Influence of physicochemical and biological parameters on drug release from microspheres adhered on vesical and intestinal mucosa

The object of our work is to develop mucoadhesive microspheres to be applied into the urinary bladder. In the present study the microspheres were prepared and the release of a model drug after their adhesion to mucosa was evaluated. The microspheres were prepared by solvent evaporation method using Eudragit RL or hydroxypropylcellulose as matrix polymers and one out of five different polymers as mucoadhesives or non-mucoadhesive references. A method for the evaluation of the drug release from microspheres adhered on guinea pig urinary bladder and small intestine mucosa was developed and the influence of the following parameters on this process was followed: mucoadhesion strength of polymeric films, swelling of polymers and the drug release from microspheres. The results showed that the detachment forces were decreasing in the following order: CMCNa > Carbopol 934P > HPC > EE.HCl = PVP/VA. Carbopol swelled to the largest volume among all polymers and the drug release from microspheres was more retarded when Eudragit RL was used as matrix polymer. When comparing the results of pipemidic acid release from microspheres adhered on intestinal mucosa with detachment forces, similar ratios among the mucoadhesive polymers can be seen. On the other hand, differences between two mucosae were observed. These differences are due to the amount of mucus on mucosa and might also be influenced by the charge of mucus. The goal of our work at this point of investigation was achieved by microspheres containing carboxymethylcellulose as mucoadhesive and Eudragit RL as matrix polymer because they provide the longest release time from microspheres adhered on vesical mucosa and sufficient high strength of mucoadhesion.     

The correlation between zeta potential and mucoadhesion strength on pig vesical mucosa

The detachment forces of various polymers are frequently measured to determine their mucoadhesion strength. As the process of mucoadhesion is a consequence of interactions between the mucus layer on mucosa and mucoadhesive polymers, it is greatly dependent on mucus and polymer structure including their charge. It is also known that the glycosaminoglycan layer, which covers the urinary bladder mucosa surface, is highly negatively charged. Therefore, by measuring the zeta potential of polymer dispersions and mucosal homogenates an insight into electrostatic interactions during mucoadhesion can be obtained. In our experiments we chose three polymers, two anionic (polycarbophil, PC; sodium carboxymethyl cellulose, CMCNa) and one cationic (chitosan hydrochloride, CH), for which we expected different zeta potential values and different mucoadhesion strengths. The correlation between the zeta potential and the detachment force was determined. In addition to that, the zeta potential of the scraped surface layer of pig urinary bladders was measured to confirm its negative value. The mucoadhesion strength decreased in the following order: CH>CMCNa=PC. The zeta potentials for all three polymers and for porcine vesical mucosal homogenates were measured in Tyrode solution and two NaCl solutions with different ionic strengths. The lower values of the detachment force correlated well with the more negative zeta potential of the polymer, which might be a consequence of the greater repulsion between negative charges of polymers and glycosaminoglycans.     

Development and characterization of mucoadhesive microspheres for nasal delivery of ketorolac

The objective of the present investigation was to prepare mucoadhesive microspheres of ketorolac for nasal administration by means of a solvent evaporation technique using carbopol (CP), polycarbophil (PL) and chitosan (CS) as mucoadhesive polymers. The prepared microspheres were characterized for morphology, swelling behavior, mucoadhesion, interaction studies, drug encapsulation efficiency, in vitro drug release, release kinetics, and ex vivo nasal cilio toxicity studies. The effects of various process variables on the particle size of the microspheres were investigated. Drug encapsulation efficiency and particle size of the microspheres ranged from 52-78% w/w and 14-46 microm respectively. Interaction studies revealed that there were no drug-polymer interactions. The in vitro release profiles showed prolonged-release of the drug. In vitro release data showed a good fit with the Higuchi model, and indicated Fickian diffusion. No severe damage was found to the integrity of nasal mucosa after ex vivo experiments.     

Preparation and in vitro evaluation of thiolated chitosan microparticles

The objective of this study was to prepare a microparticulate drug delivery system being based on a new thiomer, namely a chitosan 2-iminothiolane conjugate (chitosan-TBA conjugate). Due to thiol groups being immobilized on chitosan, chitosan-TBA conjugate exhibits improved mucoadhesive and permeation enhancing properties. Because of these features microparticulate drug delivery systems based on chitosan-TBA conjugate might be a promising tool for the non-invasive administration of hydrophilic macromolecular drugs. Chitosan-TBA conjugate microspheres were prepared by the emulsification/solvent evaporation method. Fluorescein-isothiocyanate labelled dextran (FITC-dextran) was chosen as a model hydrophilic drug. Microspheres have been characterized by morphological analysis, thiol group content, swelling behaviour, polymer degradation drug load determination, dissolution test and mucoadhesion studies. Results reported in this work demonstrated the possibility to obtain stable microspheres without cross-linking agents. Thiolated chitosan microspheres seem to be more stable in aqueous media with respect to unmodified chitosan. The degradability by lysozyme appears quite similar for both polymers, showing that chemical modification does not influence the biodegradable properties of chitosan. Microspheres were able to control the drug release for at least 1?h, exhibiting comparatively strong mucoadhesive properties. The chitosan-TBA conjugate microparticles remain on the mucosa in a 2.5-fold higher concentration with respect to unmodified chitosan microparticles. These data suggest that chitosan-TBA conjugate microspheres have the potential to be used as a mucoadhesive drug delivery system.     

Development and characterization of mucoadhesive microspheres bearing salbutamol for nasal delivery

Mucoadhesive drug delivery systems are those that provide intimate contact of the drug with the mucosa for an extended period of time. In our present work, mucoadhesive chitosan microspheres were prepared by emulsion solvent method. Formulations were characterized for various physicochemical attributes, shape, surface morphology, size, and size distribution, drug payload, swelling ability, and mucoadhesion. The effect of drug, citric acid, and permeation enhancer concentration on the physicochemical properties was studied. Crosslinked chitosan microspheres showed very good mucoadhesion, which was decreased on increasing the drug concentration and citric acid concentration, and slightly improved upon incorporation of permeation enhancer. The in vitro drug release and in vitro drug permeability through mucous membrane were performed, and slow release/permeation was noted with chitosan citrate complexed microspheres compared with noncomplexed chitosan microspheres. The in vivo performance of mucoadhesive microspheres formulations showed prolonged and controlled release of salbutamol as compared with oral administration of conventional dosage form.     

Preparation and in vitro evaluation of thiolated chitosan microparticles

The objective of this study was to prepare a microparticulate drug delivery system being based on a new thiomer, namely a chitosan 2-iminothiolane conjugate (chitosan-TBA conjugate). Due to thiol groups being immobilized on chitosan, chitosan-TBA conjugate exhibits improved mucoadhesive and permeation enhancing properties. Because of these features microparticulate drug delivery systems based on chitosan-TBA conjugate might be a promising tool for the non-invasive administration of hydrophilic macromolecular drugs. Chitosan-TBA conjugate microspheres were prepared by the emulsification/solvent evaporation method. Fluorescein-isothiocyanate labelled dextran (FITC-dextran) was chosen as a model hydrophilic drug. Microspheres have been characterized by morphological analysis, thiol group content, swelling behaviour, polymer degradation drug load determination, dissolution test and mucoadhesion studies. Results reported in this work demonstrated the possibility to obtain stable microspheres without cross-linking agents. Thiolated chitosan microspheres seem to be more stable in aqueous media with respect to unmodified chitosan. The degradability by lysozyme appears quite similar for both polymers, showing that chemical modification does not influence the biodegradable properties of chitosan. Microspheres were able to control the drug release for at least 1 h, exhibiting comparatively strong mucoadhesive properties. The chitosan-TBA conjugate microparticles remain on the mucosa in a 2.5-fold higher concentration with respect to unmodified chitosan microparticles. These data suggest that chitosan-TBA conjugate microspheres have the potential to be used as a mucoadhesive drug delivery system.     

挤出滚圆法制备马来酸曲美布汀胃黏附微球

目的利用适合于工业化生产的方法制备具有较好生物黏附能力和适宜缓释效果的马来酸曲美布汀胃黏附微球。方法通过挤出滚圆法制备马来酸曲美布汀胃黏附微球 ;以动物体内外胃黏膜表面滞留程度 ,考察CP的含量和微球粒径对微球黏附能力的影响 ;以体外释药速率评价热处理 ,CP的含量 ,CP、SA与EC间的比例 ,TM含量 ,微球粒径对微球缓释效果的影响 ;以镇痛效果考察最终处方的药效。结果CP比例增加 ,微球的黏附性增强 ,药物缓释效果降低 ,呈现负相关 ;TM含量增加 ,微球的黏附性降低 ,缓释效果降低 ;微球粒径增大 ,微球的黏附性降低 ,缓释效果增加 ;最佳处方的作用时间延长 ,作用强度增强。结论载药量在 2 0 % (w)以下 ,粒径为 5 0 0～ 90 0 μm,CP含量为 1 3 3 0 % (w)的TM微球在胃黏膜表面具有良好的黏附特性 ,且药物缓释可达 8h。     

Chitosan-based mucoadhesive microspheres of clarithromycin as a delivery system for antibiotic to stomach

The objective of the present study was to develop chitosan-based mucoadhesive microspheres of clarithromycin to provide prolonged contact time for drug delivery of antibiotics to treat stomach ulcers. Microspheres based mucoadhesive formulation were extensively evaluated and characterized for in vitro performance followed by investigation of in vivo pharmacokinetics in rats. Microspheres were prepared by emulsification technique using glutaraldehyde as a crosslinking agent. Formulation conditions were optimized for percent drug entrapment and mucoadhesion, by varying different formulation and process parameters like drug to polymer ratio, concentration of crosslinking agent and time of crosslinking. Prepared microspheres were evaluated extensively for particle size, percent drug entrapment, swelling kinetics, in vitro mucoadhesion using rat stomach membrane and in vitro drug release studies. In vitro permeation studies across rat stomach membrane were carried out to determine diffusion parameters and drug retention in the stomach membrane of the formulation and the plain drug. Finally in vivo performance of microsphere formulation in comparison to plain drug was evaluated by pharmacokinetic studies in albino rats. Drug entrapment upto 74% was obtained. Swelling studies indicated that with an increase in cross-linking, the swelling ability decreased. The in vitro drug release and in vitro mucoadhesion studies showed a dependence on the extent of cross-linking and concentration of chitosan. Extent of cross-linking exhibited an inverse relation to drug release rate as well as mucoadhesion, whereas polymer concentration exhibited an inverse correlation with drug release while linear relationship with mucoadhesion (up to 86%). In vitro permeation studies across stomach tissue showed higher accumulation of drug in the stomach tissue with microspheres formulation as compared to that of free drug. This is evident from higher value of K (partition coefficient) and Qm/Csf values for microspheres (68.34 and 106.42X10(3), respectively) as compared to that of free drug (1.86 and 173.00, respectively). These findings when analyzed showed an increase in the bioavailability of clarithromycin from microsphere formulation as compared to plain drug suspension in vivo, with AUC 0-->alpha being 91.7 (microg h/ml)and 24.9 (microg h/ml) respectively. Results of the study demonstrated good mucoadhesion of the microspheres with the stomach mucosa as well as higher accumulation of drug in the stomach membrane. Microspheres also exhibited sustained release of drug. Thus chitosan microspheres appear, technically, promising mucoadhesive drug delivery systems for delivering clarithromycin to treat stomach ulcers.     

Stomach specific anti-helicobacter pylori therapy: preparation and evaluation of amoxicillin-loaded chitosan mucoadhesive microspheres

The purpose of this research was to formulate and systematically evaluate in vitro and in vivo performances of mucoadhesive amoxicillin microspheres for the potential use of treating gastric and duodenal ulcers, which were associated with Helicobacter pylori. Amoxicillin mucoadhesive microspheres containing chitosan as mucoadhesive polymer were prepared by simple emulsification phase separation technique using glutaraldehyde as a cross-linking agent. Results of preliminary trials indicate that volume of cross-linking agent, time for cross-linking, polymer-to-drug ratio, and speed of rotation affected characteristics of microspheres. Microspheres were discrete, spherical, free flowing and also showed high percentage drug entrapment efficiency. In vitro mucoadhesive test showed that amoxicillin mucoadhesive microspheres adhered more strongly to gastric mucous layer and could retain in gastrointestinal tract for an extended period of time. A 3(2) full factorial design was employed to study the effect of independent variables, polymer-to-drug ratio (X(1)), and stirring speed (X(2)) on dependent variables i.e. percentage mucoadhesion, t(80), drug entrapment efficiency, particle size and swelling index. The best batch exhibited a high drug entrapment efficiency of 70 % and a swelling index of 1.39; percentage mucoadhesion after 1 h was 79 %. The drug release was also sustained for more than 12 h. The polymer-to-drug ratio had a more significant effect on the dependent variables. The morphological characteristics of the mucoadhesive microspheres were studied using scanning electron microscopy. In vitro release test showed that amoxicillin released slightly faster in pH 1.0 hydrochloric acid than in pH 7.8 phosphate buffer. In vivo H. pylori clearance tests were also carried out by administering amoxicillin mucoadhesive microspheres and powder, to H. pylori infectious Wistar rats under fed conditions at single dose or multiple dose(s) in oral administration. The results showed that amoxicillin mucoadhesive microspheres had a better clearance effect than amoxicillin powder. In conclusion, the prolonged gastrointestinal residence time and enhanced amoxicillin stability resulting from the mucoadhesive microspheres of amoxicillin might make contribution complete eradication of H. pylori.     

An Improvement of the Efficacy of Moxifloxacin HCl for the Treatment of Bacterial Keratitis by the Formulation of Ocular Mucoadhesive Microspheres

The aim of this study was to prepare novel ocular mucoadhesive microspheres of Moxifloxacin HCl to increase its residence time on the ocular surface and to enhance its therapeutic efficacy in ocular bacterial keratitis. Microspheres were fabricated with different grades of Methocel and Sodium CMC as polymers. Microspheres were evaluated for their particle size, morphology, encapsulation efficiency, mucoadhesion, antimicrobial efficacy, and in vitro drug release studies. In vivo studies were carried out for the promising formulation on eyes of albino rabbits by inducing bacterial keratitis. A sterile microspheres suspension in light mineral oil was applied to infected eyes twice a day. A marketed conventional eye drop was used as a positive control. Eyes were examined daily for improvement of clinical signs of bacterial keratitis by an ophthalmologist. The average particle size of microspheres was found to be less than 80 μm. Methocel microspheres were found to have a smoother surface than Sodium CMC. Entrapment efficiency was enhanced with an increased polymer concentration and viscosity. The formulation containing Methocel K100M with a drug: polymer ratio of 1:2 exerted longer corneal and conjunctival mucoadhesion time of 8.45±0.15 h and 9.40±0.53 h respectively. In vitro release of Moxifloxacin HCl from microspheres was retarded with increased viscosity and concentration of polymers, and was controlled by diffusion as well as polymer relaxation. All formulations showed comparable antimicrobial activity in comparison with conventional marketed eye drops. The formulation containing Methocel K100M with a drug: polymer ratio of 1:2 was found to be a promising formulation and was used for the in vivo studies. The in vivo studies revealed that microspheres demonstrated significantly lower clinical scores and reduced the total duration of therapy than the marketed Moxifloxacin HCl eye drops. In vitro and in vivo studies showed that ocular mucoadhesive microspheres of Moxifloxacin HCl were found to have an improved efficacy in the treatment of ocular bacterial keratitis in comparison with the marketed formulation.     

Formulation and evaluation of stomach-specific amoxicillin-loaded carbopol-934P mucoadhesive microspheres for anti-Helicobacter pylori therapy

The purpose of this research was to formulate and systemically evaluate in vitro and in vivo performances of mucoadhesive amoxicillin microspheres for the potential use in the treatment of gastric and duodenal ulcers, which were associated with Helicobacter pylori. Amoxicillin mucoadhesive microspheres containing carbopol-934P as mucoadhesive polymer and ethyl cellulose as carrier polymer were prepared by an emulsion-solvent evaporation technique. Results of preliminary trials indicate that quantity of emulsifying agent, time for stirring, drug-to-polymers ratio and speed of rotation affected the characteristics of microspheres. Microspheres were discrete, spherical, free flowing and showed a good percentage of drug entrapment efficiency. An in vitro mucoadhesive test showed that amoxicillin mucoadhesive microspheres adhered more strongly to the gastric mucous layer and could retain in the gastrointestinal tract for an extended period of time. A 3(2) full factorial design was employed to study the effect of independent variables, drug-to-polymer-to-polymer ratio (amoxicillin-ethyl cellulose-carbopol-934P) (X(1)) and stirring speed (X(2)) on dependent variables, i.e. percentage mucoadhesion, drug entrapment efficiency, particle size and t(80). The best batch exhibited a high drug entrapment efficiency of 56%; mucoadhesion percentage after 1 h was 80% and the particle size was 109 μm. A sustained drug release was obtained for more than 12 h. The drug-to-polymer-to-polymer ratio had a more significant effect on the dependent variables. The morphological characteristics of the mucoadhesive microspheres were studied under a scanning electron microscope. In vitro release test showed that amoxicillin released slightly faster in pH 1.2 hydrochloric acid than in pH 7.8 phosphate buffer. In vivo H. pylori clearance tests were also carried out by administering amoxicillin powder and mucoadhesive microspheres to H. pylori infectious Wistar rats under fed conditions at single dose or multiple dose(s) in oral administration. The results showed that amoxicillin mucoadhesive microspheres had a better clearance effect than amoxicillin powder. In conclusion, the prolonged gastrointestinal residence time and enhanced amoxicillin stability resulting from the mucoadhesive microspheres of amoxicillin might make a contribution to H. pylori complete eradication.     

The influence of magnesium stearate on the characteristics of mucoadhesive microspheres

Microspheres containing the mucoadhesive polymer chitosan hydrochloride, with matrix polymer Eudragit RS, pipemidic acid as a model drug and agglomeration preventing agent magnesium stearate were prepared by the solvent evaporation method. The amount of magnesium stearate was varied and the following methods were used for microsphere evaluation: sieve analysis, drug content and dissolution determination, scanning electron microscopy, x-ray diffractometry, DSC and FTIR spectroscopy. The results showed that average particle size decreased with increasing amount of magnesium stearate used for microsphere preparation. This is probably a consequence of stabilization of the emulsion droplets with magnesium stearate. Higher pipemidic acid content in the microspheres was observed in larger particle size fractions and when higher amounts of magnesium stearate were used. It was also found that these two parameters significantly influenced the dissolution rate. The important reason for the differences in drug content in microspheres of different particle sizes is the diffusion of pipemidic acid from the acetone droplets in liquid paraffin during the preparation procedure. The physical state of pipemidic acid changed from crystalline to mostly amorphous with its incorporation in microspheres, as shown by x-ray diffractometry and differential scanning calorimetry. No differences were observed in the physical state of pipemidic acid and in microsphere shape and surface between different size fractions of microspheres, prepared with different amounts of magnesium stearate. Additionally, no correlation between the physical state of the drug in different microspheres and their biopharmaceutical properties was found.     

Design and development of nasal mucoadhesive microspheres containing tramadol HCl for CNS targeting

In the present study, tramadol HCl microspheres were designed in order to accomplish rapid delivery of drug to the brain. For this purpose, lower viscosity grade HPMC (E15) was chosen as mucoadhesive polymer and used at different drug/polymer ratios in the microspheres formulations. The spray-dried microspheres were evaluated with respect to the production yield, incorporation efficiency, particle size, mucoadhesive property, in vitro drug release, histopathological study, and radio imaging study in rabbits. DSC and XRD study showed molecular dispersion and conversion of the drug into amorphous form. Size and surface morphology of microspheres was analyzed by SEM and found to be spherical in shape with smooth surface. It was found that the particle size, swelling ability, and incorporation efficiency of microspheres increase with increasing drug-to-polymer ratio. Microspheres show adequate mucoadhesion and do not have any destructive effect on nasal mucosa. In vitro drug release of optimized formulation was found to be 94% after 90?min. The radio imaging study indicated localization of drug in the brain. Hence, tramadol HCl microspheres based on a HPMC E15 may be a promising nasal delivery system for CNS targeting.     

Design and development of nasal mucoadhesive microspheres containing tramadol HCl for CNS targeting

In the present study, tramadol HCl microspheres were designed in order to accomplish rapid delivery of drug to the brain. For this purpose, lower viscosity grade HPMC (E15) was chosen as mucoadhesive polymer and used at different drug/polymer ratios in the microspheres formulations. The spray-dried microspheres were evaluated with respect to the production yield, incorporation efficiency, particle size, mucoadhesive property, in vitro drug release, histopathological study, and radio imaging study in rabbits. DSC and XRD study showed molecular dispersion and conversion of the drug into amorphous form. Size and surface morphology of microspheres was analyzed by SEM and found to be spherical in shape with smooth surface. It was found that the particle size, swelling ability, and incorporation efficiency of microspheres increase with increasing drug-to-polymer ratio. Microspheres show adequate mucoadhesion and do not have any destructive effect on nasal mucosa. In vitro drug release of optimized formulation was found to be 94% after 90 min. The radio imaging study indicated localization of drug in the brain. Hence, tramadol HCl microspheres based on a HPMC E15 may be a promising nasal delivery system for CNS targeting.     

Bioavailability enhancement of ondansetron after nasal administration of Caesalpinia pulcherrima-based microspheres

Abstract

Context: Natural polymers have attracted a great deal of attention for use as potential carriers in site-specific delivery over past decades. Mucoadhesive microspheres are useful tools for nasal drug delivery.

Objectives: To prepare and evaluate mucoadhesive microspheres as mode for nasal delivery of ondansetron using Caesalpinia pulcherrima galactomannan (CPG).

Materials and methods: Conventional spray-dried CPG nasal microspheres loaded with ondansetron for intranasal drug delivery in order to avoid the first pass metabolism with improved therapeutic efficiency in treatment of nausea and vomiting as an alternative therapy to parenterals. Developed microspheres were evaluated for characteristics like particle size, entrapment efficiency, zeta potential, swelling ability, in-vitro mucoadhesion, in-vitro drug release, DSC, XRD study and histopathological evaluation of tissue. CPG-based ondansetron microspheres were studied in rabbits for screening nasal absorption potential of nasal formulation.

Results: Developed nasal microspheres possess entrapment efficiency of 80–89%, higher mucoadhesion of 72–84% across goat nasal mucosa. In-vivo study showed that microspheres based on mucoadhesive polymer were able to promote quick drug absorption as well as enhanced bioavailability of drug.

Discussion: Histopathological studies evaluated biocompatible and nontoxic nature of CPG in nasal cavity. Developed mucoadhesive microspheres by nasal route showed enhancement of bioavailability as compared to oral route in rabbits.

Conclusion: CPG-based mucoadhesive microspheres can successfully deliver ondansetron intranasally, sustain its effect, avoid first pass effect, an alternative route of administration to injection and thus enhance systemic bioavailability of ondansetron hydrochloride.     

Preparation and characterization of spray-dried mucoadhesive microspheres of ketorolac for nasal administration

The objective of this investigation was to prepare mucoadhesive microspheres of ketorolac for nasal delivery to avoid gastrointestinal side effects of conventional dosage form. Mucoadhesive microspheres were prepared using carbopol, polycarbophil and chitosan as polymer by spray drying method. The process and formulation parameters were varied to study the effect on the yield and particle size. Microspheres were characterized for surface morphology, encapsulation efficiency, swelling behavior, mucoahesion properties, interaction studies using FTIR and DSC, in vitro drug release, ex vivo nasal cilio toxicity studies and in vivo anti-inflammatory and analgesic activity. Prepared microspheres were discrete, bulky, free flowing and showed an average encapsulation efficiency ranging from 79-92%. The results showed that the process parameters significantly affect the particle size (10.29-16.75 μm) and yield of microspheres (36.53-56.69%). Interaction studies revealed that there were no drug to polymer interactions. Prepared microspheres exhibited good swelling and mucoadhesion strength which confined the strong mucoadhesive property of microspheres. Ketorolac release from the microspheres was extended up to 8 h and exhibited fickian drug release kinetics with best fit to higuchi model. The drug loaded microspheres were found to be nontoxic to nasal mucosa. The anti-inflammatory and analgesic effects of formulation showed a significant increase (p < 0.05) in percent inhibition value of up to 8 h when compared with ketorolac. In conclusion, spray dried microspheres based on chitosan could be suitable nasal delivery system for the administration of ketorolac.     

Mucoadhesive Microspheres for Gastroretentive Delivery of Acyclovir: In Vitro and In Vivo Evaluation

The aim of the present investigation was to evaluate the potential use of mucoadhesive microspheres for gastroretentive delivery of acyclovir. Chitosan, thiolated chitosan, Carbopol 71G and Methocel K15M were used as mucoadhesive polymers. Microsphere formulations were prepared using emulsion-chemical crosslinking technique and evaluated in vitro, ex-vivo and in-vivo. Gelatin capsules containing drug powder showed complete dissolution (90.5 +/- 3.6%) in 1 h. The release of drug was prolonged to 12 h (78.8 +/- 3.9) when incorporated into mucoadhesive microspheres. The poor bioavailability of acyclovir is attributed to short retention of its dosage form at the absorption sites (in upper gastrointestinal tract to duodenum and jejunum). The results of mucoadhesion study showed better retention of thiolated chitosan microspheres (8.0 +/- 0.8 h) in duodenal and jejunum regions of intestine. The results of qualitative and quantitative GI distribution study also showed significant higher retention of mucoadhesive microspheres in upper GI tract. Pharmacokinetic study revealed that administration of mucoadhesive microspheres could maintain measurable plasma concentration of acyclovir through 24 h, as compared to 5 h after its administration in solution form. Thiolated chitosan microsphere showed superiority over the other formulations as observed with nearly 4.0-fold higher AUC(0-24) value (1,090 +/- 51 ng h/ml) in comparison to drug solution (281 +/- 28 ng h/ml). Overall, the result indicated prolonged delivery with significant improvement in oral bioavailability of acyclovir from mucoadhesive microspheres due to enhanced retention in the upper GI tract.     

Development and in vivo evaluation of buccal tablets prepared using danazol-sulfobutylether 7 beta-cyclodextrin (SBE 7) complexes

The aim of the present work was to develop a mucoadhesive controlled-release formulation of danazol-sulfobutylether 7 beta-cyclodextrin (SBE 7) complex and to evaluate the feasibility of improving the bioavailability of danazol via the buccal route. Different types of polymers, polycarbophil (PC) and hydroxypropylmethyl cellulose (HPMC) were mixed with danazol-SBE 7 complex and compressed into tablets. These tablets were evaluated for their dissolution and mucoadhesion properties and for drug absorption in female beagle dogs. Increased mucoadhesion was observed for PC-containing tablets compared with HPMC tablets. As the concentration of polymer increased, drug release decreased, and PC-containing tablets gave slower release compared to HPMC tablets. In vivo bioavailability performed in dogs showed that the perorally administered danazol-SBE 7 complex and the danazol-SBE 7 (in PC matrix) buccal tablets had absolute bioavailabilities of 64% and 25%, respectively, that are significantly greater than 1.8% observed for the commercial formulation Danocrine. The increased bioavailability was attributed to the enhanced solubility consequent to complexation, and the possible avoidance of first-pass metabolism upon buccal administration.     

Mucoadhesive therapeutic compositions: a patent review (2011-2014)

Introduction: With the introduction of mucoadhesion in 1980, pharmaceutical researchers have gained interest in mucoadhesive compositions. This interest has led to the development of mucoadhesive drug delivery systems aiming (I) to target a specific tissue, (II) to overcome barriers to absorption as well as (III) to control drug release of the therapeutic compositions.

Areas covered: In this review, the term mucoadhesion and a variety of targetable mucosa are described through review of the literature. Mucoadhesive drug delivery systems and mucoadhesive polymers, such as thiomers, which are reported within the patent literature or in related publications are described in detail, including their therapeutic uses.

Expert opinion: Mucoadhesion is associated with benefits such as controlled, sustained release, prolonged residence time at the site of action, the ability to target specific mucosae and ease of application which leads to higher rates of patient compliance. Although many research groups are investigating in this domain, not many drug delivery systems based on mucoadhesive polymers have got from bench to market. The most promising and advanced applications seen in patent literature within the last five years seems to be for oral application.     

The influence of magnesium stearate on the characteristics of mucoadhesive microspheres

Microspheres containing the mucoadhesive polymer chitosan hydrochloride, with matrix polymer Eudragit RS, pipemidic acid as a model drug and agglomeration preventing agent magnesium stearate were prepared by the solvent evaporation method. The amount of magnesium stearate was varied and the following methods were used for microsphere evaluation: sieve analysis, drug content and dissolution determination, scanning electron microscopy, xray diffractometry, DSC and FTIR spectroscopy. The results showed that average particle size decreased with increasing amount of magnesium stearate used for microsphere preparation. This is probably a consequence of stabilization of the emulsion droplets with magnesium stearate. Higher pipemidic acid content in the microspheres was observed in larger particle size fractions and when higher amounts of magnesium stearate were used. It was also found that these two parameters significantly influenced the dissolution rate. The important reason for the differences in drug content in microspheres of different particle sizes is the diffusion of pipemidic acid from the acetone droplets in liquid paraffin during the preparation procedure. The physical state of pipemidic acid changed from crystalline to mostly amorphous with its incorporation in microspheres, as shown by x-ray diffractometry and differential