A prodrug approach involving in situ depot formation to achieve localized and sustained action of diclofenac after joint injection.

Long-acting nonsteroidal anti-inflammatory drug formulations for intra-articular injection might be effective in the management of joint pain and inflammation associated sports injuries and osteoarthritis. In this study, a prodrug-based delivery system was evaluated. The synthesized diclofenac ester prodrug, a weak base (pKa 7.52), has relatively high solubility at low pH (6.5 mg mL(-1) at pH 4) and much lower solubility at physiological pH (4.5 µg mL(-1) at pH 7.4) at 37°C. In biological media including 80% (v/v) human synovial fluid (SF), the prodrug was cleaved to diclofenac mediated by esterases. In situ precipitation of the prodrug was observed upon addition of a concentrated slightly acidic prodrug solution to phosphate buffer or SF at pH 7.4. The degree of supersaturation accompanying the precipitation process was more pronounced in SF than in phosphate buffer. In the rotating dialysis cell model, a slightly acidic prodrug solution was added to the donor cell containing 80% SF resulting in a continuous appearance of diclofenac in the acceptor phase for more than 43 h after an initial lag period of 8 h. Detectable amounts of prodrug were found in the rat joint up to 8 days after knee injection of the acidic prodrug solution.

Prolonged naproxen joint residence time after intra-articular injection of lipophilic solutions comprising a naproxen glycolamide ester prodrug in the rat.

Intra-articular injection of oil solutions of lipophilic prodrugs that rapidly degrade to their parent compound in synovial fluid may constitute a feasible approach to increase the joint residence time of non-steroidal anti-inflammatory drugs. In this in vivo study, oil solutions of the N,N-diethyl glycolamide ester prodrug of naproxen (16 mg/ml) were injected into the rat knee joint by dosing 6 µl formulation per 100g body weight. The sustained release properties were compared to those of intra-articularly injected aqueous and oil solutions of naproxen by monitoring the naproxen serum concentrations over time. Two oils, medium-chain triglycerides and castor oil, differing with respect to viscosity were tested. After intra-articular administration of oil prodrug solutions, a significant increase in the time to maximum naproxen serum concentration from around 40 to 245 min, an increase in the MRT(j) from around 0.11 to 3.3h and a 30% reduction in the maximum serum concentration were observed compared to that of the parent naproxen. The similar serum profiles obtained using the two oils indicate that the release was not affected by the oil viscosity. A prolonged naproxen joint residence time in rats was shown by intra-articular injection of an oil prodrug solution.

Modification of concomitant drug release from oil vehicles using drug-prodrug combinations to achieve sustained balanced analgesia after joint installation.

Intra-articular injection of two drugs in a sustained drug delivery system combining the use of lipophilic solution with the prodrug approach may provide efficient and prolonged postoperative pain treatment after arthroscopic procedures. In the present study, the concomitant release of N,N-diethyl glycolamide ester of naproxen and ropivacaine from an oil vehicle consisting of medium-chain triglycerides were investigated in vitro. The release into both phosphate buffer and 80% (v/v) synovial fluid at pH 7.4 was examined in two dialysis membrane-based release models. The ester prodrug exhibited high solubility in medium-chain triglyceride, a high partition coefficient and was rapidly converted to naproxen in synovial fluid. Compared to naproxen, the release of the prodrug from the oil was sustained. In synovial fluid, the reconversion to naproxen resulted in faster release compared to that observed using buffer. In both release models, the use of ropivacaine-prodrug combination provided concomitant release from the oil into synovial fluid with ropivacaine being released faster than naproxen. The use of lipophilic prodrugs that are converted fast to the parent drug in synovial fluid seems to be a feasible approach to obtain prolonged joint residence time.

In vitro release from oil injectables for intra-articular administration: Importance of interfacial area, diffusivity and partitioning.

Most in vitro methods for evaluating parenteral oil based depots are focusing on intramuscular or subcutaneous injection. For intra-articular injection other mechanisms may control the overall drug release rate due to a relatively smaller interfacial area and longer transport distance of the drug substance in the oil to the oil-synovial fluid interface. In the current work, an in vitro model for testing drug release from oil solutions intended for intra-articular injection was evaluated. The release of the model drugs naproxen, piroxicam and ropivaciane from a well-defined surface area of the lipophilic solutions were followed using an in vitro model based on a modified USP II paddle apparatus with modest agitation (50rpm) of the oil formulation. By alteration of the viscosity of the oil, the oil-water interfacial area, the oil volume and the stirring efficiency of the release medium, it was shown that the drug release rate was dependent on the drug diffusivity in the oil and the degree of agitation generated in the oil vehicle. In addition, the partitioning of the drug between the oil vehicle and the release media was found to influence the release rate. In combination with an improved understanding of in vivo drug release and distribution, the present work may form a promising foundation for future in vivoin vitro correlations.

Thiol-disulfide interchange in the tocinoic acid/glutathione system during freezing and drying.

Thiol-disulfide interchange ("disulfide scrambling") is a common mechanism of covalent aggregation for protein drugs. Using tocinoic acid (cyclo-S-Cys-Tyr-Ile-Gln-Asn-Cys-(S); TA(ox)) and glutathione (γGlu-Cys-Gly; GSH), our previous work demonstrated that thiol/disulfide interchange is affected by lyophilization in a manner consistent with irreversible and regioselective loss of TA(ox) (Zhang et al., 2009, J Pharm Sci 98/9: 3312-3318). Here, we explore the contributions of stages of the lyophilization cycle to perturbations in thiol/disulfide interchange in the TA/GSH system. TA(ox) and GSH were co-lyophilized from phosphate buffer in the presence or absence of various excipients, then analyzed for TA(ox) and mixed disulfide products by reverse phase high performance liquid chromatography (rp-HPLC). Perturbations were found to occur primarily during freezing, before significant amounts of ice were removed by sublimation. Addition of a lyoprotectant (sucrose), a cryoprotectant (Tween-20) and flash-freezing influenced the product distribution only while ice was still present. Decreasing the redox potential by the addition of oxidized glutathione (GSSG) affected the product distribution differently in lyophilized samples and solution controls, but in neither case led to increased conservation of TA(ox).