Bioadhesive Tablets Research Articles

Preparation and Evaluation of Buccal Bioadhesive Tablets Containing Clotrimazole

Buccal bioadhesive tablets of clotrimazole (CTZ) and clotrimazole: hydroxypropyl-beta-cyclodextrin (CTZ-HPbetaCD) complex were prepared by using polymer xanthan gum in combination with carbopol 974P. The prepared buccal bioadhesive tablet formulations were evaluated for physicochemical characteristics (weight, hardness, friability, diameter, and drug content), swelling index, microenvironment pH, in-vitro drug release, bioadhesion strength, residence time and duration of antifungal activity (in-vitro). The dissolution of CTZ from the prepared tablets into phosphate buffer (pH 6.8) was controlled up to 8 h. All the prepared tablets gave reasonable in-vitro residence time (7.13 - 9.34 h). X-ray diffraction (XRD) studies of the CTZ-HPbetaCD complex, made by kneading and freeze-dried method, showed no CTZ crystal signals, demonstrating the inclusion of CTZ in the hydrophobic cavity of hydroxypropyl-beta-cyclodextrin (HPbetaCD) and formation of amorphous inclusion complex. Duration of the antifungal activity was measured by the inhibition zone of Candida albicans by agar diffusion assay. It is evident from the results obtained, the prepared buccal bioadhesive tablets of CTZ would markedly prolong the duration of the antifungal activity and may prove to be a viable alternative to the conventional local oral medication.

Buccal Bioadhesive Delivery System of 5-Fluorouracil: Optimization and Characterization

The objective of this work was to apply the response surface approach in the development of buccal bioadhesive tablets of 5-fluorouracil (5-FU). Experiments were performed according to a 32 factorial design to evaluate the effects of two polymers, Gantrez MS-955 (X1) and hydroxypropylmethyl cellulose (HPMC) K15M (X2) on the bioadhesive force, percentage drug release in 8 h (Rel8 h), time taken for 50% drug release (t50%), and diffusion coefficient (n). The effect of the two independent variables on the response variables was studied by response surface plots and contour plots generated by the Design Expert® software. The compatibility between 5-FU and the tablet excipients was confirmed by differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) studies. Both the polymers were found to have synergistic effect on bioadhesion but the effect of Gantrez was more pronounced. A nonlinear twisted relationship was obtained for Rel8 h at the intermediate and high levels of the polymers, which indicated an interaction between them at the corresponding factor levels. Kinetic treatment to the dissolution profiles revealed that the drug release ranged from Fickian to anomalous transport, which was mainly dependent on both the independent variables. The desirability function was used to optimize the response variables, and the observed responses were in agreement with the experimental values.

A novel ketoconazole bioadhesive effervescent tablet for vaginal delivery: Design, in vitro and ‘in vivo’ evaluation

Bioadhesive tablet formulations of ketoconazole for vaginal delivery were studied. Carbomer (Carbopol 974P, Carbopol 934P), hydroxypropylmethyl cellulose (HPMC) and hydroxypropyl cellulose (HPC) were used as candidate bioadhesive polymers. Effervescent was incorporated into the formulations as a disintegration agent. The swelling behavior and bioadhesive strength of the drug-free tablets were investigated. Carbopol 934P was selected as biopolymer in combination with HPMC or HPC at different ratios to develop five drug-loaded formulations. The swellings, tackiness and in vitro release were studied on the tablets. A good sustained effect and a moderate bioadhesion were obtained with the tablets. The formulation containing 100 mg of effervescent, with the Carbopol 934P:HPC ratio of 1:9, seemed to be the optimum one for the tablet. In vivo drug residence tests were carried out by administering the preferred formulation to female rats. The results showed that the drug remaining followed a one-order model. Even after 24 h of administration in vagina of rats, 17% of the original employed drug was retained on the vaginal tissue. Our study may provide a potential vaginal tablet formulation of ketoconazole against Candida albicans.

Formulation and evaluation of lactoferrin bioadhesive tablets

For the treatment of chronic inflammation in the oral cavity, we attempted to develop bioadhesive tablets of bovine lactoferrin (B-LF) which has antibacterial properties and immune regulatory functions. B-LF tablets containing pectin, tamarind gum or carboxymethylcellulose (CMC) were prepared by direct compression. Tablets consisting of B-LF, pectin and xylitol passed through 60- or 100-mesh sieves were also prepared. The tablets containing CMC had insufficient bioadhesive force. Although the tablets containing tamarind gum showed the longest residence time in the oral cavity, an unpleasant taste gradually developed. The tablets containing pectin showed the highest value of bioadhesive force and the taste was acceptable. The characteristics of the B-LF tablets were improved by adding an appropriate amount of xylitol and using the ingredients sieved by a 100-mesh sieve. The therapeutic effect was evaluated by using rats with an ulcer on the oral mucosa. In the present study, swelling on the periphery of the ulcer was observed after administration of the B-LF tablets, and then the ulcer has reduced overall.

Influence of Pectins on Preparation Characteristics of Lactoferrin Bioadhesive Tablets

For the treatment of chronic inflammation in the oral cavity, we attempted to develop bioadhesive tablets of bovine lactoferrin (B-LF). Pectin was used as a bioadhesive polymer, and the influence of the degree of esterification and the molecular weight of pectins on the characteristics of B-LF tablets were investigated. Concerning bioadhesive force, a tendency increasing the value according to increase of the esterification of the pectin was confirmed. Sustained release of B-LF from the tablets was observed as the esterification increased, and a possibility for prediction of the time required to release 50% of B-LF by using the equation given by the degree of esterification and the logarithm of the molecular weight was suggested. Pectin cross-linked with Ca(2+) (Ca-PC) was also used for the preparation of the B-LF tablets. Prolonged release of B-LF from the tablets was observed as the Ca(2+) in Ca-PC increased. Our findings suggest that pectin with a high degree of esterification is suitable as a bioadhesive polymer since high bioadhesive force and sustained release are shown. Furthermore, a possibility that the B-LF release could be controlled by adjusting the Ca(2+) concentration in Ca-PC was suggested.

Bioadhesive Controlled Release Systems of Ornidazole for Vaginal Delivery

Our objective was to develop a bioadhesive vaginal tablet formulation of ornidazole by using different polymer mixtures, to evaluate the bioadhesive tablet properties, and to investigate the irritation potential of the formulations to the rat vaginal tissue. Vaginal tablets of ornidazole were directly compressed with bioadhesive and swellable polymer mixtures as release-controlled agents. Carbopol 934 (Cp), pectin (Pc), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (Na CMC), and guar gum (GG) were used in different ratios. Bioadhesive properties, swelling capacity, release studies, and histological studies of the formulations were carried out. The bioadhesive strength between bovine vagina and surface of the tablets was determined by tensile experiments, and it was found to be dependent on Cp content. The release mechanism was described and found to be non-Fickian for all formulations. Dissolution data were evaluated statistically. No histological damage was found except one formulation containing high amount of guar gum.

The mechanism of diclofenac sodium release from non-disintegrating bioadhesive tablets

The mechanism of diclofenac sodium release from non-disintegrating bioadhesive tablets was studied. Diclofenac sodium was embedded in Carbopol 941 to produce bioadhesive granules, which were later, incorporated into a structure-forming material, paraffin wax. The tablets were formulated by pour moulding in a well-lubricated plastic mould. The tablets were thereafter evaluated as compressed uncoated tablets using the following parameters: weight uniformity, friability, hardness, thickness, absolute drug content and release studies. The release study was undertaken in simulated intestinal fluid (SIF) without pancreatin. The result of the study showed that the release of diclofenac sodium was extended in all the tablets. The tablets conformed to pharmacopoeia specification as applied to uncoated compressed tablets. The mechanism of release of diclofenac sodium appeared to have followed different release models. Key words: Diclofenac sodium, bioadhesive tablets, non-disintegrating tablets, release mechanism. Journal of Pharmaceutical and Allied Sciences Vol.2(2) 2005: 202-208

Spray-dried Amioca ® starch/Carbopol ® 974P mixtures as buccal bioadhesive carriers

In the present study, spray-dried Amioca ® starch/Carbopol ® 974P mixtures were evaluated as potential buccal bioadhesive tablets. Carbopol ® (C 974P) concentrations from 5 to 75% were tested. All spray-dried mixtures showed a comparable or better bioadhesive capacity compared to a reference formulation (DDWM/C 974P 95/5). The bioadhesive capacities of Amioca ®/Carbopol ® 974P mixtures were improved by spray-drying. All spray-dried mixtures showed significantly higher work of adhesion values compared to their equivalent physical mixtures. The influence of Carbopol ® concentration on the in vivo adhesion time of placebo tablets and in vitro miconazole nitrate release was tested. The ratio Amioca ®/C 974P 70/30 showed the longest in vivo adhesion time (24.5 ± 8.5 h). Lower and higher C 974P concentrations had a shorter in vivo adhesion time. The mixtures containing between 15 and 30% C 974P could all sustain the in vitro miconazole nitrate release over 20h. Again, lower and higher C 974P concentrations showed a faster in vitro miconazole release. The drug loading capacity of a spray-dried mixture containing 20% C 974P was investigated in vivo in dogs using testosterone as model drug. The spray-dried mixture could be loaded with 60% drug without loosing its in vivo bioadhesive and pharmacokinetic properties.

Effect of a buccal bioadhesive nystatin tablet on the lifetime of a Provox™ silicone tracheoesophageal voice prosthesis

Conclusion. Daily application of a buccal bioadhesive slow-release nystatin tablet (100 000 IU per tablet) significantly increased the voice prosthesis lifetime in laryngectomized patients compared to conventional local cleaning of the prosthesis with an antimicrobial agent on a brush. Objective. To investigate the effect of a buccal bioadhesive nystatin tablet on the lifetime of a Provox™ tracheoesophageal voice prosthesis in post-laryngectomy patients. Material and methods. A buccal bioadhesive tablet, based on a spray-dried Amioca®/Carbopol® 974P mixture containing 10% (w/w) Carbopol® 974P, was loaded with 100 000 IU of nystatin. Patients were included in the study when replacement of their voice prosthesis was required and were divided into three groups. Conventional daily local cleaning of the voice prosthesis by means of an oral nystatin suspension on a brush (Group 1; n=7) was compared with application of one nystatin buccal bioadhesive tablet per day, after breakfast, on the gingiva above the upper canine (Group 2; n=7). The control group (n=5) used no antimicrobial agents. The lifetime of the prosthesis was followed and expressed in days. Results. The lifetime of the voice prosthesis was significantly increased in Group 2 compared to Group 1 (p<0.05; paired t-test), indicating that sustained release of nystatin in the oral cavity, by means of erosion of the tablet over a period of ≈8 h, is more effective at preventing microbial colonization of the prosthesis than local cleaning.

An Alternative Evaluation Method for Swelling Studies of Bioadhesive Tablet Formulations

A new and alternative evaluation method is preferred for swelling studies of bioadhesive tablet formulations. CIELAB color coordinates, related to visual color response, are used for the first time to follow the swelling state and to calculate the swelling volume. The results are evaluated statistically. A simple equation is given to explain the relation between the swelling volume change % and color difference for three different bioadhesive formulations. It was found that the estimated equation is in good agreement with observed swelling volume results.

Efficacy of a new ketoconazole bioadhesive vaginal tablet on Candida albicans

To develop more effective treatment for vaginal candidasis, ketoconazole (KTZ) was formulated in bioadhesive tablet formulations that increase the time of contact of drug with the vaginal mucosa. The bioadhesive vaginal tablets delivery of KTZ was prepared by direct compression of sodium carboxymethyl cellulose or polyvinylpyrrolidone or hydroxypropylmethyl cellulose (HPMC-E 50). Dissolution studies of bioadhesive tablets and commercial ovules were carried out with a new basket method (horizontal rotating basket). In vitro, a good sustained release action was obtained with bioadhesive tablets containing 1:1 and 1:2 drug/polymer ratio using HPMC-E 50. These bioadhesive tablets containing 400 mg of KTZ showed a zero-order drug release kinetic. KTZ solutions at increasing concentrations (0.16, 0.33, 0.5 and 0.66 mg/ml) were prepared for microbiological trials. These concentrations correspond to 25%, 50%, 75% and 100% of KTZ released from bioadhesive tablets, respectively. Yeast mixture was mixed with each concentration of KTZ at ratio of 1:10. One hundred microliters of this mixture was transferred in 900 μl liquid Sabouraud medium after a certain time interval for each concentration of KTZ and incubation at 37 °C for 24 h. Then this culture streaked onto Sabouraud-dextrose–agar plates, which were incubated at 37 °C for 48 h. The 0.16 and 0.33 mg/ml concentrations of KTZ showed fungistatic effect in 120 min. The 0.5 mg/ml concentration of KTZ was fungistatic in 90 and 120 min; and the 0.66 mg/ml concentration of the drug was fungistatic in 120 min as well as in 180 min. It was found that, in vitro antifungal activity of KTZ was dependent on its concentration and contact time with yeast cells. These results indicated that a new bioadhesive vaginal tablet formulations might be further developed for safe convenient and effective treatment of vaginal candidasis.

Mucoadhesive Delivery Systems. I. Evaluation of Mucoadhesive Polymers for Buccal Tablet Formulation

Different types of mucoadhesive polymers, intended for buccal tablet formulation, were investigated for their comparative mucoadhesive force, swelling behavior, residence time and surface pH. The selected polymers were carbopols (CP934, and CP940), polycarbophil (PC), sodium carboxymethyl cellulose (SCMC) and pectin representing the anionic type, while chitosan (Ch) as cationic polymer and hydroxypropylmethyl cellulose (HPMC) as a non‐ionic polymer. Results revealed that polyacrylic acid derivatives (PAA) showed the highest bioadhesion force, prolonged residence time and high surface acidity. SCMC and chitosan ensured promising bioadhesive characteristics, whilst HPMC and pectin exhibited weaker bioadhesion. Different polymer combinations as well as formulations were evaluated to improve the mucoadhesive performance of the tablets. Bioadhesive tablet formulations containing either 5% CP934, 65% HPMC and 30% spray‐dried lactose or 2% PC, 68% HPMC and 30% mannitol showed optimum mucoadhesion and suitable residence time. SCMC, when formulated individually, exhibited promising bioadhesion, acceptable swelling, convenient residence time and surface pH. In‐vivo trials of these formulations proved non‐irritative and prolonged residence of the mucoadhesive tablets on human buccal mucosa for 8 to 13 h.

An in vitro investigation for vaginal bioadhesive formulations: bioadhesive properties and swelling states of polymer mixtures

Bioadhesive tablet formulations have been developed for mucosal application. Sixteen different bioadhesive tablet formulations were prepared and evaluated. Their bioadhesion to vaginal mucosa were studied by tensile testing method. The swelling behaviour of the tablets in three different solutions was also investigated. In addition, the effect of the formulations on pH of the medium was followed. The most favorable formulation resulted a mixture of Carbopol 934 and Pectin (2:1). The highest bioadhesive strength, the highest swelling volume and the lowest pH reduction were obtained with this formulation.

Preparation and In Vitro/In Vivo Evaluation of the Buccal Bioadhesive Properties of Slow-Release Tablets Containing Miconazole Nitrate

Slow-release buccal bioadhesive tablets of miconazole nitrate were prepared by using polymer mixtures of buccoadhesive materials such as hydroxypropylmethylcellulose, sodium carboxymethylcellulose, carbopol 934p, and sodium alginate. The physicochemical properties, swelling index, microenvironment pH, in vitro drug release, in vivo buccoadhesion time, and miconazole salivary concentrations of the prepared tablets were shown to be dependent on the type and composition of the buccoadhesive materials used. The dissolution of miconazole from all the prepared tablets into phosphate buffer (pH 6.8) was controlled and followed non-Fickian release mechanisms. All the prepared tablets gave reasonable buccoadhesion time (2.45–3.65 hr). Infrared spectroscopy and differential scan calorimetry studies revealed the absence of significant interactions between miconazole nitrate and the selected buccoadhesive materials. Duration of the antifungal activity as measured by the inhibition zone of Candida albicans by extracted human saliva was significantly longer (p<0.05), compared with commercial miconazole oral gel (Daktaren®oral gel). Based on the results obtained, the prepared slow-release buccoadhesive tablets of miconazole would markedly prolong the duration of the antifungal activity with more patient convenience.

Delivery of Didanosine from Enteric-Coated, Sustained-Release Bioadhesive Formulation

The aim of our study is to assess the release characteristics, in vitro permeation, and stability of an enteric-coated, bioadhesive, sustained-release formulation of didanosine (ddI). Enteric-coated tablets of ddI, containing Polyox® WSRN-303 and Methocel K4M, were prepared using hydroxypropylmethylcellulose phthalate (HPMCP 5.5). The enteric-coated formulation was resistant to dissolution in 0.1 N HCl solution but dissolved within 10 min (±2 min) in pH 7.4 phosphate buffered saline. The release profiles were linear with square root time. Stability studies indicate that the formulations were stable at 4°C, room temperature, and 40°C upon storage for 6 months. Polyox® WSRN-303 tablets exhibited a higher ddI permeation ratio across live intestinal tissue compared with conventional tablets. Enteric-coated, sustained-release, bioadhesive tablets deliver ddI in small doses and at the same time prevent acid-induced degradation and hence hold a potential to improve ddI's oral bioavailability.

Local treatment of bacterial vaginosis with a bioadhesive metronidazole tablet

Objectives: Oral metronidazole is still the drug of choice in the treatment of bacterial vaginosis. Yet, side effects have been reported, and dosage as well as duration of therapy are still controversial. This study presents a possible alternative treatment using a single dose of metronidazole administered in a vaginal bioadhesive tablet. Study design: Double blind, randomised, placebo-controlled trial. Subjects: The 116 patients were allocated to placebo; metronidazole 100; 250; 500 mg in a 1:1:1:1 ratio. Results: A cure rate of 64% was obtained with a single 100 mg dose of metronidazole formulated in a bioadhesive vaginal tablet compared to a cure rate of 29% in the placebo group. The cure rates with the higher doses were similar 61.5% for 250 mg dose and 68% for the 500 mg dose. No side effects were reported. Conclusions: Treatment of bacterial vaginosis with a single application of 100 mg metronidazole in a bioadhesive vaginal tablet was found to be a valid alternative. Further research in relation to tablet shaping and optimal dose finding might increase the cure rate.

Buccal absorption of ergotamine tartrate using the bioadhesive tablet system in guinea-pigs

The buccal administration of ergotamine tartrate (ET) combined with polyvinyl alcohol (PVA) gel brought about higher plasma concentration of ET compared with that of oral administration of capsules in guinea-pigs. T max of ET in plasma of buccal administration was significantly smaller than that of oral administration. For the buccal dosage form of ET, the bioadhesive tablet system (BTS) was newly developed. It consisted of a reservoir of drug and an adhesive region. BTS showed better absorption of ET compared with PVA gel in guinea pigs. Among several pharmaceutical bases in the reservoir of BTS, Witepsol W-35 was most effective. It is likely that the high lipophilic property of Witepsol W-35 in which ET was dissolved facilitated the drug release by its relatively low melting point (around 35 °C), consequently a rapid absorption. In addition, the enhancing activity of the cod-liver oil extract (CLOE) in hydrophilic ointment on the in vivo buccal ET absorption was clarified to be comparable to that in the in vitro study utilizing the keratinized epithelial-free membrane (KEF-membrane) of the hamster cheek pouch.

Ex vivo bioadhesion and in vivo testosterone bioavailability study of different bioadhesive formulations based on starch- g-poly(acrylic acid) copolymers and starch/poly(acrylic acid) mixtures

Starch- g-poly(acrylic acid) copolymers or grafted starches synthesized by 60Co irradiation or chemical modification and co-freeze-dried starch/poly(acrylic acid) mixtures were evaluated on their ex vivo bioadhesion capacity. The buccal absorption of testosterone from a bioadhesive tablet formulated with the grafted starches or starch/poly(acrylic acid) mixtures was investigated. The results were compared to a reference formulation (physical mixture of 5% Carbopol ® 974P and 95% Drum Dried Waxy Maize). Rice starch-based irradiated grafted starches showed the best bioadhesion results. Partial neutralization of the acrylic acid with Ca 2+ ions resulted in significantly higher bioadhesion values compared to the reference. Ca 2+ and Mg 2+ partially neutralized maltodextrin-based irradiated grafted starches showed significantly higher bioadhesion values compared to the reference formulation. The chemically modified grafted starches showed significantly higher adhesion force values than for the reference tablet. None of the co-freeze-dried starch/poly(acrylic acid) mixtures showed significantly higher bioadhesion results than the reference (Bonferroni test, P<0.05). A chemically modified grafted starch could sustain the 3 ng/ml plasma testosterone target concentration during ±8 h ( T >3 ng/ml). By lyophilization of a partially neutralized irradiated grafted starch, the in vivo adhesion time (22.0±7.2 h) and the T >3 ng/ml (13.5±1.3 h) could be increased. The absolute bioavailability of the lyophilized formulation approached the reference formulation. Some of the grafted starches showed to be promising buccal bioadhesive drug carriers for systemic delivery.

Evaluation of Bioadhesive Glipizide Spheres and Compacts from Spheres Prepared by Extruder/Marumerizer Technique

The objective of this study was to attempt to deliver glipizide from spheres and compacts containing the natural polymer Carrageenan (Gelcarin, GP 812) and prepared by extruder/marumerizer technique. A second objective was to evaluate the mucoadhesive strength of the bioadhesive spheres onto the mucus membrane of rabbit. The effects of polymer, drug level, and type of spheronizing material were evaluated. All sphere formulations were compacted into tablets using a rotary Manesty B-3B machine equipped with 12/32 flat face tooling. Results show drug release from spheres and compacts decreased as the level of Carrageenan was increased. However, as the level of drug was increased drug release also increased. Spheres containing Avicel PH-101 gave higher drug release than spheres of the same composition but prepared with Avicel RC-581. In general, the drug release from tablets was higher than its corresponding spheres and drug release from spheres and tablets containing Carrageenan was higher than control spheres and tablets of the same composition but without Carrageenan. Tablet formulations compacted from spheres containing Avicel RC-581 gave higher release rate constants than tablet formulations of the same composition but prepared with Avicel PH-101. The bioadhesion study showed that mucoadhesion strength between spheres and mucus membrane of the rabbit depends on the levels of polymer, drug, and type of spheronizing material. Developed bioadhesive spheres and tablets increase the solubility of glipizide which may increase its bioavailability and also increased the adherence of the bioadhesive systems to the mucous membrane so that once daily dose can be administered.

Oral Sustained-Release Bioadhesive Tablet Formulation of Didanosine

The objective of this study was to formulate a hydrogel-forming bioadhesive drug delivery system for oral administration of didanosine (ddI). The aim of this tablet dosage form is to improve the oral absorption of ddI by delivering it in small doses over an extended period and localizing it in the intestine by bioadhesion. Compressed tablets of ddI using Polyox® WSRN-303, Carbopol® 974P-NF, and Methocel® K4M as the bioadhesive release rate-controlling polymers were prepared. The effect of polymer concentration on the release profile and in vitro bioadhesion of the matrix tablets was studied. Tablet formulations with Polyox WSRN-303 (10%) and Methocel K4M (30%) showed 93 and 90% drug release, respectively, after 12 h. The drug release was found to be linear when fitted in the Higuchi equation (square-root time equation), suggesting zero-order release. Carbopol 974-P-NF was found to inhibit the complete release of ddI because of drug-polymer interaction; hence, is not suitable for formulation of ddI. Drug diffusion and swelling of the polymer (anomalous Fickian release) was found dominant in ddI release. In general, in vitro bioadhesion increased with an increase in polymer concentration. Tablets containing a single polymer can be designed to form hydrogels serving the dual purpose of bioadhesion and sustained release.