Design And Evaluation Of Indapamide Transdermal Delivery System

Indapamide is a long-acting antihypertensive with both diuretic and vasodilative actions and is defined by the 1999 WHO/ISH Hypertension Guidelines and JNCⅦas a first-line drug for the treatment of hypertension.Indapamide is marketed as immediat release and sustained release oral preparations,however,oral delivery of this medicine has certain disadvantage,such as hyponatremia and hypopotassaemia.Additionally,since anti-hypertensive drug is usually intended to be taken for a long period,patient compliance is also very important.Transdermal drug delivery offers many advantages,such as reduced side effects,less frequent administration to produce the desired constant plasma concentrations associated with improved patient compliance,elimination of the first-pass effect,sustained drug delivery and interruption of treatment when necessary.Since there are no published reports about the transdermal use of indapamide,we have investigated the feasibility of its transdermal application.In the first place,physicochemical properties of indapamide relevant to transdermal drug delivery were determined,mainly the solubility in distilled water and n-octanol at 32℃,the partition coefficient（Poct/water） at 32℃.The result indicated that indapamide has a low solubility in water and a high solubility in n-octanol.The logPoct/water was 1.90 which makes it a good candidate for transdermal delivery.Using in vitro transdermal absorption experiments,the transdermal delivery properties of indapamide from solution formulations were studied.The transdermal absorption behavior of indapamide saturated solution in isopropyl myristate was studied first,and the effect of propylene glycol and ethanol on the permeation of indapamide was determined,then the effect of four kinds of commonly used permeation enhancers and eight kinds of commonly used organic acids on the permeation of indapamide was studied.The result obtained indicated that after 12h application the cumulative permeated amount of indapamide from indapamide saturated solution in isopropyl myristate was extremely low,only permeated 8.45μg/cm².Propylene glycol and ethanol can significantly promote the transdermal absorption of indapamide.After adding 20%propylene glycol or ethanol,the cumulative permeated amount increased to 2.75-fold and 35.22-fold respectively.Ethanol is more effective than propylene glycol.The permeation of indapamide increased with the increase of ethanol concentration.All the 4 permeation enhancers studied potently promoted the transdermal absorption of indapamide which occurred in the order of 5% N-dodecylazepan-2-one＞5%N-methyl-2-pyrrolidone＞5%menthol＞5%oleic acid.All 8 organic acids significantly（p＜0.05） promoted the permeation of indapamide,and the permeability coefficient increased from more than 3-fold to 9-fold.Lactic acid had the greatest enhancing effect,followed by fumaric acid,succinic acid,maleic acid,citric acid, adipic acid,oxalic acid and acetic acid in the order.Three kinds of indapamide and organic acids complexes were prepared with indapamide and organic acids.DSC method was used to determine the melting point of indapamide ant its complexes,and FT-IR method was used to identify the chemical structure.Physicochemical properties of indapamide and its complexes were determined,mainly the solubility in distilled water and n-octanol at 32℃,the partition coefficient（Poct/water） at 32℃.The result indicated that there were certain changes to some extent.The transdermal absorption of indapamide and its complexes was studied in the identical solvent system,and the result showed that the accumulative amount of indapamide permeated was significantly increased.Five kinds of acrylic adhesives were screened.The results indicated that DURO-TAK^? adhesive 87-2852 is a suitable and compatible polymer.The formulation of indapamide patch was optimized by single-factor research methods.The final formulation contained 4% N-dodecylazepan-2-one,6%l-menthol and 3%isopropylmyristate.The in vitro transdermal absorption experiment was carried out for 6 days to study the transdermal absorption behaviour of the optimized formulation.The results indicated that the transdermal absorption of indapamide patch fit Higuchi model.The assay method was established for the determination of indapamide in patch,The HPLC method established is simple and rapid,and there is good linear correlation when the concentration of indapamide is between 0.97μg·mL^-1 and 19.44μg·mL^-1.The results of 3 batch of samples content determination were good.Some quality control index,such as the tack of the patches,the shear adhesion of the patches and the peel strength of the patches were also established.The tack value of indapamide patch was that of ball number 29.The shear strength values of indapamide patch was between 20 and 30 rain.The peel strength was from 0.4 to 0.6 kN/m.A simple,sensitive HPLC method was established to determine indapamide in rat whole blood.The pharmacokinetics of indapamide patch was studied using indapamide suspension orally as reference.The results for the oral administration of indapamide indicated that it was rapidly absorbed from the rat gastrointestinal tract with a Cmax of 2.25±0.73μg/ml at a Tmax of 2.17±0.98 h after the first administration,with a Cmax of 2.22±0.44μg/ml at a Tmax of 2.33±0.82 h after the second administration after 24h.Transdermal administration of indapamide achieved a Cmax of 1.97±0.43μg/ml at a Tmax of 2.67±1.03 h,and the whole blood concentration of indapamide declined more slowly than that following oral administration.Upon removal of the transdermal patch,normal elimination similar to that after oral administration was observed.Compared with two oral administrations without dose normalization,the AUC_0-t values were significantly increased:44.16±10.82μg/（ml h） for indapamide transdermally versus 35.43±6.37μg/（ml h） for indapamide orally,and the MRT values were prolonged:20.774±1.03 h for indapamide transdermally versus 18.014±2.35 h for indapamide orally.Similarly,the apparent T_1/2 values were also markedly increased: 18.17±2.45 h for indapamide transdermally versus 7.19±2.37 h for indapamide orally.These findings indicated that the transdermal application of indapamide is feasible and the prospective goal of the paper was satisfactorily arrived.