An Injectable Oil-Based Depot Formulation of <i>N</i>-Acyloxymethyl Prodrug of Ropivacaine for Long-Acting Local Analgesia: Formulation Development and In Vitro/In Vivo Evaluation
<b>Objectives:</b> The development of novel long-acting injectables for local anesthetics is necessary to effectively manage the acute postoperative pain. The aim of this study was to prepare an injectable oil-based formulation of ropivacaine (ROP) prodrug (ropivacaine stearoxil, ROP-ST)...
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| author | Xiaowei Liu Ruihan Zhao Peijie Xu Jianqiang Qian Peiyan Zhang Xudong Xie Yong Ling Qimin Ge Yong Chen |
| author_facet | Xiaowei Liu Ruihan Zhao Peijie Xu Jianqiang Qian Peiyan Zhang Xudong Xie Yong Ling Qimin Ge Yong Chen |
| author_sort | Xiaowei Liu |
| collection | DOAJ |
| description | <b>Objectives:</b> The development of novel long-acting injectables for local anesthetics is necessary to effectively manage the acute postoperative pain. The aim of this study was to prepare an injectable oil-based formulation of ropivacaine (ROP) prodrug (ropivacaine stearoxil, ROP-ST) and to investigate the pharmacokinetics and pharmacodynamics after injectable administration. <b>Methods:</b> A novel <i>N</i>-acyloxymethyl prodrug of ROP, i.e., ROP-ST, was synthesized and its physicochemical properties such as log P, solubility and stability characterized. A soybean oil-based depot of ROP-ST was prepared, and the in-vitro release of ROP-ST was evaluated using an “inverted-cup” method. Pharmacokinetic profiles and tissue retention properties were investigated after intramuscular administration of the formulation in rats. The analgesic efficacy was assessed via a von Frey monofilaments test by measuring the paw withdrawal thresholds. <b>Results:</b> The structure of ROP-ST was ascertained with clear <sup>1</sup>H NMR assignment and accurate mass-to-charge ratio. The high Log P value of ROP-ST (9.16) demonstrated extremely low aqueous solubility, but the prodrug is biolabile when in contact with plasma or liver esterase. Intramuscular injection of ROP-ST oil solution in rats provided a significantly higher mean residence time without a very clear plasma peak of ROP. In a postoperative pain model of rats, the injection of ROP-ST oil solution into the vicinity of the sciatic nerve in the right ankle effectively controlled the postoperative pain for at least 72 h. <b>Conclusions:</b> The injectable oil-based depot formulation of <i>N</i>-acyloxymethyl prodrug of ROP may provide a new opportunity of long-acting local analgesia for postoperative pain. |
| format | Article |
| id | doaj-art-cd952b40eb6f43ef849c5624f2ae4788 |
| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj-art-cd952b40eb6f43ef849c5624f2ae47882025-01-24T13:45:40ZengMDPI AGPharmaceutics1999-49232024-12-011713710.3390/pharmaceutics17010037An Injectable Oil-Based Depot Formulation of <i>N</i>-Acyloxymethyl Prodrug of Ropivacaine for Long-Acting Local Analgesia: Formulation Development and In Vitro/In Vivo EvaluationXiaowei Liu0Ruihan Zhao1Peijie Xu2Jianqiang Qian3Peiyan Zhang4Xudong Xie5Yong Ling6Qimin Ge7Yong Chen8School of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, ChinaSchool of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, ChinaSchool of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, ChinaSchool of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, ChinaSchool of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, ChinaSchool of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, ChinaSchool of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, ChinaSchool of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, ChinaSchool of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, China<b>Objectives:</b> The development of novel long-acting injectables for local anesthetics is necessary to effectively manage the acute postoperative pain. The aim of this study was to prepare an injectable oil-based formulation of ropivacaine (ROP) prodrug (ropivacaine stearoxil, ROP-ST) and to investigate the pharmacokinetics and pharmacodynamics after injectable administration. <b>Methods:</b> A novel <i>N</i>-acyloxymethyl prodrug of ROP, i.e., ROP-ST, was synthesized and its physicochemical properties such as log P, solubility and stability characterized. A soybean oil-based depot of ROP-ST was prepared, and the in-vitro release of ROP-ST was evaluated using an “inverted-cup” method. Pharmacokinetic profiles and tissue retention properties were investigated after intramuscular administration of the formulation in rats. The analgesic efficacy was assessed via a von Frey monofilaments test by measuring the paw withdrawal thresholds. <b>Results:</b> The structure of ROP-ST was ascertained with clear <sup>1</sup>H NMR assignment and accurate mass-to-charge ratio. The high Log P value of ROP-ST (9.16) demonstrated extremely low aqueous solubility, but the prodrug is biolabile when in contact with plasma or liver esterase. Intramuscular injection of ROP-ST oil solution in rats provided a significantly higher mean residence time without a very clear plasma peak of ROP. In a postoperative pain model of rats, the injection of ROP-ST oil solution into the vicinity of the sciatic nerve in the right ankle effectively controlled the postoperative pain for at least 72 h. <b>Conclusions:</b> The injectable oil-based depot formulation of <i>N</i>-acyloxymethyl prodrug of ROP may provide a new opportunity of long-acting local analgesia for postoperative pain.https://www.mdpi.com/1999-4923/17/1/37ropivacaineprodrugoil depotlong-acting injectablessustained releaselocal analgesia |
| spellingShingle | Xiaowei Liu Ruihan Zhao Peijie Xu Jianqiang Qian Peiyan Zhang Xudong Xie Yong Ling Qimin Ge Yong Chen An Injectable Oil-Based Depot Formulation of <i>N</i>-Acyloxymethyl Prodrug of Ropivacaine for Long-Acting Local Analgesia: Formulation Development and In Vitro/In Vivo Evaluation Pharmaceutics ropivacaine prodrug oil depot long-acting injectables sustained release local analgesia |
| title | An Injectable Oil-Based Depot Formulation of <i>N</i>-Acyloxymethyl Prodrug of Ropivacaine for Long-Acting Local Analgesia: Formulation Development and In Vitro/In Vivo Evaluation |
| title_full | An Injectable Oil-Based Depot Formulation of <i>N</i>-Acyloxymethyl Prodrug of Ropivacaine for Long-Acting Local Analgesia: Formulation Development and In Vitro/In Vivo Evaluation |
| title_fullStr | An Injectable Oil-Based Depot Formulation of <i>N</i>-Acyloxymethyl Prodrug of Ropivacaine for Long-Acting Local Analgesia: Formulation Development and In Vitro/In Vivo Evaluation |
| title_full_unstemmed | An Injectable Oil-Based Depot Formulation of <i>N</i>-Acyloxymethyl Prodrug of Ropivacaine for Long-Acting Local Analgesia: Formulation Development and In Vitro/In Vivo Evaluation |
| title_short | An Injectable Oil-Based Depot Formulation of <i>N</i>-Acyloxymethyl Prodrug of Ropivacaine for Long-Acting Local Analgesia: Formulation Development and In Vitro/In Vivo Evaluation |
| title_sort | injectable oil based depot formulation of i n i acyloxymethyl prodrug of ropivacaine for long acting local analgesia formulation development and in vitro in vivo evaluation |
| topic | ropivacaine prodrug oil depot long-acting injectables sustained release local analgesia |
| url | https://www.mdpi.com/1999-4923/17/1/37 |
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