to polyelectrolyte complexes formation. Transport studies across Caco-2 cells evidenced a significant (p > 0.05) drug permeation increase from all beads with respect to drug alone, attributable to the enhancer and/or mucoadhesion properties of the polymers, and Ca-pectinate-chitosan beads were more effective than the Zn-containing ones. Beads formulated as enteric-coated tablets demonstrated good colon-targeting properties, and no differences were observed in drug-release profiles from Zn- or Ca-pectinate-chitosan beads. Therefore, Ca-pectinate-chitosan beads emerged as the choice formulation, joining colon-targeting specificity with better permeation enhancer power.

Improvement of oxaprozin solubility and permeability by the combined use of cyclodextrin, chitosan, and bile components.

The effect of the combined use of randomly methylated ß-cyclodextrin (RAMEB), chitosan (CS), and bile components (dehydrocholic (DHCA) or ursodeoxycholic (UDCA) acids and their sodium salts) on solubility and permeability through Caco-2 cells of oxaprozin (a very poorly water-soluble non-steroidal anti-inflammatory drug) has been investigated. Addition of CS, bile acids, and their sodium salts increased the RAMEB solubilizing power of 4, 2, and 5 times, respectively. Drug-RAMEB-CS co-ground systems showed very higher dissolution rate than corresponding drug-RAMEB systems. Addition of bile components further improved drug dissolution rate. The CS presence enabled a significant increase in drug permeability through Caco-2 cells with respect to drug-RAMEB systems. Moreover, CS and NaDHC showed a synergistic enhancer effect, enabling a 1.4-fold permeability increase in comparison with systems without bile salt. However, unexpectedly, no significant differences were found between physical mixtures and co-ground products, indicating that drug permeation improvement was due to the intrinsic enhancer effect of the carriers and not to drug-carrier interactions brought about by co-grinding, as instead found in dissolution rate studies. The combined use of RAMEB, CS, and NaDHC could be exploited to develop effective oral dosage forms of oxaprozin, with increased drug solubility and permeability, and then improved bioavailability.

New "drug-in cyclodextrin-in deformable liposomes" formulations to improve the therapeutic efficacy of local anaesthetics.

The combined approach of cyclodextrin complexation and entrapment in liposomes was investigated to develop a topical formulation of local anaesthetics. For both benzocaine (BZC) and butamben (BTM), hydroxypropyl-beta-cyclodextrin (HPbetaCD) was a better partner than betaCD; drug-HPbetaCD coevaporated products showed the best solubility and dissolution properties, and were selected for loading into liposomes. Addition of stearylamine to the phosphatidylcholine-cholesterol mixture of the vesicle bilayer allowed obtainment of deformable liposomes with improved permeation and in vivo drug anaesthetic effect (P<0.05). Double-loaded deformable liposomes were obtained by adding the drug-HPbetaCD complex at its maximum aqueous solubility in the vesicles hydrophilic phase, and the remaining amount up to 1% as free drug in the lipophilic phase. The properties of double-loaded liposomes were compared with those of classic single-loaded ones, obtained by adding 1% free drug in the aqueous or lipophilic phase of the vesicles. Size, charge, morphology and entrapment efficiency of the different batches were investigated, respectively, by light scattering, confocal laser scanning microscopy and dialysis, while their therapeutic efficacy was evaluated in vivo on rabbits. For both drugs, double-loaded liposomes, exploiting the favourable effects of drug-CD complexation, allowed a significant (P<0.05) enhancement of intensity and duration of anaesthetic effect with respect to those single-loaded.

Response surface methodology in the optimization of chitosan-Ca pectinate bead formulations.

This study describes the application of a multi-varied experimental design methodology to the optimization of a bead formulation based on a mixed network of Ca pectinate and chitosan. The effect of varying the relative percent of the three components used for the bead production, i.e. pectin, chitosan and CaCl(2), has been systematically investigated with the aim of identifying their best levels to optimize drug encapsulation efficiency (considered as the experimental response to be maximized), as well as to highlight possible interactions among the components. The study was applied to two different drugs, i.e. prednisone and theophylline, selected, respectively, as model insoluble and relatively soluble drugs, in order to evaluate the influence of this parameter as well. Different bead batches were prepared according to Doehlert and D-optimal design and randomly evaluated for drug encapsulation efficiency. Analysis of response surface plots allowed identification of the best combination of the three bead components in order to maximize drug encapsulation efficiency. The most effective compositions were chitosan 3% (w/v), pectin 9% (w/v), CaCl(2) 4% (w/v) for the theophylline-loaded beads and chitosan 0.75% (w/v), pectin 6% (w/v), CaCl(2) 7.9% (w/v) for the prednisone-loaded ones. The good correspondence between calculated and experimental values indicated in both cases the validity of the generated statistical models for the prediction of microsphere encapsulation efficiency. The different results obtained for the two drugs indicated the importance of the greater or lesser drug lipophilicity in determining the optimal bead composition with the highest encapsulation efficiency.

Microspheres for colonic delivery of ketoprofen-hydroxypropyl-beta-cyclodextrin complex.

A new multiparticulate system, with the potential for site-specific delivery to the colon, has been developed using ketoprofen as model drug. The system simultaneously exploits cyclodextrin complexation, to improve drug solubility, and vectorization in microspheres (MS) based on Ca-pectinate and chitosan. The effect of complexation with hydroxypropyl-beta-cyclodextrin (HPbetaCyd) and of chitosan presence on drug entrapment efficiency and release properties, as well on the drug permeation rate across Caco-2 cells has been investigated. Solid-state interactions between the components have been investigated by FTIR spectroscopy, differential scanning calorimetry and X-ray powder diffractometry. The morphology of MS was examined by scanning electron microscopy. Release studies revealed a different behaviour for MS containing drug alone or as complex: drug alone was released faster than in the presence of cyclodextrin from MS without chitosan, due to a reservoir effect. The opposite was found for MS containing chitosan, due to a competition effect between polymer and drug for the cyclodextrin. Cytotoxicity tests demonstrated the safety of these formulations. Permeation studies showed an increased permeation of the drug formulated as MS, particularly marked when it was used as complex, thus revealing an enhancing power of both cyclodextrin and chitosan with a synergistic effect in improving drug permeation.

Simultaneous effect of cyclodextrin complexation, pH, and hydrophilic polymers on naproxen solubilization.

The effect of pH variation on complexation and solubilization of naproxen (pK(a) 4.2) with natural betaCyclodextrin (betaCyD) and various neutral, cationic and anionic betaCyD-derivatives has been investigated. The combined effect of pH variation and hydrophilic polymer addition on CyD solubilizing and complexing efficiency has also been determined. Phase-solubility analysis in buffered aqueous solutions (pH from 1.1 to 6.5) was used to study the interaction of the drug with each CyD, in the presence or not of the water-soluble polymer. A clear influence of the substituent type was observed, the methylderivative being the most efficient agent; on the contrary, unexpectedly, no influence of the CyD charge in the interaction with the ionizable drug was detected. As expected, total drug solubility increased with increasing pH; however, the solubility increment with respect to drug alone obtained by CyD complexation progressively decreased, with a parallel reduction of the complex stability, attributed to the reduced affinity of charged drug for the hydrophobic CyD cavity. The addition of the polymer in part counterbalanced the destabilizing effect obtained with increasing pH, by improving the CyD complexation power towards naproxen. In particular, the presence of PVP allowed an increase of the complex stability constant with hydroxypropyl betaCyD up to 60% with respect to the corresponding drug-CyD binary system. Therefore, the combined strategy of pH control and polymer addition to the CyD complexing medium can be successfully exploited to improve naproxen solubilization and reduce the amount of CyD needed. The construction of theoretical drug solubility curves as a function of pH for any given CyD and polymer concentration enables selection of the best experimental conditions for obtaining the desired drug solubility value.

Influence of cyclodextrins and chitosan, separately or in combination, on glyburide solubility and permeability.

The effect of chitosan and of different concentrations of beta- or hydroxypropyl-beta-cyclodextrins, separately or in various (w/w) combinations, on the dissolution characteristics of glyburide (an oral hypoglycemic agent subject to incomplete and variable bioavailability) and on its permeability through Caco-2 cells has been investigated. Cyclodextrins (and particularly the hydroxypropyl-derivative, in virtue of its higher water solubility) were clearly more effective than chitosan in enhancing the drug dissolution properties: the aqueous glyburide solubility was improved 40-fold in the presence of 25 mM hydroxypropyl-beta-cyclodextrin, 25-fold in the presence of 13 mM beta-cyclodextrin (saturation solubility) and only 3-fold in the presence of chitosan at its saturation concentration (0.5% w/v). When chitosan and cyclodextrin were simultaneously present, a strong reduction of the cyclodextrin solubilizing efficiency towards the drug was observed, and it was attributed to a possible competition effect of polymer and glyburide for the interaction with the macrocycle. By contrast, permeation studies revealed that chitosan was more powerful than cyclodextrins in enhancing the glyburide permeability through Caco-2 cells. This was probably in virtue of the polymer's favourable effect on the tight junctions opening, as demonstrated by the significant decrease in the transepithelial electrical resistance recorded in its presence. Moreover, interestingly, when using the carriers together, conversely from solubility studies, a significant (P < 0.05) synergistic effect in enhancing glyburide apparent permeability was revealed in permeation experiments.

Influence of formulation and process variables on in vitro release of theophylline from directly-compressed Eudragit matrix tablets.

Extended-release theophylline (TP) matrix tablets were prepared by direct compression of drug and different pH-dependent (Eudragit L100, S100 and L100-55) and pH-independent (Eudragit RLPO and RSPO) polymer combinations. The influence of varying the polymer/polymer (w/w) ratio and the drug incorporation method (simple blend or solid dispersion) was also evaluated. Drug release, monitored using the Through Flow Cell system, markedly depended on both the kind of Eudragit polymer combinations used and their relative content in the matrix. Maintaining a constant 1:1 (w/w) drug/polymers ratio, the selection of appropriate mixtures of pH-dependent and pH-independent polymers enabled achievement of a suitable control of TP release. In particular, matrices with a 0.7:0.3 w/w mixture of Eudragit L100-Eudragit RLPO showed highly reproducible drug release profiles, with an almost zero-order kinetic, and allowed 100% released drug after 360 min. As for the effect of the drug incorporation method, simple blending was better than the solid dispersion technique, which not only did not improve the release data reproducibility, but also caused, unexpectedly, a marked slowing down in drug release rate.

Characterization and dissolution properties of ketoprofen in binary and ternary solid dispersions with polyethylene glycol and surfactants.

The effect of incorporation of an anionic [sodium dodecyl sulfate (SDS) or dioctylsulfosuccinate (DSS)] or nonionic [Tween 60 (TW60)] surfactant on the properties of ketoprofen solid dispersions in polyethylene glycol 15000 (PEG) has been investigated. Physicochemical and morphological properties of the various solid systems were determined by differential scanning calorimetry, hot stage microscopy, X-ray powder diffraction analysis, and scanning electron microscopy. The results from dissolution studies, performed according to the USP 24 basket method, indicated that all ternary dispersed systems were significantly (p < 0.001) more efficacious than the corresponding binary ones, by virtue of the additive wetting and solubilizing effect due to the presence of the surfactant. The relative effectiveness of the incorporated surfactant was in the same order as found in phase-solubility studies (i.e., SDS > DSS > TW60). With regard to the solid dispersion preparation method, coevaporated products always gave better results than the corresponding cofused ones; however, this effect was statistically significant (p < 0.001) only in the initial phase of the dissolution process. The most effective solid dispersion was the 10-80-10 w/w drug-PEG-SDS ternary coevaporate, which allowed dissolution of 50% drug after only 6 min (in comparison with > 120 min for drug alone and 17 min for the binary coevaporate) and dissolution of about 100% drug after 30 min (in comparison with > 120 min for the binary coevaporate).

Interaction of naproxen with ionic cyclodextrins in aqueous solution and in the solid state.

The possible role of the cyclodextrin charge in the interaction with an acidic drug such as naproxen (pKa 4.8) has been evaluated. Sulfobutylether-beta-cyclodextrin (SBE-betaCyd) and trimethylammonium-beta-cyclodextrin (TMA-betaCyd) were selected as, respectively, anionically and cationically charged carriers and their performance was compared with that of the parent beta-cyclodextrin (betaCyd) and of its methyl-derivative (Me betaCyd) previously found as the best partner for the drug. Interactions in solution were investigated by phase-solubility, fluorescence and circular dichroism analyses. Equimolar drug-carrier products prepared by different techniques (blending, cogrinding, sealed-heating, colyophilization) were characterized by differential scanning calorimetry and X-ray powder diffractometry and tested for drug dissolution properties. Anionic charges of SBE-betaCyd did not negatively influence interactions in unbuffered aqueous solutions (pH approximately 5) with the acidic drug. In fact, it was a very effective carrier, exhibiting solubilizing and complexing properties considerably better than the parent betaCyd and comparable to those of Me betaCyd. On the contrary, the positive charges of TMA-betaCyd did not favour interactions with the counter-ionic drug (despite the presence of about 60% ionised drug) and it was less efficacious also than native betaCyd. Therefore, the role of the Cyd charge on the complexing and solubilizing properties towards naproxen was not important whereas other factors, such as steric hindrance effects and favourable hydrophobic interactions were significant in determining the drug affinity for the Cyd inclusion. Solid state studies evidenced similar amorphizing properties of both charged Cyds towards naproxen. On the other hand, dissolution tests, in agreement with solution studies, showed that all products with SBE-betaCyd exhibited significantly better dissolution properties than the corresponding ones with TMA-betaCyd. A clear influence of the preparation method of drug-Cyd solid systems on the performance of the end product was also observed. Colyophilization was the most effective technique, followed by the cogrinding one. Colyophilized product with SBE-betaCyd allowed a 10-times increase in drug dissolution efficiency (D.E.) (with respect to the five-times increase obtained with the corresponding coground product) and a reduction of t(50%) from about 60 min (for the coground product) to less than 2 min.

Determination of stability constant values of flurbiprofen-cyclodextrin complexes using different techniques.

Three new experimental approaches for calculating the stability constant (K(st)) of complexes of flurbiprofen with natural beta-cyclodextrin (betaCyd) and the hydroxyethyl- (HEbetaCyd) and the methyl- (Me betaCyd) derivatives were tested and compared to the classic phase-solubility procedure: (a) the membrane permeation technique through a lipophilic synthetic membrane permeable to the drug but not to the Cyd molecules, by analysing the permeation profiles with a non-linear least-squares method; (b) the affinity capillary electrophoresis (ACE) technique, where K(st) were calculated from the relationship between Cyd concentration in solution and drug electrophoretic mobility, using three different linear plotting methods; (c) the molecular modeling technique, based on the relationship between the docking energies and the experimental K(st) values. The study allowed evaluation of the advantages and limits of each examined method, providing a useful guide for the choice of the most suitable one depending on the kind of host-guest system to be investigated. The K(st) values obtained with the various techniques were rather different, probably due to the very different experimental conditions required by each one. However, all the methods indicated the methyl-derivative as the most powerful complexing agent for the drug, showing the general trend: K(st)(Me betaCyd)>>K(st)(HEbetaCyd)>K(st)(betaCyd). Only in the case of the ACE method was an inversion of the trend found between HEbetaCyd and betaCyd; this was probably due to the lower molecular weight of the natural Cyd, which, in this case, became more important in determining the complex electrophoretic mobility than the different affinity of the drug for these two Cyds.

Optimization of glibenclamide tablet composition through the combined use of differential scanning calorimetry and D-optimal mixture experimental design.

A systematic analysis of the influence of different proportions of excipients on the stability of a solid dosage form was carried out. In particular, a d-optimal mixture experimental design was applied for the evaluation of glibenclamide compatibility in tablet formulations, consisting of four classic excipients (natrosol as binding agent, stearic acid as lubricant, sorbitol as diluent and cross-linked polyvinylpyrrolidone as disintegrant). The goal was to find the mixture component proportions which correspond to the optimal drug melting parameters, i.e. its maximum stability, using differential scanning calorimetry (DSC) to quickly obtain information about possible interactions among the formulation components. The absolute value of the difference between the melting peak temperature of pure drug endotherm and that in each analysed mixture and the absolute value of the difference between the enthalpy of the pure glibenclamide melting peak and that of its melting peak in the different analyzed mixtures, were chosen as indexes of the drug-excipient interaction degree.

Development and evaluation of glyburide fast dissolving tablets using solid dispersion technique.

Glyburide is a poorly water-soluble oral hypoglycemic agent, with problems of variable bioavailability and bio-inequivalence related to its poor water-solubility. This work investigated the possibility of developing glyburide tablets, allowing fast, reproducible, and complete drug dissolution, by using drug solid dispersion in polyethylene glycol. Phase-solubility studies were performed to investigate the drug-carrier interactions in solution, whereas differential scanning calorimetry, X-ray powder diffraction, and infrared spectroscopy were used to characterize the solid state of solid dispersions. The effects of several variables related to both solid dispersion preparation (cofusion or coevaporation technique, drug-to-carrier ratio, polyethylene glycol molecular weight) and tablet production (direct compression or previous wet-granulation, tablet hardness, drug, and solid dispersion particle size) on drug dissolution behavior were investigated. Tablets obtained by direct compression, with a hardness of 7-9 Kp, and containing larger sized solid dispersions (20-35 mesh, i.e., 850-500 microm) of micronized glyburide in polyethylene glycol 6000 prepared by the cofusion method gave the best results, with a 135% increase in drug dissolution efficiency at 60 min in comparison with a reference tablet formulation containing the pure micronized drug. Moreover, the glyburide dissolution profile from the newly developed tablets was clearly better than those from various commercial tablets at the same drug dosage.