| Finasteride is the first of a new class of 5a-reductase inhibitors which belongs to a 4-aza-3-oxosteroid compound and has been extensively used for treatment of benign prostatic hyperplasia (BPH) and androgenetic alopecia (AGA). The mechanism of action of this medication is to block the conversion of testosterone to stronger androgenic dihydrotestosterone in target organs such as the prostate and scalp hair without affecting circulating levels of testosterone thus preserving the desired androgen mediated effects on normal body function. Finasteride is a white crystalline powder with its molecular weight 372.54 and a melting point near 250℃. It is freely soluble in chloroform and in lower alcohol solvents but is practically insoluble in water. The purpose of this paper was to investigate the percutaneous absorption characteristics and aimed to develop a transdermal drug delivery system for providing an alternative choice for treating the symptoms of BPH or AGA.The main three parts of the present study are: (1) the preformulation study involving screening the proper enhancers for transdermal absorption of finasteride;(2) investigation of the ethosomal lipid vesicles and other colloidal drug delivery systems (solid lipid nanoparticles (SLN), microemulsions, and biphasic lipid vesicles) as drug carriers on percutaneous permeation of finasteride;(3) formulation study and developing a monolithic drug-in-adhesive transdermal patch of finasteride using polyacrylate copolymer as pressure sensitive adhesives (PSA).In the preformulaiton study, the ultraviolet spectrum and HPLC methods for the assay of finasteride were established firstly and then the physicochemical properties, especially the octanol/water partition coefficient (Koct) and the solubility in various solvent systems such as alcohol, propylene glycol, PEG400, ethoxydiglycol, lauryl alcohol, isopropyl myristate, and octanol were examined. With the known physicochemical parameters, the skin permeability of finasteride was predicted usingthree different predicting models, i.e, simple membrane partition-diffusion model (Pott-Guy model), partition coefficient method and Magnusson model. The predicting permeability was then compared with actual transdermal parameters obtained from the in-vitro diffusion study using human cadaver skin set on modified Franz diffusion cell system, and feasibility of drug transdermal absorption was then analyzed. The results indicated that finasteride was a proper candidate for transdermal delivery with it logKoa value at 1.35 + 0.19, but the low solubility (less than 10|ig/ml in cold water, 61.6ug/ml at 37°C) might bring some formulating troubles and limit the delivering flux of drug from the transdermal drug delivery syetem, which was partly proved by the in-vitro transdermal study. Study on transdermal penetration enhancers showed that the ethanol and propylene glycol were good vehicles for transdermal permeation of finasteride. Lauryl alcohol, Azone, oleic acid and urea could also increase the flux, with enhancing intensity sequene: oleic acid > lauryl acid > urea > Azone. However, the maximum flux was obtained by using the enhancer combination of propylene glycol (20%) and oleic acid (5%), with which the flux reached to 0.92±0.05ug/cm2/h, the 5.11 times of flux from satiated aqueous solution of drug. Despite this, the flux was still not so sufficient to satisfy the clinical dosing need, therefore, it was necessary to look for a new enhancing vehicle or drug carriers to improve the flux of finasteride.It has been widely reported the colloidal drug carrier systems, especially vesicular formulation, mostly referring to liposomes, novel liposomes, and noisomes, could modulate skin barrier properties and thus enhance or retard substance permeation through skin barrier. In this paper, ethosomes, which is a novel liposomal system specially designed for enhanced delivery, were studied as vesicular colloid carriers of finasteride aimed to improve drug permeability. The finasteride ethosomes investigated here were prepared by injection method. And their physicochemical properties, including morphology, particle size, zeta potential, encapsulation/loading efficiency, stability and percutraneous characteristics, were studied and compared with traditional liposomes. The results revealed that, in contrast to liposomes, ethosomes presented more condensed vesicular structure and charged oppositely. Theflux of finasteride through human cadaver skin from ethosomes (1.34±0.11ug/cm2/h) was 7.4, 3.2 and 2.6 times higher than that from aqueous, liposomes and hydroethanolic solutions, respectively. Data also showed that ethosomes exhibited significant (P<0.01) increases in skin accumulation, especially when it came to the deeper skin layers, dermis, which reached to 18.2+1.8 ug/cm2 versus 5.3 + 0.7 (xg/cm2, the maximum accumulation of the other three controls. The results demonstrated that ethosomes owning more attractiveness versus liposomes could be good carriers for percutaneous absorption of finasteride and the obtained flux seemed to be high enough to meet clinical need.Among other three colloidal carrier systems, microemulsion showed some (enhancing rate: 1.17, vs. aqueous) enhancing effect of skin permeation, but its flux still maintained so low level that its enhancing effect could be neglected. Adversely, SLN and biphasic vesicles showed significant retarding effect, which retarded drug transport from carrier systems through human skin. The flux of SLN decreased to 50% of drug-saturated aqueous solution and its lag time was extended by 3-4 folds. These results showed that, through rational design, colloidal carrier systems could decrease transdermal drug delivery to systematic circulation thus reduce side effects which was quite favorable in developing local formulations and improving topical targeting.In the last part of this paper, a monolithic drug-in-adhesive transdermal patch of finasteride was developed using Eudragit El 00 and modified polyacrylate copolymer (Na- II) as PSA matrix. The formulating factors such as the effects of different plasticizers (isopropyl myristate, glycerin, PEG400), penetration enhacners (propylene glycerol, oleic acid), PVP-K30 on the physical quality of patches were investigated through adhesive performance test which included rolling ball tack test, 180° peel intensity and creep resistance test. The in-vitro transdermal performance of the different formulations as well as other evaluation indexes such as drug content, release profiles, skin irritation, was also studied. The obtained results indicated that Na-II, as well as Eudragit El00, possessed good compatibility with several other excipients examined in this study. By addition of a secondary plasticizer, or otheradditives, the adhesion behaviors of the monolithic patches were significantly changed. The adhesion strength (peel intensity) of the patches without secondary plastrcizer was too low to obtain a good adhesfdn"between skin arid the drug delivery system. The facts that the adhesive property of the patches was significantly affected by addition of penetration enhancers suggested the propylene glycerol or oleic acid did not serve as a simple penetration enhancer, but acted as an additive by molecularly dispersing in the PSA matrix. The modified acrylic PSA, Na- II, had some attractive attributes such as improved hydrophilicity, good biocompatibility, avoid of using organic solvents. In this study, it was found that Na- II in combination with PVP-K30 (Na- II /PVP-K30 = 3/2, w/w) could provide a good new water-soluble PSA matrix for transdermal patch development.
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