Preparation and characterization of intramuscularly long-acting celecoxib nanosuspensions for postoperative pain management

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most popular over-the-counter drugs. Celecoxib (CEL) is an orally administrated NSAID that inhibits prostaglandin synthesis by selectively blocking cyclooxygenase 2, used for pain management and arthritis treatment with numerous publications reporting its newfound anticarcinogenic and other pharmacological effects. The development of CEL long-acting injectable dosage forms for postoperative pain management is highly desirable. However, CEL is a Biopharmaceutical Classification System (BCS) Class II drug with low water solubility and high permeability. The development of new dosage forms and applications of CEL is compromised due to its dissolution characteristics.

In this current study, CEL is formulated into nanosuspensions, a type of drug delivery system tailored to increase drug dissolution rate and stimultaneously offer physical stability. The engineering of reducing particle size is critical to in vivo behaviors of CEL nanosuspensions when they are injected via intramuscular route to form a sustained-release depot. Based on the solubility study of CEL in water and various solvents and the safety data available, factoring in a safety ratio, Transcutol® HP was chosen as the solvent for the preparation of injectable CEL nanosuspensions. The nanosuspensions were prepared by the solvent exchange (anti-solvent) method. CEL nanosuspensions were characterized using various techniques including particle size (PS) analysis, powder X-ray diffraction, differential scanning calorimetry, and attenuated total reflection–Fourier transform infrared spectroscopy. In vitro release and in vivo pharmacokinetic studies of the optimal formulation were performed.

CEL nanosuspensions were produced by the solvent exchange method using Transcutol® HP and three different stabilizers (sodium lauryl sulfate, polyvinylpyrrolidone K12, and polyvinylpyrrolidone K30). PS of CEL nanosuspensions were 989–2018.4 nm, and the size varied depending on the type of surfactant. CEL nanosuspensions remained in the same crystalline state as raw CEL. In vitro release studies revealed sustained release over 5 days, and in vivo pharmacokinetic studies demonstrated that the nanosuspension formulations exhibited higher AUC (2.02- and 2.20-fold) compared to that of raw CEL, thus highlighting their potential for prolonged postoperative pain management. The relationship between PS and in vitro, in vivo behavior of CEL nanosuspensions was discussed.

These findings suggest that intramuscular CEL nanosuspensions have great potential as anti-inflammatory therapeutics for postoperative pain management.