Cartilage targeted chemical delivery of naproxen and ibuprofen for the treatment of arthritis.

NSAIDs are among the most widely used prescription drugs, for the treatment of pain and inflammation, particularly arthritis. Inhibitor of COX and NSAIDs relieve the signs and symptoms of inflammation by decreasing PG production but may cause GI and renal damage. Synthesis, stability studies and Y-imaging studies are carried out. Cartilage targeting strategy for conventional NSAIDs has been explored for reducing their local and systemic side effect of the NSAIDs site specific delivery of quarternary ester derivatives could have to be an effective strategy for long term therapy of inflammatory conditions like arthritis.

NSAIDs are among the most widely used prescription drugs, for the treatment of pain and inflammation, particularly arthritis. As inhibitors of COX isozymes, traditional NSAIDs relieve the signs and symptoms of inflammation by decreasing prostaglandin (PG) production but may cause serious gastrointestinal (GI) and renal damage, especially with the long term use. To improve the GI tolerance of NSAIDs by masking the free carboxylic group temporarily, numerous ester and amide prodrugs of NSAIDs have been designed and evaluated in the past. However, it is still not possible to avoid the systemic side effects of the parent drugs by the prodrug approach. An alternative way to reduce the adverse reactions is to carry the drugs selectively to their target tissue. The observation that quaternary ammonium (QA) compounds are selectively and intensively concentrated in the cartilaginous tissue prompted us to study the tropinol esters of some NSAIDs after quaternization, for their localization into the inflamed tissues and their antiinflammatory activity in a chronic model. Tropinol esters specifically were chosen for the study due to their higher stability in the in vitro experiments.[1]

Materials and Methods

All the reagents used are of laboratory reagent grade and solvents were of analytical grade. Ibuprofen and naproxen were provided by Macleods pharmaceutical Pvt. Ltd. as gift samples. EDC. HCl, methyl iodide and other reagents were purchased from sigma chemicals. High performance liquid chromatography (HPLC) method has been developed for the determination of purity and stability study of synthesized derivatives.

Result and Discussion

Synthesis

Naproxen (8) and ibuprofen (9) were coupled with tropinol (3) using ethyl dimethylamino propyl carbodimide (EDC) and dimethylaminopyridine (DMAP) to obtain the esters (4-5) as oily products. The esters (4-5) were quaternized with methyl iodide to obtain the desired quaternary derivatives (6-7) as shown in Scheme 1. All the compounds were characterized by their spectral and elemental data.

Scheme 1

Stability study

HPLC method has been developed for the determination of purity and stability study of the synthesized derivatives in phosphate buffer ph 7.4 and in human plasma. All synthesized derivatives shows good stability in phosphate buffer at pH 7.4 (half life of disappearance 30-45 h) but get hydrolysed fast in human plasma (half life 8-12 h).

γ-Imaging studies

In order to check the site specific concentration of these quaternary derivatives (6-7) radiolabelling was done using radioactive 99mTc, Radiolabeling of the compounds with 99mTc was carried out by direct labeling method to form complex and study their site specific localization tendency in the inflamed tissue. The in vitro stability of radiolabeled complexes was determined in sodium chloride (0.9%) and in human serum. Once the complexed derivatives (99mTc–QA) were found to be stable then imaging study was performed in Sprague-Dawley rats using a Single Photon Emission Computerized Tomography gamma camera and both derivatives shows higher affinity towards cartilage than parent NSAID.

Conclusions

Cartilage targeting strategy for the conventional NSAIDs has been explored for reducing their local and systemic side effects the NSAIDs. These esters showed the tendency for selective accumulation into the inflamed tissues. Selective concentration of these ester derivatives into the tissue in demand could also allow reduction in their doses. It could be concluded that site specific delivery of these quaternary ester derivatives could prove to be an effective strategy for long term therapy of inflammatory conditions like arthritis.[23]