A randomized trial: The safety, pharmacokinetics and preliminary pharmacodynamics of ropivacaine oil delivery depot in healthy subjects.

INTRODUCTION: Ropivacaine oil delivery depot (RODD) can slowly release ropivacaine and block nerves for a long timejavascript:;. The aim of the present work was to investigate the safety, pharmacokinetics, and preliminary pharmacodynamics of RODD in subcutaneous injection among healthy subjects. METHODS: The abdomens of 3 subjects were subcutaneously administered with a single-needle RODD containing 12~30 mg of ropivacaine. The irritation, nerve blocking range and optimum dose were investigated. Forty-one subjects were divided into RODD groups containing 150, 230, 300, 350 and 400 mg of ropivacaine and a ropivacaine hydrochloride injection (RHI) 150 mg group. Multineedle subcutaneous injection of RODD or RHI was performed in the abdomens of the subjects. The primary endpoint was a safe dose or a maximum dose of ropivacaine (400 mg). Subjects' vital signs were observed; their blood was analyzed; their cardiovascular system and nervous systems were monitored, and their dermatological reactions were observed and scored. Second, the ropivacaine concentrations in plasma were determined, pharmacokinetic parameters were calculated, and the anesthetic effects of RODD were studied, including RODD onset time, duration and intensity of nerve block. RESULTS: Single-needle injection of RODD 24 mg was optimal for 3 subjects, and the range of nerve block was 42.5±20.8 mm. Multineedle subcutaneous injection of RODD in the abdomens of subjects was safe, and all adverse events were no more severe than grade II. The incidence rate of grade II adverse events, such as pain, and abnormal ST and ST-T segment changes on electrocardiography, was approximately 1%. The incidence rate of grade I adverse events, including erythema, papules, hypertriglyceridemia, and hypotension was greater than 10%. Erythema and papules were relieved after 24 h and disappeared after 72 h. Other adverse reactions disappeared after 7 days. The curve of ropivacaine concentration-time in plasma presented a bimodal profile. The results showed that ropivacaine was slowly released from the RODD. Compared with the 150 mg RHI group, Tmax was longer in the RODD groups. In particular, Tmax in the 400 mg RODD group was longer than that in the RHI group (11.8±4.6 h vs. 0.77±0.06 h). The Cmax in the 150 mg RODD group was lower than that in the 150 mg RHI group (0.35±0.09 vs. 0.58±0.13 µg·mL-1). In particular, the Cmax increased by 48% when the dose was increased by 2.6 times in the 400 mg group. Cmax, the AUC value and the intensity of the nerve block increased with increasing doses of RODD. Among them, the 400 mg RODD group presented the strongest nerve block (the percentage of level 2 and 3, 42.9%). The corresponding median onset time was 0.42 h, and the duration median was 35.7⁓47.7 h. CONCLUSIONS: RODD has a sustained release effect. Compared with the RHI group, Tmax was delayed in the RODD groups, and the duration of nerve block was long. No abnormal reaction was found in the RODD group containing 400 mg of ropivacaine after subcutaneous injection among healthy subjects, suggesting that RODD was adequately safe. TRIAL REGISTRATION: Chictr.org: CTR2200058122; Chinadrugtrials.org: CTR20192280.

Pharmacodynamics, toxicology and toxicokinetics of ropivacaine oil delivery depot.

BACKGROUND: Ropivacaine oil delivery depot (RODD) can be used to treat postoperative incision pain. The aim was to study pharmacodynamics, toxicity and toxicokinetics of RODD. METHODS: The base research of RODD were conducted. Thirty rabbits were randomly divided into saline, solvent, ropivacaine aqueous injection (RAI) 0.9 mg, RODD 0.9 mg and RODD 3 mg groups. The sciatic nerve of rabbits were isolated, dripped with RODD and the effect of nerve block were observed. In toxicity study, the rats were divided into saline, solvent and RODD 75, 150 and 300 mg/kg groups, 30 rats per group. In toxicokinetics, rats were divided into RODD 75, 150 and 300 mg/kg groups, 18 rats per group. The rats were subcutaneously injected drugs. RESULTS: The analgesic duration of RODD 3 mg and RAI 0.9 mg blocking ischiadic nerve lasted about 20 h and 2 h, respectively, and their blocking intensity was similar. The rats in RODD 75 mg/kg did not show any toxicity. Compared with saline group, in RODD 150 mg/kg group neutrophils and mononuclear cells increased, lymphocytes decreased and albumin decreased(P < 0.05), and pathological examination showed some abnormals. In RODD 300 mg/kg group, 10 rats died and showed some abnormalities in central nerve system, hematologic indexes, part of biochemical indexes, and the weights of spleen, liver, and thymus. However, these abnormal was largely recovered on 14 days after the dosing. The results of toxicokinetics of RODD 75 mg/kg group showed that the Cmax was 1.24 ± 0.59 µg/mL and the AUC(0-24 h) was 11.65 ± 1.58 h·µg/mL. CONCLUSIONS: Subcutaneous injection RODD releases ropivacaine slowly, and shows a stable and longer analgesic effect with a large safety range.

Preparation and Evaluation of Lipid Emulsion Containing 13 Vitamins for Injection Without Anaphylactoid Reactions.

OBJECTIVE: Multivitamins containing Tween 80 can cause anaphylactoid reactions. The objective of this study was to develop a new lipid emulsion containing 13 fat- and water-soluble vitamins for injection (13V-LE) that were simultaneously dissolved in one bottle and to evaluate the stability of and anaphylactoid reactions to 13V-LE. METHODS: Particle size, ζ-potential, and polydispersity of 13V-LE were assayed with a Zetasizer Nano ZS. Entrapment efficiency of 13V-LE was determined with HPLC. Behavior, histamine, and blood pressure of beagle dogs were investigated by observation, fluorospectrophotometry, and sphygmomanometry. RESULTS: The 13V-LE with the smallest particles and highest entrapment efficiency with stable ζ-potential was composed of soybean oil, glycerin (2.25%, w:v), egg lecithin (1.2%, w:v), and purified water. There was no obvious change in characteristics of the 13V-LE samples in terms of appearance, size distribution, ζ-potential, pH value, or concentration over 6 months. In anaphylactoid reactions tests, when being administered with the multivitamin Infuvite Adult containing Tween 80, six beagles showed grade IV symptoms (P<0.01 vs control), low blood pressure, and high plasma-histamine concentrations (P<0.05 or P<0.01). However, there were no significant differences in behavior, blood pressure, or histamine concentration in the dogs before and after administration in the 13V-LE group. CONCLUSION: The 13V-LE formulation is a suitable intravenous lipid emulsion without anaphylactoid reactions.

[Property of liposomal fusion induced by acid-sensitive polymer].

The fusion between liposome-liposome, liposome-biomembarnes induced by acid-sensitive polymers has been systematically investigated. The polymer-liposomes were constructed by post-insertion method with the poly (2-ethylacrylic acid) (PEAA) alkylamide derivatives. The liposomal fusion was studied by use of fluorescence resonance energy transfer assay, particle size, fluorescent-photometer. The results indicated that the poly (2-ethylacrylic acid)-liposomes has very strong acidic induced fusion capability. Under acidic conditions, acid-sensitive polymer liposomes fused each other, the fusion closely related to the molecular weight of acid sensitivity polymer on the surface of liposomes. The acidic fusion of polymer-liposomes was dependent upon the lipids composition, the degree of fusion was reversely related to the cholesterol contents. Acid-en ci-nsitive polymer liposomes fused with erythrocyte ghosts. The liposomal fusion induced by acid-sensitive polymer associated with the increase of membrane permeability. The good acid-sensitivity of PEAA has been further demonstrated by membrane fusion in current experiments, and the liposomes prepared with lipid anchored-poly (2-ethylacrylic acid) were developeds s a potential pH sensitive delivery system.

[Preparation and thermo-sensitivity behavior of polymer liposomes made of poly(2-ethylacrylic acid) alkylamide derivatives].

The temperature-sensitive liposomes were constructed by poly (2-ethylacrylic acid) (PEAA) alkylamide derivatives that were synthesized for partially modification of carboxylic groups. The thermal characteristics of liposomes were investigated by using fluorescent indicator, particle size device and fluorescence spectrophotometer system. The results showed that the liposome made of fatty amine-modified poly(2-ethylacrylate) had a marked thermal sensitive release of drugs, which is correlated with the structure of molecular of polymer and the initial ratio of composition of phospholipid. The PEAA-associated-liposomes were also shown pH-sensitive drug release under acidic condition. The poly (2-ethylacrylate) for the preparation of medium-induced thermal liposomes in vitro experiments showed a good thermal characteristics and the methods of preparing temperature-sensitive liposomes were convenient and stability.