| Letrozole is an FDA-approved third generation aromatase inhibitor for the treatment of breast cancer. On account of its more potent, better tolerated and selective inhibitors of aromatase comparison to the other aromatase inhibitors, letrozole is now widely used as a first-line drug in the endocrine treatment of estrogen-dependent breast cancer in postmenopausal patients. However, at present the only commercial dosage form of letrozole is oral tablets, which requires dosing daily. Otherwise, letrozole has some adverse events that are caused by the circulating estrogen fast depletion, for example hot flushes and bone damage. Accordingly developing a letrozole transdermal patch for site-specific delivery that is to adhere to the breast, in situ release drug from the patch, increase local tissue concentration in the application position, decrease drug level in plasma, easy to administer; easy to comply, is worthwhile. Since there are no published reports about the transdermal use of letrozole, we have investigated the feasibility of its transdermal application.A high performance liquid chromatographic (HPLC) method was established to determine the concentration of letrozole in vitro. Physicochemical property of letrozole relevant to transdermal drug delivery was determined, such as the partition coefficient (logPoct/water) at 32℃. The result indicated that the logPoct/water was 1.73 which makes it a good candidate for transdermal delivery.Using horizontal two-chamber side-by-side diffusion cells containing excised rat skin was investigated the permeability of letrozole in vitro. The transdermal absorption behavior of letrozole in isopropyl myristate (IPM) with the different permeation enhancers was studied firstly, then the effect of propylene glycol and ethanol on the permeation of letrozole was determined, subsequently the effect of five kinds of used organic acids on the permeation of letrozole was evaluated. The result obtained indicated that all the enhancers used in the experiments increased the penetration of letrozole through the skin. Among the percutaneous enhancers investigated, NMP exhibited the most potent enhancing effect on letrozole, whose enhancing ratio was 4.29-fold. Furthermore, NMP showed concentration dependent activities on the cumulative amount after an 8 hour application (Q8) across rat skin. However, when the concentration of NMP was more than 5%, there was a rapid decrease in the cumulative amount of letrozole. Propylene glycol and ethanol could significantly promote the transdermal absorption of letrozole. Ethanol is more effective than propylene glycol. Furthermore, the permeation of letrozole increased with the increase of ethanol concentration. All five organic acids markedly (p<0.05) promoted the permeation of letrozole. Maleic acid had the greatest enhancing effect, followed by citric acid, succinic acid, fumaric acid and lactic acid in the order.In vitro transdermal permeabilities of letrozole from patches were also evaluated through excised rat skin using two-compartment horizontal diffusion cells. The formulation of letrozole patch was optimized by single-factor research methods. The optimized formulation of letrozole patch was determined to be 1.5%(w/w) letrozole,10%(w/w) Azone,5%(w/w) propylene glycol and (83.5%) DURO-TAK(?) 87-4098 adhesive. In addition, the observed steady-state plasma levels were in good agreement with the predicted steady-state plasma levels from the in vitro data and a good in vitro/in vivo correlation was established. Furthermore, The evaluation of quality of letrozole patch in vitro was carried out by tack, shear strength, peel strength, the drug content and drug release rate of the patch and so on as indexes. They provided some proofs for controlling quality of letrozole patch.A reversed-phase HPLC method has been developed for determination of letrozole in mice plasma, excised skin and muscle samples at different time in order to study drug local tissue disposition after transdermal and oral administration. These findings suggested that the letrozole patches had the potential to maintain higher drug levels in local skin and muscle tissues and low drug concentrations in plasma. Therefore, the letrozole transdermal patch for site-specific delivery not noly can effectively treat the breast cancer but also can avoid the risk of systemic side effects caused by the circulating estrogen depletion compared with oral administration.These results also proved that it was feasible to produce site-specific delivery for letrozole transdermal patches. Therefore, these finding indicated that the transdermal patch for site-specific delivery of letrozole was promising in practice and the prospective goal of the paper was satisfactorily arrived. |
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