pH Sensitive Interpenetrating Network Bio Containers of Gum Ghatti for Sustained Release of Glipizide.

OBJECTIVE: A novel natural polymer, Gum Ghatti (GG) was explored to develop a new polymeric system that will combine the biodegradable and biocompatible properties of GG and mechanical properties of poly vinyl alcohol (PVA) for drug delivery application. METHODS: Smart pH sensitive, porous, glutaraldehyde (GA) crosslinked interpenetrating network (IPN) microspheres loaded with glipizide were developed by the emulsion crosslinking method. The drug entrapment efficiency was 92.85±1.5%. FTIR confirmed the formation of IPN structure. Drug release can be extended upto 7 hours by modulating the concentration of crosslinking agent. Swelling study and diffusion co-efficient (D) of water transport were performed in order to understand the phenomenon of water penetration through the microsphere. In vivo antidiabetic activity performed on alloxane induced diabetic rats indicated that in case of pure glipizide sudden reduction of elevated blood glucose was observed after 3 hours. RESULTS: In case of rats treated with glipizide loaded IPN microparticles, the initial percentage reduction of blood glucose level was slow within the first 3 hours of administration, as compared to pure glipizide but after 6 hours 90% reduction was observed which confirmed sustained release nature of microspheres. CONCLUSION: Thus IPN microparticles were found suitable for sustained delivery of BCS class II drug glipizide.

Development of smart hydrogels of etherified gum ghatti for sustained oral delivery of ropinirole hydrochloride.

Gum Ghatti (GG) is a water soluble complex polysaccharide obtained from Anogeissus latifolia. Due to its non toxic and excellent emulsifying characteristics, it was widely used in different pharmaceutical preparations. Currently another facet was explored for its utility as release retardant polymer in oral controlled drug delivery system. As GG solely was incapable of forming microspheres therefore modification of GG to Sodium carboxymethyl (NaCMGG) derivative was done by carboxymethylation process and its gel forming capacity was explored by the use of trivalent cation (Aluminium chloride) which results into complete microbead system in a complete aqueous environment for controlled delivery of Ropinirole Hydrochloride (RHCl). Rheological property of NaCMGG showed pseudoplastic shear thinning behavior. Spherical shape of bead was observed under scanning electron microscope. Depending upon the formulation variables, Drug entrapment efficiency (DEE) varies from 47.66±3.51 % to 71.4±2.65%., and 80 to 90% drug was released in 6h in pH 6.8 phosphate buffer. Drug release was governed by both fickian diffusion and polymer relaxation simultaneously. Compatible environment for drug entrapment was established by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). Thus the modified derivative NaCMGG could be a promising polymer in biomedical application.

Novel gastroulcer protective micro(hydro)gels of sulfated locust bean gum-aluminium complex for immediate release of diclofenac sodium.

In this study, carboxymethyl sulfate derivative (CLBS) of locust bean gum (LBG) was synthesized by varying the strength of sulfating reagent. CLBS was characterized by Fourier transform infrared (FTIR) spectroscopy, elemental analysis, and viscosity measurements. Furthermore, the degree of sulfation and carboxymethylation in CLBS was determined. Novel micro(hydro)gel particles of CLBS were fabricated in basic aluminum chloride solution and different concentration of diclofenac sodium was incorporated into these particles. Differential scanning calorimetry and FTIR analyses did not suggest any drug-polymer interaction. Spherical morphological structures of the particles were evident under scanning electron microscope. Regardless of the formulation variables, a maximum of ~60% drug entrapment efficiency was achieved. For a higher degree of substitution, CLBS particles disintegrated rapidly (~20 min) and released >80% drug in acidic medium (pH1.2 and pH4.0) in 60 min. However, the particles liberated only ~60% drug in phosphate buffer medium (pH6.8) during this period. Following disintegration of the particles, the pH of gastric environment elevated. In stomach histopathology, the ulcers were scored and it was estimated that CLBS afforded ~86% protection to the gastric mucosa from ulceration. Thus, the micro(hydro)gel particles of CLBS-aluminium complex could be useful for immediate analgesic effect of the drug without any significant gastric distress.

Smart reticulated hydrogel of functionally decorated gellan copolymer for prolonged delivery of salbutamol sulphate to the gastro-luminal milieu.

A partially hydrolysed poly(acrylamide)-grafted-gellan (HPAmGG) copolymer was synthesised and characterised. Temperature- and concentration-dependent rheology and gel-like property of Gelrite gellan (GG) disappeared in HPAmGG copolymer. Smart HPAmGG hydrogel was fabricated with variation in aluminium chloride (AlCl(3)) strength and initial drug loading. The hydrogel reticulates seemed spherical and showed a maximum of ∼65% drug retention, but the assay was ∼22% lower for GG hydrogel. The drug release rate was inversely proportional to AlCl(3) strength in simulated intestinal milieu (pH 7.4), but approximated a proportional relationship with drug load. HPAmGG hydrogel liberated only 10-17% content in simulated gastric milieu (pH 1.2) in 2 h. The release data correlated well with the pH-dependent swelling of hydrogel and indicated the anomalous drug diffusion mechanism. Differential scanning calorimetry, X-ray diffraction, and high-performance liquid chromatography analyses confirmed the amorphous nature of the drug and its stability in fresh and aged hydrogel. Hence, smart HPAmGG hydrogel had the potential to prolong drug release mimicking the variable pH of the gastrointestinal tract.

Development and evaluation of xanthan gum-facilitated ethyl cellulose microsponges for controlled percutaneous delivery of diclofenac sodium.

In this study, xanthan gum-facilitated ethyl cellulose microsponges were prepared by the double emulsification technique and subsequently dispersed in a carbopol gel base for controlled delivery of diclofenac sodium to the skin. Scanning electron microscopy revealed the porous, spherical nature of the microsponges. Increase in the drug/polymer ratio (0.4:1, 0.6:1, 0.8:1, m/m) increased their yield (79.1-88.5%), drug entrapment efficiency (50.0-64.1%), and mean particle diameter (181-255 µm). Compared to the microsponges with high drug/polymer ratio (0.8:1, m/m), the flux of entrapped drug through excised rat skin decreased by 19.9% and 17.0%, respectively, for the microsponges prepared at low and intermediate drug/polymer ratios. When an equivalent amount of pure drug (not entrapped into microsponges) was dispersed into the gel base and the flux was compared, the microsponges (drug/polymer ratio 0.8:1, m/m) were found to reduce the flux by 33.3%. Whether the drug was dispersed either in un-entrapped or entrapped form into the gel base, the drug permeation through rat skin followed Higuchi's diffusion kinetic model. The microsponges prepared at the lowest drug/polymer ratio exhibited a comparatively slower drug permeation profile and were hence considered most suitable for controlled drug delivery application. FTIR spectroscopy and DSC analyses indicated the chemically stable, amorphous nature of the drug in these microsponges. The gel containing these optimized microsponges was comparable to that of a commercial gel formulation and did not show serious dermal reactions. Hence, the microsponge system obtained at the lowest drug/polymer ratio could be useful for controlled release of diclofenac sodium to the skin.

Nanovesicular formulation of brimonidine tartrate for the management of glaucoma: in vitro and in vivo evaluation.

In this study, nanovesicles were developed for brimonidine tartrate by film hydration technique and dispersed in viscous carbopol solution for ocular delivery. Scanning electron microscopy revealed spherical shape of the vesicles. As high as 32.27% drug entrapment efficiency was achieved depending upon the surfactant/cholesterol molar ratio (7:4 to 7:8). The vesicles were in the size range of 298.0-587.9 nm. Release study showed a biphasic drug-release pattern for the lyophilized vesicular formulation in buffered saline solution, i.e., initial burst release followed by gradual release over the period of 8 h. On contrary, the isolated vesicles reduced the burst effect in 3 h by two to three times and the drug release was comparatively slower at the intermediate ratio in both cases. With variation in cholesterol content, the drug release followed either first order or Higuchi's kinetics. Physically the lyophilized vesicular formulations were more stable at refrigerated temperature. DSC and X-RD analyses indicated loss of drug crystallinity in the vesicles. FTIR spectroscopy did not reveal any interaction between drug and excipients. The lyophilized formulation showed better ocular hypotensive activity than marketed drops on albino rabbits and in vivo efficacy was sustained up to 7.5 h. Furthermore, the formulation was found to be non-irritant to the rabbit eye. Hence, the lyophilized vesicles, when dispersed in viscous carbopol solution, had the potential in reducing dosing frequency and could improve patient compliance.

Novel interpenetrating network microspheres of xanthan gum-poly(vinyl alcohol) for the delivery of diclofenac sodium to the intestine--in vitro and in vivo evaluation.

Xanthan gum (XG), a trisaccharide branched polymer and poly vinyl alcohol (PVA), was used to develop pH-sensitive interpenetrating network (IPN) microspheres by emulsion cross-linking method in the presence of glutaraldehyde as a cross-linker to deliver model anti-inflammatory drug, diclofenac sodium (DS) to the intestine. Various formulations were prepared by changing the ratio of XG:PVA, extent of cross-linking in order to optimize the formulation variables on drug encapsulation efficiency, and release rate. Formation of interpenetrating network and the chemical stability of DS after penetration of microspheres was confirmed by Fourier Transform infrared (FTIR) spectroscopy. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis were done on the drug loaded microspheres which confirmed molecular dispersion of DS in the IPN. Microspheres formed were spherical with smooth surfaces, as evidenced by scanning electron microscopy (SEM), and mean particle size, as measured by laser light scattering technique ranged between 310.25-477.10 microm. Drug encapsulation of up to 82.94% was achieved as measured by UV method. Both equilibrium and dynamic swelling studies and in vitro release studies were performed in pH 1.2 and 6.8. Release data indicated a Fickian trend of drug release which depends on the extent of cross-linking and the ratio of XG:PVA present in the microsphere. When subjected to in vivo pharmacokinetic evaluation in rabbits, microparticles show slow and prolonged drug release when compared with DS solution. Based on the results of in vitro and in vivo studies it was concluded that these IPN microspheres provided oral controlled release of water-soluble DS.

Polyethyleneimine-treated xanthan beads for prolonged release of diltiazem: in vitro and in vivo evaluation.

The purpose of the study was to develop a multiunit sustained release dosage form of diltiazem hydrochloride using a natural polymer, sodium carboxymethyl xanthan gum and polyethyleneimine (PEI) from a completely aqueous environment. PEI treated diltiazem resin complex loaded beads were characterized by morphology, drug entrapment efficiency, in vitro and in vivo release behaviour. 40% and 80% drug was released in 2 hour in pH 1.2 and in 5 to 6 h in pH 6.8 respectively depending on the formulation variables. The prolonged release was attributed to decreased swelling of the beads due to PEI treatment. Maintaining the shape throughout the dissolution process, PEI treated diltiazem resin complex beads released the drug following non-Fickian transport phenomena. In vivo pharmacokinetic evaluation in rabbits shows slow and prolonged drug release when compared with diltiazem solution. The designed beads are suitable for prolonged release of a water soluble drug under a complete aqueous environment using natural gum.

Tailoring of locust bean gum and development of hydrogel beads for controlled oral delivery of glipizide.

In this study, carboxymethyl derivative of locust bean gum was prepared, characterized, and its gelling ability with different concentrations (1-5% w/v) of aluminum chloride (AlCl(3)) was utilized for the development of glipizide-loaded beads in a completely aqueous environment. The beads were spherical when observed under a scanning electron microscope. Increase in gelling ion concentration decreased the drug entrapment efficiency from 97.68% to 95.14%. The beads swelled more slowly in pH 1.2 KCl-HCl buffer and exhibited a slower drug release pattern than that observed in pH 7.4 phosphate buffer. Irrespective of the dissolution media, the drug release became slower at higher AlCl(3) concentration. The drug release in alkaline medium was found to be controlled by a combination of diffusion as well as polymer relaxation phenomena. Comparing the release profiles, it was observed that the beads treated with 5% AlCl(3) provided slower drug release up to 10 h in alkaline medium without any sign of disintegration and, thus, this formulation was selected for further studies. Fourier transform infrared (FTIR) spectroscopy indicated the stable nature of the drug in the beads. Differential scanning calorimetry and X-ray diffraction analysis showed that most of the drug remained in amorphous state in the beads. Stability study indicated no statistical significant difference in drug entrapment efficiency of the beads. In vivo activity of the beads was tested and a prolonged hypoglycemic effect was achieved. Hence, carboxymethyl locust bean beads could be a potential carrier for controlled oral delivery of glipizide.

Controlled delivery of bovine serum albumin from carboxymethyl xanthan microparticles.

Bovine serum albumin (BSA)-loaded carboxymethyl xanthan (CMX) microparticles were prepared following gelation of sodium carboxymethyl xanthan (SCMX) gum with different concentrations (1-5%) of aluminium chloride (AlCl3). The microparticles prepared using 1% AlCl3 were subsequently coated with 0.5% aqueous solution of either SCMX gum or sodium alginate. Both uncoated and coated microparticles were characterized for entrapment efficiency, surface morphology, particle size, in vitro release and protein stability. The uncoated microparticles became non-spherical and the mean diameter was found to increase with increasing AlCl3 concentration. Higher concentration of AlCl3 decreased BSA entrapment efficiency of the uncoated microparticles from 86-61%. Furthermore, BSA entrapment in coated microparticles was found lower (78-79%) than uncoated microparticles prepared using 1% AlCl3. Although, the uncoated microparticles released almost half of its content in NaCl-HCl buffer solution (pH 1.2) in 2 h, the alginate and xanthan coated microparticles did not liberate a substantial amount of entrapped protein within the same period and prolonged the release in PBS solution (pH 7.4) up to 10 and 12 h, respectively. The microparticles released the protein via diffusion and swelling of the polymer matrix. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that BSA integrity was well retained in the CMX microparticles.

Investigation on processing variables for the preparation of fluconazole-loaded ethyl cellulose microspheres by modified multiple emulsion technique.

Fluconazole-loaded ethyl cellulose microspheres were prepared by alginate facilitated (water-in-oil)-in-water emulsion technology and the effects of various processing variables on the properties of microspheres were investigated. Scanning electron microscopy revealed spherical nature and smooth surface morphology of the microspheres except those prepared at higher concentration of emulsifiers and higher stirring speeds. The size of microspheres varied between 228 and 592 mum, and as high as 80% drug entrapment efficiency was obtained depending upon the processing variables. When compared up to 2 h, the drug release in pH 1.2 HCl solution was slower than in pH 7.4 phosphate buffer saline solution. However, this trend was reversed at high shear conditions. The microspheres provided extended drug release in alkaline dissolution medium and the drug release was found to be controlled by Fickian-diffusion mechanism. However, the mechanism shifted to anomalous diffusion at high shear rates and emulsifier concentrations. The aging of microspheres did not influence the drug release kinetics. However, the physical interaction between drug and excipients affected the drug dissolution behaviors. X-ray diffractometry (X-RD) and differential scanning calorimetry (DSC) analysis revealed amorphous nature of drug in the microspheres. Fourier transform infrared (FTIR) spectroscopy indicated stable character of fluconazole in the microspheres. The stability testing data also supported the stable nature of fluconazole in the microspheres. The fluconazole extracted from 80% drug-loaded formulation showed good in vitro antifungal activity against Candida albicans. Thus, proper control of the processing variables involved in this modified multiple emulsion technology could allow effective incorporation of slightly water soluble drugs into ethyl cellulose microspheres without affecting drug stability.

Adipic acid dihydrazide treated partially oxidized alginate beads for sustained oral delivery of flurbiprofen.

In this study, periodate oxidation of sodium alginate was controlled such that the oxidized alginate could form isolatable beads with Ca(+2) ions. The beads of oxidized alginate having a degree of oxidation 1 mol%, entrapped 89% flurbiprofen and released almost all of its content within 1.5 h in pH 7.2 phosphate buffer solution. The beads were covalently crosslinked with adipic dihydrazide (ADH) in addition to ionic crosslinks and were characterized. Scanning electron microscopy revealed that the beads were spherical having smooth surfaces. The drug entrapment efficiency decreased (90-86%) with increasing concentration of ADH (2-6% w/v) in the gelation medium. However, the beads prolonged the drug release in alkaline dissolution medium up to 8 h depending upon the concentration of ADH. The beads prepared with 2% ADH swelled more rapidly and led to faster drug release in either pH 1.2 HCl solution or pH 7.2 phosphate buffer solution. The swelling tendencies were reduced and the drug release became slower with higher concentrations in either fluid. The drug diffusion from the beads followed super case II transport mechanism. FTIR spectroscopy indicated stable nature of flurbiprofen in the beads and therefore had potential as sustained oral delivery system for the drug.

Preliminary investigation on the development of diltiazem resin complex loaded carboxymethyl xanthan beads.

The objective of this study was to develop a multiunit sustained release dosage form of diltiazem using a natural polymer from a completely aqueous environment. Diltiazem was complexed with resin and the resinate-loaded carboxymethyl xanthan (RCMX) beads were prepared by interacting sodium carboxymethyl xanthan (SCMX), a derivatized xanthan gum, with Al(+3) ions. The beads were evaluated for drug entrapment efficiency (DEE) and release characteristics in enzyme free simulated gastric fluid (SGF, HCl solution, pH 1.2) and simulated intestinal fluid (SIF, USP phosphate buffer solution, pH 6.8). Increase in gelation time from 5 to 20 min and AlCl(3) concentration from 1 to 3% decreased the DEE respectively from 95 to 79% and 88.5 to 84.6%. However, increase in gum concentration from 1.5 to 2.5% increased the DEE from 86.5 to 90.7%. The variation in DEE was related to displacement of drug from the resinate by the gel forming Al(+3) ions. While 75-82% drug was released in 2 h in SGF from various beads, 75 to 98% drug was released in 5 hour in SIF indicating the dependence of drug release on pH of dissolution media. Although the beads maintained their initial integrity throughout the dissolution process in both media, as evident from scanning electron microscopic studies, the faster release in SGF was accounted for higher swelling of the beads in SGF than in SIF. When release data (up to 60%) was fitted in power law expression, the drug release was found to be controlled by diffusion with simultaneous relaxation phenomena.

Carboxymethyl xanthan microparticles as a carrier for protein delivery.

Xanthan gum (XG) was derivatized to sodium carboxymethyl xanthan gum (SCMXG) and then cross-linked with aluminium ions (Al(+3)) to prepare BSA-loaded microparticles (MPs) from a completely aqueous environment. The derivatized gum was characterized by various physical methods. Discrete and spherical BSA-loaded MPs were obtained from SCMXG solution, the pH of which was adjusted to 6 and 7 and the BSA entrapment efficiency was found to reach as high as 82%. The protein release in acidic dissolution medium was faster than that in alkaline dissolution medium and was accounted for the higher swelling ratio of the MPs in acidic environment. Moreover, the pH of the gum solution used to prepare the MPs also influenced the swelling and consequently protein release considerably.