Chitosan based pentazocine microspheres for intranasal systemic delivery: development and biopharmaceutical evaluation

Bioadhesive chitosan microspheres (Ms) of pentazocine (Pz) for intranasal systemic delivery were prepared with the aim of avoiding the first pass effect, and thus improving the bioavailability and achieving sustained and controlled blood level profiles, as an alternative therapy to injection and to obtain improved therapeutic efficacy in the treatment of chronic pain such as cancer, trauma and post-operative pain, etc. The formulation variables were drug loading, polymer concentration, stirring rate during crosslinking and oils. The microspheres (Ms) were subjected to evaluation for physical characteristics, such as particle size, incorporation efficiency, swelling ability, in vitro bioadhesion, in vitro drug release characteristics and in vivo performance in rabbits. Application of in vitro data to various kinetic equations indicated matrix diffusion controlled drug delivery from chitosan Ms. Drug loading, polymer concentration and stirring speed influenced the drug release profiles significantly while oils had negligible effect. In vivo studies indicated significantly improved bioavailability of Pz from Ms with sustained and controlled blood level profiles as compared to i.v., oral and nasal administration of drug solution. Good correlation was observed between in vitro and in vivo data.     

Sodium alginate microspheres of metformin HCl: formulation and in vitro evaluation

Metformin microspheres with sodium alginate alone and in combination with gellan were prepared using an emulsion-cross linking method. The prepared microspheres were evaluated for their physico-chemical characteristics like particle size, morphology using SEM, incorporation efficiency, equilibrium water content (swelling) and in vitro drug release. The effect of various formulation variables like polymer concentration (sodium alginate; and proportion of gellan in microspheres prepared by a combination of sodium alginate and gellan), drug loading, crosslinking agent concentration and cross-linking time on the in vitro dissolution of the prepared microspheres were evaluated. The results showed that both the particle size and the incorporation efficiency were proportional to the polymer concentration. In case of microspheres containing both sodium alginate and gellan, the mean diameter and the incorporation efficiency were higher than the corresponding microspheres containing only alginate, both increasing with an increase in proportion of gellan. The prepared microspheres were found to be discrete and spherical in shape and were successful in sustaining the drug release for 8 hours. Incorporation of gellan caused a significant decrease in drug release. The release followed a biphasic profile, in all cases, characterized by an initial phase of moderate drug release followed by a phase of higher release. Further, the kinetic treatment of the dissolution data revealed the prevalence of matrix diffusion kinetics.     

Preparation and release characteristics of polymer-coated and blended alginate microspheres

To prevent a rapid drug release from alginate microspheres in simulated intestinal media, alginate microspheres were coated or blended with polymers. Three polymers were selected and evaluated such as HPMC, Eudragit RS 30D and chitosan, as both coating materials and additive polymers for controlling the drug release. This study focused on the release characteristics of polymer-coated and blended alginate microspheres, varying the type of polymer and its concentration. The alginate microspheres were prepared by dropping the mixture of drug and sodium alginate into CaCl(2) solution using a spray-gun. Polymer-coated microspheres were prepared by adding alginate microspheres into polymer solution with mild stirring. Polymer-blended microspheres were prepared by dropping the mixture of drug, sodium alginate and additive polymer with plasticizer into CaCl(2) solution. In vitro release test was carried out to investigate the release profiles in 500 ml of phosphate buffered saline (PBS, pH 7.4). As the amount of polymer in sodium alginate or coating solution increase, the drug release generally decreased. HPMC-blended microspheres swelled but withstood the disintegration, showing an ideal linear release profiles. Chitosan-coated microspheres showed smooth and round surface and extended the release of drug. In comparison with chitosan-coated microspheres, HPMC-blended alginate microspheres can be easily made and used for controlled drug delivery systems due to convenient process and controlled drug release.     

Evaluation of furosemide-loaded alginate microspheres prepared by ionotropic external gelation technique

Alginate microspheres containing furosemide were prepared by the ionotropic external gelation technique using Ca2+, Al3+ and Ba2+ ions. The incorporation efficiency of the prepared microspheres ranged between 65% and 93%. The effect of sodium alginate concentration, cross-linking ions and drying conditions was evaluated with respect to entrapment efficiency, particle size, surface characteristics and in vitro release behavior. Infrared spectroscopic study confirmed the drug-polymer compatibility. Differential scanning calorimetric analysis revealed that the drug was molecularly dispersed in the alginate microsphere matrices. Scanning electron microscopic study of microspheres showed the rough surface due to higher concentration of drug molecules dispersed at molecular level in the alginate matrices. The mean particle size and entrapment efficiency were found to be varied by changing various formulation parameters. The in vitro release profile could be altered significantly by changing various formulation parameters to give a sustained release of drug from the microspheres. The kinetic modeling of the release data indicate that furosemide release from the alginate microspheres follow anomalous transport mechanism after an initial lag period when the drug release mechanism was found to be Fickian diffusion controlled.     

Evaluation and preparation of controlled release lipid micropheres of sulphamethizole by a congealable disperse phase encapsulation method

A congealable disperse phase encapsulation method was used to prepare controlled release lipid microspheres of sulphamethizole as a model drug. Hydrogenated cotton seed oil (HCSO) and stearic acid were employed as the lipid matrix materials. Tween 60 was the droplet stabilizer used to form microspheres. In in vitro dissolution tests, the drug release was found to be affected by the type of lipid material depending on hydrophilicity. Generally, an initial rapid release followed by a slower release of the drug from the lipid microspheres was observed. Lipid microspheres were also compressed in the tablet form to prevent the initial rapid release of the drug. But the drug release drastically decreased. To achieve a controlled release of the drug. Eudragit L as a channeling agent was added internally to HCSO-microspheres. Although the drug release increased, the controlled release pattern was not achieved. The external addition of polyethyleneglycole 4000 to HCSO-microspheres before compressing tablets, did not produce an affirmative change in the release profile. The lipid microspheres prepared by stearic acid released all of the drug within 1 h. Upon compression, the drug release was very low. Therefore, stearic acid-microspheres were compressed in the tablet form adding disintegrating agents, sodium alginate and Ac-Di-Sol (cross-linked sodium carboxymethylcellulose). A pH-dependent drug release was obtained from the tablets containing sodium alginate. With the tablets of stearic acid-microspheres containing Ac-Di-Sol, the controlled release could be achieved due to gradual disintegration from the tablet to aggregates, and to individual microspheres. Furthermore, in vivo study on 6 healthy volunteers confirmed the controlled release pattern of this dosage form.     

Improved bioavailability through floating microspheres of lovastatin

BACKGROUND AND THE PURPOSE OF THE STUDY: Lovastatin is an antihyperlipidemic agent which has low bioavailability due to the extensive first pass metabolism. It was sought to increase gastric retention of lovastatin by development of a sustained release gastroretentive drug delivery system leading to reduced fluctuation in the plasma concentration and improved bioavailability. MEHODS: Floating microspheres were prepared by emulsion solvent diffusion technique, using various polymers and their blends. The in vitro performance was evaluated for drug-polymer compatibility, percent yield, particle size, drug entrapment efficiency, in vitro onset and duration of floatation, in vitro drug release as well as in vivo determination of serum cholesterol level. RESULTS: The mean particle size of microspheres was observed to be between 6.9 to 9.5 μm and the maximum particle size was around 50 μm. In vivo studies of the selected batches indicated lower level of serum cholesterol compared to the marketed tablet at the same dose but was not significant. MAJOR CONCLUSION: The data obtained in this study suggested that a microparticulate floating dosage form of lovastatin can be successfully designed to yield controlled delivery with improved therapeutic efficacy.     

Chitosan-based mucoadhesive microspheres of clarithromycin as a delivery system for antibiotic to stomach

The objective of the present study was to develop chitosan-based mucoadhesive microspheres of clarithromycin to provide prolonged contact time for drug delivery of antibiotics to treat stomach ulcers. Microspheres based mucoadhesive formulation were extensively evaluated and characterized for in vitro performance followed by investigation of in vivo pharmacokinetics in rats. Microspheres were prepared by emulsification technique using glutaraldehyde as a crosslinking agent. Formulation conditions were optimized for percent drug entrapment and mucoadhesion, by varying different formulation and process parameters like drug to polymer ratio, concentration of crosslinking agent and time of crosslinking. Prepared microspheres were evaluated extensively for particle size, percent drug entrapment, swelling kinetics, in vitro mucoadhesion using rat stomach membrane and in vitro drug release studies. In vitro permeation studies across rat stomach membrane were carried out to determine diffusion parameters and drug retention in the stomach membrane of the formulation and the plain drug. Finally in vivo performance of microsphere formulation in comparison to plain drug was evaluated by pharmacokinetic studies in albino rats. Drug entrapment upto 74% was obtained. Swelling studies indicated that with an increase in cross-linking, the swelling ability decreased. The in vitro drug release and in vitro mucoadhesion studies showed a dependence on the extent of cross-linking and concentration of chitosan. Extent of cross-linking exhibited an inverse relation to drug release rate as well as mucoadhesion, whereas polymer concentration exhibited an inverse correlation with drug release while linear relationship with mucoadhesion (up to 86%). In vitro permeation studies across stomach tissue showed higher accumulation of drug in the stomach tissue with microspheres formulation as compared to that of free drug. This is evident from higher value of K (partition coefficient) and Qm/Csf values for microspheres (68.34 and 106.42X10(3), respectively) as compared to that of free drug (1.86 and 173.00, respectively). These findings when analyzed showed an increase in the bioavailability of clarithromycin from microsphere formulation as compared to plain drug suspension in vivo, with AUC 0-->alpha being 91.7 (microg h/ml)and 24.9 (microg h/ml) respectively. Results of the study demonstrated good mucoadhesion of the microspheres with the stomach mucosa as well as higher accumulation of drug in the stomach membrane. Microspheres also exhibited sustained release of drug. Thus chitosan microspheres appear, technically, promising mucoadhesive drug delivery systems for delivering clarithromycin to treat stomach ulcers.     

Preparation of sodium alginate microspheres containing hydrophilic β-lactam antibiotics

Alginate microspheres were prepared by the emulsification process as a drug delivery system of ampicillin sodium (AMP-Na). The preparation parameters such as the concentration of calcium chloride, the stirring time and the amount of AMP-Na were investigated. The alginate microspheres containing hydroxypropylmethylcellulose (HPMC) were found to be generally spherical, discrete and had smoother surfaces when compared to without HPMC. However, there was no significant difference in the release profile of AMP-Na from alginate microspheres prepared with or without HPMC. The concentration of calcium chloride solution and the stirring time in the preparation of alginate microspheres influenced the aggregation of alginate microspheres. The amount of AMP-Na in alginate microspheres influenced the surface morphology and the practical drug content in microspheres.     

Development and in vitro evaluations of gelatin A microspheres of ketorolac tromethamine for intranasal administration

Gelatin A microspheres (MS) of ketorolac tromethamine (KT) for intranasal systemic delivery were developed with the aim to avoid gastro-intestinal complications, to improve patient compliance, to use as an alternative therapy to conventional dosage forms, to achieve controlled blood level profiles, and to obtain improved therapeutic efficacy in the treatment of postoperative pain and migraine. Gelatin A microspheres were prepared using the emulsification-crosslinking technique. The drug was dispersed in polymer gelatin and formulated into a w/o emulsion with liquid paraffin, using glutaraldehyde as a crosslinking agent. The formulation variables were drug loading and the concentrations of polymer (gelatin), co-polymer (chitosan) and the crosslinking agent. All the prepared microspheres were evaluated for physical characteristics, such as particle size, incorporation efficiency, swelling ability, in vitro bioadhesion on rabbit small intestine and in vitro drug release characteristics in pH 6.6 phosphate buffer. All the microspheres showed good bioadhesive properties. Gelatin A and chitosan concentrations, percentage of the crosslinking agent and also the drug loading affected significantly the rate and extent of drug release. The data indicated that the KT release followed Higuchi's matrix model.     

Development, optimization and in vitro evaluation of alginate mucoadhesive microspheres of carvedilol for nasal delivery

The present research work was aimed at development and optimization of alginate mucoadhesive microspheres of carvedilol for nasal delivery to avoid first pass metabolism and to improve the therapeutic efficacy in the treatment of hypertension and angina pectoris. The microspheres were prepared by a water-in-oil (w/o) emulsification technique. A 2(3) factorial design was employed with drug : polymer ratio, calcium chloride concentration and cross-linking time as independent variables while particle size of the microspheres and in vitro mucoadhesion were the dependent variables. Regression analysis was performed to identify the best formulation conditions. Particle size was analysed by dynamic laser light diffraction technique and found to be in the range of 26.36-54.32 microm, which is favourable for intranasal absorption. The shape and surface characteristics were determined by scanning electron microscopy (SEM) which depicted the spherical nature and nearly smooth surfaces of the microspheres. The percentage encapsulation efficiency was found to be in the range between 36.62-56.18. In vitro mucoadhesion was performed by adhesion number using sheep nasal mucosa and was observed in a range from 69.25-85.28. Differential scanning calorimetry and X-ray diffraction results indicated a molecular level dispersion of carvedilol in the microspheres. In vitro release studies in pH 6.2 phosphate buffer indicated non-Fickian or anomalous type of transport for the release of carvedilol from the microspheres.     

Design and characterization of chitosan-alginate microspheres for ocular delivery of azelastine

Abstract

The use of mucoadhesive biopolymers is one of the best approaches to prolong the drug residence inside the cul-de-sac, consequently increasing the bioavailability. Thus, the focus of this work was to develop mucoadhesive microspheres to overcome the limitations of ocular drug delivery. The chitosan-sodium alginate microspheres of azelastine hydrochloride were fabricated using modified ionotropic gelation technique. The particle size, zeta potential, entrapment efficiency and drug release kinetics were evaluated and characterized by SEM, FT-IR, DSC, in vitro mucoadhesion and in vivo study. The microspheres had average particle size in the range of 3.55 to 6.70?µm and zeta potential +24.55 to +49.56?mV. The fabricated microspheres possess maximum drug entrapment of 73.05% with 65% mucin binding efficiency and revealed a controlled release over the 8-h period following a non-Fickian diffusion. SEM showed that microspheres were distinct solid with irregular shape. FT-IR and DSC results concluded the drug entrapment into microspheres. In vivo studies on ocular rat model revealed that azelastine microspheres had better efficacy. Chitosan sodium alginate microspheres prepared were in particle size range suitable for ocular purpose. In vitro release and in vivo efficacy studies revealed that the microspheres were effective in prolonging the drug’s presence in cul de sac with improved therapeutic efficacy.     

In vitro and in vivo evaluation of anti-inflammatory agents using nanoengineered alginate carriers: towards localized implant inflammation suppression

The aim of this research was to develop nanoengineered alginate microspheres for localized delivery of anti-inflammatory drugs (dexamethasone and diclofenac sodium) for implantable "Smart tattoo" glucose biosensor used for continuous glucose monitoring. The formulation was prepared and characterized for in vitro drug release from uncoated and polyelectrolyte-coated microparticles. Biocompatibility was then tested using L929 cell-line; pilot in vivo studies with Sprague-Dawley (SD) rat subjects were performed to test the suppression of inflammation and fibrosis associated with implantation and was analyzed using standard hematoxylin and eosin staining method. The drug-loaded microspheres were able to deliver the drug for 30 days at a controlled rate with zero-order kinetics. The layer-by-layer self-assembly technique was used to effectively limit the burst release of drug from the matrix. Cell culture studies prove that the material are not cytotoxic and showed acceptable >80% cell viability in all the tested samples. In vivo studies show that both drugs were successful in controlling the implant/tissue interface by suppressing inflammation at the implant site. It was clearly evident that the combined approach of drug loaded carriers along with implanted biosensor shows promise in improving sensor biocompatibility and functionality. Thus, suggesting potential application of alginate microspheres as "smart-tattoo" glucose sensors.     

Chitosan-based Floating Microspheres of Trimetazidin Dihydrochloride; Preparation and In vitro Characterization

The aim of present study involves preparation and characterization of floating microspheres using trimetazidin dihydrochloride as a model drug to increase the residence time in the stomach without contact with the mucosa, Floating microspheres were prepared by the capillary extrusion technique using chitosan as polymer and sodium lauryl sulphate as cross linking agent. The surface morphology of the prepared microspheres was characterized by the optical microscopic method. The effect of the stirring rate during preparation, polymer concentration and cross linking concentration on the percent yield, in vitro floating behavior, physical state of the incorporated drug, drug loading and in vitro drug release were studied. The prepared microspheres exhibited prolonged drug release (12 h) and remained buoyant for more than 11 h. The microspheres were found to be regular in shape and highly porous. The trimetazidin dihydrochloride release rate was higher in the case of microspheres prepared at a higher agitation speed and decreased with increasing the polymer and cross linking agent concentration. All formulations demonstrated favorable in vitro floating characteristics. The drug entrapment increased from 65.13 to 85.3% with increasing polymer to drug ratio. Diffusion was found to be the main release mechanism. Thus, the prepared floating microspheres may prove to be potential candidates for multiple-unit delivery devices adaptable to any intragastric conditions.     

Ionically cross-linked chitosan microspheres for controlled release of bioactive nerve growth factor

Controlled release of neurotrophic factors to target tissue via microsphere-based delivery systems is critical for the treatment strategies of diverse neurodegenerative disorders. The present study aims to investigate the feasibility of the controlled release of bioactive nerve growth factor (NGF) with ionically cross-linked chitosan microspheres (NGF-CMSs). The microspheres were prepared by the emulsion-ionic cross-linking method with sodium tripolyphosphate (STPP) as an ionic cross-linking agent. The size and distribution of the microspheres, SEM images, Fourier transform infra red spectroscopy (FT-IR), encapsulation efficiency, in vitro release tests and bioactivity assay were subsequently evaluated. We found that the microspheres had relatively rough surfaces with mean sizes between 20 and 31μm. FT-IR results provided evidence of ionic interaction between amino groups and phosphoric groups of chitosan and STPP. The NGF encapsulation efficiency ranged from 63% to 88% depending on the concentration of STPP. The in vitro release profiles of NGF from NGF-CMSs were influenced by the concentration of STPP. NGF-CMSs which were cross-linked with higher concentration of STPP showed slower but sustained release of NGF. In addition, the released NGF from NGF-CMSs was capable of maintaining the viability of PC12 cells, as well as promoting their differentiation. Taken together, our findings suggest that NGF-CMSs are capable of releasing bioactive NGF over 7 days, thus having potential application in nerve injury repair.     

Synthesis and characterization of cross-linked chitosan microspheres for drug delivery applications

The present study deals with the synthesis and characterization of cross-linked chitosan microspheres containing an hydrophilic drug, hydroquinone. The microspheres were prepared by the suspension cross-linking method using glutaraldehyde as the cross-linking agent of the polymer matrix. Perfectly spherical cross-linked hydrogel microspheres loaded with hydroquinone were obtained in the size range of 20–100 μm. The effect of the degree of polymer cross-linking, chitosan molecular weight, chitosan concentration and amount of the encapsulated drug on the hydroquinone release kinetics was extensively investigated. It was found that slower drug release rates were obtained from microspheres prepared by using a higher initial concentration of chitosan, a higher molecular weight of chitosan or/and a lower drug concentration. Most importantly, it was shown that the release rate of hydroquinone was mainly controlled by the polymer cross-linking density and, thus, by the degree of swelling of the hydrogel matrix.     

Synthesis and characterization of cross-linked chitosan microspheres for drug delivery applications

The present study deals with the synthesis and characterization of cross-linked chitosan microspheres containing an hydrophilic drug, hydroquinone. The microspheres were prepared by the suspension cross-linking method using glutaraldehyde as the cross-linking agent of the polymer matrix. Perfectly spherical cross-linked hydrogel microspheres loaded with hydroquinone were obtained in the size range of 20-100 microm. The effect of the degree of polymer cross-linking, chitosan molecular weight, chitosan concentration and amount of the encapsulated drug on the hydroquinone release kinetics was extensively investigated. It was found that slower drug release rates were obtained from microspheres prepared by using a higher initial concentration of chitosan, a higher molecular weight of chitosan or/and a lower drug concentration. Most importantly, it was shown that the release rate of hydroquinone was mainly controlled by the polymer cross-linking density and, thus, by the degree of swelling of the hydrogel matrix.     

Preparation of gelatin microspheres containing lactic acid--effect of cross-linking on drug release

In this study, gelatin microspheres containing lactic acid were prepared by the polymerization technique using glutaraldehyde as the cross-linking agent. Dried microspheres were loaded by immersing them in an aqueous solution of lactic acid. In order to prepare microspheres with an appropriate drug release profile, the effect of time of cross-linking and the amount of cross-linking agent on the swelling properties of microspheres and their release profile were investigated. The microencapsulation efficiency, microspheres appearance, particle size, swelling ratio and drug release profile were also studied. Microspheres prepared with a larger amount of cross-linking agent, or after longer cross-linking time, showed a reduced swelling ratio in aqueous media. In vitro release pattern of lactic acid from gelatin microspheres showed a biphasic profile and the release rates were reduced upon increasing the amount of cross-liking agent and prolonging the cross-linking time.     

Chitosan hydrochloride based microspheres of albendazole for colonic drug delivery

Microspheres of chitosan hydrochloride (CH) were prepared in order to deliver albendazole specifically into the colon. Microspheres were prepared by an emulsion method using different ratios of drug and CH (1:1 to 1:5), agitation speeds (500 to 1500 rpm) and concentrations of glutaraldehyde in toluene as the cross-linking agent (0.25 to 1.0% w/v). The effect of polymer concentration, stirring rate and concentration of cross-linking agent on the particle size and drug loading was studied. With an increase in CH concentration, the average particle size was increased. Increased agitation speed reduced the size of the microspheres but higher agitation speed resulted in irregularly shaped microspheres. Increasing the concentration of cross-linking agent produced more regularly shaped microspheres of smaller size. The drug loading was highest at a drug: CH ratio of 1:3, stirring speed 1000 rpm and 0.75% w/v concentration of cross-linking agent. The effect of CH concentration on in vitro drug release from the microspheres was evaluated in simulated g.i.t fluids. A comparative in vitro drug release study of the optimized formulation was carried out in simulated colonic fluid, with and without 2% rat caecal content. The drug release in 24 h was 48.9% in colonic fluid without rat caecal content, and 76.5% in colonic fluid with rat caecal contents.     

A novel impinging aerosols method for production of propranolol hydrochloride-loaded alginate gel microspheres for oral delivery

Propranolol hydrochloride was directly encapsulated in alginate gel microspheres (40-50?μm in diameter) using a novel method involving impinging aerosols of CaCl(2) cross-linking solution and sodium alginate solution containing the drug. Microspheres formulated using 0.1?M CaCl(2) exhibited the highest drug loading (14%, w/w of dry microspheres) with 66.5% encapsulation efficiency. Less than 4% and 35% propranolol release occurred from hydrated and dried microspheres, respectively, in 2?h in simulated gastric fluid (SGF). The majority of the drug load (90%) was released in 5 and 7?h from hydrated and dried microspheres, respectively, in simulated intestinal fluid (SIF). Prior incubation of hydrated microspheres (cross-linked using 0.5?M CaCl(2)) in SGF prolonged the time of release in SIF to 10?h, which has implications for the design of protocols and correlation with in?vivo release behaviour. Restricted propranolol release in SGF and complete extraction in SIF demonstrate the potential of alginate gel microspheres for oral delivery of pharmaceuticals.     

Ca-alginate microspheres encapsulated in chitosan beads

Chitosan beads (CBs) incorporating Ca-alginate microspheres (CAMs), containing a drug, were prepared as an oral sustained delivery system. Stable and monodisperse Ca-alginate microspheres loaded with drug were obtained by a membrane emulsification method. The Ca-alginate microspheres were encapsulated in chitosan beads by the ionotropic gelation method with a polyelectrolyte complex reaction between two oppositely charged polyions. The surface and internal characteristics of the beads were improved by ionic cross-linking in tripolyphosphate (TPP) solution adjusted to pH 5.0. The release experiments were performed using lidocaine·HCl (cationic drug) and sodium salicylate (anionic drug) as model drugs. Initial release of drugs depended on the degree of swelling. Ca-alginate microspheres encapsulated in chitosan beads were superior to both drug-loaded CBs and CAMs beads for sustained release because they had a three-layer composition; a calcium alginate core bounded by an inter-phasic chitosan-alginate membrane, which itself was surrounded by a layer of chitosan-TPP.