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.     

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.     

Development of a buccal bioadhesive nicotine tablet formulation for smoking cessation

Bioadhesive buccal tablet formulations for delivery of nicotine into the oral cavity were developed. Carbomer (Carbopol)974P NF) (CP) and alginic acid sodium salt (NaAlg) were used as bioadhesive polymers in combination with hydroxypropyl methylcellulose (HPMC) at different ratios. Magnesium carbonate was incorporated into the formulations as a pH increasing agent. In vitro release and bioadhesion studies were performed on the developed tablets. In the formulations containing CP:HPMC, the NHT released increased with the increasing HPMC concentration whereas a decrease was observed with increasing HPMC concentration in formulations containing NaAlg:HPMC. The bioadhesive properties of the tablets containing NaAlg:HPMC was not affected by the concentration of the NaAlg (P>0.05) but increased significantly with the increasing CP concentration (P>0.05). A decrease in pH of the dissolution medium to acidic values was avoided by incorporation of magnesium hydroxide into the formulations. The developed formulations released NHT for 8h period, and remained intact except for the formulation containing CP:HPMC at 20:80 ratio.     

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.     

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.     

Histological and bioadhesion studies on buccal bioadhesive tablets containing a penetration enhancer sodium glycodeoxycholate

For many drugs, buccal route offers many advantages over conventional routes of delivery with an improved bioavailability due to the avoidance of degradation in the gastrointestinal tract and hepatic first-pass metabolism. However, the major limitation to buccal drug delivery is the permeability barrier in the buccal mucosa. Use of penetration enhancers appears to be a pertinent approach to increase the drug permeation through the buccal epithelium. Buccal bioadhesive tablet formulations enable a delivery with a plasma drug level of the desired therapeutic response for a defined period of time, and also provides a means of confining the drug and penetration enhancer to a defined region of the mucosa. In this study, a bioadhesive tablet formulation for buccal delivery was designed using a mixture of hydroxypropyl methylcellulose and carbomer, incorporated with a penetration enhancer, sodium glycodeoxycholate (GDC). In vitro bioadhesion property of the formulated tablet was examined and histological study was carried out to examine an in vivo interaction between the tablet and tissue. GDC did not affect the adhesiveness of the tablet which makes it an acceptable excipient for a buccal bioadhesive drug delivery system. Histological changes such as loss of upper cell layers and formation of vacuoles as well swelling in the cells were observed in the buccal epithelium, after 4 h contact with the tablets containing GDC. Studies on reversibility of the interaction are in progress.     

Novel sustained release, swellable and bioadhesive gastroretentive drug delivery system for ofloxacin

Oral sustained release gastroretentive dosage forms offer many advantages for drugs having absorption from upper gastrointestinal tract and improve the bioavailability of medications that are characterized by a narrow absorption window. A new gastroretentive sustained release delivery system was developed with floating, swellable and bioadhesive properties. All these properties were optimized and evaluated. Various release retarding polymers like psyllium husk, HPMC K100M and a swelling agent, crosspovidone in combinations were tried and optimized to get the release profile for 24 h. Formulations were evaluated for in vitro drug release profile, swelling characteristics and in vitro bioadhesion property. The in vitro drug release followed Higuchi kinetics and the drug release mechanism was found to be of anomalous or non-Fickian type. For the developed formulation, the value of n was found to be 0.5766 while for the marketed formulation the value was 0.5718 indicating the anomalous transport. The high water uptake leading to higher swelling of the tablet supported the anomalous release mechanism of ofloxacin. The similarity factor f2 was found to be 91.12 for the developed formulation indicating the release was similar to that of the marketed formulation (Zanocin OD). The swelling properties were increased with increasing crosspovidone concentration and contributed significantly in drug release from the tablet matrix. The bioadhesive property of the developed formulation was found to be significant (P < 0.005) in combination as compared to HPMC K100M and psyllium husk alone.     

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.     

Chitosan-polycarbophil interpolyelectrolyte complex as an excipient for bioadhesive matrix systems to control macromolecular drug delivery

The in vitro performance of monolithic matrix systems containing the interpolyelectrolyte complex between chitosan and polycarbophil as excipient was evaluated in terms of their swelling, bioadhesive, and drug release properties. The different matrix systems showed excellent swelling properties without erosion, except for the formulation containing the highest quantity chitosan-polycarbophil complex that exhibited surface erosion in addition to swelling. All the different matrix systems exhibited significantly higher bioadhesive properties than the control group. Furthermore, they showed controlled insulin release without an initial burst release effect. However, only the matrix system that exhibited surface erosion in combination with swelling approached zero-order release.     

小檗碱生物黏附缓释片的制备及体外评价

目的 测定小檗碱生物黏附缓释片和大鼠离体胃组织的黏附力,探究其体外释药作用,制备小檗碱生物黏附缓释片。方法 以羟丙基甲基纤维素(HPMC)和卡波姆(carbopol,CP)为生物黏附材料,通过正交试验对辅料用量进行优化。测定生物黏附缓释片的释放度,溶出介质为人工胃液(pH=1.2)。通过自制黏附力测定装置测定、比较小檗碱生物黏附缓释片和盐酸小檗碱片对大鼠离体胃组织的黏附力。结果 每片生物黏附缓释片中974P/971P为1/3,卡波姆用量为20 mg,羟丙基甲基纤维素为15 mg。生物黏附缓释片的体外释放达到缓释制剂要求,与普通片剂相比其对大鼠离体胃组织的黏附力更大。结论 小檗碱生物黏附缓释片的处方和工艺能够达到设计要求。     

Bioavailability of morphine after administration of a new bioadhesive buccal tablet

A new bioadhesive buccal morphine tablet was developed for controlled release delivery of drug and improved bioavailability compared with oral controlled release tablet. In order to characterize the pharmacokinetic properties of this bioadhesive buccal formulation, a bioavailability study was performed in 12 healthy volunteers who received: a 30 mg oral controlled release tablet (A); a 20 mg aqueous solution retained in the mouth for 10 min (B); and the 60 mg bioadhesive buccal tablet placed between the lower gum and lip for 6 h (C). The mean amount of morphine absorbed from the solution was very low, only 2 mg of the 20 mg dose. After administration of forms A and C, plasma levels exhibit typical sustained release concentration–time curves. The mean amount of drug recovered from the residual bioadhesive buccal tablet after 6 h indicated that approximately 50% of the dose was released from the bioadhesive buccal tablet. The relative bioavailability of the buccal tablet (corrected for residual unabsorbed dose) compared with the controlled-release tablet was 98% based on the morphine AUC values. Good correlations between the AUC and the C_max of the bioadhesive tablet for the drug and metabolite plotted versus the amount of morphine absorbed were found. © 1998 John Wiley & Sons, Ltd.     

Development and in vitro/in vivo evaluations of bioadhesive buccal tablets for nicotine replacement therapy

Buccal bioadhesive tablet formulations of nicotine hydrogen tartrate (NHT) for nicotine replacement therapy (NRT) were developed using chitosan and carbomer at different ratios. Magnesium hydroxide was incorporated into the formulations as pH increasing agent. In vitro release and bioadhesion properties of the tablets were investigated. Release of NHT from the tablets was increased with the increasing amount of chitosan in formulations whilst the bioadhesion of the tablet was decreased. In vivo studies were carried out in healthy, non-smoker volunteers in comparison to a commercially available transdermal patch. Plasma nicotine and cotinine levels were determined using gas chromatography-mass spectrophotometry. No significant difference was found between the maximum plasma nicotine concentrations (Cmax) obtained with the buccal tablet and the transdermal patch (p > 0.05). Time to reach the Cmax was 2.9 +/- 0.2 h and 11.5 +/- 1.3 h, and AUC0-24 values were 59.3 +/- 5.1 ng x h x mL(-1) (0-12 h) and 204.1 +/- 31.2 ng x h x mL(-1) for buccal tablet and transdermal patch, respectively.     

Salivary fluoride concentrations following applications of bioadhesive tablets and mouthrinses.

Presence of elevated fluoride concentration in saliva is important for the prevention of caries. In the present study, we developed an intra-oral bioadhesive tablet aimed at delivering F(-) in the mouth over a prolonged period of time. Various tablet formulations were tested in vivo for their tolerance and adhesiveness. Two formulations were selected for further studies on salivary fluoride clearance. For comparison, mouthrinses with increasing F(-) concentrations were also examined. Results indicate that a bioadhesive tablet located on the upper gingiva is able to sustain salivary F(-) concentrations for about 10h without major side effects. Mouthrinses with high F(-) concentration were able to prolong salivary fluoride retention for more than 6h.     

Benzydamine hydrochloride buccal bioadhesive gels designed for oral ulcers: Preparation,rheological, textural,mucoadhesive and release properties

This study developed and examined the characterization of Benzidamine hydrochloride (BNZ) bioadhesive gels as platforms for oral ulcer treatments. Bioadhesive gels were prepared with four different hydroxypropylmethylcellulose (HPMC) types (E5, E15, E50 and K100M) with different ratios. Each formulation was characterized in terms of drug release, rheological, mechanical properties and adhesion to a buccal bovine mucosa. Drug release was significantly decreased as the concentration and individual viscosity of each polymeric component increased due to improved viscosity of the gel formulations. The amount of drug released for the formulations ranged from 0.76?±?0.07 and 1.14?±?0.01 (mg/cm²?±?SD). Formulations exhibited pseudoplastic flow and all formulations, increasing the concentration of HPMC content significantly raised storage modulus (G′), loss modulus (G″), dynamic viscosity (?′) at 37°C. Increasing concentration of each polymeric component also significantly improved the hardness, compressibility, adhesiveness, cohesiveness and mucoadhesion but decreased the elasticity of the gel formulations. All formulations showed non-Fickian diffusion due to the relaxation and swelling of the polymers with water. In conclusion, the formulations studied showed a wide range of mechanical and drug diffusion characteristics. On the basis of the obtained data, the bioadhesive gel formulation which was prepared with 2.5% HPMC K 100M was determined as the most appropriate formulation for buccal application in means of possessing suitable mechanical properties, exhibiting high cohesion and bioadhesion.     

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 microl liquid Sabouraud medium after a certain time interval for each concentration of KTZ and incubation at 37 degrees C for 24 h. Then this culture streaked onto Sabouraud-dextrose-agar plates, which were incubated at 37 degrees 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.     

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.     

冬凌草甲素纳米结晶黏附性缓释片的制备及体外评价

目的制备冬凌草甲素纳米结晶黏附片,考察其体外释放性、黏附性和结晶药物形态。方法采用高压均质法将冬凌草甲素制成纳米结晶,以羟丙甲纤维素(HPMC)和卡波姆为生物黏附材料,甘露醇为稀释剂和支架剂制备冬凌草纳米结晶生物黏附性缓释片。采用紫外分光光度法测定冬凌草甲素的含量,采用正交设计结合多元线性回归,以累计释放率为主要考察指标,考察了HPMC、卡波姆、甘露醇的用量对药物溶出的影响,确定了片剂的优化处方,并对片剂的黏附性和体外药物释放做了考察。结果最佳处方含HPMC31.0%,卡波姆21.7%,甘露醇7.44%。片剂中药物以纳米结晶形式从片剂中溶出,而且具有黏附和缓释作用。结论以最佳制备工艺条件制备纳米结晶片,制备工艺简单,重现性好。同时体外实验表明,冬凌草甲素纳米结晶生物黏附性缓释片显示了纳米结晶与生物黏附的双重优点。     

Development and testing of bioadhesive, fluoride-containing slow-release tablets for oral use.

The bioadhesive characteristics of tablets for oral use made from modified starch, polyacrylic acid (PAA), polyethylene glycol (PEG) and sodium carboxymethylcellulose (CMC) were investigated. Adhesion force and energy were determined in-vitro and maximal adhesion time was evaluated in-vivo in human subjects. In-vitro, PAA showed the best bioadhesive properties, followed by modified maize starch and PEG with a mol. wt of 300,000-400,000 daltons. The presence of 0.1 mg of fluoride as NaF did not lead to significant differences in adhesion force and energy for the same formulation. The in-vivo bioadhesion was not strongly correlated to the in-vitro data. PAA, despite its excellent adhesion, proved to be irritating to the mucosa. PEG with a mol, wt of 200,000 daltons was subject to erosion. CMC showed good bioadhesive properties but the mechanical strength of the tablets was low. Modified maize starch tablets containing 5% (w/w) PAA and PEG with a mol. wt of 300,000 daltons proved to be the most suitable formulations for a fluoride-slow-release tablet with bioadhesive properties. In-vitro, the tablets released all of the fluoride within the 8 h period, with a high initial release. The release rate was related to the water absorption rate of the tablets. The PAA-containing formulations and the CMC formulations had the fastest release. In-vivo, fluoride levels with a minimum of 150 and a maximum of 1000 micrograms mL-1 were maintained for 8 h in the oral cavity. These fluoride levels were sustained significantly longer than those obtained with the administration of fourfold the amount of fluoride in the form of a fluoride-containing toothpaste. The release characteristics in-vivo exhibited a high variation. The use of bioadhesive polymers in oral pharmacotherapy seems promising.     

复方酮替长效阴道黏附片的制备及体外评价

目的制备复方酮替黏附性阴道片,并进行体外评价。方法对HPMC 60SH-4000,90SH-4000,60SH-10000,90SH-10000黏附材料进行溶胀率和黏附性的考察基础上,选用HPMC 60SH-4000为黏附剂,加入泡腾剂,PEG-6000,F68设计8种复方酮替黏附片处方,比较不同处方的溶胀率、黏附力、体外释放度等指标。结果处方最佳组成为HPMC 60SH-4000300mg,PEG-6000 50mg,泡腾剂50mg(摩尔比NaHCO3:Citric acid=3:1),替硝唑和酮康唑24h累积释放度为90.07%和86.54%。结论复方酮替黏附性阴道片制备方便,具有缓释的效果,有望成为治疗妇科感染的新剂型。     

Development and evaluation of a buccal bioadhesive system for smoking cessation therapy

The objective of the present study was to develop a bilayered buccal bioadhesive film formulation of nicotine hydrogen tartrate for smoking cessation therapy, comprising a bioadhesive drug layer and a backing layer, which releases the drug at a pre-determined rate for a period of 4 h. Formulations were prepared using various bioadhesive polymers and were evaluated for physical parameters like peelability, flexibility, softness, bioadhesive strength, tensile strength, dispersion time and pharmaceutical parameters such as thickness, swelling, content uniformity, water vapour permeability and drug release. Based on these parameters formulation N2, containing hydroxypropyl methylcellulose and polycarbophil as the bioadhesive polymers, was selected as the optimized formulation. The formulation showed suitable adhesion and an initial burst release of 40% drug in first 15 min followed by a total 80% drug release in a characteristic manner until 4 h; which is the desired time of application. This release pattern is beneficial for patients suffering from emergent cravings. Backing layers of the films were studied by a moisture vapor permeability test and it was observed that the percentage of moisture which permeated through single layered films was much higher than through bilayered films implying that a backing layer would prevent washing out of drug by the saliva.