Formulation: TRANSDERMAL THERAPEUTIC SYSTEMS
Transdermal Drug Formulation
Citral found to be a potent permeation enhancer
Transdermal therapeutic systems (TTS) are increasingly popular due to their demonstrated effectiveness for the percutaneous absorption of many types of drugs. Chien and Zatz have worked extensively on the development and evaluation of TTS.1-3 Continuous intravenous infusion (IV) is recognized as a superior mode of drug administration not only for bypassing hepatic first-pass metabolism but also for maintaining a constant and prolonged drug level in systemic circulation. The IV route also has the advantage of allowing drugs to enter the circulatory system directly. This mode of drug administration has certain risks, however, that necessitate hospitalization and close medical supervision.
It has recently become evident that the benefits of IV can be closely duplicated using skin as a drug delivery route.4 But, although it provides continuous drug infusion into systemic circulation, the transdermal route is limited by the barrier properties of the skin. Only the most potent drugs with low daily doses and appropriate physicochemical properties are suitable candidates. To circumvent the low permeability of human skin, researchers are looking for safe and effective penetration enhancers.5 Of the large numbers of penetration enhancers available, terpenes have shown promising results.6
Diclofenac sodium is an effective nonsteroidal anti-inflammatory drug (NSAID) that rapidly absorbs after oral administration. But it undergoes first-pass metabolism, and only about 60% of the absorbed drug reaches systemic circulation.7 It also has a short plasma half-life of two hours.8 These properties make diclofenac sodium a suitable candidate for development of TTS. In the present investigation, we attempted to develop and characterize the matrix and reservoir type TTS of ethyl cellulose and polyvinyl alcohol containing diclofenac sodium. We investigated the influence of citral in combination with propylene glycol and their effect on the permeation of the drug across mice and rabbit skin.
Materials and Methods
We obtained diclofenac sodium IP (DS) from Ontop Pharmaceuticals, Ltd. (Banga-lore, India). We purchased ethyl cellulose (EC), 22 cps, ethoxy content 49 %, from Loba Chemie Pvt., Ltd. (Mumbai, India) and polyvinyl alcohol (PVA) with a molecular weight of 15,000 from CDH Labs (Mumbai, India). We obtained citral (density 0.89 g/ml) from Sigma-Aldrich Corp. (St. Louis) and propylene glycol IP (PG) and dichloromethane IP from S.D. Fine-Chem, Ltd. (Mumbai, India).
We prepared matrix systems by casting on a mercury surface.9-10 At room temperature, we dissolved 4% weight/volume (w/v) of EC in a solvent system containing chloroform-dichloromethane (1:1). We loaded 40 mg of diclofenac sodium into each formulation, using dibutyl phthalate (40% w/w of polymer) as a plasticizer. Citral, alone and in combination with PG at concentrations of 10%, 15%, and 20%, served a permeation enhancer. The polymeric solutions were mixed thoroughly using a magnetic stirrer, and we poured 5 ml within a glass bangle placed on the mercury surface in a Petri dish. We controlled the rate of evaporation by inverting the cut funnel over the Petri dish. After drying at room temperature for 24 hours, the TTS were taken out and stored in a desiccator.
We used Kulkarni and Doddayya'S method to prepare the reservoir systems.11 A drug-free film of EC served as a rate-controlling membrane; PVA was the drug reservoir, and aluminum foil served as the backing membrane. We dissolved 4% w/v of EC in a solvent system containing chloroform-dichloromethane (1:1) at room temperature, along with dibutyl phtha-late and citral at concentrations of 10% and 15%. We cast the polymeric solution onto the mercury surface to obtain films of 60� thickness.
Next, we dissolved 4% w/v of PVA in distilled water along with glycerol and 40 mg of the drug, then poured 5 ml of this solution over the previously prepared rate-controlling membrane and dried it in an oven at 45o C for eight hours. After the drying process, we used distilled water to moisten the surface of the drug reservoir slightly and then allowed it to dry at room temperature for 24 hours. We stored the dried films in a desiccator. We then evaluated the TTS for estimation of drug content, water vapor transmission (WVT), skin irritation, and in vitro drug permeation through mice and rabbit skin.12-13
In Vitro Permeation
We used vertically assembled KesharyChien diffusion cells with a downstream volume of 20 ml for the study. The magnetic stirrer was set at 100 rpm, distilled water was used as receptor solution, and the whole assembly was maintained at 37o C. We mounted a film with an area of 2 cm2 on the donor compartment and fixed mice/rabbit skin to the donor compartment with an adhesive. We determined the amount of drug released by withdrawing 5 ml samples at specific time periods for 24 hours using an ultraviolet spectrophotometer at 276 nm.
The prepared formulations were smooth, thin, and flexible. Thickness and drug contents were found to be uniform. All the systems were permeable to water vapors, and water vapor permeation nearly followed zero order kinetics; it was decreased in the order of PVA>EC>ECCLPG20 >EC-CL15. A skin irritation study revealed that the formulations containing 15% and 20% citral produced very slight erythema compared to control, whereas there was no evidence of edema. This result indicates that these formulations are compatible with skin and are safe for topical application.
The PVA system offered low resistance to the movement of the drug and showed maximum release of 90% through mice skin at the end of 18 hours. High permeation levels occurred in the initial hours; later, the drug release was prolonged up to 18 hours. Only 59% of the drug had been released from the EC system at the end of 24 hours. The presence of citral in the EC system enhanced the permeation of the drug across mice skin. The permeation of the drug from EC-CL10, EC-CL15, and EC-CL20 was 67%, 75%, and 64%, respectively, at the end of 24 hours
We observed an increase in drug permeation when the concentration of citral was increased from 10% to 15%, but there was a decrease in the permeation rate as the concentration was increased to 20%. This may be due to excessive delipidization and accumulation of citral in the stratum corneum, leading to low permeation of drug. Further, we combined the citral with PG in a 1:1 ratio in three concentrations (5%+5%, 7.5%+7.5%, and 10%+10%) in order to determine the effect.
The combination of citral and PG showed enhancer synergism; we observed a significant increase in permeation rates. The drug release from EC-CLPG10, EC-CLPG15, and EC-CLPG20 was 65%, 75%, and 81% at the end of 24 hours ). The mechanism of drug release from all these systems was diffusion controlled. The study also showed that drug permeation was low across rabbit skin compared to mice skin. We prepared PVA-based reservoir systems using EC as a rate-controlling membrane. The percentage of drug release from EC(R)10 and EC(R)15 was 68% and 79% at the end of 24 hours; the mechanism of drug release from reservoir systems nearly followed zero order kinetics.
The present study revealed that citral is a potent permeation enhancer; it showed enhancer synergism when used in combination with PG. Combination of citral with PG at a concentration of 20% (1:1 ratio) was effective with respect to the permeation of diclofenac sodium across mice skin. �
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