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Advanced Drug Delivery Reviews (v.57, #11)
Mucoadhesive polymers: strategies, achievements and future challenges
by Andreas Bernkop-Schnürch theme editor / (pp. 1553-1555).
The basics and underlying mechanisms of mucoadhesion by John D. Smart (pp. 1556-1568).
Mucoadhesion is where two surfaces, one of which is a mucous membrane, adhere to each other. This has been of interest in the pharmaceutical sciences in order to enhance localised drug delivery, or to deliver ‘difficult’ molecules (proteins and oligonucleotides) into the systemic circulation. Mucoadhesive materials are hydrophilic macromolecules containing numerous hydrogen bond forming groups, the carbomers and chitosans being two well-known examples. The mechanism by which mucoadhesion takes place has been said to have two stages, the contact (wetting) stage followed by the consolidation stage (the establishment of the adhesive interactions). The relative importance of each stage will depend on the individual application. For example, adsorption is a key stage if the dosage form cannot be applied directly to the mucosa of interest, while consolidation is important if the formulation is exposed to significant dislodging stresses. Adhesive joint failure will inevitably occur as a result of overhydration of a dosage form, or as a result of epithelia or mucus turnover. New mucoadhesive materials with optimal adhesive properties are now being developed, and these should enhance the potential applications of this technology.
Keywords: Mucoadhesion; Mucoadhesives; Bioadhesion; Bioadhesives; Mucosal delivery; Carbomers
Thiomers: A new generation of mucoadhesive polymers by Andreas Bernkop-Schnürch (pp. 1569-1582).
Thiolated poly mers or designated thiomers are mucoadhesive basis polymers, which display thiol bearing side chains. Based on thiol/disulfide exchange reactions and/or a simple oxidation process disulfide bonds are formed between such polymers and cysteine-rich subdomains of mucus glycoproteins building up the mucus gel layer. Thiomers mimic therefore the natural mechanism of secreted mucus glycoproteins, which are also covalently anchored in the mucus layer by the formation of disulfide bonds—the bridging structure most commonly encountered in biological systems. So far the cationic thiomers chitosan–cysteine, chitosan–thiobutylamidine as well as chitosan–thioglycolic acid and the anionic thiomers poly(acylic acid)–cysteine, poly(acrylic acid)–cysteamine, carboxy-methylcellulose–cysteine and alginate–cysteine have been generated. Due to the immobilization of thiol groups on mucoadhesive basis polymers, their mucoadhesive properties are 2- up to 140-fold improved. The higher efficacy of this new generation of mucoadhesive polymers in comparison to the corresponding unmodified mucoadhesive basis polymers could be verified via various in vivo studies on various mucosal membranes in different animal species and in humans. The development of first commercial available products comprising thiomers is in progress. Within this review an overview of the mechanism of adhesion and the design of thiomers as well as delivery systems comprising thiomers and their in vivo performance is provided.
Keywords: Mucoadhesion; Thiolated polymers; Thiomers; Disulfide bonds; Thiolated poly(acrylic acid); Thiolated chitosan
Novel mucoadhesion tests for polymers and polymer-coated particles to design optimal mucoadhesive drug delivery systems by Hirofumi Takeuchi; Jringjai Thongborisute; Yuji Matsui; Hikaru Sugihara; Hiromitsu Yamamoto; Yoshiaki Kawashima (pp. 1583-1594).
To design an effective particulate drug delivery system having mucoadhesive function, several mucoadhesion tests for polymers and the resultant particulate systems were developed. Mucin particle method is a simple mucoadhesion test for polymers, in which the commercial mucin particles are used. By measuring the change in particle size or zeta potential of the mucin particle in a certain concentration of polymer solution, we could estimate the extent of their mucoadhesive property. BIACORE method is also a novel mucoadhesion test for polymers. On passing through the mucin suspension on the polymer-immobilized chip of BIACORE instrument, the interaction was quantitatively evaluated with the change in its response diagram. By using these mucoadhesion tests, we detected a strong mucoadhesive property of several types of chitosan and Carbopol.Evaluation of mucoadhesive property of polymer-coated particulate systems was demonstrated with the particle counting method developed by us. To detect the mucoadhesive phenomena in the intestinal tract, we observed the rat intestine with the confocal laser scanning microscope (CLSM) after oral administration of the particulate systems. The resultant photographs clearly showed a longer retention of submicron-sized chitosan-coated liposomes (ssCS-Lip) in the intestinal tract than other liposomal particles tested such as non-coated liposomes and chitosan-coated multilamellar one. These observations explained well the superiority of the ssCS-Lip as drug carrier in oral administration of calcitonin in rats than other liposomal particles.
Keywords: Mucoadhesion; Mucin particle; BIACORE; Confocal laser scanning microscopy; Peptide drug; Oral administration
The use of mucoadhesive polymers in ocular drug delivery by Annick Ludwig (pp. 1595-1639).
In the present update on mucoadhesive ocular dosage forms, the tremendous advances in the biochemistry of mucins, the development of new polymers, the use of drug complexes and other technological advances are discussed. This review focusses on recent literature regarding mucoadhesive liquid (viscous solutions, particulate systems), semi-solid (hydrogel, in situ gelling system) and solid dosage forms, with special attention to in vivo studies. Gel-forming minitablets and inserts made of thiomers show an interesting potential for future applications in the treatment of ocular diseases.
Keywords: Abbreviations; BSA; bovine serum albumin; CAP; cellulose acetate hydrogen phthalate; DSPE-PEG; pegylated distearoylphosphatidylethanolamine; EC; ethylcellulose; EDTA; ethyldiaminetetraacetic acid; FITC; fluorescein isothiocyanate; HA; hyaluronic acid; (HP-β-CD); hydroxypropyl-beta-cyclodextrin; HPC; hydroxypropylcellulose; HPMC; hydroxypropylmethylcellulose; 15-(; S; )-HETE; 15-(; S; )-hydroxy-5,8,11,13 eicosatetraenoic acid; IOP; intraocular pressure; MMA; methylmethacrylate; MC; methylcellulose; MUC; mucin gene; NaCMC; sodium carboxymethylcellulose; NAC; N; -acetylcysteine; PAA; poly(acrylic acid); PAA; 450; poly(acrylic acid) 450 kDa; PACA; polyalkyl cyanoacrylate; PECL; poly(epsilon-caprolacton); PEG; poly(ethylene glycol); PEO; poly(ethylene oxide); PNIPAAm; poly-; N; -isopropylacrylamide; PLA; poly(; d; ,; l; -lactic acid); PLGA; poly(; d; ,; l; -lactide-co-glycolide); PVA; poly(vinyl alcohol); PVP; povidone; REV; reverse-phase evaporation method; RhEGF; human epithelial growth factor; SLN; solid lipid nanoparticles; SPM; sulfopropylmethacrylate; TFF; trefoil factorMucoadhesion; Mucins; Viscous solution; Particulate systems; Hydrogel; In situ gelling system; Minitablet; Insert
Nasal mucoadhesive drug delivery: Background, applications, trends and future perspectives by Michael I. Ugwoke; Remigius U. Agu; Norbert Verbeke; Renaat Kinget (pp. 1640-1665).
Nasal drug delivery has now been recognized as a very promising route for delivery of therapeutic compounds including biopharmaceuticals. It has been demonstrated that low absorption of drugs can be countered by using absorption enhancers or increasing the drug residence time in the nasal cavity, and that some mucoadhesive polymers can serve both functions. This article reviews the background of nasal mucoadhesive drug delivery with special references to the biological and pharmaceutical considerations for nasal mucoadhesive drug administration. Applications of nasal mucoadhesives for the delivery of small organic molecules, antibiotics, proteins, vaccines and DNA are also discussed. Furthermore, new classes of functionalized mucoadhesive polymers, the characterization and safety aspects of nasal drug products as well as the opportunities presented by nasal drug delivery are extensively discussed.
Keywords: Absorption enhancer; Microparticles; Microspheres; Mucoadhesion; Mucociliary clearance; Nasal absorption; Nasal drug delivery; Polymer
The use of mucoadhesive polymers in buccal drug delivery by Nazila Salamat-Miller; Montakarn Chittchang; Thomas P. Johnston (pp. 1666-1691).
Buccal delivery of the desired drug using mucoadhesive polymers has been the subject of interest since the early 1980s. Advantages associated with buccal drug delivery have rendered this route of administration useful for a variety of drugs. This review highlights the use of mucoadhesive polymers in buccal drug delivery. Starting with a review of the oral mucosa, mechanism of drug permeation, and characteristics of the desired polymers, this article then proceeds to cover the theories behind the adhesion of bioadhesive polymers to the mucosal epithelium. Additionally, we focus on the new generation of mucoadhesive polymers such as thiolated polymers, followed by the recent mucoadhesive formulations for buccal drug delivery.
Keywords: Buccal drug delivery; Mucoadhesive; Polymers
The use of mucoadhesive polymers in vaginal delivery by Claudia Valenta (pp. 1692-1712).
The vagina is an important area of the reproductive tract and serves as a potential route of drug administration. Beside locally acting drugs it is also of importance for systemic drug delivery, uterine targeting or even vaccination. Currently available dosage forms have several limitations, therefore novel concepts and dosage forms are needed. In this field mucoadhesive polymers will play a major role. After discussion of the anatomy and physiology of the vagina this review highlights the most important studies based on mucoadhesive polymer-systems like poly(acrylates), chitosan, cellulose derivatives, hyaluronic acid derivatives, pectin and traganth, starch, poly(ethylene glycol), sulfated polysaccharides, carrageenan, Na-alginate and gelatine.
Keywords: Poly(acrylates); Chitosan; Cellulose derivatives; Hyaluronic acid; Pectin; Traganth; Starch; Sulfated polysaccharides; Carrageenan; Na-alginate
Comparison of the mucoadhesive properties of various polymers by Vjera Grabovac; Davide Guggi; Andreas Bernkop-Schnürch (pp. 1713-1723).
In this study the mucoadhesive potential of nineteen different, most often referred mucoadhesive polymers was evaluated and characterized by adhesion time and total work of adhesion (TWA) of the polymer to porcine small intestinal mucosa. In addition, the influence of pH of the polymer and of method of drying on adhesion was evaluated. Aqueous polymer solutions were therefore adjusted to pH 3.0 and 7.0. Solutions were either dried by lyophilization (lyo.) or precipitated (pr.) in organic solvent and air-dried. Results of this study led to the following rank order of adhesion time: chitosan-4-thiobuthylamidine pH 3 lyo. >chitosan-4-thiobuthylamidine pH 6.5 pr.>polycarbophil-cysteine pH 3 lyo.>chitosan-4-thiobuthylamidine pH 6.5 lyo.>PAA450-cysteine pH 3 lyo.>pH 7 pr.>Carbopol 980 pH 7 pr.>Carbopol 974P pH 7 pr.>polycarbophil pH 7 pr.>980 pH 3 lyo. The rank order obtained for adhesion time was in agreement with the rank order obtained for total work of adhesion. The highest mucoadhesion was shown by thiolated polymers at pH 3.0, dried by lyophilization. In contrary, polyacrylates were most mucoadhesive in form of precipitated neutral sodium salts. Other tested polymers like natural polysaccharides, cellulose derivatives, polyvinylpirrolidone and polyethylenglycole, although previously reported as good mucoadhesives, showed low to almost no mucoadhesion. The pH of polymer and drying method were found to be important factors influencing the mucoadhesive potential of polymers.
Keywords: Mucoadhesive polymers; Adhesion studies; Influence of pH; Influence of drying method