Development of mucoadhesive microspheres for intranasal delivery of fluconazole as an alternative treatment of cryptococcal meningitis infection in patients with acquired immunodeficiency.

INTRODUCTION: Cryptococcal meningitis is a deadly disease with few treatment options. Its incidence is still high and closely linked to the HIV/AIDS epidemic. This study aimed to develop a mucoadhesive microsphere delivery system for fluconazole for the intranasal route. METHOD: Microspheres of mucoadhesive fluconazole formulation variables such as different amounts of drug concentration and polymer concentration were prepared by a simple emulsion-crosslinking method. The prepared microspheres' surface was characterised by SEM (Scanning electron microscopy) and evaluated for particle size, entrapment efficiency, production yield, infrared spectroscopic study, in-vitro muco-adhesion, and in-vitro drug release. RESULTS: The results showed that formula 1 is the optimal mucoadhesive microsphere preparation, with a particle size of 56.375m, a spherical surface shape, an entrapment efficiency of 99.96%, and a greater mucoadhesive capability during 6-hour evaluation. Furthermore, wash-off examination revealed that the mucoadhesive ability of this delivery system has a long duration and may release the active material at the right time. CONCLUSION: The result of the researches suggesting that the formulation of mucoadhesive microspheres of fluconazole could be used to treat cryptococcal meningitis infection in HIV/AIDS patients.

Polymeric nanoparticle technologies for oral drug delivery.

Biologics increasingly are being used for the treatment of many diseases. These treatments typically require repeated doses administered by injection. Alternate routes of administration, particularly oral, are considered favorable because of improved convenience and compliance by patients, but physiological barriers such as extreme pH level, enzyme degradation, and poor intestinal epithelium permeability limit absorption. Encapsulating biologics in drug delivery systems such as polymeric nanoparticles prevents inactivation and degradation caused by low pH and enzymes of the gastrointestinal tract. However, transport across the intestinal epithelium remains the most critical barrier to overcome for efficient oral delivery. This review focuses on recent advances in polymeric nanoparticles being developed to overcome transport barriers and their potential for translation into clinical use.

Bacterial cellulose adhesive patches designed for soft mucosal interfaces.

The wet environment in the oral cavity is challenging for topical disease management approaches. The compromised material properties leading to weak adhesion and short retention (<8 h) in such environment result in frequent reapplication of the therapeutics. Composites of bacterial cellulose (BC) and carbene-based bioadhesives attempt to address these shortcomings. Previous designs comprised of aqueous formulations. The current design, for the first time, presents dry, shelf-stable cellulose patches for convenient ready-to-use application. The dry patches simultaneously remove tissue surface hydration while retaining carbene-based photocuring and offers on-demand adhesion. The dry patch prototypes are optimized by controlling BC/adhesive mole ratios and dehydration technique. The adhesion strength is higher than commercial denture adhesives on soft mucosal tissues. The structural integrity is maintained for a minimum of 7 days in aqueous environment. The patches act as selective nanoporous barrier against bacteria while allowing permeation of proteins. The results support the application of BC-based adhesive patches as a flexible platform for wound dressings, drug depots, or combination thereof.

Enzyme-Triggered Intestine-Specific Targeting Adhesive Platform for Universal Oral Drug Delivery.

Patient adherence to chronic therapies can be suboptimal, leading to poor therapeutic outcomes. Dosage forms that enable reduction in dosing frequency stand to improve patient adherence. Variation in gastrointestinal transit time, inter-individual differences in gastrointestinal physiology and differences in physicochemical properties of drugs represent challenges to the development of such systems. To this end, a small intestine-targeted drug delivery system is developed, where prolonged gastrointestinal retention and sustained release are achieved through tissue adhesion of drug pills mediated by an essential intestinal enzyme catalase. Here proof-of-concept pharmacokinetics is demonstrated in the swine model for two drugs, hydrophilic amoxicillin and hydrophobic levodopa. It is anticipated that this system can be applicable for many drugs with a diverse of physicochemical characteristics.

Bacterial cellulose adhesive composites for oral cavity applications.

Topical approaches to oral diseases require frequent dosing due to limited retention time. A mucoadhesive drug delivery platform with extended soft tissue adhesion capability of up to 7 days is proposed for on-site management of oral wound. Bacterial cellulose (BC) and photoactivated carbene-based bioadhesives (PDz) are combined to yield flexible film platform for interfacing soft tissues in dynamic, wet environments. Structure-activity relationships evaluate UV dose and hydration state with respect to adhesive strength on soft tissue mimics. The bioadhesive composite has an adhesion strength ranging from 7 to 17 kPa and duration exceeding 48 h in wet conditions under sustained shear forces, while other mucoadhesives based on hydrophilic macromolecules exhibit adhesion strength of 0.5-5 kPa and last only a few hours. The work highlights the first evaluation of BC composites for mucoadhesive treatments in the buccal cavity.

Dry mouth diagnosis and saliva substitutes-A review from a textural perspective.

The aim of this review is to assess the objective and subjective diagnosis, as well as symptomatic topical treatment of dry mouth conditions with a clear focus on textural perspective. We critically examine both the current practices as well as outline emerging possibilities in dry mouth diagnosis and treatment, including a patent scan for saliva substitutes. For diagnosis, salivary flow rates and patient-completed questionnaires have proven to be useful tools in clinical practice. To date, objective measurements of changes in mechanical properties of saliva via rheological, adsorption, and tribological measurements and biochemical properties of saliva such as assessing protein, mucins (MUC5B) are seldom incorporated into clinical diagnostics; these robust diagnostic tools have been largely restricted to application in non-clinical settings. As for symptomatic treatments of dry mouth, four key agents including lubricating, thickening, adhesive, and moisturizing agents have been identified covering the overall landscape of commercial saliva substitutes. Although thickening agents such as modified celluloses, polysaccharide gum, polyethylene glycol, and so forth are most commonly employed saliva substitutes, they offer short-lived relief from dry mouth and generally do not provide boundary lubrication properties of real human saliva. Innovative technologies such as self-assembly, emulsion, liposomes, and microgels are emerging as novel saliva substitutes hold promise for alternative approaches for efficient moistening and lubrication of the oral mucosa. Their adoption into clinical practice will depend on their efficacies, duration of relief, and ease of application by the practitioners and patient compliance.

Mucoadhesive electrospun nanofibers for drug delivery systems: applications of polymers and the parameters' roles.

Electrospun nanofibers have been widely studied for many medical applications. They can be designed with specific features, including mucoadhesive properties. This review summarizes the polymeric scaffolds obtained by the electrospinning process that has been applied for drug release in different mucosal sites such as oral, ocular, gastroenteric, vaginal, and nasal. We analyzed the electrospinning parameters that have to be optimized to create reproducible and efficient mucoadhesive nanofibers, among them are: electrical field, polymer concentration, viscosity, flow rate, needle-collector distance, solution conductivity, solvent, environmental parameters, and electrospinning setup. We also revised the mucoadhesive theories as well as the mucoadhesive properties of the polymers used. This review shows that the most studied mucosal site is the oral cavity, because it is accessible and easy to evaluate, while the rest are uncomfortable for the patient and difficult to assess in vivo. We found problems that need to be solved for mucoadhesive electrospun nanofibers, such as improving adhesion strength and mucosal permanence time, and the design of unidirectional release, multilayer systems for the treatment of several pathologies, to ensure the drug concentration in the tissue or target organ.

Intranasal immunization with dry powder vaccines.

Vaccination represents a cost-effective weapon for disease prevention and has proven to dramatically reduce the incidences of several diseases that once were responsible for significant mortality and morbidity worldwide. The nasal cavity constitutes the initial stage of the respiratory system and the first contact with inhaled pathogens. The intranasal (IN) route for vaccine administration is an attractive alternative to injection, due to the ease of administration as well as better patient compliance. Many published studies have demonstrated the safety and effectiveness of IN immunization with liquid vaccines. Currently, two liquid IN vaccines are available and both contain live attenuated influenza viruses. FluMist® was approved in 2003 in the United States, and Nasovac® H1N1 vaccine was approved in India in 2010. Preclinical studies showed that IN immunization with dry powder vaccines (DPVs) is feasible. Although there is not a commercially available DPV yet, DPVs have the inherent advantage of being relatively more stable than liquid vaccines. This review focuses on recent developments of DPVs as next-generation IN vaccines.

Clinicopathological evaluation of Newcastle disease virus vaccination using gums from Cedrela odorata and Khaya senegalensis as delivery agents in challenged chickens.

Following previous studies on delivery potential and immune response of chickens given Newcastle disease vaccine with gums, this study was conducted to evaluate the protective ability of vaccines delivered with plant gums against clinicopathological features of Newcastle disease (ND). Processed gums from incised trunks of Cedrela odorata and Khaya senegalensis trees were combined with ND vaccine in ratio 2:2:1 and administered at 21 days to white leghorn cockerels after weaning of maternal antibodies. The birds were grouped into gum-vaccine-oral (GVOR), vaccine-oral (VOR), gum-vaccine-ocular (GVOC), vaccine-ocular (VOC), gum-oral (GOR), gum-ocular (GOC), no-gum-no-vaccine/challenged (NGNV/C), no-gum-no-vaccine/unchallenged (NGNV/U). Vaccination was boosted with the same preparation at day 42 while birds were challenged with live ND virus (KUDU strain) at day 84. Clinical signs (Dullness, Diarrhoea, Paralysis, Torticollis) Post infection (Pi), terminal weakness, gross and histology lesions were scored on a severity scale from absent (0-), mild (1+) to moderate (2+) and severe (3+). Scores were assigned a quantitative score of 0, 10, 20, 30 respectively. Clinical signs scores for the 5 week Pi were subjected to Friedman test to assess the significance of severity among the groups. The test was significant at 1% significance level which implies that the clinical signs ranked highest in the NGNV/C, followed by the Gum alone groups, the vaccine alone groups and the gum-vaccine groups irrespective of route. Moribund birds subsequently euthanized were seen in the GOR and GOC group at 21% each and at 57% in NGNV/C group alone. No signs were seen in the NVNG/U group. Grossly, mild to moderate lesions were seen in all groups except GVOR and NGNV/U. At histology, pulmonary congestion, acute pneumonia, cecal tonsilar haemorrhages, gliosis and neuronophagia were present at different proportions in all groups except the GVOR and NGNV/U. Overall, lesion severity was least in the gum-vaccine groups while the oral groups had less lesion score compared to the ocular. From this study, phytogenic mucoadhesives polymers used hold immense potential as a delivery agent capable of improving protection against clinicopathologic features of Newcastle disease in previously vaccinated birds.

Ex-vivo evaluation of the mucoadhesive properties of Cedrela odorata and Khaya senegalensis gums with possible applications for veterinary vaccine delivery.

BACKGROUND: Few studies have investigated the interaction of bioadhesives with biologic tissues for veterinary application. Hence, this study evaluates the mucoadhesive property and vaccine delivery properties of polymers from phytogenic origin. Gums from Cedrela odorata and Khaya senegalensis were harvested, purified, dried and compressed into 500 mg tablets individually and in combined ratios. The time taken for these tablets, placed on freshly excised (5 × 5 cm) trachea and duodenal tissues of cattle, chicken, pig, sheep and goat and fastened to the basket end of a tablet dissolution machine probe set at 50 rev/min in a phosphate buffer 6.8 pH at 37 °C, to fall off the tissue was the peak adhesion time (PAT). Gum with best PAT was combined with Newcastle disease vaccine and the procedure repeated. Haemagglutination assay (HA) was conducted on the gum polymer-vaccine mix with gum and vaccine individually as controls. RESULTS: On intestinal and trachea tissues, Cedrela gum polymer averagely had prolonged PAT (≈1 h 30 min and 1 h respectively) while average PAT values of Khaya gums followed the same trend but too transient PAT (≈6 and 0.3 min respectively). However on combination, Cedrela-Khaya polymer mix (1:1) was best on chicken, cattle and sheep trachea and intestinal tissues (PAT of 1 h 30 min and 2 h 24 min respectively). On combination with vaccine, the PAT of the gums reduced slightly on cattle and sheep tissues while other animal tissue showed varied results. The HA results showed the gum polymer boosted the HA property of the vaccine (Log 10(5)), when compared to vaccine alone (Log 10(4)). CONCLUSION: Hence, mucoadhesives from phytogenic sources have potential for non-invasive vaccine application.

Polymeric nanoparticle drug delivery technologies for oral delivery applications.

INTRODUCTION: Many therapeutics are limited to parenteral administration. Oral administration is a desirable alternative because of the convenience and increased compliance by patients, especially for chronic diseases that require frequent administration. Polymeric nanoparticles (NPs) are one technology being developed to enable clinically feasible oral delivery. AREAS COVERED: This review discusses the challenges associated with oral delivery. Strategies used to overcome gastrointestinal (GI) barriers using polymeric NPs will be considered, including mucoadhesive biomaterials and targeting of NPs to transcytosis pathways associated with M cells and enterocytes. Applications of oral delivery technologies will also be discussed, such as oral chemotherapies, oral insulin, treatment of inflammatory bowel disease, and mucosal vaccinations. EXPERT OPINION: There have been many approaches used to overcome the transport barriers presented by the GI tract, but most have been limited by low bioavailability. Recent strategies targeting NPs to transcytosis pathways present in the intestines have demonstrated that it is feasible to efficiently transport both therapeutics and NPs across the intestines and into systemic circulation after oral administration. Further understanding of the physiology and pathophysiology of the intestines could lead to additional improvements in oral polymeric NP technologies and enable the translation of these technologies to clinical practice.

Sustain-release of various drugs from leucaena leucocephala polysaccharide.

This study examines the sustained release behavior of both water-soluble (acetaminophen, caffeine, theophylline and salicylic acid) and water-insoluble (indomethacin) drugs from Leucaena leucocephala seed Gum isolated from Leucaena leucocephala kernel powder. It further investigates the effect of incorporation of diluents like microcrystalline cellulose and lactose on release of caffeine and partial cross-linking of the gum (polysaccharide) on release of acetaminophen. Applying exponential equation, the mechanism of release of soluble drugs was found to be anomalous. The insoluble drug showed near case II or zero-order release mechanism. The rate of release was in the decreasing order of caffeine, acetaminophen, theophylline, salicylic acid and indomethacin. An increase in release kinetics of drug was observed on blending with diluents. However, the rate of release varied with type and amount of blend in the matrix. The mechanism of release due to effect of diluents was found to be anomalous. The rate of release of drug decreased on partial cross-linking and the mechanism of release was found to be super case II.

In vivo mucoadhesive strength appraisal of gum Manilkara zapota

The mucilage (MMZ) extracted from the seeds of Manilkara zapota(Linn.) P. Royen syn. using maceration techniques was evaluated for mucoadhesive strength by various in vitro and in vivo methods. The result showed that mucoadhesive strength of seeds mucilage have comparable property toward natural and synthetic polymers such as Guar Gum and hydroxyl propyl methyl cellulose (HPMC E5LV) under the experimental conditions used in this study. Briefly, it could be concluded that the seed mucilage of Manilkara zapota can be used as a pharmaceutical excipient in oral mucoadhesive drug delivery systems. Further, it may be appropriate to study the changes in these properties after chemical modifications.

Mucilagem (MMZ) extraída das sementes de Manilkara zapota(Linn.) P. Royen syn utilizando técnicas de maceração foi avaliada por sua força mucoadesiva por vários métodos in vitro e in vivo. O resultado mostrou que a força mucoadesiva das sementes mucilaginosas tem propriedade comparável aos polímeros naturais e sintéticos, tais como goma Guar e hidroxipropilmetil celulose (HPMC E5LV) nas condições experimentais utilizadas neste estudo. Brevemente, se pode concluir que a mucilagem de semente de Manilkara zapota pode ser usada como um excipiente farmacêutico em sistemas de liberação de fármacos mucoadesivos por via oral. Pode ser apropriado o estudo posterior de mudanças nessas propriedades após modificações químicas.