Solubility Enhancement of Indomethacin with Poly(amidoamine) Dendrimers and Targeting to Inflammatory Regions of Arthritic Rats

Abstract

This work includes investigation on solubility enhancement of indomethacin (IND) in the presence of poly(amidoamine) (PAMAM) dendrimers and passive targeting of the PAMAM/IND complex so formed to the inflamed regions in an animal model. The complex formation was confirmed by infrared and (1)H nuclear magnetic resonance spectroscopy methods. Solubility of IND in aqueous G4-PAMAM followed Higuchi's A(N) curve depending on pH of the solubilizing medium. The solubility was decreased upon addition of dendrimer to the IND saturated solution at various pH, indicating aggregation behavior of the PAMAM/IND complex and conforming to the Higuchi's A(N) solubility profile. The in vitro release of IND from the PAMAM/IND complex through a cellophane membrane, from a Franz diffusion cell, showed 79 +/- 3.2% drug release in 24 h. The drug release was further retarded in the presence of human serum albumin (HSA) suggesting the significance of complex HSA binding in altering in vivo behavior of the complex. Intravenous administration of the PAMAM/IND complex formulation in rats showed a two-compartment pharmacokinetic profile. Enhanced effective IND concentrations in the inflamed regions were obtained for the prolonged time period with the PAMAM/IND complex compared to the free drug in arthritic rats indicating preferred accumulation of IND to the inflamed region. The targeting efficiency of PAMAM/IND complex was 2.29 times higher compared to free drug. In contrast to the previous investigations, two interesting findings reported here are: (a) solubility behavior of IND in G4-PAMAM dendrimer deviates from linearity with increasing concentrations of dendrimer at acidic to neutral pH values and (b) inspite of lymphatic drainage, retention of PAMAM/IND complexes occurs at the inflammatory site.

Molecular Complex Consisting of Two Typical External Medicines: Intermolecular Interaction between Indomethacin and Lidocaine

“…Since IDM is, however, practically insoluble (ca. 2.5 mg/ml) in water, cyclodextrins, 8,9) poly(amidoamine) dendrimers, 10) and several additives 11) have been utilized to improve its dissolution. Furthermore, skin permeation of IDM was enhanced by the complexation of additives with L-menthol 12) or smectite.…”

The Development of Targeted Drug Delivery Systems for Rheumatoid Arthritis Treatment

“…Thus, folate may serve as an effective means of actively targeting the pannus tissue. In support of this, folate-tagged cationic and anionic poly(amidoamine) (PAMAM) dendrimers loaded with indomethacin were more effective at treating arthritic rats than indomethacin-loaded dendrimers that were folate-free (Chandrasekar et al, 2007a;Chandrasekar et al, 2007b;Chauhan et al, 2004).…”

EDA Çekirdekli Amin, TRIS ve Karboksil Sonlu PAMAM Dendrimerleri Kullanarak Ketoprofenin Çözünürlüğünü Geliştirme

“…KETO için λmax = 261 nm iken PAMAM dendrimerlerin λmax = ~280 nm dir. KETO-PAMAM dendrimer komplekslerinin ve KETO'nun 261 nm'deki absorbans bantları gösteriyor ki, dendrimerler KETO ile elektrostatik etkileşim ve enkapsülasyon yaparak KETO'nun çözünürlüğünün artmasına neden olmuşlardır [27].…”