Bioadhesive Delivery System Research Articles

Bioadhesive Systems Targeting Site-Specific Mucosal Delivery

Abstract: One of the major limitations to drug delivery at mucosal administration sites is the limited retention of the dose at the tissue surface. Bioadhesive delivery systems increase the residence time/retention of the dosage form at the application site. To retain the drug at the site of administration for improved absorption and ease of administration, the identification of polymer systems based on site-specific physiological conditions is important. This review outlines diverse kinds of polymer systems and their mechanism of mucoadhesion. This review presents a brief description of bioadhesive strategies for the formulation and development of a buccal and esophageal delivery system based on its site-specific physiological considerations.

Advances in Drug Delivery and Theranostics

Advances in Drug Delivery and Theranostics

Formulation and in-vitro Evaluation of Oral Captopril Bioadhesive Delivery System

Abstract: Background: Captopril is considered as the drug of choice in the treatment of hypertension and congestive heart failure. It has a very short duration of action and a biological half-life of 1-2 hr. This requires its administration in 2-3 times daily which is not convenient for the management of a chronic disease like hypertension. Objectives: Captopril is unstable at the alkaline pH of the gastrointestinal tract. Therefore, it is difficult to be delivered orally in a sustained release formulation. This defect can be overcome by using bioadhesive or floating delivery systems which could increase the residence time of the drug in the stomach. Methods: Different formulations of bioadhesive chitosan microspheres containing captopril were prepared using the cross-linking method. Characterization of these microspheres was performed by measuring percent yield, particle size, swelling and bioadhesive properties, drug content and in-vitro release of captopril. Results: Chitosan microspheres prepared from 2% high molecular weight chitosan in acetic acid with 5ml glutaraldehyde and a cross-linking time of 3 hr gave the highest yield percent (83%), the highest entrapment efficiency (55%) and sustained release over 8 hr, compared with other examined formulations of chitosan. The release kinetics from all the prepared microspheres were diffusion-controlled mechanism and the drug release from microspheres was dependent on its concentration. Conclusion: In conclusion, chitosan microspheres with their particle size and release behavior seem to be a good carrier for captopril. Key words: Chitosan, Microspheres, Bioadhesion, Captopril, In-vitro release.

Vaginal residence and pharmacokinetic preclinical study of topical vaginal mucoadhesive W/S emulsions containing ciprofloxacin

The aim of this work is to test the in vivo behavior of a mucoadhesive vaginal emulsion resistant to the clearance of vaginal fluids using ciprofloxacin (CPX) as an anti-infective model of drug. CPX is a broad-spectrum antibiotic used in the treatment of sexual tissues infections, as intravenous injection in a dose of 20 mg every 12 h. In this study, CPX was incorporated in water in silicone (W/S) mucoadhesive emulsions and the in vivo residence time and the CPX in vivo absorption and distribution to the sexual organs was studied using the rat as animal model. W/S emulsion shows excellent in vitro bioadhesion having high resistance to the vaginal fluids clearance. The drug release profiles show a constant release of CPX during at least 6 h according to a zero-order kinetics. In vivo computerized PET/CT Image Analysis after intravaginal administration to rats indicates that W/S emulsions remain in the vaginal area for a long time and shows a good absorption of the radiotracers used as markers through the vaginal mucosa. Ciprofloxacin pharmacokinetic studies developed after the single intravaginal administration of W/S emulsion shows a good absorption and distribution of CPX on the uterus and ovarian tissue. A significant concentration of CPX in the sexual tissues was observed after 24 h of administration of W/S emulsion. Therefore, W/S emulsions have a good in vivo residence and drug release in the vaginal mucosae showing a great potential for the treatment of sexual tissues infections, as vaginal bioadhesive delivery systems of antinfectious drugs.

Development and in vitro evaluation of chitosan based system for local delivery of atorvastatin for treatment of periodontitis

In recent years, statin group drugs have been widely investigated in treatment of periodontal diseases due to their anti-inflammatory effect. The efficacy of statins can be enhanced by local administration into the periodontal pocket by appropriate delivery systems. The aim of our study was to develop a bioadhesive delivery system for local delivery of atorvastatin in treatment of periodontal disease. For this purpose, gel formulations were prepared using different types of chitosan (base and water soluble) and viscosity, bioadhesivity and syringeability of the gels as well as in vitro drug release properties were investigated vitro. Furthermore, anti-inflammatory effect of the formulations was studied in vitro using tumor necrosis factor (TNF)-alfa induced human gingival fibroblast (hGF) cells. Release of proinflammatory (IL-1β, IL-6, IL-8) and anti-inflammatory (TGF-β1, TGF-β2, TGF-β3, IL-10) cytokines were measured after incubating the hGF cells with the formulations. The viscosity of the formulations was found to be suitable for a local application into periodontal pocket. In presence of drug, bioadhesive property of the formulations was found to increase, and bioadhesion force was within the range, which would retain the delivery system at the application site, subsequently maintain drug levels at desired amount for longer period of time. The release of atorvastatin from the gels was found to be slower than that of the solution. The cytokine levels were found to decrease following application of the formulations, and anti-inflammatory effect was observed to enhance in presence of chitosan. No significant differences were found between base and water-soluble chitosan.

Development Michrosphere Bioadhesive Delivery System From Secondary Metabolit Actynomycetes M10a Rhizosphere Mangrove As Supportive Therapy of Colon Cancer Patients

Colon cancer is a cancer that occurs in the large intestine when abnormal cells grow in the colon or rectum layer. Inflammation Symptoms in the colon are usually characterized by a polyp that has cancer risk. Approximately 96% of colon cancer cases are caused by adenocarcinomas that develop from the glandular tissue. Utilization of secondary metabolites from Actynomycetes Mangrove forests can be used as supportive therapy for colon cancer patients that have already through apoptotic testing so it can directly treat the target of illness. This study was prepared in the form of Michrosphere Bioadhesive using secondary metabolite Actynomycetes M10a rhizosphere mangrove. The purpose of this study was to obtain the development of Michosphere Bioadhesive preparations from secondary metabolites Actynomycetes M10a rhizosphere mangrove as supportive therapy for colon cancer patients. Method of the research is base on Laboratory experiment which started with Purification of Actynomycetes isolate, Secondary Metabolite Fermentation, Michrosphere Bioadhesive Formulation and evaluation of Michrosphere Bioadhesive preparation. The concentration of secondary metabolite Actynomycetes M10a rhizosphere mangrove that been used for each formula are 400 μl, 500 μl, and 600 μl, where the percentage of submerged in F1, F2, and F3 are 93,94%, 96,96%, and 94, respectively, 12%. Particular Particle Size Distribution is F1 (3.1μm), F2 (4.4 μm), F3 (3.9 μm). The rest angles obtained are F1 (0.002O), F2 (0.002O), F3 (0.0016O), respectively. Applied efficiency was obtained by F1 (214 nm), F2 (210 nm), F3 (211 nm). Dissolution results show the absorbance results at 266 nm wavelength. From the results obtained that meet the specifications seen in Formula 2. Keywords: Colon Cancer, Actynomycetes M10a rhizosphere mangrove, Michosphere Bioadhesive.

Preparation and Evaluation of a Bio-Erodible Bio-Adhesive Drug Delivery System Designed for Intraoral Extended Release of Flurbiprofen: In Vitro and In Vivo Assessments

Site-specific drug delivery for the local treatment of the diseases in the oral cavity is far superior to the systemic administration, for both safety and efficacy reasons. This study presents the design and development of an innovative bio-adhesive delivery system (BDS) based on a bio-erodible semi-interpenetrating polymeric network (semi-IPN) for intraoral extended release of flurbiprofen (FBP). A unique combination of hydrolyzed gelatin (HG) cross-linked by tannic acid (TA) and Eudragit S, as the linear polymer, was used to compose the structure of the semi-IPN. The effect of structural factors, associated with the composition of the semi-IPN, on the release profile of FBP from the system was assessed using an in vitro dissolution method. The release rate of the drug in the oral cavity of healthy volunteers was also studied. The degree of cross-linking of HG and the weight ratio between the cross-linked polymer and the linear polymer were found to be crucial factors affecting the release profile of FBP from the system. Likewise, the presence of a high concentration of plasticizer was essential for achieving a proper flexibility of the system as proved by a DSC method. The in vivo tests demonstrated a disparity between the volunteers in the FBP concentration found in the saliva, especially after 120 min post-administration of BDS. Both f1 and f2 tests indicated that the packaged BDS can be absolutely stable for at least 6 months at 30 °C.

DESIGN AND OPTIMIZATION OF ORAL BIOADHESIVE NANOCURCUMIN DELIVERY USING NOVEL HYDROPHILIC CARRIER FOR CANCER TREATMENT: AN ALTERNATIVE TO PARENTERAL CHEMOTHERAPY

Present study involves the design and optimization of oral bioadhesive delivery system of curcumin. Solid dispersion of curcumin was developed using novel hydrophilic carrier, Gelucire® 50/13, by melt granulation technique. Based on HPMC K 100 LV(X1) and carbopol 934P (X2), bio-adhesive tablets containing curcumin solid dispersion was developed by direct compression, using central composite designs for two factors at three levels. Tablet formulation was optimized for t50%, Rel24h and bioadhesive strength. The drug release mechanism was found to be by fickian diffusion, approaching zero-order kinetics. Average plasma uptake of curcumin was found to be 0.289μg/mL as compared to plain curcumin tablet formulation. The results were found highly significant (p<0.05). The swelling matrices behavior over the time period studied showed that the gelling layer thickness increases continuously. From this study, it may be concluded that the oral controlled bioadhesive curcumin delivery may be an alternative to parenteral chemotherapy.

Bioadhesive polymers: Novel tool for drug delivery

Mucoadhesive drug delivery systems came into picture in the early 1980s and are one of the most studied novel delivery systems. Several researchers have focused on the investigations of the interfacial phenomena of mucoadhesion with the mucus. Mucoadhesion can be defined as a state in which two components, of which one is of biological origin, are held together for an extended period of time by the help of interfacial forces. A number of polymers have shown characteristics of bioadhesion and have been used in the formulation of various conventional and novel drug delivery systems. Studies demonstrated that these carriers not only increase the local therapeutic activity, but also increase the systemic availability of the drugs by increasing the residence time at the site of application. The current review is an attempt to throw some light on the basics of the mucoadhesion: the mechanism of bioadhesion and the polymers that are used in the design of the bioadhesive delivery system with their properties that affect the bioadhesion.

Floating and bioadhesive delivery system of metoprolol succinate: Formulation, development and in vitro evaluation

Floating and bioadhesive delivery system of metoprolol succinate: Formulation, development and in vitro evaluation

Moxifloxacin in situ gelling microparticles–bioadhesive delivery system

Antibiotic use for ocular treatments has been largely limited by poor local bioavailability with conventional eyedrops formulations. Here, we developed a controlled delivery system composed of moxifloxacin-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles encapsulated in a chondroitin sulfate-based, two-component bioadhesive hydrogel. Using a simple and fast electrohydrodynamic spray drying (electrospraying) technique, surfactant-free moxifloxacin-loaded microparticles were fabricated with diameters on the order of 1μm. A mixed solvent system of methanol/dichloromethane (MeOH/DCM) was employed to prepare the microparticles for the electrospraying processing. Extended release of moxifloxacin using a series of MeOH/DCM mixed solvents was accomplished over 10 days with release concentrations higher than the minimum inhibitory concentration (MIC). In contrast, moxifloxacin loaded directly in hydrogels was released rapidly within 24h. We observed a decrease of the drug release rate from the microparticles when using an increased percentage of methanol in the mixed solvent from 10% to 30% (v/v), which can be explained by the mixed solvent system providing a driving force to form a gradient of the drug concentrations inside the microparticles. In addition, the delivery system developed in this study, which incorporates a bioadhesive to localize drug release by in situ gelling, may potentially integrate antibiotic prophylaxis and wound healing in the eye.

Floating and bioadhesive delivery system of metoprolol succinate: Formulation, development and in vitro evaluation

Aim of this study was to develop gastroretentive sustained release floating and bioadhesive drug delivery system (FBDDS) to prolong the gastric retention time of Metoprolol succinate. Tablets were prepared employing hydroxypropyl methylcellulose (HPMC K100M) as hydrophilic gel material, sodium bicarbonate as gas-generating agent and Sodium CMC (SCMC) as bioadhesive polymer. A 32 full factorial design and response surface methodology were used for designing of experiment, mapping change in responses and deriving optimum formulation. Selected independent variables were amounts HPMC K100M and SCMC polymer while floating lag time (FLT), bioadhesive strength, t50 (time taken to release 50% of drug) and t90 (time taken to release 90% of drug) were selected as dependent variables. Investigation of functionality of individual polymer to predict effect on dependent variable were statistically analyzed using the RSM.Tablets were also evaluated for physical properties, swelling and matrix erosion. Increase in concentration of HPMC and decrease in concentration of SCMC resulted in retardation of drug release. Furthermore, combination of HPMC K100M and sodium bicarbonate along with SCMC was found to affect buoyancy, bioadhesion strength and drug release. Optimized formulation showed values of dependent variables close to predicted values. Optimized formulation follows Higuchi kinetics with short buoyancy lag time, total buoyancy time of more than 24 hours and could maintain drug release for 24 hours. Content uniformity, hardness, friability, weight variation were all lying within limits. Hence, FBDDS was found to be very promising and alternative approach to increase gastric retention of dosage form and may improve bioavailability.

Toxicity comparison of intraocular azithromycin with and without a bioadhesive delivery system in rabbit eyes

To determine whether the addition of a bioadhesive drug-delivery system to topical azithromycin induces intraocular inflammation and damage when introduced intraocularly by different approaches and in varying doses. John A. Moran Eye Center, Salt Lake City, Utah, USA. Experimental study. Commercial topical azithromycin 1.0% was duplicated, including the benzalkonium chloride, but without inclusion of the Durasite bioadhesive drug-delivery system. Injections of 50 μL, 25 μL, and 10 μL of the antibiotic solutions were administered in a masked fashion to 2 rabbits; 1 eye (study eye) in each rabbit was randomized to receive azithromycin with the delivery system and the fellow eye (control eye) to receive azithromycin without the delivery system. Two rabbits had topical drops of each solution placed after a 2.8 mm incision was created. Masked slitlamp examinations, pachymetry, and intraocular pressure (IOP) were determined 1 day and 2 days postoperatively. The animals were humanely killed, and the endothelial density and histopathology were examined. The IOP (P<.001), pachymetry (P<.001), and signs of inflammation (P=.38 to .003) were consistently higher in the study eye, especially at the 50 μL dose, than in the control eye. This was confirmed by histopathology. If the drug-delivery system gains access to the anterior chamber, it may cause substantial corneal edema and inflammation, even at low doses and after topical administration.

Improvement of an encapsulation process for the preparation of pro- and prebiotics-loaded bioadhesive microparticles by using experimental design

The purpose of this study was to design a new vaginal bioadhesive delivery system based on pectinate–hyaluronic acid microparticles for probiotics and prebiotics encapsulation. Probiotic strains and prebiotic were selected for their abilities to restore vaginal ecosystem. Microparticles were produced by emulsification/gelation method using calcium as cross-linking agent. In the first step, preliminary experiments were conducted to study the influence of the main formulation and process parameters on the size distribution of unloaded microparticles. Rheological measurements were also performed to investigate the bioadhesive properties of the gels used to obtain the final microparticles. Afterwards an experimental design was performed to determine the operating conditions suitable to obtain bioadhesive microparticles containing probiotics and prebiotics. Experimental design allowed us to define two important parameters during the microencapsulation process: the stirring rate during the emulsification step and the pectin concentration. The final microparticles had a mean diameter of 137 μm and allowed a complete release of probiotic strains after 16 h in a simulated vaginal fluid at +37 °C.

Formulation and Evaluation of Mucoadhesive Tablet: Influence of Some Hydrophilic Polymers on the Release Rate and In Vitro Evaluation

Extending the residence time of a dosage form at a particular site and controlling the release of drug from the dosage form are useful especially for achieving controlled plasma level of the drug as well as improving bioavailability. The objective of this study was to extend the GI residence time of the dosage form and control the release of Tramadol HCl using mucoadhesive tablet to achieve controlled plasma level of the drug which is especially useful for 12 hrs. Matrix tablets of Tramadol HCl were formulated using different mucoadhesive polymers namely guar gum, xanthan gum and Methocel (HPMC K15M and HPMC K100M). Formulations were evaluated for preformulation parameters, in vitro drug release profile and release kinetics. The formulations were found to have good preformulation characteristics. FTIR spectroscopy indicated the absence of any significant chemical interaction within dug and excipients. The release mechanism of Tramadol HCl from matrix tablets indicated anomalous (non-Fickian) transport mechanism and followed zero order kinetics. The retention time of the mucoadhesive tablet on the mucous membrane were investigated to develop a bioadhesive polymer-based controlled release delivery system and to evaluate the performance of such a delivery devices. The combination of HPMC K15: HPMC K100: Xanthan gum (1:2:1) and HPMC K 100: Xanthan gum (2:2) showed a greater bioadhesive strength as compared to single gum and other hydrophilic polymer combination tablet. The stability studies were performed on optimized formulation as per ICH guideline, result showed that there was no significant change in physical characteristic, adhesive strength and In vitro release.

Development and Evaluation of Mucoadhesive Chlorhexidine Tablet Formulations

Purpose: To formulate mucoadhesive chlorhexidine tablets and evaluate their drug release characteristics and mechanism. Methods: Chlorhexidine buccal adhesive tablets were prepared by direct compression using a blend of hydroxypropyl methylcellulose (HPMC) and chitosan as the bioadhesive polymers. Their dissolution properties were assessed according to USP 24 (paddle method). In order to determine the mode of drug release from the tablets, the release data were subjected to various release kinetic models. The bioadhesive strength of the tablets was also evaluated. Results: The results showed that as the proportion of HPMC in the blend increased, drug release rate decreased, with the lowest release rate observed when HPMC alone was used as the bioadhesive polymer (p < 0.001). Both the type and ratio of the polymers used influenced release kinetics. Also, bioadhesion force increased with increasing proportion of HPMC in the tablets, with the highest adhesion force shown when HPMC was the only polymer used, and lowest when chitosan was used alone (p < 0.01). Conclusion: The chlorhexidine formulations developed showed promise as a bioadhesive delivery system for the drug.

New strategies to improve the intranasal absorption of insulin

Recently, intranasal delivery of insulin as an alternative route of parenteral administration has been widely studied because it bears close resemblance to the 'pulsatile' pattern of endogenous insulin secretion during meal time. However, insulin is not well absorbed through nasal mucosa because of its large molecular size, hydrophilicity and low permeability through the membrane. This review describes the main barriers preventing nasal insulin absorption, and special attention is given to new approaches to improve the intranasal absorption of insulin, including the application of new safe absorption enhancers and the use of appropriate delivery systems. It seems that bioadhesive delivery systems or water-insoluble powders with absorption enhancers are the most promising methods for intranasal delivery of insulin.

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.

In vitro and in vivo characteristics of a thermogelling and bioadhesive delivery system intended for rectal administration of quinine in children

The aim of this work was to improve the rectal bioavailability of quinine hydrochloride by designing thermosensitive and mucoadhesive gels intended for rectal delivery. The rheological and mucoadhesive properties of poloxamer 407 solutions have been modulated by addition of hydroxypropylmethycellulose (HPMC) and propanediol-1,2. In vitro release and rectal absorption of quinine have been highlighted by a dialysis dissolution testing method and by the determination of bioavailability of the different formulations in rabbits. Increasing the proportions of HPMC and poloxamer in the formulations resulted in a prolonged release of quinine. Indeed, compared to the DT 50% of a rectal solution and a simple HPMC gel (27 and 65 min, respectively) the DT 50% of thermosensitive ternary systems was increased and ranged between 80 and 138 min, depending on the system composition. The release rate depended strongly on the elasticity of the gels after thermogelation. The absolute rectal bioavailability of quinine determined in rabbits was significantly improved with these thermosensitive and adhesive systems. It increased from 62% for the rectal solution to 98% for a ternary system 16/0.5/30 (poloxamer (16%)/HPMC (0.5%)/propanediol-1,2 (30%)). As a result of combined bioadhesion and prolonged release of quinine in vivo, higher average values of MRT and t max (9.1 ± 0.2 h and 30 min, respectively) were obtained compared to the rectal solution (6.9 ± 0.9 h and 15 min, respectively). Moreover, these formulations presented a very good rectal tolerance. Modulation by HPMC of the viscoelastic and mucoadhesive properties of poloxamer 407 thermogelling solutions allowed a prolonged release of quinine hydrochloride and an improvement of bioavailability in rabbit.

The cumulative effect of urea 40% combined with essential fatty acids in a bioadhesive delivery system and ketoconazole cream 2% for the treatment of moccasin tinea pedis in diabetics

The cumulative effect of urea 40% combined with essential fatty acids in a bioadhesive delivery system and ketoconazole cream 2% for the treatment of moccasin tinea pedis in diabetics