Dissertation > Medicine, health > Pharmacy > Pharmacology

A Model to Evaluate the Pharmacokinetics and Pharmacodynamics of Poly(Lactide-co-glycolide) Containing-dexamethasone Ropivacaine Microspheres

Author YuRangHui
Tutor ChenZhongQing
School Southern Medical University,
Course Anesthesiology
Keywords Ropivacaine Dexamethasone acetate Polylactic acid- glycolic acid copolymer Microspheres w1/o/w2 double emulsion - solvent evaporation method High Performance Liquid Chromatography Pharmacodynamic Pharmacokinetics
Type Master's thesis
Year 2010
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Research background and purpose of postoperative pain in the peri-operative treatment process is an important problem. Injection of local anesthetic analgesic method is the most direct and effective treatment of postoperative pain. Local anesthetics reversibly block the application or injection of local nerve conduction of a specific area of ??the body to produce a temporary feeling of loss, but the clinical application of water-soluble local anesthetics can not be achieved by a single injection of a long town pain requirements. Currently, the analgesic time over 12 hours after the longest aging water-soluble local anesthetic is administered once. Often intermittent injection of local anesthetic or continuous administration through an indwelling catheter implanted in the clinical approach to achieve the the prolonged analgesic requirements, but requires expensive equipment and continuous monitoring. Administered too many times can cause drug accumulation can lead to the inhibition of respiration and circulation, may cause local anesthetic toxicity; prone to prolonged catheter infection or catheter shift and discounts, so these methods do not solve the long time analgesic good way. The lack of effective prolonged analgesic treatment highlights the need for new treatments in the field of pain therapy. Micro into a ball for nearly 40 years, a new technology applied to the field of pharmaceutical preparations, which is characterized by the use of natural or synthetic polymer carrier wrapped drugs as a controlled drug release, slow release of the drug, in order to prolong time for the purpose of drug action. Release microspheres have been used in many studies of anti-cancer drugs, antibiotics, eye diseases, gene therapy and the treatment of diabetes. The PLA and PLGA microspheres used in the study of the local anesthetic for about 30 years history. As early as 1981, Wakiyama N prepared PLA microspheres containing several local anesthetic the 1994 Le Corre research preparation and in vitro release of bupivacaine PLA and PLGA microspheres have proved wrapped in biodegradable material microsphere sustained release formulation of the local anesthetic bupivacaine preparation is feasible and can significantly extend the local anesthetic role in aging. The 1990s, Jean, MM, Fletcher D, Passcal LC, Jean PE number of scholars in different animals as subjects of bupivacaine release microspheres of drug pharmacokinetic and pharmacodynamic characteristics, the results showed that the cloth than tetracaine release microspheres can significantly extend the single-dose analgesic effect of time, and significantly reduce the fluctuations in the concentration of the drug in the body. 1996, Joanne C, 1998 Christiane D the local anesthetics microspheres containing a small amount of dexamethasone can be further extended on the basis of ordinary bupivacaine microspheres local anesthetic analgesic action time. But so far still no Department of Domestic ropivacaine release microspheres research reports. Ropivacaine structure, nature and metabolic pathways similar to bupivacaine, but with the central nervous system (CNS) and low toxicity characteristics of the cardiovascular system, the more prominent ropivacaine has a high degree of feeling - Sports nerve block separation characteristics, increase the possibility of the patient can quickly restore movement, is more suitable for the treatment of intractable pain for postoperative analgesia advanced cancer and trigeminal neuralgia, loaded PLGA microspheres prepared applications in the the analgesic field of very far-reaching research value. For these reasons, our group preliminary study the release characteristics of the of ropivacaine loaded PLGA microspheres and in vitro and in vivo animal experiments show that the new long-acting local anesthetic ropivacaine parcels drug carrier preparation PLGA The sustained-release microspheres are feasible, and having a significant sustained release effect. The purpose of this experiment using the W / O / W double emulsion method - dexamethasone loaded PLGA microspheres prepared ropivacaine Ropivacaine - dexamethasone acetate copolymer microspheres of PLGA implanted heat next to the rat sciatic nerve pain block the aging mice plasma concentration observed, examine ropivacaine - dexamethasone acetate the PLGA copolymer microspheres pharmacokinetics and pharmacodynamic characteristics. Research methods Rop-Dex-PLGA-MS Preparation: to adopt W1/o/W2 double emulsion - solvent evaporation method Luo the piperazine Ka Yinjia or without dexamethasone acetate PLGA microspheres, namely (1) accurately weighed PLGA and a certain amount of ropivacaine and dexamethasone acetate (OT) with double-distilled water and methanol dissolved as the water phase; (2) and the other to take appropriate emulsifier dissolved in dichloromethane as the organic phase, then the (1) and (2) were mixed with a high speed dispersion homogenizer homogeneous 90s made colostrum; (3) then the colostrum with a syringe is moved to the PVA aqueous solution, the external aqueous phase using high speed dispersion homogenizer homogeneous 90s obtained multiple emulsion; (4) the multiple emulsion on the thermostat on a magnetic stirrer stirring was continued centrifugation, filtration, double-distilled water three times, the microspheres were collected, vacuum freeze drying, storage in a temperature of 4 ° C in a dryer to be using high-performance liquid chromatography (HPLC). Rop-PLGA-MS and Rop-Dex-of PLGA-MS ropivacaine or (and) dexamethasone content. Animal preparation and grouping Kunming mice 165, the average body weight (30 ± 1.231) g, fasted for 12 h, free access to water, were randomly divided into three groups: ropivacaine - dexamethasone microsphere group (A , n = 55), ropivacaine microsphere group (B, n = 55) the blank microspheres group (C, n = 55); each group was implanted microspheres, 0.5, 1, 2, of 4,8,16,24,36,48,72,96 h time points were divided into 11 groups (n = 5). Method of administration and specimens collected after the mice were anesthetized group were implanted in the muscles around the gap in the sciatic nerve blank microspheres, microspheres of ropivacaine and ropivacaine - dexamethasone microspheres 400 mg.kg- Determination of the mice hind foot licking response latency time, every time, each implanted microspheres 0.5,1,2,4,8,16,24,36,48,72,96 h time point heat pedal law point determination of five mice, each mouse was measured five times at intervals of 5 min. Mice immediately after the end of each time point heat pedal Determination eyeball blood was about 0.8 of 1.0 ml, 0.1 ml of 1/2000 heparin, 3500 r / min centrifugation 8 min, 0.5 ml of extract plasma at -20 ° C to save , is detected to be a high performance liquid chromatograph (HPLC). Specimens and parameters HPLC Conditions Column: Shimpack VP-ODS 250 X 4.6 mm column temperature: room temperature; the flow: methanol: acetonitrile: water (20mMNaH2PO4, pH = 4.6) = 18:26:56 ( V: V: V), a flow rate of 1.0 ml.min-1; detection wavelength: Ropivacaine and Bupivacaine for 210 nm; neonatal dexamethasone treatment for the detection of a wavelength of 240 nm; internal standard solution: Bupivacaine; quantitative methods: external standard method. The injection volume of 20 ul, the minimum detection limit of 0.010 ug.ml-1. WinNonlin3P87DAS2.1.1 software line pharmacokinetic parameters of blood pharmacokinetic parameters calculated two sets of ropivacaine microspheres under the curve area (AUC), peak concentration (Cmax), peak concentration time (Tmax), elimination half-life time (t1 / 2). Statistically analyzed all experimental data using SPSS13.0 software and Origin6.0 of image software for statistical analysis and mapping, microspheres pharmacodynamics and plasma concentration data was used to compare the random unit group factorial analysis factor approach, two microspheres group blood at different time points with the two-sample t-test; WinNonlin3P87DAS2.1.1 software pharmacokinetic parameters P lt; 0.05 difference was statistically significant. Results nature of PLGA and PLGA microspheres ropivacaine W1/O/W2 prepared ropivacaine - dexamethasone acetate stability, and good reproducibility. Ropivacaine drug loading (7.60 ± O.08)%, encapsulation efficiency (74.10 ± 1.42)%; dexamethasone acetate drug loading (1.54 ± 0.02)%, encapsulation efficiency (60.16 ± 1.55)%. Pharmacodynamic results: ropivacaine - dexamethasone PLGA microspheres group (Rop-Dex-PLGA-MS of the PLGA microspheres ropivacaine group (Rop-PLGA-MS) and blank microspheres (of PLGA- latency in mice at different time points between MS) were statistically significant (P lt; 0.001), both the interaction between the microspheres group and time point (P = 0.000). 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 ??hours, 72 hours, ropivacaine, tetracaine - dexamethasone PLGA microspheres with blank PLGA microspheres group there is a significant difference (P lt; 0.001); 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, the PLGA microspheres ropivacaine group (Rop-PLGA-MS) and blank microspheres 48 hours and 72 hours Luo significant difference (P lt; 0.001); Rop - dexamethasone microspheres ropivacaine microspheres group was significantly different sex (P lt; 0.001) 3. pharmacokinetic results: Ropivacaine - Dexamethasone the PLGA microspheres Group (Rop-Dex -PLGA-Ms) and ropivacaine PLGA microspheres group (Rop-PLGA-Ms) plasma concentrations at different time points were statistically significant difference (P lt; 0.001). the two groups microspheres ropivacaine pharmacokinetic parameters Cmax, Tmax, AUC, MRT, t1 / 2 were 117.8 and 119.8 ng ml-1, 24 and 12 h, 8793.2 and of 6861.15 ng.h. ml-1, 43.7491 and 38.7743 h, 65.799 and 46.166 h. A Conclusion 1., B, C three groups could not be detected dexamethasone plasma concentration data the C group ropivacaine ropivacaine and dexamethasone plasma concentrations were not measured. PLGA as a carrier material, the use of the W / O / W emulsion - diffusion solvent evaporation prepared Rop-PLGA-MS and ROP-Dex-PLGA-MS is feasible. pharmacodynamic study shows that: (1) the analgesic effect of the carrier material PLGA; (2) Rop -Dex-PLGA-MS and Rop-PLGA-MS the two groups microspheres motor block little effect; (3) Rop-Dex-PLGA-MS sensory block for 72 hours compared with Rop-PLGA-MS blockade 36 hours significantly extended package into dexamethasone significantly prolonged narcotic analgesic effect of ropivacaine ropivacaine polylactic acid - glycolic acid microspheres. 3. the pharmacokinetics studies show: Rop-Dex-PLGA- MS Rop-PLGA-MS vivo release bimodal sample S-shaped curve, the former drug half-life than the latter significantly extended, and the drug peak plasma concentration time is 2 times Rop-PLGA-MS.

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