Stability and compatibility of admixtures containing bupivacaine hydrochloride and ketorolac tromethamine for parenteral use.

OBJECTIVE: Bupivacaine hydrochloride (BH) and ketorolac tromethamine (KT) are commonly used in parenteral admixtures to manage postoperative pain. However, stability and compatibility data for these admixtures applicable to current practice are limited, posing the patient to potential risk. METHODS: The stability of BH/KT admixtures in commonly used parenteral fluids was studied in Eppendorf tubes and glass vials at ambient room temperature using a newly developed and validated stability-indicating high-performance liquid chromatography (HPLC) method capable of the simultaneous quantification of both drugs. The chemical compatibility of BH/KT was assessed using Fourier transform infrared spectroscopy (FTIR) and thermal analysis. Additionally, the validity of the developed HPLC method for the quantification of BH/KT in human plasma was evaluated. RESULTS: BH and KT demonstrated <10% loss of their initial concentrations when prepared in Ringer, normal saline or dextrose solution at ambient temperature for up to 4 weeks. FTIR and thermal analysis demonstrated mild intermolecular interactions between BH and KT in solution, with no evidence of incompatibility. The developed HPLC method demonstrated satisfactory accuracy and precision for the simultaneous quantification of BH and KT in human plasma over the range of 0.2-3.2 µg·mL-1. CONCLUSION: BH/KT parenteral admixtures are chemically stable for a period of 4 weeks when stored at room temperature. The stability-indicating HPLC method is valid for BH/KT simultaneous determination in human plasma, facilitating pharmacokinetics studies.

Increasing the Hydrophobic Component of Poloxamers and the Inclusion of Salt Extend the Release of Bupivacaine from Injectable In Situ Gels, While Common Polymer Additives Have Little Effect.

Various strategies have been applied to reduce the initial burst of drug release and sustain release from poloxamer-based thermoresponsive gels. This work focussed on investigating different formulation approaches to minimise the initial burst of release and sustain the release of the small hydrophilic drug bupivacaine hydrochloride from poloxamer-based thermoresponsive gels. Various in situ gel formulations were prepared by varying the polypropylene oxide (PPO)/polyethylene oxide (PEO) ratio and by adding additives previously described in the literature. It was observed that increasing the PPO/PEO ratio from 0.28 to 0.30 reduced the initial burst release from 17.3% ± 1.8 to 9.1% ± 1.2 during the first six hours and extended the release profile from 10 to 14 days. Notably, the inclusion of sodium chloride (NaCl 0.4% w/w) further reduced the initial burst release to 1.8% ± 1.1 over the first 6 h. Meanwhile, physical blending with additive polymers had a negligible effect on the burst release and overall release profile. The findings suggest that extended release of bupivacaine hydrochloride, with reduced initial burst release, can be achieved simply by increasing the PPO/PEO ratio and the inclusion of NaCl.

In situ gelling system for sustained intraarticular delivery of bupivacaine and ketorolac in sheep.

Suboptimal control of postoperative pain following knee arthroplasty can slow recovery and reduce patient satisfaction. Intraarticular (IA) administration of bupivacaine and ketorolac offers efficient pain control and minimizes opioid consumption. However, the clinical benefits of this approach are short lived due to rapid clearance of drugs from the joint cavity. Here, we describe a poloxamer based thermoresponsive in situ gelling system for the sustained IA delivery of bupivacaine hydrochloride (BH) and ketorolac tromethamine (KT) following knee surgery in an ovine model. Drug loaded formulations were prepared using poloxamer 407, poloxamer 188 and sodium chloride. In vitro characterization was conducted, followed by in vivo evaluation of sustained drug release and safety in an ovine model of knee joint surgery. Rheological studies revealed a Newtonian-like flow of the developed formulation at room temperature, confirming its injectability, followed by a transition to a viscous gel as temperature approached body temperature. The developed formulation successfully sustained the in vivo release of BH for 72 h and KT for 48 h, as determined by circulating drug levels, compared to 24 and 8 h for marketed drug solutions. The concentrations of BH and KT in the synovial fluids at 72 h were 11.5 and 1.8 times that of marketed products, suggesting a significant increase in the IA residence time. The developed formulation induced a comparable inflammatory response compared to the marketed drug solutions, however a significantly higher chondrotoxicity was observed following administration of the gel formulations. Poloxamers based in situ gelling systems are promising delivery platforms for the sustained and localised IA delivery of BH and KT, with potential clinical benefits in managing the postoperative pain following knee arthroplasty.

Injectable In Situ Gelling System for Sustained Nicotine Delivery as a Replacement Therapy for Smoking Cessation.

Nicotine replacement therapy (NRT) is widely used to limit the withdrawal symptoms associated with cigarette smoking cessation. However, the available NRT formulations are limited by their short release profiles, requiring frequent administrations along with local side effects. Thus, the objective of this study is to develop an NRT formulation that offers prolonged, sustained nicotine release. Thermoresponsive in situ gelling systems containing nicotine were prepared using poloxamer 407 (P407) and poloxamer 188 (P188). The system was optimized using a three-factor, two-level full factorial design (23). A formulation composed of P407 (20% w/w), P188 (5% w/w), and loaded with nicotine (0.5% w/w) exhibited sol-to-gel transition at a suitable temperature close to physiological temperature (30 °C). The rheological analysis demonstrated a Newtonian-like flow at room temperature, suggesting ease of administration via injection, and semisolid gel status at physiological temperature. The optimized formulation successfully sustained nicotine in vitro release over 5 days following single administration. The findings suggest that poloxamer based in situ gelling systems are promising platforms to sustain the release of nicotine.

Injectable thermoresponsive gels offer sustained dual release of bupivacaine hydrochloride and ketorolac tromethamine for up to two weeks.

Bupivacaine and ketorolac are commonly used in combination to reduce perioperative pain. This study aimed to develop and characterize an injectable system that offers simultaneous and prolonged release of bupivacaine and ketorolac. Formulations were prepared using poloxamer 407 with increasing concentrations of poloxamer 188 and sodium chloride. Small Angle X-ray Scattering (SAXS) experiments demonstrated that the poloxamers form gels with a cubic lattice arrangement regardless of the matrix composition, whereas the system porosity is driven by poloxamers concentration. Drug loading slightly reduced the intermicellar spacing. Fourier transform infrared spectroscopy and thermal analysis suggested electrostatic interactions between the loaded drugs and poloxamers. Mechanical and rheological studies confirmed the formulations exhibit Newtonian-like flow at room temperature followed by a transition to a viscous gel at body temperature. Importantly, the developed formulations demonstrated steady and sustained release of both bupivacaine and ketorolac over two weeks. Sodium chloride reduced the initial burst release over the first six hours for BH, from 8.6 ± 0.18% to 1.6 ± 0.11%, and KT, from 7.7 ± 0.27% to 1.5 ± 0.10%. Hence, poloxamer-based thermoresponsive gelling systems are promising delivery platforms for the sustained delivery of bupivacaine and ketorolac, with potential clinical benefits for managing perioperative pain.

Sustained Delivery of Lactoferrin Using Poloxamer Gels for Local Bone Regeneration in a Rat Calvarial Defect Model.

Lactoferrin (LF) is a multifunctional milk glycoprotein that promotes bone regeneration. Local delivery of LF at the bone defect site is a promising approach for enhancement of bone regeneration, but efficient systems for sustained local delivery are still largely missing. The aim of this study was to investigate the potential of the poloxamers for sustained delivery of LF to enhance local bone regeneration. The developed LF/poloxamer formulations were liquid at room temperature (20 °C) transforming to a sustained releasing gel depot at body temperature (37 °C). In vitro release studies demonstrated an initial burst release (~50%), followed by slower release of LF for up to 72 h. Poloxamer, with and without LF, increased osteoblast viability at 72 h (p < 0.05) compared to control, and the immune response from THP-1 cells was mild when compared to the suture material. In rat calvarial defects, the LF/poloxamer group had lower bone volume than the controls (p = 0.0435). No difference was observed in tissue mineral density and lower bone defect coverage scores (p = 0.0267) at 12 weeks after surgery. In conclusion, LF/poloxamer formulations support cell viability and do not induce an unfavourable immune response; however, LF delivery via the current formulation of LF200/poloxamer gel did not demonstrate enhanced bone regeneration and was not compatible with the rat calvarial defect model.

Formulation strategies to modulate drug release from poloxamer based in situ gelling systems.

Introduction: Poloxamer based in situ gelling systems offer numerous advantages in drug delivery; however, their application as prolonged-release delivery platforms is limited mainly due to their weak mechanical properties and the interconnected aqueous network causing fast gel erosion and drug diffusion.Area covered: The focus of this review is to provide an insightful discussion on the formulation strategies that can be employed to sustain/prolong the drug release from poloxamer based in situ gelling systems. The review also outlines the formulation factors, influencing drug release from these systems.Expert opinion: The nature, composition, and concentration of poloxamers are the most critical factors in defining the rate of drug release from an in situ gelling matrix. Hydrophobic gel matrices have compact micellar arrangements resulting in slow diffusion and erosion. Depending on the intended clinical application, gel characteristics can be modulated, either by physical blending or by chemical crosslinking with additive materials, to slow release and improve residence time at the administration site. Incorporating drug-loaded particles into poloxamer gels sustains drug release by creating multiple rate-limiting release barriers. Chemical modification of poloxamers appears to be a promising strategy to obtain prolonged sustained release for parenteral application without compromising the rheological properties of the formulation.