Synthesis of thiolated alginate and evaluation of mucoadhesiveness, cytotoxicity and release retardant properties

Modification of polymers by covalent attachment of thiol bearing pendant groups is reported to impart many beneficial properties to them. Hence in the present study, sodium alginate–cysteine conjugate was synthesized by carbodiimide mediated coupling under varying reaction conditions and the derivatives characterized for thiol content. The thiolated alginate species synthesized had bound thiol content ranging from 247.8±11.03–324.54±10.107 ΅mol/g of polymer depending on the reaction conditions. Matrix tablets based on sodium alginate-cysteine conjugate and native sodium alginate containing tramadol hydrochloride as a model drug were prepared and mucoadhesive strength and in vitro drug release from the tablets were compared. Tablets containing 75 mg sodium alginate-cysteine conjugate could sustain release of 10 mg of model drug for 3 h, whereas 90% of the drug was released within 1 h from corresponding tablets prepared using native sodium alginate. An approximately 2-fold increase in the minimal detachment force of the tablets from an artificial mucin film was observed for sodium alginate–cysteine conjugate as compared to native sodium alginate. In vitro cytotoxicity studies in L-929 mouse fibroblast cells studied using an MTT assay revealed that at low concentrations of polymer, sodium alginate–cysteine conjugate was less toxic to L-929 mouse fibroblast cell line when compared to native sodium alginate. Hence, thiolation is found to be a simple route to improving polymer performance. The combination of improved controlled drug release and mucoadhesive properties coupled with the low toxicity of these new excipients builds up immense scope for the use of thiolated polymers in mucoadhesive drug delivery systems.     

Mucoadhesive microspheres for nasal administration of an antiemetic drug, metoclopramide: in-vitro/ex-vivo studies

Microparticulate delivery systems designed for the nasal administration of an antiemetic drug, metoclopramide hydrochloride, were prepared. Microspheres composed of sodium alginate, chitosan hydrochloride, or both, were obtained using a spray-drying method; some batches of drug-free microparticles were prepared as a comparison. The morphology, in-vitro swelling behaviour, mucoadhesive properties and drug release from microparticles were evaluated. Ex-vivo drug permeation tests were carried out using sheep nasal mucosa; permeation test of the drug solution was performed as comparison. During ex-vivo permeation tests, transmission electron microscopy (TEM) analyses were carried out on the nasal mucosa to study the morphological changes of epithelial cells and tight junctions, while the change in microsphere morphology was examined using photostereo microscopy (PM). Spray-dried microparticles had a mean diameter (d(vs)) in the range of about 3-10 microm. They showed good in-vitro mucoadhesive properties. In-vitro release profiles and swelling behaviour depended on their composition: the drug release occurred in 1-3 h. Ex-vivo studies showed that drug permeation through the mucosa from microparticles based on chitosan was higher than from those consisting of alginate alone. This can be related to the penetration enhancing properties of chitosan. Complexation of chitosan with alginate led to a control of the drug release. Microscopy observation of microspheres during the permeation tests revealed that microparticles swelled and gelled, maintaining their shape. TEM analyses of the mucosa after exposure to the microparticles consisting of alginate/chitosan showed opened tight junctions. This preliminary study shows that alginate/chitosan spray-dried microspheres have promising properties for use as mucoadhesive nasal carriers of an antiemetic drug.     

Poloxamer/Cyclodextrin/Chitosan-Based Thermoreversible Gel for Intranasal Delivery of Fexofenadine Hydrochloride

To enhance permeation and solubility of an intranasal delivery system of fexofenadine hydrochloride (FXD HCl), a new formulation using poloxamer 407 (P407)/hydroxypropyl-β-cyclodextrin (HP-β-CD)-based thermoreversible gels with chitosan, was developed. Prepared gels were characterized by gelation temperature, viscosity, viscoelasticity, and drug release profile. The in vitro permeation study was performed in primary human nasal epithelial cell monolayers cultured by air–liquid interface method. The addition of chitosan caused the slight elevation of gelation temperature and viscosity-enhancing effect. Viscosity enhancement by the incorporation of chitosan caused the retardation of drug release from P407 gels in in vitro release test. The in vitro permeation profile showed that the increase in chitosan content (0.1% and 0.3%, w/v) significantly enhanced the permeation of FXD HCl. After intranasal administration of P407/HP-β-CD–based thermoreversible gels containing 0.1% and 0.3% of chitosan in rabbits at 0.5 mg/kg dose, plasma concentrations of FXD HCl were significantly higher than those of nasal solutions (p < 0.05). In particular, the bioavailability of the optimized thermoreversible gel containing 0.3% chitosan was about 18-fold higher than that of the solution type. These results suggested the feasibility that thermosensitive gels could be used as an effective dosage form to enhance the nasal absorption of FXD HCl.     

Polymer based solutions of bupranolol hydrochloride for intranasal systemic delivery

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

Development of novel mucoadhesive pellets of metformin hydrochloride

Mucoadhesive polymer-coated pellets containing metformin hydrochloride were prepared by the powder-layering technique using a centrifugal fluidizing (CF)-granulator. Four high-viscosity polymers were applied to make the pellets: 1) hydroxymethylcellulose (HPMC), 2) sodium alginate (Na-Alg), 3) HPMC/Carbopol, and 4) sodium carboxylmethylcellulose (Na-CMC). The physical crushing test, mucoadhesive test, zeta-potential test, in vitro release study and observation of gastroretention state of the dosage form were performed to investigate the pellets. The strong adhesive interaction between the Na-CMC-coated pellets and the mucin disc was obtained by mucoadhesive test. Na-Alg was most effective among the polymers used in changing the value of zeta potential of the mucin solution by the interaction between a polymer and a mucin particle. Results from drug dissolution study showed that over 95% of the drug from all the four pellets was released before 2 h, while Na-CMC- and Na-Alg-coated pellets showed a moderate sustained-release in SGF (simulated gastric fluid) and SIF (simulated intestine fluid), respectively. In conclusion, Na-CMC and Na-Alg seem to be promising candidates for mucoadhesive formulation and further studies to improve the sustained-release property are underway for achieving the ultimate goal of once-a-day formulation of metformin hydrochloride.     

Formulation and evaluation of nitrendipine buccal films

A mucoadhesive drug delivery system for systemic delivery of nitrendipine, a calcium channel blocker through buccal route was formulated. Mucoadhesive polymers like hydroxypropylmethylcellulose K-100, hydroxypropylcellulose, sodium carboxymethylcellulose, sodium alginate, polyvinyl alcohol, polyvinyl pyrrolidone K-30 and carbopol-934P were used for film fabrication. The films were evaluated for their weight, thickness, percentage moisture absorbed and lost, surface pH, folding endurance, drug content uniformity, In vitro residence time, In vitro release and ex vivo permeation. Based on the evaluation of these results, it was concluded that buccal films made of hydroxylpropylcellulose and sodium carboxymethylcellulose (5±2% w/v; F-4), which showed moderate drug release (50% w/w at the end of 2 h) and satisfactory film characteristics could be selected as the best among the formulations studied.     

Formulation and ex vivo evaluation of rofecoxib gel for topical application

The potential gastrointestinal disorders associated with oral administration of rofecoxib can be avoided by delivering the drug to the inflammation site at a sustained, concentrated level over an extended period of time. Hydroxypropylmethylcellulose (HPMC), sodium alginate and Carbopol 940 were used in an attempt to develop topical gel formulations of rofecoxib. The effects of polymer composition on the rate of drug release from the gel formulations were examined through cellulose membrane mounting on a Keshary-Chien diffusion cell. The effects of initial drug concentration and viscosity on the permeation rate of rofecoxib from the gel formulations were evaluated using rat epidermis at 37 +/- 0.5 degrees C. The anti-inflammatory activity of the rofecoxib gel formulation was evaluated using the rat hind paw edema model. The gel formulation consisting of 4% w/w sodium alginate-Carbopol 940 at 3:1 ratio was found to be suitable for topical application based on in vitro evaluation and ex vivo permeation studies. The drug permeation rate increased with an increase of the initial drug concentration in gels up to 25% w/w. An inverse relationship was observed between the in vitro drug release rate/ex vivo permeation rate and viscosity of the gel formulations. The anti-inflammatory activity of 4% w/w sodium alginate-Carbopol 940 gel containing 25% w/w rofecoxib in the rat hind paw edema model reveals that the drug was delivered to the inflammation site at a controlled level over a period of 6 h. These results suggest the feasibility of the topical gel formulation of rofecoxib.     

Utility of Gastric-Retained Alginate Gels to Modulate Pharmacokinetic Profiles in Rats

A gastric-retentive formulation amenable to dosing in rodents has the potential to enable sustained release in a preclinical setting. This may be useful to provide systemic exposure over a longer duration or to increase duration of exposure for compounds with targets localized in the gastrointestinal tract. Previous work has shown that a mixture of 1% sodium alginate and 0.625% karaya gum in the presence of a calcium chelator can form gels in situ that are gastric retained in rats. The aim of this work was to define the physicochemical boundaries of compounds within this technology and their relation to in vivo release using a series of model compounds with high permeability but varying solubility. In vitro data demonstrated a good correlation between solubility and initial release rates from the gels. In vivo studies were conducted in Sprague–Dawley rats to compare the exposure profile of compounds dosed in gel relative to a standard formulation. In vivo data were consistent with trends from the in vitro studies. These data suggest that, in conjunction with an understanding of compound solubility, sodium alginate/karaya gum gels may be a useful tool to modulate exposure profiles in rodent models in a preclinical setting.     

Thermally reversible xyloglucan gels as vehicles for nasal drug delivery

The aim of this study was to investigate the potential application of thermosensitive gels formed by a xyloglucan polysaccharide derived from tamarind seed for nasal drug delivery. Xyloglucan that had been partially degraded by β-galactosidase to eliminate 45% of galactose residues formed gels at concentrations of 2.5% w/w at gelation temperatures decreasing over the range 27–28°C. The in vitro release of ondansetron hydrochloride from the enzyme-degraded xyloglucan gels followed higuchi kinetics over a period of 5?h at 34°C by anomalous transport mechanism. The ex vivo permeation of ondansetron hydrochloride from the gels was sustained. Histological examination of nasal mucosa following a single administration of the gels showed no evidence of mucosal damage. Finally, the bioavailability study in rabbits revealed that the absolute bioavailability of ondansetron hydrochloride was significantly increased from 28.64% in the case of the oral drug solution to 52.79% in the case of the nasal in situ gel. The results of this study suggest the potential of the enzyme-degraded xyloglucan gels as vehicles for nasal delivery of drugs.     

Enhanced Permeation of an Antiemetic Drug from Buccoadhesive Tablets by Using Bile Salts as Permeation Enhancers: Formulation Characterization,In Vitro,and Ex Vivo Studies

Buccal bioadhesive bilayer tablets of prochlorperazine maleate were designed and formulated by using buccoadhesive polymers such as hydroxypropylmethyl cellulose, Carbopol 934P, and sodium alginate. Physicochemical characteristics like the uniformity of weight, hardness, thickness, surface pH, drug content, swelling index, microenvironment pH, in vitro drug release, and in vivo buccoadhesion time of the prepared tablets were found to be dependent on the type and composition of the buccoadhesive materials used. The effect of bile salts on the permeation was studied through porcine buccal mucosa and it was found that out of three bile salts incorporated (sodium glycholate, sodium taurocholate, and sodium deoxycholate), sodium glycholate enhanced the permeation rate of prochlorperazine maleate by an enhancement factor of 1.37.     

An alternative approach to wound healing field; new composite films from natural polymers for mupirocin dermal delivery

In this study, novel adhesive films were prepared for Mupirocin dermal delivery. Natural polymers as chitosan, sodium alginate and carbopol were used for films development to evaluate possible interactions and drug release properties. Solvent evaporation method was used for films preparation. Preliminary studies involved FT-IR spectroscopy and Scanning Electron Microscopy to specify interactions and morphology. Thickness, tensile strength and water uptake in phosphate buffer saline were evaluated whereas in vitro release studies were also performed. In vitro drug release studies demonstrated that mupirocin release was improved. Ex vivo bioadhesion and permeation studies using Balb-c mice were performed to check the suitability of the films. Antimicrobial ability was evaluated by agar well diffusion tests. Finally, excisional wound model applied to test the wound healing effect and evaluated macroscopic and histopathologically. One formulation was found more effective compared to the market product for wound healing at Balb-c mice.     

Carbopol 934-Sodium Alginate-Gelatin Mucoadhesive Ondansetron Tablets for Buccal Delivery: Effect of pH Modifiers

The present work aims at developing mucoahesive tablets of ondansetron hydrochloride using bioadhesive polymers like carbopol-934, sodium alginate and gelatin. Tablets prepared by direct compression using different polymer with varying ratio were evaluated for hardness, friability, uniformity of weight, disintegration time, microenvironmental pH, bioadhesion and in vitro release. Hardness, friability disintegration time and drug release were found within pharmacopoeial limit. Microenvironmental pH decreased whereas bioadhesive strength, water uptake, and in vitro release increased with increase in carbopol-934. Increasing sodium alginate and gelatin increased the microenviromental pH and decreased bioadhesive strength, water uptake and in vitro release. With a view to investigate the modulation of drug release from formulation by addition of pH modifiers viz. citric acid and sodium bicarbonate, the tablets with carbopol-934 (2.0), sodium alginate (0.5) and gelatin (6.5) were used and the effect of pH modifiers on microenvironmental pH, bioadhesion, water uptake, in vitro permeation and in vitro release was studied. Microenvironmental pH, bioadhesive strength, water uptake, in vitro release and permeation decreased with increasing concentration of citric acid whereas microenvironmental pH, water uptake and release were enhanced and bioadhesive strength was lowered with increase in sodium bicarbonate. Present study demonstrates carbopol-934, sodium alginate, gelatin polymer system with added pH modifier can be successfully formulated for buccal delivery of ondansetron with desired release profile.     

Evaluation of Phosphorylated Psyllium Seed Polysaccharide as a Release Retardant

The aim of the present study was to modify psyllium seed polysaccharide and evaluate the modified polysaccharide as release retardant in tablets employing ciprofloxacin hydrochloride as model drug. Studies on polysaccharide from psyllium husk has been reported but no work has been reported on characterization and modification of the polysaccharide present in the psyllium (Plantago ovata) seed and the use of the modified polysaccharide as a release retardant in tablets. In this study, the seed gum was modified using sodium trimetaphosphate as crosslinking agent. Sustained release matrix tablets of ciprofloxacin hydrochloride were prepared by wet granulation using various drug-polymer ratios. The polymers investigated were psyllium polysaccharide, phosphorylated psyllium polysaccharide and widely used release retardant hydroxypropyl methylcellulose K100M. The tablets were evaluated for hardness, friability, drug content, swelling profile and in vitro dissolution studies. The matrix tablets containing 1:3 proportion of drug-phosphorylated psyllium polysaccharide was found to have higher hardness as compared to tablets containing 1:1 and 1:2 proportions. The results of swelling behavior in water showed that the tablets containing 1:3 drug:phosphorylated psyllium polysaccharide ratio had swelling comparable to that of tablets containing 1:3 drug:hydroxypropyl methylcellulose ratio. The in vitro dissolution studies shows that the dissolution rate was retarded from 98.41 to 37.6% in 6 h with increase in concentration of phosphorylated psyllium polysaccharide from 100 to 300 mg. Formulations containing psyllium polysaccharide showed complete drug release in 8 h whereas those formulated with phosphorylated psyllium polysaccharide exhibited extended drug release over the 12 h period. Drug release kinetic studies revealed that drug release followed Korsmeyer-Peppas model.     

The influence of Surelease and sodium alginate on the in-vitro release of tamsulosin hydrochloride in pellet dosage form

The objective of this study was to prepare controlled-release pellets containing 0.2 mg tamsulosin hydrochloride using a pelletizer-equipped piston extruder and double-arm counter-rotating rollers with Surelease and sodium alginate. The release of tamsulosin HCl from pellets coated with the commercial aqueous ethylcellulose dispersion (Surelease) was investigated at different coating loads. In addition, the effect of sodium alginate on drug release was investigated by varying the ratio of sodium alginate to microcrystalline cellulose (MCC). Dissolution studies were first performed in 500 mL simulated gastric fluid (pH 1.2) containing 0.003% (w/w) polysorbate 80 and then in simulated intestinal fluids (pH 7.2). The morphology of pellet surfaces and cross sections were examined by scanning electron microscopy (SEM). Apparently, the spherical pellets were prepared using a pelletizer-equipped piston extruder and double-arm counter-rotating rollers. The release profiles of tamsulosin HCl from Surelease-coated pellets were significantly affected by changing the content of Surelease, the pH of the dissolution medium and the ratio of sodium alginate to MCC. The drug release rates not only decreased with increase in the coating load, but also increased when the pH of the dissolution medium was increased from 1.2 to 7.2 regardless of the sodium alginate-to-MCC ratio. Moreover, the drug release rate at pH 7.2 was gradually increased by increasing the ratio of sodium alginate to MCC. SEM showed smooth surfaces of Surelease-coated pellets. These results suggest that Surelease and sodium alginate would be useful excipients in the preparation of controlled-release pellets with the desired release profiles.     

Preparation of a novel floating ring capsule-type dosage form for stomach specific delivery

Study objectives were to develop a unique floating ring capsule dosage form which combines gastric soluble and insoluble portions, and to evaluate its suitability for stomach specific drug delivery. New floating ring capsules were developed using different polymers and were compared for various parameters. The formulation with HPMC and sodium CMC has better floating properties. The effects of polymers concentration on drug release were studies by in vitro release studies. The interaction studies of combined drug with polymers were determined using FT-IR spectroscopy. The entrapped air within the gel barrier and lower densities of HPMC and sodium CMC resulted in better floating behavior. Steady slow gel formations showed prolonged drug release. The in vitro release rates were generally found to be faster with low concentration of carbopol showing release within 2 h, while formulations containing high amount of HPMC showed release in 8 h. In particular, the higher concentration of HPMC formulation shows the best drug release performance. A very low change in peak shift was observed only with sodium alginate formulations. Further, FT-IR measurements confirmed the absence of any chemical interactions. Results indicate that new floating ring capsule is a promise dosage form for stomach specific delivery.     

Multiunit Controlled-Release Diclofenac Sodium Capsules Using Complex of Chitosan with Sodium Alginate or Pectin

This study explored the application of chitosan–alginate (CA) and chitosan–pectin (CP) complex films as drug release regulator for the preparation of multiunit controlled-release diclofenac sodium capsules. Pellets containing drug and microcrystalline cellulose, in a ratio of 3:5, were prepared in a fluidized rotary granulator. The pellets were coated with CA, CP, sodium alginate, pectin, and chitosan solutions. The pellets, equivalent to 75 mg drug, were filled into capsules. After 2 h of dissolution test in acidic medium, the amount of the drug released from any preparation was negligible. The pellets were further subject to pH 6.8 phosphate buffer. More than 80% drug release at 12 h was observed with the uncoated pellets and those coated with sodium alginate, pectin or chitosan. Both 1% CA and 3% CP coated pellets exhibited drug release profiles similar to that of Voltaren SR75. It was found that approximately 60% and 85% of the drug were released at 12 and 24 h, respectively. Both Differential thermal analysis (DTA) and Fourier transform infrared spectroscopy (FTIR) analyses revealed complex formation between chitosan and these anionic polymers. It could be concluded that CA and CP complex film could be easily applied to diclofenac sodium pellets to control the release of the drug.     

Enhanced permeation of triamcinolone acetonide through the buccal mucosa.

To develop new formulations that have suitable bioadhesive force and provide sustained release in buccal area for an extended period of time, bioadhesive gels containing triamcinolone acetonide were prepared using two polymers, carbopol 934 and poloxamer 407 which were selected for their bioadhesiveness and gelling property, respectively. The drug release profiles from the gels were studied as a function of drug concentration and temperature. Different enhancers such as bile salts, glycols and non-ionic surfactants were used for the enhancement of its permeation through buccal mucosa. Among the enhancers used, sodium deoxycholate showed the best enhancing effects.     

Formulation and evaluation of once-a-day transdermal gels of diclofenac diethylamine

The present study was undertaken to prepare and evaluate transdermal gels of diclofenac diethylamine (DDEA) containing penetration enhancers such as olesan oil and dimethyl sulfoxide (DMSO). Transdermal gels were prepared using different polymers such as carbopol-940, polyvinyl alcohol (PVA), hydroxy propyl methyl cellulose-K(4) M, hydroxy propyl cellulose-M, and sodium carboxy methyl cellulose. The formulated gels were subjected to physicochemical studies, in vitro release studies and in vitro skin permeations studies and were evaluated for drug content, viscosity, extrudability, spreadability, and pH. The in vitro release studies of prepared gels were performed using specially designed Fites cell and in vitro skin permeation studies were performed using keshary-chien diffusion cell through rat skin. Selected formulations were evaluated for their antiinflammatory activity using the carrageenan-induced paw edema in rats. The carbopol-940 and PVA gels containing 10% DMSO showed best in vitro skin permeation of DDEA. In vivo study for the selected formulation showed a sustained reduction in inflammation in the carrageenan induced paw edema in rats. The efficacies of carbopol-940 and PVA gels were also compared with that of the marketed Voveran gel,(R) and it was found that carbopol and PVA gels produced better results than the Voveran gel. (c) 2006 Prous Science. All rights reserved.     

Hybrid drug delivery system for oropharyngeal,cervical and colorectal cancer – in vitro and in vivo evaluation

The present investigation was designed with the intention to formulate a versatile 5-fluorouracil(5-FU) matrix tablet surpassing issues associated with current conventional chemotherapeutic drug delivery systems. The novel 5-FU matrix tablet fulfills therapeutic needs by engineering matrix tablets utilizing chitosan–sodium alginate interpolyelectrolyte complex (IPEC). IPEC was characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The matrix tablets were formulated utilizing IPEC alone and in combination with chitosan, sodium alginate and sodium deoxycholate as permeation enhancer. Pharmaceutical properties, swelling studies, in vitro dissolution and diffusion studies, mucoadhesive studies and in vivo studies were performed for formulated 5-FU. The selected chitosan–sodium alginate IPEC offers pH independent 5-FU release in comparison to alone or physical mixture of chitosan and sodium alginate. Furthermore, novel matrix tablets demonstrated significantly higher bioadhesive properties with controlled 5-FU release without the initial burst effect and also demonstrated a higher permeation of 5-FU. To conclude, the developed novel 5-FU matrix tablets pave way as an excellent alternative for cancer treatment which could potentially minimize the dose dependent side effects and provide better patient compliance.     

Optimization of pH-independent release of nicardipine hydrochloride extended-release matrix tablets using response surface methodology

The purpose of this study was to optimize the pH-dependent release of nicardipine hydrochloride extended release formulations by using simultaneously combination two hydrophilic polymers: hydroxypropylmethylcellulose (HPMC) and sodium alginate as retardant and avicel as additive. The constrained mixture experimental design was used to prepare systematic model formulations which were composed of three formulation variables: the content of HPMC (X1), avicel (X2), and sodium alginate (X3). The response surface methodology (RSM) and multiple response optimization utilizing the polynomial equation were used to search for the optimal formulation with specific release rate at different time intervals and to quantify the effect of each formulation variables. The drug release percent at 3, 6 and 12 h were the target responses and were restricted to 10-30% (Y3h), 40-65% (Y6h) and not less than 80% (Y12h), respectively. The results showed that the effect of combination of HPMC and sodium alginate was the most influence factor on the drug release from extended-release matrix tablets. The observed results of Y3h, Y6h and Y12h coincided well with the predictions in the RSM optimization technique, indicating it was quite useful for optimizing pharmaceutical formulation. The mechanism of drug release from extended-release matrix tablets was dependent on the added amount of alginate. The release kinetic of drug from HPMC matrix tablets with alginate was followed the zero-order release pattern.