Transdermal and transbuccal routes offer attractive alternatives for systemic delivery of drugs due to their distinct advantages: non-invasive, avoidance of first-pass effect, improved bioavailability and reduction of systemic side effects.

The objective of this work is to overcome these barriers to significantly enhance transdermal and transbuccal delivery of hydrophilic drugs without causing major damage to skin and buccal tissue. In this work, iontophoresis, chemical enhancers and their combination are being investigated for their enhancement effects on transdermal and transbuccal delivery of hydrophilic drugs with different therapeutic indications: lidocaine HCl (LHCl) for pain management, nicotine hydrogen tartrate (NHT) for smoking cessation, diltiazem HCl (DHCl) for anti-hypertension and ondansetron HCl (ODAN HCl) for anti-vomiting. Chemical enhancers used are dodecyl 2-(N, N-dimethyl amino) propionate (DDAIP), its HCl salt dodecyl-2-(N, N-dimethylamino) propionate hydrochloride (DDAIP HCl),N-(4-bromobenzoyl)-S,S-dimethyliminosulfurane(Br iminosulfurane).Their enhancement effects are evaluated using in vitro Franz cell diffusion model via porcine skin and buccal tissue.

The results demonstrated that iontophoresis alone significantly enhanced transdermal and transbuccal delivery of LHCl, NHT, DHCl and ODAN HCl. DDAIP HCl alone significantly enhanced transbuccal delivery of these four drugs. DDAIP and Br-iminosulfurane significantly enhanced transdermal delivery of LHCl and ODAN HCl. Synergistic enhancement effects were observed on transdermal delivery of LHCl and NHT, ODAN HCl when using DDAIP or Br-iminosulfurane in

combination with iontophoresis. Light microscopy, DSC and SEM studies showed that treatment with chemical enhancers and iontophoresis did not cause major morphological changes in the skin and buccal tissue. EpiOral™ MTS cytotoxicity study demonstrated that DDAIP HCl at less than 5% (w/v) in water did not have significant detrimental effects on buccal tissue. In conclusion, iontophoresis and chemical enhancers or their combination are feasible approaches to enhance transdermal and transbuccal delivery of LHCl, NHT, DHCl and ODAN HCl.