Mucoadhesive polymers

Borchard, G. LueBen, H.L. deBoer, A. G. Verhoef, J. C. Lehr, C.-M. Junginger, H.E., The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption. Ill Effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro, j. Control. Rel. 39, 131-138 (1996). 

NM Davies, SJ Farr, J Hadgraft, IW Kellaway. (1991). Evaluation of mucoadhesive polymers in ocular drug delivery. I. Viscous solutions. Pharm Res 8 1039-1043. 

CM Lehr, YH Lee, VHL Lee. (1994). Improved ocular penetration of gentamicin by mucoadhesive polymer polycarbophil in the pigmented rabbit. Invest Ophthalmol Vis Sci 35 2809-2814. 

Solid dosage forms based on mucoadhesive polymers are used mainly for buccal delivery of drugs, whereas micro- or nanoparticulate formulations are preferred for the delivery of therapeutics in the nasal and intestinal tract [5]. 

FIG. 1. Three stages in the interaction between a mucoadhesive polymer and mucin glycoprotein according to the interpenetration theory. 

FIG. 2. Experimental setup to measure the force of detachment of mucoadhesive polymer films from mucosal tissue. 

Rossi et al. [30] evaluated rheologically mucins of different origin with polyacrylic acid and sodium carboxymethyl cellulose. The same group also reported a novel rheological approach based on a stationary viscoelastic test (creep test) to describe the interaction between mucoadhesive polymers and mucins [31,32]. Jabbari et al. [33] used attenuated total-reflection infrared spectroscopy to investigate the ehain interpenetration of polyaciylic acid in the mucin interface. 

TABLE 2 Drug Products Available for Buccal and/or Sublingual Application Using Mucoadhesive Polymers ... 

The periodontal pocket is another site for drug delivery in the oral cavity. Needleman et al. [46] investigated three mucoadhesive polymers (cationic chitosan, anionic xanthan gum, neutral polyethylene oxide) in vitro, using organ cultures, and in vivo in patients on their periodontal and oral mucosa. Of the polymers studied, chitosan displayed the longest adhesion in vitro and on the periodontal pockets, and the shortest adhesion on oral mucosa. 

Oechslein et al. [50] studied various powder formulations of mucoadhesive polymers for their efficacy to increase the nasal absorption of octreotide in rats. Although... 

The benzyl ester of hyaluronic acid (HYAFF 11) is a highly mucoadhesive polymer which can be processed into microspheres. Such microspheres containing salmon calcitonin were intravaginally administered to rats as a dosage form for the prevention of ovariectomy osteopenia [65]. In recent studies, HYAFF 11-salmon calcitonin microspheres were formulated as single-dose pessaries, resulting in sustained plasma concentrations of calcitonin [67]. 

The failure in increasing residence time of mucoadhesive systems in the human intestinal tract has led scientists to the evaluation of multifunctional mucoadhesive polymers. Research in the area of mucoadhesive drug delivery systems has shed light on other properties of some of the mucoadhesive polymers. One important class of mucoadhesive polymers, poly(acrylic acid) derivatives, has been identified as potent inhibitors of proteolytic enzymes [72-74]. The interaction between various types of mucoadhesive polymers and epithelial cells has a direct influence on the permeability of mucosal epithelia by means of changing the gating properties of the tight jrmctions. More than being only adhesives, some mucoadhesive polymers can therefore be considered as a novel class of multifunctional macromolecules with a number of desirable properties for their use as delivery adjuvants [72,75]. 

FIG. 5. Intestinal absorption of octreotide acetate in rats using mucoadhesive polymers. (From Thanou et al. unpublished data). 

Another trend observed during the past decade was the coating of liposomes with mucoadhesive polymers. Liposomes are coated with chitosan, long-ehain polyvinyl alcohol, and polyacrylates bearing a cholesteryl group [90]. Chitosan-eoated liposomes showed superior adhesion properties to rat intestine in vitro than the other polymer-eoated liposomes. In vivo, chitosan-coated liposomes containing insulin substantially reduced blood glueose levels after oral administration in rats, whieh were sustained up to 12 hr after administration [90]. 

Madsen, F., Eberth, K., and Smart, J.D., A rheological assessment of the nature of interactions between mucoadhesive polymers and a homogenised mucus gel. Biomaterials, 19 1083-1092 (1998). 

Lee, Y.L., and Chien, Y.W., Oral mucosa controlled delivery of LHRH by bilayer mucoadhesive polymer systems, J. Control. Rel., 37 251-261 (1995). 

LueBen, H.L., Verhoef, J.C., Borchard, G., Lehr, C.-M., De Boer, A.G., and Junginger, H.E., Mucoadhesive polymers in peroral peptide drug delivery. II. Carbomer and polycarbophil are potent inhibitors of the intestinal proteolytic enzyme trypsin, Pharm. Res., 12 1293-1298 (1995). 

Bernkop-Schnurch A., and Krajicek, M.E., Mucoadhesive polymers as platforms for peroral peptide delivery and absorption synthesis and evaluation of different chitosan-EDTA conjugates, J. Control. Rel., 50 215-223 (1998). 

Bernkop-Schnurch, S.A., Schwarz, V., and Steininger, S., Polymers with thiol groups A new generation of mucoadhesive polymers Pharm. Res., 16 876-881 (1999). 

Utilize nontoxic excipients (both diluents and the mucoadhesive polymers) which do not irritate or damage the mucosa and do not stimulate salivary secretion. 

LueBen, H.L., De Leeuw, J., Perard, D., et al. (1996). Mucoadhesive polymers in peroral peptide drug delivery. I. Influence of mucoadhesive excipients on the proteolytic activity of intestinal enzymes. Eur. J. Pharmaceut. Sci., 4, 117-128. 

Drug release and retention at the site of absorption are very important for the enhancement of the bioavailability, particularly when the absorption sites are localized to a certain area of the GI route. This control of the transition of the drug can be achieved using bioadhesive excipients. Chlorothiazide (CT), a diuretic and antihypertensive drug, was better orally absorbed when administered with mucoadhesive polymers [25], The absorption of CT is considered to be saturable and site-specific, because a low dose is better absorbed, and a decreased stomach emptying rate and slow GI transition rate are better for increased absorption. As chitosan is a mucoadhesive polymer, the absorption of CT is expected to be enhanced... 

Thiolated Chitosan as a Strongly Mucoadhesive Polymer and Its Applications... 

Lehr, C.M., et al. 1992. Effects of the mucoadhesive polymer polycarbophil on the intestinal absorption of a peptide drug in the rat. J Pharm Pharmacol 44 402. 

Bernkop-Schnurch, A., V. Schwarz, and S. Steininger. 1999. Polymers with thiol groups a new generation of mucoadhesive polymers Pharm Res 16 876. 

Mucoadhesive Polymers Exhibiting Enzyme Inhibitory Activity. 93... 

Unfortunately, bacitracin causes nephrotoxicity [36] and so its use as a suitable adjuvant to overcome the enzymatic barrier is quite questionable. Interestingly, it was demonstrated recently that bacitracin, when covalently linked to a mucoadhesive polymer, still displays its inhibitory activity [30]. The immobilization to an unabsorbable drug carrier matrix is believed to lead to an exclusion of systemic toxic side effects, but detailed toxicological studies are necessary to prove this hypothesis. 

Mucoadhesive polymers exhibiting strong complexing properties are capable of inhibiting intestinal brush border membrane-bound proteases through a far distance inhibitory effect [65]. In vivo, the mucoadhesive polymer is separated from the brush border membrane by a mucus layer [30]. Although there is no direct contact between polymer- and membrane-bound enzymes, it could be shown that inhibition takes place. The exploitation of this far distance effect seems to be a very promising alternative to small molecular mass inhibitors, which are currently used as inhibitors of brush border membrane-bound proteases. 

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