| Non-steroidal anti-inflammatory drugs are widely used as anti-inflammatory drug in awide range of clinical applications. However, almost all of the Non-steroidalanti-inflammatory drugs formulations applied in clinical are for oral, there is a relativelyshortage of Non-steroidal anti-inflammatory drugs formulations for injection. Ibuprofen isa safe and effective Non-steroidal anti-inflammatory drugs that have applied in clinical formany years. But the injection form of ibuprofen just have one recently availableformulation in market, that is ibuprofen injection which made up of ibuprofen and arginine.However, this injection has some drawbacks, such as it was eliminated fast in vivo andneeded large amount of drug to get desired effect. So in this study we developed a passivetargeting ibuprofen lipid emulsion.Firstly, we optimized the lipid emulsion formulation and manufacturing parameters.We used high pressure homogenization method to prepare ibuprofen lipid emulsion.Ibuprofen lipid emulsion formulation and manufacturing parameters were optimized bysingle factor investigation.The optimized formulation and manufacturing parameters are asfollows.10percentage of soybean oil and MCT(1:1) was used as oil phase.1.2percentageof egg lecithin (PL-100M) was used as the emulsifying agent,2.25percentage of glycerinwas used as isoosmotic adjusting agent, the drug concentration is2mg/mL，the optimizedmanufacturing progress are that first we mixed the oil phase and the water phase with ashearing machine to prepare colostrum, The homogenizing procedure are thathomogenizing at15000psi for two times.Secondly, we studied the physical and chemical properties of ibuprofen lipid emulsion.First we established the particle size and drug concentration detecting method. Then weinvestigated the sterilization stability, encapsulation efficiency and phase distribution ofibuprofen lipid emulsion. The result showed that the drug concentration particle size andpH value of ibuprofen lipid emulsion have no significant change before and aftersterilization. In the encapsulation efficiency study, the results showed that when the pHvalue is smaller than6, the encapsulation efficiency meets the requirements of ChinesePharmacopoeia, the encapsulation efficiency is more than80%. In the phase distributionstudy, ibuprofen was detected in three phases of ibuprofen emulsion system.The aqueousphase of ibuprofen emulsion was separated by the methods of ultrafiltration centrifugationused a ultrafiltration tubes, the oil phase was separated by the method of ultracentrifugation.The result showed that in aqueous phase the concentration of ibuprofen was affect by pHvalue, ibuprofen concentration in oil phase decreased when pH value increased. Ibuprofenin O/W interface was relatively stable that keep up at about20percentage of all the totalibuprofen concentration.Thirdly, we studied the affecting factors of the stability of ibuprofen lipid emulsion,and we also carried on the accelerated stability and long term stability test of ibuprofenlipid emulsion according to Chinese pharmacopoeia. In this study, we selected drug concentration, the percentage of aqueous phase drug concentration, pH value and particlesize as index in the stability investigation. We found that the pH value and the percentageof aqueous phase drug concentration were decreased at high temperature,while the drugconcentration and the particle size was not affected.Light is basically have no effect on thestability of ibuprofen lipid emulsion.The same result occurred in the acceleration and longterm stability test.Fourthly, we studied the vitro release of ibuprofen from ibuprofen lipid emulsion bydialysis membrane method. PBS solution which pH value is7.4was used as releasemedium. The result showed that, after3h the formulation released82.08±1.05percentageof the drug, after12h the formulation almost released all of ibuprofen into the releasemedium.Fifthly, we studied the phamacokinetics of ibuprofen lipid emulsion and ibuprofeninjection. We established ibuprofen HPLC detection method in plasma. Acetonitrile wasused to precipitate protein in plasma, flufenamic acid was used as an internal standard, themobile phase was consist of0.1%phosphoric acid acetonitrile aqueous solution(60/40;v/v),the detection wavelength was220nanometers. After analyzed by Pksolver software usingtwo-compartment model, the result showed that ibuprofen lipid emulsion could prolong theibuprofen half-life in vivo to about1.43times of the ibuprofen injection, and increase AUCand MRT to about1.57and1.5times of ibuprofen injection.The result also showed thatthe clear rate of ibuprofen in ibuprofen injection is1.4times larger than that of ibuprofenlipid emulsion.Sixthly, we compared the effect of analgesic, anti-inflammatory and antipyreticactivities of ibuprofen lipid emulsion with ibuprofen injection. In the acetic acid-inducedwrithing and hot plate experiment we discovered that ibuprofen lipid emulsion cansignificantly improved the analgesic effect and prolonged the latency period to ibuprofeninjection. In carrageenan-iduced rat paw edema the result showed that ibuprofen lipidemulsion can obviously reduced the rate of rat paw edema and prolong the effect ofanti-inflammatory activity. In the experiment of LPS-induced rat fever we discovered thatibuprofen lipid emulsion can significantly prolong the antipyretic time and increase theeffect of antipyretic.Finally, we studied the tissue distribution and passive targeting effect of ibuprofenlipid emulsion. First of all, we successfully established the model of granuloma in ICRmice. Secondly, we established ibuprofen HPLC detection method in tissue, we usedmethyl tert-butyl ether to extract ibuprofen from tissue, acetonitrile aqueoussolution(60/40;v/v) consist of0.1%phosphoric acid was used as mobile phase andflufenamic acid was used as an internal standard, the detection wavelength was220nanometer, then we measured the drug concentration of ibuprofen lipid emulsion andibuprofen injection in heart, liver, spleen, lung, kidney and granuloma. The result showedthat ibuprofen lipid emulsion has an obvious liver, spleen and inflammatory tissuetargeting effect. In the inflammatory tissue the AUC of ibuprofen lipid emulsion wasalmost twice than that of ibuprofen injection. In kidney ibuprofen injection showed much high drug concentration than that of ibuprofen lipid emulsion, which suggested thatibuprofen injection eliminated much faster than ibuprofen lipid emulsion, the result wasconsistent with the pharmacokinetic studies.Overall, In this study we explored the preliminary preparation of ibuprofen lipidemulsion, and then we evaluated it’s stability in vitro, At last we investigated the effect ofanalgetic anti-inflammatory and antipyretic characteristic of ibuprofen lipid emulsion invivo. From the result of the study we believe that ibuprofen lipid emulsion has a brightfuture in clinic. |
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