Dendritic Polymer Polyamide - Amines - Preparation Of The Complexes Of Puerarin And Its Impact On The Cornea

Dendrimer polyamidoamine (PAMAM) is a new type of hyper branched and three dimensional macromolecule which possesses properties of monodispersion, non immunogenicity, low cytotoxicity and biodegradation. As drug carrier, PAMAM can increase the solubility of the drug, delay drug release, increase the skin permeability coefficient, prolong the residence time in cornea and increase the bioavailability of the drug. It might be a potential and novel drug carrier. In our study, puerarin was choosen as the model drug, and PAMAM PUE complexes were prepared. In order to investigate whether PAMAM can become a suitable carrier for ocular drugs, several important characteristics of the complexes were determined, including the maximum incorporated number and drug loading mechanisms, in vitro release, corneal permeation, and ocular residence time in rabbits.PAMAM PUE complexes were prepared, typically, 43, 56, 125 and 170 molecules of puerarin could be incorporated into G3.5, G4, G4.5 and G5 PAMAM dendrimer molecule. Higher pH increased the puerarin to dendrimer ratio of the G4 PAMAM PUE complex, however, pH had little effect on the ratio in G3.5 PAMAM PUE complex. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) studies showed that PAMAM PUE complexes formed primarily by hydrogen bonding interactions. The PAMAM PUE complexes produced different release profiles in different release solutions. The in vitro release rate of puerarin complexed with full generation dendrimers was lower than that with half generation dendrimers. Higher generation dendrimers tended to slow the release of puerarin. Puerarin was released more slowly from PAMAM PUE complexes than free puerarin in deionized water. The release rate was slower with the pH increased and the ion concentration decreased.Permeation studies were performed using excised cornea of rabbits by a Valia Chien diffusion apparatus. The permeability coefficient of puerarin in PAMAM PUE physical mixture was enhanced by 2.48 (G3), 1.99 (G4) and 1.36 (G5) times on average, respectively compared to control. With the ratio of PAMAM dendrimer and PUE increased, the permeability coefficient reached to be steady or decreased. After cornea was treated with PAMAM dendrimers, the cumulative amount and the permeability coefficient of puerarin increased. Higher generation of PAMAM dendrimers, larger the permeability efficient ratios. However, no significant permeability enhancement of puerarin in PAMAM PUE complex was found compared to control. The free drug concentration plays an important role in drug corneal permeation. The corneal hydration levels were determined lower than 79% when each permeation test was over, Which indicate that the dendrimer did not cause any damage to the epithelium and/or endothelium during the studies. PAMAM PUE complexes produced longer ocular residence times in rabbits compared with puerarin eye drops. Under physiological conditions, PAMAM dendrimers can interact with the cornea and loosen the epithelium cell junctions of cornea to increase the drug corneal permeability and prolong the ocular residence time. In conclusion, PAMAM dendrimers can represent a potential ocular drug delivery system to improve the efficacy of drug treatment.