MICRONEEDLE-ASSISTED TRANSDERMAL DELIVERY OF NALTREXONE SPECIES: \u3cem\u3eIN VITRO\u3c/em\u3e PERMEATION AND \u3cem\u3eIN VIVO\u3c/em\u3e PHARMACOKINETIC STUDIES

Naltrexone (NTX) is a drug used primarily in the management of alcohol dependence and opioid dependence. Based on several drawbacks associated with the oral and injectable intramuscular dosage forms of naltrexone currently available on the market, there is substantial interest in delivering naltrexone transdermally. Although naltrexone does not permeate skin at the rate sufficient to reach therapeutic plasma concentrations in humans, novel flux enhancement methods such as microneedles help address this challenge. Earlier work in humans has demonstrated that the use of microneedles achieves plasma concentrations in the lower end of expected therapeutic values. Further flux enhancement is desired to decrease the patch area while increasing drug transport rates. In the present work, several strategies aiming at in vitro flux maximization were employed including: formulation optimization, naltrexone salt screening, and naltrexone prodrug design. While naltrexone prodrugs did not reveal any improved permeation characteristics formulation optimization through decrease in vehicle microviscosity allowed a 5-fold increase in the percutaneous transport rates, and naltrexone glycolate salt selection provided an additional 1.5-fold enhancement in flux. One of the key observations was a good correlation (R2 = 0.99) between vehicle microviscosity and drug transport rates across the microchannel pathway. This finding alone allowed for formulation optimization and, at the same time, provided a potential explanation for the low permeation of high-concentration naltrexone salts and prodrugs. In vivo studies were carried out in Yucatan minipigs using a “poke and patch” microneedle method to deliver NTX•HCl. These studies demonstrated that initial plasma concentrations spiked to 2.5 ng/ml but rapidly dropped to a plateau of below 1 ng/ml. This pharmacokinetic profile could be explained by the use of a mathematical model which identified the importance of microchannel closure kinetics on drug transport. Also, an estimate of diffusional resistance of the viable tissue associated with percutaneous NTX•HCl delivery through microchannels was obtained. Its relatively large value suggests that the effect of diffusional resistance of the dermis in vivo should not be ignored and must be accounted for in order to obtain a good in vitro-in vivo correlation

Progress in microneedle array patch (MAP) for vaccine delivery

A microneedle array patch (MAP) has been developed as a new delivery system for vaccines. Preclinical and clinical trials with a vaccine MAP showed improved stability, safety, and immunological efficacy compared to conventional vaccine administration. Various vaccines can be delivered with a MAP. Currently, microneedle manufacturers can mass-produce pharmaceutical MAP and cosmetic MAP and this mass-production system can be adapted to produce a vaccine MAP. Clinical trials with a vaccine MAP have shown comparable efficacy with conventional administration, and discussions about regulations for a vaccine MAP are underway. However, there are concerns of reasonable cost, mass production, efficacy, and safety standards that meet FDA approval, as well as the need for feedback regarding the best method of administration. Currently, microneedles have been studied for the delivery of many kinds of vaccines, and preclinical and clinical studies of vaccine microneedles are in progress. For the foreseeable future, some vaccines will continue to be administered with syringes and needles while the use of a vaccine MAP continues to be improved because of the advantages of less pain, self-administration, improved stability, convenience, and safety