The synthesis and transdermal delivery of stavudine derivatives / Estée-Marie Holmes

• Main Author: Holmes, Estée-Marie
• Published: North-West University 2009
• Online Access: http://hdl.handle.net/10394/1387

The skin is an amazingly flexible and relatively impermeable barrier that provides protective, perceptive and communication functions to the human body. The interest in transdermal drug delivery may be attributed to the advantages associated with this method of drug delivery. Some of these advantages include more consistent drug levels, the avoidance of hepatic first pass metabolism, and the accommodation of patients who cannot tolerate oral dosage forms. Transdermal therapy, however, is not without limitations. The outermost layer of the skin, the stratum corneum, is the main barrier for penetration of most drugs through the skin and is very selective with respect to the type of molecule that can be transported across this outer covering. This is because the skin serves a protective function, inhibiting compounds from crossing it. Only drugs with the appropriate physicochemical properties are enabled to cross this barrier. Many drugs that possess a hydrophilic structure penetrate too slowly to be of therapeutic benefit. However, drugs with a lipophilic character are better suited for transdermal delivery but compounds with both lipid and water solubilities penetrate much better than substances with either high water or high lipid solubility. Stavudine (2',3'-didehydro-2',3'-dideoxythymidine, d4T), a synthetic antiretroviral agent, is an inhibitor of nucleoside reverse transcriptase and is used against HIV-1 and HIV-2. It is required to be in combination with other antiretroviral agents and is indicated for the management of mainly HIV-1 infection in adults and paediatric patients. Another important use for stavudine is for post exposure prophylaxis (PEP) that can help decrease the risk of infection after exposure to HIV. Adverse effects, related to stavudine therapy, are mostly due to mitochondria1 toxicity resulting from the inhibition of human DNA polymerase gamma. The major adverse effect, peripheral neuropathy, is dependant on the dosage and the duration of the treatment. Pheroids is a patented system comprising of a unique submicron emulsion type formulation and is capable of encapsulating a variety of drugs and delivering these drugs with high efficacy to target sites in the body. The Pheroid consists primarily of plant and essential fatty acids and is stable within a novel therapeutic system. They are manipulated in a special manner to ensure important advantages over other delivery systems such as high entrapment capabilities, fast rate of transport, delivery and stability. The primary aim of this study was to synthesise a series of new derivatives of the anti- HIV drug stavudine, and to study the effects of the different substituents on transdermal penetration with and without the use of Pheroids as delivery system. Furthermore, it was to be established if any correlation between the transdermal penetration and selected physicochemical properties of the penetrants existed. The six derivatives of stavudine were prepared by esterification of stavudine with six different acid chlorides at room temperature. The structures of the products were confirmed by nuclear magnetic resonance spectroscopy (NMR), mass spectroscopy (MS) and infrared spectroscopy (IR). The experimental aqueous solubility and partition coefficients were determined for stavudine and its different derivatives at a pH of 7,0. Interactive analysis (IA) prediction software was used to predict aqueous solubility values while IA, Kow Win and ACD Labs prediction software were used to predict the log P values for each derivative. ACD Labs prediction software gave values relatively close to the experimental partition coefficients that were measured at pH 7,0. The experimental aqueous solubility, partition coefficient and transdermal flux values were determined for stavudine and each of the derivatives. The experimental aqueous solubility of stavudine (104,75 mg/ml) was much higher than that of the synthesised derivatives, and the partition coefficient of stavudine (-0,846) was lower than that of its derivatives. As could be expected, a direct correlation exists between the aqueous solubility data and the partition coefficients. Stavudine-5'-decanoate had a log P value of approximately 3, but had no flux. This can be ascribed for this specific derivative being insoluble in water. This just proves once again that for a compound to cross the stratum corneum, it should possess both hydrophilic and lipohillic properties. The aqueous solubility, molecular mass and log D values showed an excellent correlation with the flux values of the compounds in PBS, while no correlation existed between the melting point and the integrity (either before or after) with the flux. The data showed no correlation between the flux values of the compounds in Pheroids for any of the determined physicochemical properties. The experimental transdermal flux of stavudine (1,46 x 10-2 g/cm2.h) in PBS was much higher than that of its derivatives, while the propionyl (1,86 x 10-2 g/cm2.h) and the buteryl derivative (2,02 x102 g/cm2.h) were the compounds with the highest transdermal flux in Pheroids. The flux of stavudine improved from 1,46 x 10 g/cm2.h to 2,02 x10-2 g/cm2.h by synthesising the buteryl derivative and using Pheroids as delivery system which constitutes a 38% enhancement in flux. This study has confirmed that transdermal flux is dependent on several factors such as the aqueous solubility of the drug, the partition coefficient, molecular size, melting point and the alkyl chain length, to name a few, and in some instances minor modifications to the drug may be necessary. The best results in this study were achieved by synthesising the propionyl and buteryl derivatives and using Pheroids as delivery system. === Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2007