Synthesis Of Aryl Propionic Acid NSAIDs Prodrugs And Study On Its Microemulsion And Submicroemulsion

Naproxen and Flurbiprofen are typical drugs of aryl propionic acid non-steroidalanti-inflammatory drugs (NSAIDs), with anti-inflammatory, anagesic properties.However, some research have indicate that long-term oral administration ofNSAIDs may cause gastrointestinal adverse reactions, mainly gastrointestinal ulcersand arising therefrom gastrointestinal bleeding and gastric perforation.The use ofcarboxyl group structure in NSAIDs synthesizing prodrug is one of effective ways toreduce gastrointestinal toxic and side effects.Eugenol is the main component of the clove volatile oil. In recent years, studiesshowed that eugenol have effects of antibiotic, analgesic and anesthetic, mainly usedfor dental caries, dental pulp analgesic clinically. Due to phenolic hydroxyl group inthe structure, it is easy oxidation metamorphism when contacting air for a long time.It is not esay to preserve and preparate drugs with the special smell. This article usednaproxen and flurbiprofen which have similar pharmacological activity and eugenolas the raw materials, and made them into prodrug with combination principle. Weexpect to find new prodrug through structure reform which can reduce NSAIDsgastrointestinal adverse reactions and improve the stability of eugenol.This article synthesized two prodrugs firstly, and studied the physical andchemical properties and stability. On this basis we designed and prepared emulsion fororal administration and submicroemulsion for intravenous injection. Based on thevivo pharmacokinetics, tissue distribution and pharmacodynamic studies of thesedrugs, the purpose of the research is exploring new direction of structuremodification and preparations.Using naproxen(or flurbiprofen)and eugenol as the raw materials, with oxalyl chloride(or thionyl chloride) as acylating agent, synthesized the prodrug of naproxeneugenol ester(NEE) and flurbiprofen eugenol ester(FEE) via acylation. The structureof NEE and FEE were confirmed by IR、MS and1H-NMR spectrum. HPLC methodwas established for assay of FEE and NEE. Preliminary stability and physical andchemical properties of the NEE and FEE were studied. The stability test showed thatNEE and FEE are relatively stable in the high temperature, high humidity andlight conditions. Solubility experiments demonstrate that NEE and FEE areundissolved in water. However, the solubility of FEE in short chain alcohol and oilphrase is better than the one of NEE. Using emulsion as the carrier, the drug hasto own certain solubility in the oil phase. Considering this problem, this articleselects FEE as imitate drug for preparation and pharmacokinetic studies. Stabilitystudy in different pH buffer indicated that FEE relatively stable in neutral andacidic conditions, but accelerated the hydrolysis rate in alkaline condition.In order to improve the absorption of the drug and enhance thebioavailability, according to physical and chemical properties study, we selectedmicroemulsion as a drug carrier and prepared for oral administration. Referencetitration drawing pseudo-ternary phase diagrams, using the size of the O/Wmicroemulsion region as the main evaluation index, we investigated the effect ofdifferent factors such as oil phase, surfactants and co-surfactants. For themicroemulsions, Ethyl Oleate (EO) is chosen as oil phase, Cremophor EL asSurfactant, PEG-400as co-surfactant. The consist of optimize formulation wasEO：Cremophor EL：PEG-400：Water=5：20：10：65. We studied the physical andchemical properties of the emulsion: It is globular under TEM; The averageparticle size and distribution is26.74±5.52nm; Potential is-7.88±2.88mV;Conductivity is48.8μs/cm; Viscosity is59.7mPa s; Phase-transition temperature is72℃. The emulsion is unstable under the condition of high temperature.At the same time, in order to expand different administration routes, to meetdifferent needs of patient to medicine, the FEE submicroemulsion which wasused by intravenous injection was obtained by passing the two-step homogenization method. Applying particle size, Zeta and stability coefficient Keas evaluation index, we studied the prescription and process optimization byorthogonal experiment design and signal factor studies. The best formulation was:the oil phase was20%soybean oil, the total amount of emulsifier was1.5%(soyabean lecithin:F68=3:1), the oleic acid was0.1%. we got the emulsionunder the condition8000rpm/min by high-speed shearing dispersion machine,8minutes. In high pressure homogenizer, the condition was12000psi,12times,sealed with nitrogen and sterilized. The particle size is220nm, potential is about-40mV. Stability tests showed that there was no signigicant changes of thepartical size and potential when the emulsion was diluted by saline or glucose.High temperature, illumination and low temperature stability experiment showedthe peparation should be stored away from light.A HPLC method was established to determine flurbiprofen in plasma andtissue homogenate. Plasma and liver homogenate in vitro degradation kineticsexperiments show that, FEE have the condition to become a prodrug because itcan quickly convert to flurbiprofen. Take rats as test object, we studied thepharmacokinetic of FEE microemulsion for oral and FEE submicroemulsion forintravenous. We calculated pharmacokinetic parameters with pharmacokineticsoftware BAPP2.0, and compared with flurbiprofen suspension and injectionhomemade. The result show that:1The pharmacokinetic process of flurbiprofensuspension lavage conform to open one compartment model, and FEEmicroemulsion conform to open two compartment model; Using flurbiprofensuspension as the reference preparation, the studies showed that the Tmaxof FEEemulsion is later than flurbiprofen. AUC has distinguished difference.2FEEsubmicroemulsion and flurbiprofen solution conform to open two compartmentmodel, there is no significant difference of the curve and pharmacokineticparameters. The distribution study after intravenous administration indicated thatthis drug concentration in liver and lung, minimum in brain.Acute toxicity results suggested that the LD50of FEE emulsion for oral is 514.4mg/kg, the LD50of FEE submicroemulsion for intravenous injection is279.7mg/kg. The pharmaceutical safety test results indicated that none of thenegative effects of FEE submicroemulsion preparation in vitro. There isnonirritant for rabbit intravenous injection. Pharmacodynamics experiments showthat the analgesic activity of this drug was the same as the contrast drug in miceutilizing hot plate method and acetic acid writhing analgesic method. In addition,it has good inhibitory effect for mice ear swelling caused by dimethylbenzene.