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Fractal Dimension of Mucoadhesive Polymer Hyaluronan for Pharmaceutical Formulations
* 1 , 2
1  Institut Universitari de Ciència Molecular, Universitat de València
2  Cátedra Energesis de Tecnología Interdisciplinar, Universidad Católica de Valencia San Vicente Mártir

Abstract: Mucoadhesive polymers are used in pharmaceutical formulations to elaborate drugs applicable in mucous zones, e.g., gastrointestinal/vaginal tracts, ocular mucous membrane and nasal cavity. They can interact and become fixed to mucus via mechanisms, e.g., molecular interpenetration, van der Waals forces, hydrophobic interactions, electrostatic forces, hydrogen bonds, etc., which allows augmenting the residence period in the organism and increasing the bioavailability of the drugs that they deliver. The physicochemical properties of drug/polymers, e.g., molecular weight, grade of ionization, concentration and polymer swelling kinetics, affect formulation mucoadhesion magnitude, rheological behaviour and drug absorption. Drug fractal dimension was examined for homologous series of transdermal-delivery drug models: percutaneous enhancers phenyl alcohols/4-alkylanilines. Here, method is extended to polymers. Hyaluronan is selected as mucoadhesive/biodegradable polymer. Geometric, topological and fractal analyses are carried out with our program TOPO. Reference calculations are performed with our version of program GEPOL. Program TOPO underestimate molecular volume and surface area by 0.7% and 5%, respectively. Molecular globularity is overestimated by 5% and rugosity, underestimated by 5%. Sovent-accessible surface area is underestimated by 3%. When going from hexamer hyaluronan3– to hyaluronan·3Ca to hyaluronan·3Ca·9H2O, the hydrophobic solvent-accessible surface area increases by 42% and decays by 26%; the hydrophilic solvent-accessible surface area decays by 14% and increases by 58%. Fractal dimension of hyaluronan turns out to be 1.57. On going to hyaluronan·3Ca to hyaluronan·3Ca·9H2O, it increases by 2% and 1%. Fractal dimension averaged for non-buried atoms of hyaluronan results 1.73. When going to hyaluronan·3Ca to hyaluronan·3Ca·9H2O, it increases by 4% and 0.3%. Provisional conclusions follow. (1) Hyaluronan is an important component of articular cartilage, where it is present as a coat around each chondrocyte. When aggrecan monomers bind to hyaluronan in the presence of link protein, large highly anionic aggregates form, which imbibe water and are responsible for cartilage resistance to compression. The molecular weight of hyaluronan in cartilage decays with age but the amount increases. (2) Fractal dimension of hyaluronan results 1.57. On going to hyaluronan·3Ca/·9H2O, it increases by 2/1%. Fractal dimension averaged for non-buried atoms of hyaluronan results 1.73. When going to hyaluronan·3Ca/·9H2O, it increases by 4/0.3%. (3) Polymer rheological behaviour formulated in pH 4–7 does not differ, which is proper of unstructured systems. pH < 4 generate gels because of hydrophobic interactions/hydrogen bonds; gels result promising for administration on skin/mucous membranes.
Keywords: Fractal dimension, Percutaneous absorption, Percutaneous enhancer, Transdermal drug delivery, Mucoadhesive polymer, Mucus, Metal hyaluronate