Improved percutaneous delivery of some NSAIDs for the treatment of arthritis.

Arthritis is a heterogeneous group of conditions that leads to joint symptoms and signs which are associated with defective integrity of articular cartilage. Major classes of drugs which are widely used for the treatment of arthritis are Non-Steroidal Anti-inflammatory Drugs (NSAIDs). Development of an efficient means of percutaneous delivery can increase drug concentration in local soft-tissues and joints while reducing the systemic distribution of a drug and its side effects. The present work is aimed at synthesisand evaluation of prodrugs of some NSAIDs for percutaneous drug delivery for the treatment of arthritis.

Arthritis is a heterogeneous group of conditions that leads to joint symptoms and signs which are associated with defective integrity of articular cartilage. Major classes of drugs which are widely used for the treatment of arthritis are Non-Steroidal Anti-inflammatory Drugs (NSAIDs). The percutaneous application of these drugs has recently received considerable attention due to its advantages over other drug delivery methods. Development of an efficient means of percutaneous delivery can increase drug concentration in local soft-tissues and joints while reducing the systemic distribution of a drug and its side effects. By temporary masking of the ionizable carboxylic acid group by hydrophilic moiety via simple esterification has been investigated as a promising means of increasing the dermal permeation of NSAIDs. The present work is aimed at synthesisand evaluation of prodrugs of some NSAIDs for percutaneous drug delivery for the treatment of arthritis.

Materials and Methods

All the reagents used are of laboratory reagent grade or analytical grade. Reagents like Bromoethanol, EDCHCl, N-methylpiperazine, N-ethylpiperazine, N-acetylpiperazine, N-phenylpiperazine, potassium dihydrogen phosphate, 1-octanol.

High performance liquid chromatography (HPLC) method has been developed for the determination of various evaluation parameters such as aqueous solubility, partition coefficient etc.

Results and Discussion

Synthesis of prodrugs

Prodrugs should be designed in such a way that they should fulfill the ideal properties required for percutaneous drug delivery i.e. pKa, molecular weight, log P etc. Designed derivatives which fulfill thecriteria have been synthesized and characterized by spectral studies (UV, IR, Mass, and NMR) for structural confirmation and further evaluated.

Aqueous solubility

Aqueous solubility of the derivatives was determined at room temperature by dissolving excess of the compound in 0.5-1 ml of the phosphate buffer (0.20 M) at both pH 5.0-5.5 and 7.4.

Partition coefficient (log P)

Partition coefficients of the derivatives were determined at room temperature in 1-octanol and phosphate buffer (0.20 M) at both pH 5.0-5.5 and 7.4. Before use, 1-octanol was saturated with phosphate buffer for 24 h by stirring vigorously.

Stability study

Stability study of the derivatives was performed in phosphate buffer (USP, 0.20 M) at both pH 5.0 and 7.4 and also in human plasma.

In vitro skin permeation study

Rat abdominal skin was used for the skin permeation study. The permeation studies were carried out using the Franz-type diffusion cell. The receptor medium (0.05 M isotonic phosphate buffer solution of pH 7.4) was stirred and kept at 37°C throughout the study.

Conclusion

Designed prodrugs were synthesized and their structures confirmed by various analytical techniques and their physicochemical properties like aqueous solubility and log P were also evaluated. Derivatives 5a-b showed increased aqueous solubility in comparison to the parent NSAID but derivative 5c-d showed reduced aqueous solubility than the parent NSAID. Stability data indicated that prodrugs are stable in phosphate buffer but got quickly hydrolyzed in plasma due to presence of ester group in prodrugs and released active drug in skin to show activity. From the skin permeability study it was concluded that derivatization of free carboxylic acid group by hydrophilic moiety increases skin permeation. The present study shows that the permeation of NSAID through rat skin can be significantly improved by using piperazinylalkyl prodrugs. The good skin permeation observed for these prodrugs can most likely be attributed to their simultaneously high aqueous solubility and lipophilicity, the combination of which is important for permeation across the skin.[1-3]