Size control of ropivacaine nano/micro-particles by soft-coating with peptide nanosheets for long-acting analgesia.

Rationale: To meet the need of long-acting analgesia in postoperative pain management, slow-releasing formulations of local anesthetics (LAs) have been extensively investigated. However, challenges still remain in obtaining such formulations in a facile and cost-effective way, and a mechanism for controlling the release rate to achieve an optimal duration is still missing. Methods: In this study, nanosheets formed by a self-assembling peptide were used to encapsulate ropivacaine in a soft-coating manner. By adjusting the ratio between the peptide and ropivacaine, ropivacaine particles with different size were prepared. Releasing profile of particles with different size were studied in vitro and in vivo. The influence of particle size and ropivacaine concentration on effective duration and toxicity were evaluated in rat models. Results: Our results showed that drug release rate became slower as the particle size increased, with particles of medium size (2.96 ± 0.04 µm) exhibiting a moderate release rate and generating an optimal anesthetic duration. Based on this size, formulations at different ropivacaine concentrations generated anesthetic effect with different durations in rat sciatic nerve block model, with the 6% formulation generated anesthetic duration of over 35 h. Long-acting analgesia up to 48 h of this formulation was also confirmed in a rat total knee arthroplasty model. Conclusion: This study provided a facile strategy to prepare LA particles of different size and revealed the relationship between particle size, release rate and anesthetic duration, which provided both technical and theoretical supports for developing long-acting LA formulations with promising clinical application.

Preparation and evaluation of liposome with ropivacaine ion-pairing in local pain management.

Local analgesia is one of the most desirable methods for postoperative pain control, while the existing local anesthetics have a short duration of analgesic effect. Nano-drug carriers have been widely used in various fields and provide an excellent strategy for traditional drugs. Although the existing liposomes for local anesthetics have certain advantages, their instability and complexity of the preparation process still cannot be ignored. Here, we developed novel ropivacaine hydrochloride liposomes with improved stability and sustained release performance by combining ropivacaine hydrochloride with sodium oleate in liposomes via hydrophobic ion-pairing (HIP). The liposomes are easy to prepare, inexpensive, and suitable for mass production. The infrared (IR), particle size, and Zeta potential measurements adequately characterized the complex, which showed a diameter of 81.09 nm and a zeta potential of -83.3 mV. Animal behavioral experiments, including the hot plate test and von Frey fiber test, demonstrated that the liposome system had a prolonged analgesic effect of 2 h versus conventional liposome preparations, consistent with the results of in vitro release experiments. In addition, in vitro cytotoxicity evaluations in RAW264.7 cells and in vivo evaluations revealed the biocompatibility and safety of the ropivacaine-sodium oleate ion-paired liposome (Rop-Ole-Lipo) system as a suitable local anesthetic for local pain management. Our findings provide a new idea for the preparation of local anesthetics.

Physicochemical Stability of Ternary Mixtures of Sufentanil, Baclofen, and Ropivacaine in Polypropylene Syringes for Intrathecal Analgesia.

Intrathecal analgesia is a method using various molecules alone or in combination. Among these, a preparation of sufentanil-ropivacaine-baclofen is widely used. Instead of moving patients to the few expert centers taking charge of these specific preparations, it could be beneficial to transport syringes to peripheral centers who manage pump refills. The objective of this study was to determine the physicochemical compatibility and stability of a preparation of sufentanil, ropivacaine, and baclofen in polypropylene syringes. Drugs were mixed together at different concentrations and stored with light protection at 5°C ± 3°C and 25°C ± 2°C. The stabilities were determined by visual inspection, turbidity, pH measurement, and ultra-high-pressure liquid chromatography assay of drug concentrations. The concentrations of ropivacaine, baclofen, and sufentanil were stable after 7 days at 5°C ± 3°C and no degradation of product appeared. The drug mixtures were clear in appearance and no color change or precipitation was observed. Throughout this period, the absorbance and the pH value of samples remained stable. The preparations of sufentanil, baclofen, and ropivacaine remained stable for at least 7 days when stored in polypropylene syringes at 5°C ± 3°C.

Simultaneous Determination of Ropivacaine and 3-Hydroxy Ropivacaine in Cerebrospinal Fluid by UPLC-MS/MS.

In this paper, a UPLC-MS/MS method was developed for the determination of ropivacaine and its metabolite 3-hydroxy ropivacaine in cerebrospinal fluid. The cerebrospinal fluid was processed by ethyl acetate liquid-liquid extraction. The multiple reaction monitoring (MRM) mode was used for quantitative analysis by monitoring the transitions of m/z 275.3 → 126.2 for ropivacaine, m/z 291.0 → 126.0 for 3-hydroxy ropivacaine, and m/z 290.2 → 198.2 for the internal standard. Standard curves for ropivacaine and 3-hydroxy ropivacaine in cerebrospinal fluid were conducted over the concentration range of 0.2-2000 ng/mL, demonstrating excellent linearity, and the lower limit of quantification was 0.2 ng/mL. The intraday precision of ropivacaine and 3-hydroxy ropivacaine was less than 11%, while the interday precision was less than 7%. The accuracy ranged between 87% and 107%, the average extraction efficiency was higher than 79%, and the matrix effect was between 89% and 98%. The developed method was then applied to a case of suspected poisoning of ropivacaine.

Development and Evaluation of Ropivacaine Loaded Poly(Lactic-Co-Glycolic Acid) Microspheres with Low Burst Release.

BACKGROUND: The local anesthetic drugs, especially ropivacaine, were considered favorable analgesia for postoperative management because of their effective local pain relief and low adverse effects. However, the short half-life and the resulting in bolus doses lead to the indistinctive improvement of these drugs in postoperative pain relief. Therefore, the ropivacaine microspheres with sustained release and low initial burst release were anticipated. METHODS: Three methods including oil in water (O/W), water in oil in water (W/O/W), and solid in oil in water (S/O/W) emulsion solvent evaporation method were used to optimize the ropivacaine loaded PLGA microspheres. The microspheres were evaluated both in vitro and in rats. The in vitro-in vivo correlation (IVIVC) was also investigated. RESULTS: The microspheres prepared by O/W method showed more satisfactory properties and the microspheres used for evaluation were prepared by O/W method. The particle size, drug loading, encapsulation efficiency and burst release were 11.19±1.24 µm, 28.37±1.15%, 98.15±3.98%, and 10.96±5.37% for microspheres with PLGA of 12 kDa, and 6.64±0.61 µm, 19.62±0.89%, 92.74±4.21%, and 18.42±5.12% for microspheres with PLGA of 8 kDa, respectively. These microspheres were also injected into rats by subcutaneous, intramuscular and intraperitoneal route, respectively. It was indicated that the detectable concentration of ropivacaine could last for at least 20 days for both kinds of microspheres in spite of injection routes. The low burst releases at 1 d were also manifested in rats and they were 6.62%, 6.99%, 6.48% for the microspheres with PLGA of 12 kDa, and 4.72%, 4.33%, 4.48% for the microspheres with PLGA of 8 kDa by intraperitoneal, intramuscular and subcutaneous route, respectively. A linear relationship between the in vitro release and the in vivo adsorption of ropivacaine from microspheres was also established. CONCLUSION: The ropivacaine microspheres with sustained release and low burst release were acquired, which indicated that the postoperative pain relief might last longer and the side effects might get lower. Therefore, the ropivacaine microspheres prepared in this paper have great potential for clinical use.

Ultrasound/Acidity-Triggered and Nanoparticle-Enabled Analgesia.

Local anesthetics have been extensively employed to treat postoperative pain, but they generally suffer from short acting duration and potential neurotoxicity under high local concentrations, which require the controlled and sustained releasing patterns of treatment drugs. In this work, it is reported, for the first time, the construction of hollow mesoporous organosilica nanoparticles (HMONs)-based nanoplatforms for localized delivery and controlled/sustained release of loaded ropivacaine for local anesthetics, which can be repeatedly triggered by either external ultrasound irradiation or acidity triggering to release the payload, causing on-demand and long-lasting analgesia. Based on the in vivo mouse model of incision pain, the controlled and sustained release of ropivacaine achieves more than six hours of continuous analgesia, which is almost three times longer as compared to single free ropivacaine injection. The low neurotoxicity and high biocompatibility of HMONs for nanoparticle-enabled analgesia are also demonstrated both in vitro and in vivo. This designed/constructed HMONs-based nanoplatform provides a potential methodology for clinical pain management via on-demand and long-lasting pain relief.

Preclinical studies of ropivacaine extended-release from a temperature responsive hydrogel for prolonged relief of pain at the surgical wound.

Postoperative pain is a common form of acute pain that has been treated commonly by local anesthetics through regional nerve blocking. In this study, a series of experiments were conducted using rats to investigate the pharmacokinetic, distribution, and efficacy of a temperature responsive hydrogel-based drug delivery device (PF-72) containing ropivacaine (0.75%) for extended relief of postoperative pain by allowing the prolonged release of ropivacaine. When the ropivacaine was administered using PF-72, its concentration-time curve (AUClast) and peak concentration (Cmax) were 577.0 h*ng/mL and 271.9 ng/mL, respectively. In contrast when the ropivacaine solution was administered using saline solution, its AUClast and Cmax were 982.8 h*ng/mL and 423.6 ng/mL, respectively. In the tissue distribution study, the peak concentration and mean area under the curve of the ropivacaine in injection area (target tissue) were found about 2-fold higher in the case of PF-72 compared with the case of conventional ropivacaine solution. These results clearly demonstrate the capability of PF-72 hydrogel to retain the ropivacaine at the injection site for an extended period. Effective extended (at least 24 h) pain relief of ropivacaine administered using PF-72 was found in the pharmacodynamic study of prolonged analgesic effect. The results of this study indicated that local drug delivery by PF-72 hydrogel formulation may be an effective method to achieve extended relief of pain. Other advantages of ropivacaine administration using PF-72 include reduced systemic side effects and high localization of a drug in target tissues.

Sucrose Acetate Isobutyrate as an In situ Forming Implant for Sustained Release of Local Anesthetics.

OBJECTIVE: In this study, an injectable Sucrose Acetate Isobutyrate (SAIB) drug delivery system (SADS) was designed and fabricated for the sustained release of Ropivacaine (RP) to prolong the duration of local anesthesia. METHODS: By mixing SAIB, RP, and N-methyl-2-pyrrolidone, the SADS was prepared in a sol state with low viscosity before injection. After subcutaneous injection, the pre-gel solution underwent gelation in situ to form a drug-released depot. RESULT: The in vitro release profiles and in vivo pharmacokinetic analysis indicated that RP-SADS had suitable controlled release properties. Particularly, the RP-SADS significantly reduced the initial burst release after subcutaneous injection in rats. CONCLUSION: In a pharmacodynamic analysis of rats, the duration of nerve blockade was prolonged by over 3-fold for the RP-SADS formulation compared to RP solution. Additionally, RP-SADS showed good biocompatibility in vitro and in vivo. Thus, the SADS-based depot technology is a safe drug delivery strategy for the sustained release of local anesthetics with long-term analgesia effects.

Preclinical Evaluation of Ropivacaine in 2 Liposomal Modified Systems.

BACKGROUND: Our research group has recently developed liposomes with ionic gradient and in a combined manner as donor and acceptor vesicles containing ropivacaine (RVC; at 2% or 0.75%). Looking for applications of such novel formulations for postoperative pain control, we evaluated the duration of anesthesia, pharmacokinetics, and tissue reaction evoked by these new RVC formulations. METHODS: The formulations used in this study were large multivesicular vesicle (LMVV) containing sodium acetate buffer at pH 5.5 or in a combined manner with LMVV as donor and large unilamellar vesicles (LUVs) as acceptor vesicles with an external pH of 7.4. Wistar rats were divided into 6 groups (n = 6) and received sciatic nerve block (0.4 mL) with 6 formulations of RVC (LMVVRVC0.75%, LMVV/LUVRVC0.75%, LMVVRVC2%, LMVV/LUVRVC2%, RVC 0.75%, and RVC 2%). To verify the anesthetic effect, the animals were submitted to the pain pressure test and the motor block was also monitored. Histopathology of the tissues surrounding the sciatic nerve region was also assessed 2 and 7 days after treatment. Rats (n = 6) were submitted to a hind paw incision, and mechanical hypersensitivity was measured via the withdrawal response using von Frey filaments after injection of the 6 formulations. Finally, New Zealand white rabbits (n = 6) received sciatic nerve block (3 mL) with 1 of the 6 formulations of RVC. Blood samples were collected predose (0 minutes) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, and 540 minutes after injection. RVC plasma levels were determined using a triple-stage quadrupole mass spectrometer. RESULTS: Duration and intensity of the sensory block were longer with all liposomal formulations, when compared to the plain RVC solution (P < .05). Histopathological evaluation showed greater toxicity for the positive control (lidocaine 10%), when compared to all formulations (P < .05). After the hind paw incision, all animals presented postincisional hypersensitivity and liposomal formulations showed longer analgesia (P < .05). LMVVRVC0.75% presented higher time to reach maximum concentration and mean residence time than the remaining formulations with RVC 0.75% (P < .05), so LMVV was able to reduce systemic exposure of RVC due to slow release from this liposomal system. CONCLUSIONS: All new liposomal formulations containing 0.75% RVC were able to change the pharmacokinetics and enhance anesthesia duration due to slow release of RVC from liposomes without inducing significant toxic effects to local tissues.

Injectable nanocomposite analgesic delivery system for musculoskeletal pain management.

Musculoskeletal pain is a major health issue which results from surgical procedures (i.e. total knee and/or hip replacements and rotator cuff repairs), as well as from non-surgical conditions (i.e. sympathetically-mediated pain syndrome and occipital neuralgia). Local anesthetics, opioids or corticosteroids are currently used for the pain management of musculoskeletal conditions. Even though local anesthetics are highly preferred, the need for multiple administration presents significant disadvantages. Development of unique delivery systems that can deliver local anesthetics at the injection site for prolonged time could significantly enhance the therapeutic efficacy and patient comfort. The goal of the present study is to evaluate the efficacy of an injectable local anesthetic nanocomposite carrier to provide sustained analgesic effect. The nanocomposite carrier was developed by encapsulating ropivacaine, a local anesthetic, in lipid nanocapsules (LNC-Rop), and incorporating the nanocapsules in enzymatically crosslinked glycol chitosan (0.3GC) hydrogels. Cryo Scanning Electron Microscopic (Cryo SEM) images showed the ability to distribute the LNCs within the hydrogel without adversely affecting their morphology. The study demonstrated the feasibility to achieve sustained release of lipophilic molecules from the nanocomposite carrier in vitro and in vivo. A rat chronic constriction injury (CCI) pain model was used to evaluate the efficacy of the nanocomposite carrier using thermal paw withdrawal latency (TWL). The nanocomposite carriers loaded with ropivacaine and dexamethasone showed significant improvement in pain response compared to the control groups for at least 7 days. The study demonstrated the clinical potential of these nanocomposite carriers for post-operative and neuropathic pain. STATEMENT OF SIGNIFICANCE: Acute or chronic pain associated with musculoskeletal conditions is considered a major health issue, with healthcare costs totaling several billion dollars. The opioid crisis presents a pressing clinical need to develop alternative and effective approaches to treat musculoskeletal pain. The goal of this study was to develop a long-acting injectable anesthetic formulation which can sustain a local anesthetic effect for a prolonged time. This in turn could increase the quality of life and rehabilitation outcome of patients, and decrease opioid consumption. The developed injectable nanocomposite demonstrated the feasibility to achieve prolonged pain relief in a rat chronic constriction injury (CCI) model.