(T1030-07-41) Development of N-Salsalate Parenteral Nanosuspension: A Safe and Effective Analgesic for Post-Operative Pain Management

Purpose: Post-operative pain management remains a significant challenge, affecting millions of surgical patients globally each year. Current approaches primarily rely on opioids and non-opioids, both posing substantial limitations. Opioids carry a high risk of addiction, while traditional NSAIDs (non-steroidal anti-inflammatory drugs) can cause gastrointestinal complications and other serious adverse events (SAEs). These limitations highlight the critical need for safer and more effective post-operative pain management strategies. Salsalate, a derivative of salicylic acid, emerges as a promising candidate due to its safer analgesic properties and lack of addiction risk. However, it suffers from limited bioavailability, hindering its therapeutic effectiveness. It is sparingly soluble in aqueous buffers and difficult to deliver by intravenous (IV) route. To address this challenge and unlock the full potential of salsalate, we propose the development of a freeze dried nanosuspension for IV administration for post-operative pain management. This improved bioavailability has the potential to translate into reduced dose and greater therapeutic efficacy compared to traditional pain management.

Methods: For preparation of the salsalate nanosuspension (N-salsalate), a top-down approach used with dual centrifugation nano-milling. The drug was first dispersed in sterile water containing various combinations of FDA-approved (Inactive Ingredient Database) polymers and surfactants for parenteral application. Particle size, size distribution, and zeta potential of the N-salsalate were measured to assess the impact of the selected stabilizers. The optimized formulation was then scaled up from a screening size (1 mL) to a lab-scale batch size (35 mL). To optimize the freeze-drying process for long-term storage, lyoprotectants were screened to minimize damage during freezing, followed by lyophilization. The redispersion of freeze-dried powder performed in sterile water for injection, Particle size and zeta potential were again measured before and after freeze-drying to ensure their re-dispersibility. A solubilization test was performed in phosphate buffer (pH 7.4) to mimic physiological conditions relevant to potential in vivo applications. Additionally, the crystalline state and morphology of the N-salsalate were compared to its excipients using solid-state characterization techniques and electron microscopy (SEM/TEM). The chemical stability, degradation profile, and drug content of the optimized N-salsalate formulation and freeze-dried powder were evaluated using high-performance liquid chromatography (HPLC) at storage temperatures of 4°C and 25°C. Finally, to ensure sterility, the N-salsalate formulation was freeze-dried and sterilized using gamma radiation.

Results: Wet media milling with a combination of PVP-K17, mPEG-2000-DSPE, and Tween 80 yielded stable N- salsalate nanocrystals with a high drug load (45% w/w), small particle size (152 ± 11.5 nm), narrow size distribution (PDI 0.169), and negative zeta potential (-22.5 mV). Lyoprotectant screening identified a freeze-dried formulation with combination of trehalose and HP-β-CD as lyoprotectants, enabling easy redispersion in water for injection (WFI). The redispersed N-salsalate maintained a targeted particle size ( < 300 nm) and zeta potential (-30.0 mV) suitable for intravenous administration. The N-salsalate formulation shows very rapid dispersion in WFI and spontaneous solubilization in phosphate buffer saline pH 7.4 due to high solubility ( >3 mg/mL), suggesting rapid solubility in plasma for therapeutic activity. Chemical analysis of the freeze-dried product revealed less than 2% impurities, including salicylic acid. Differential Scanning Calorimetry (DSC) showed reduced crystallinity in the freeze-dried N-salsalate compared to the pure drug due to milling or freeze-drying process, while X-ray diffraction (XRPD) showed a similar 2ᶿ pattern confirmed the drug's crystalline nature remained intact after milling. Electron microscopy (SEM and TEM) confirmed significant particle size reduction and improved homogeneity at the nanoscale. The freeze-dried powder displayed a uniform matrix of nanosuspension embedded within the cryoprotectant. Gamma radiation sterilized freeze-dried powder samples showed no signs of microbial growth after inoculation with Fluid Thioglycolate Media (FTM), confirming sterility.

Conclusion: This study successfully developed a stable and injectable N-Salsalate nanosuspension formulation with a high drug load, desirable particle size and distribution, and a negative zeta potential for stability. Importantly, the N-salsalate nanosuspension readily re-dispersed and demonstrated rapid dissolution in a phosphate buffer saline (PBS) pH 7.4, suggesting its potential for quick in vivo action. The freeze-dried formulation-maintained stability and sterility, making it suitable for clinical applications.

Acknowledgements: This project was funded by RH Nanopharmaceuticals, NJ, USA

Fig. 1. Development and characterization of N-Salsalate (a) Graphical representation of nano-formulation technology, Liquid N-Salsalate (b) Hydrodynamic diameter (d.nm) peak of liquid N-Salsalate (c) Zeta potential (mV) of liquid N-Salsalate; (d) Hydrodynamic diameter (d.nm) peak for freeze-dried N-Salsalate; (e) Zeta potential (mV) peak for freeze-dried N-Salsalate.

Fig. 2. Thermal characterization of N-Salsalate (a) DSC thermograms for freeze-dried N-Salsalate compared to controls; (b) TGA curves for freeze-dried N-Salsalate compared to controls; (c) PXRD curves for freeze-dried N-Salsalate compared to controls.

Fig. 3. (a) SEM image for pure Salsalate drug (b) SEM image for freeze-dried N-Salsalate; (c) TEM image of liquid N-Salsalate; (d) Process-flow for reconstitution of freeze-dried N-Salsalate in WFI and spontaneous solubilization in phosphate buffer saline pH 7.4.