Study On Transdermal Drug Delivery System Of Terbinafine Hydrochloride Binary Ethosomes

Terbinafine hydrochloride is known as an antifungal allylamine drug, which has a highly significant effect to some deep cutaneous fungal infections and superficial cutaneous fungal infections. Terbinafine hydrochloride is mainly stored in the stratum corneum in local drug delivery. the skin retention by transdermal delivery was higher than by oral delivery administration. But the fungal hyphae and spores invaded the deeper layers of stratum corneum, even epiderm-derm. Therefore, it is difficult to cure fungal infections in the deeper layers of skin.Binary ethosomes emerged from 2010 year which raised by Zhou who were inspired by Manconi M studies. They improved the ethosomes to be a new particle transdermal drug delivery system that it’s with ethanol and propylene glycol instead of ethanol only, which then was found that the addition of propylene glycol is effective to increase the depth and transdermal drug retention in the rat skin, and has a higher stability than ethosomes. The studies of binary ethosomes were at the beginning of development and yet anti-fungal agents have been used in clinical studies.In order to increase the tansdermal depth and epidermal-dermal retention of drugs, this research focused its attantion on preparing binary ethosomes loading terbinafine hydrochloride by transdermal administration technology, rendering terbinafine hydrochloride a good function to deep mycosis. And then made into gel in order to increase stability and convenience of storage and administration for binary ethosomes, providing the theoretical foundation for the development of new tansdermal formulations. The main contents of this paper include the following aspects. 1.The preformulation study of terbinafine hydrochloride binary ethosomesAccording to the results of the preformulation study, the solubility in various solvent systems such as ethanol, isopropanol, glycerol, propylene glycol, phosphate buffer(p H6.5), phosphate buffer(p H7.4) as well as distilled water by the method from Ch P were determined, and the solubility in distilled water, saline, the series solubility of ethanol, PEG400, polysorbate-80 by Thermostatic shaker method. The oil/water partition coefficient, the oral and dermato pharmacokinetics were obtained from journal. With the known physicochemical parameters, the transdermal permeability was predicted by the Magnusson model. The results demonstrated that with the oil-water partition coefficient of 2.419±0.002, terbinafine hydrochloride was freely soluble in ethanol, isopropanol, methanol and other organic solvents, slightly in water. However, in PBS(p H = 6.5, p H = 7.4)was insoluble. It was also proved to be difficult to penetrate the skin barrier only if combining with the penetration methods can it act on the deep mycosis. According to the results of transdermal penetration in vitro of drug-saturated saline solution, which have shown the dosage of acceptable solution of 0, the stratum corneum retention and the epidermal-dermal retention was respectively 4.54±0.49μg/cm2 and 2.98±0.33μg/cm2. 2.The prescription and technology study of terbinafine hydrochloride binary ethosomesThe terbinafine hydrochloride binary ethosomes were prepared by affluxing- ultrasonic dispersion method. The particle size, Zeta potential and entrapment efficiency were taken as as the index to evaluate the effects of difference of drug to lecithin, drug contents, binary alcohol contents and so on. The prescription optimized by the L9(34) orthogonal test method. Optimal formation was as follows: ratio of drug to lecithin was 1:5; mass fraction of drug was 0.5‰; volume fraction of binary ethosomes(ethanol:propylene glycol=7:3)were 30%. The results shown that the optimal prescription is reasonable, better quality ethosome can be prepared. 3.Pharmaceutical evaluation researches on terbinafine hydrochloride binary ethosomesThe particle size and Zeta potential of binary ethosomes were tested by nano laser particle size analyzer. The entrapment efficiency of binary ethosomes was determined by reverse dialysis method with UPLC. The surface morphology of binary ethosomes was observed by transmission electron microscope. The binary ethosomes prepared by optimal prescription was with spherical or spheroidal in shape, particle size(36.2±1.0) nm, polydispersity index of 0.136±0.058, Zeta potential(-23.22±2.02) m V, drug loading(18.94 ±0.11)% and the encapsulation efficiency(98.03±0.03)% as well. The percutaneous absorption studies of different kinds of terbinafine hydrochloride liposomes were determined by Franz diffusion cells. The results of transdermal permeability in vitro of different liposomes suggested that the descending order of epidermal-dermal retention was as follows, binary ethosomes, ethosomes, flexible liposomes, liposomes, drug-saturated saline solution. Binary ethosomes up to(23.18±2.38) μg/cm2, is 3.95 times better than liposomes, and 7.78 times better than drug-saturated saline solution. All the results showed that binary ethosomes were more suitable for transdermal delivery system, comparing to other particle drug delivery systems. 4.The prescription and technology study of terbinafine hydrochloride binary ethosome gels The terbinafine hydrochloride binary ethosome gel was prepared. The method of using different materials to prepare terbinafine hydrochloride binary ethosome gels was took and their contents were measured, with the appearance and the retention of skins being evaluated to grade the gels. Then the gels’ preliminary stability and consumption of material were proceed. The best formulation was consist of the 4% CMC-Na which was as the material of terbinafine hydrochloride binary ethosome gels. CONCLUSION The terbinafine hydrochloride binary ethosome gel prepared by the optimum formulation was stable.