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L-ascorbyl Ibuprofenate Synthesis, Characterization and Evaluation

Author: DaiAJuan
Tutor: TangLuHong
School: Jiangnan University
Course: Microbial and Biochemical Pharmacy
Keywords: L- ascorbic acid L- ibuprofen ascorbate ester Transporter Acute toxicity test Analgesic Pharmacokinetics
CLC: R91
Type: Master's thesis
Year: 2010
Downloads: 93
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Abstract

Made to reduce the non-steroidal anti-inflammatory drug ibuprofen gastrointestinal irritation and increase the bioavailability of ibuprofen design ideas, the physiological activity and good water-soluble L-ascorbic acid and ibuprofen -drug-ibuprofen unitary, L-ascorbic acid (L-Ascorbyl Ibuprofenate, L-AI), mainly studied the physicochemical properties of the prodrug, in vitro and in vivo stability, pharmacokinetics in mice, and on its pharmacodynamic and toxicology acute toxicity test carried out a preliminary study. The present study is based on ibuprofen and L-ascorbic acid is synthesized from L-ascorbic acid, ibuprofen prodrug derivatives have the following advantages: First, is expected to reduce the side effects of ibuprofen on the gastrointestinal tract, and secondly as link, one of non-steroidal anti-inflammatory drug ibuprofen with L-ascorbic acid is expected to be able to as a competitive inhibitor, its analgesic effect through the SVCT2 transporter to the hub of the L-ascorbic acid sodium ion dependent transporters, play, hypothesis remains to be further studied. This is the first synthesis of ibuprofen L-ascorbic acid esterified prodrug derivatives of L-AI and purified by high-performance liquid chromatography - mass spectrometry, infrared spectroscopy, 1 H NMR and C NMR Their structures were identified. Synthesis conditions: L-ascorbic acid and ibuprofen, t-butanol as the reaction solvent, Novo435 as catalyst, reaction was carried out at 55 ° C thermostatic air oscillator oscillation. Purification method: first filtered to remove the enzyme and the unreacted L-ascorbic acid, L-ascorbic acid in the reaction liquid was removed, washed with saturated brine and then with cyclohexane and purification of L-AI. In this paper, high performance liquid chromatography - ultraviolet detection (HPLC-UV) to establish a quantitative analysis method of L-AI and ibuprofen. Also established a L-AI qualitative detection method, a thin layer fluorescence detection by spraying 0.1% KMnO4 1% sulfuric acid solution to the thin-layer silica gel plates, 105 ° C heating for 30 min, set to 365 nm UV light observation of fluorescent spots, L-AI by oxidation yellow fluorescent, and then the white material obtained after hydrolysis with sodium hydroxide is not soluble in the reaction system a thin layer analysis found the Rt value identical with ibuprofen. Acute toxicity test results show that L-AI injection administration, the LD50 in mice 150.85mg/kg. Acetic acid writhing test model results show that L-AI, ibuprofen and ibuprofen arginine salt writhing in mice, but in certain doses can reduce the analgesic effect of the three substances compared to L-AI's the best effect, the analgesic effect is significant, and the lowest dosage, the fastest onset. Hot plate test model results show that, the mice licking L-AI, ibuprofen and ibuprofen arginine salt can be suitably extended incubation period, the analgesic effect. Octanol - buffer allocation experimental results showed that the L-AI pH7.2-7.4 exhibit good solubility in water. 25 ° C under L-AI in the degradation of different pH buffer, L-AI acidic and slightly alkaline conditions degrade speed quickly, more unstable under alkaline conditions, can be completely degraded within 24 hours. Whereby under physiological pH conditions (pH7.2-7.4) buffer to configure the L-AI into a solution must be used within 2h. Employing a plasma in vitro degradation tests showed that the L-AI in human plasma can be degraded, and the L-AI of the half-life t1 / 2 = 6.1h, and the degradation can be detected after 4h ibuprofen. The preliminary study on the dynamics of L-AI in mice, as well as in mice ibuprofen arginine and L-AI of drugs - time curve comparison. While establishing the methods and conditions of the analysis of samples in the plasma, and also to establish a standard curve of L-AI and ibuprofen arginine in the plasma. Almost time of the onset of L-AI the effect of holding time Bibuluofen arginine salt long up to 90min years, and safe.

L-ascorbyl Ibuprofenate Synthesis, Characterization and Evaluation

Abstract

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