| Linalool(LL) is a catenulatus natural terpene alcohol found in spices of plants(such as anise, pepper and fennel) with several commercial applications, mainly in daily chemicals and fragrance flavor and cosmetics industries. LL is associated with numerous pharmacological activities such as anti-inflammatory, antitumor, antidepression, analgesia and antimicrobial action. However, as a classic essential oil, volatility and poor water solubility of LL which usually results in poor oral bioavailability could be one of the main factors limiting its wide applications. This study is aiming to prepare linalool loaded nanostructured lipid carriers(LL-NLC) mainly for solving the problems of solubility and volatility of linalool, as well as reaching the purpose of control release, and eventual improving the bioavailability and anti-inflammatory effect of linalool in vivo. There are five chapters in this study to introduce the main content.Chapter I ReviewThis chapter reviewed the studies on lipid nanoparticles preparations of active components extracted from spices, and mainly summarized the resent development situations of these active componments from two aspects, preparation and its applications. This review is hoping to supply more information for the following relative studies.Chapter II Preformulation studies of linalool loaded nanostructured lipidcarriersThis chapter built the HPLC analysis method of linalool. The results implied that this method is specific, and possesses good linear relation in the range of 1-800 ?g?m L-1, as well as high precision(RSD < 2%) and recovery(97.66-99.94%). Additionally, the acetonitrile solution of linalool could keep stability after storing for 48 h, and expressed no influence on its content determination. Furthermore, the results of equilibrium solubility declared that the solubility of linalool in water(3.116 mg?m L-1) was improved(11.073 mg?m L-1) when it dissolve in PBS with 0.5% Tween 80. This finding supported the basis for the confirmation of sink condition in the following in vitro release study of linalool loaded nanaostructured lipid carriers.Chapter III Preparation of linalool loaded nanostructured lipid carriersIn this chapter, linalool loaded nanostructured lipid carriers was prepared using hot high pressure homogenization method, and optimized by response surface methodology-central composite design. The final optimized results were consisted of 2.5% glycerin monostearate, 2.5% decanoyl/octanoyl-glycerides, 2.0% Span 80 and 4.0% Tween 80, linalool was added at the ratio of 1:5.5(w/w) with lipid, the melting tempreture was 78°C, and the formulation was prepared under the pressure of 1000 bar for 6 cycles. The predicted result given by softwear was 50.599 nm, and the verification experiment implied that the deviations between actural results and predicted result were less than 5%, which means response surface can not only intuitively reflect the effects and interactive effects of various factors, but also possesses high fitting degree. These results also revealed that the model could appropriately describe the response values, and more importantly predict the optimized formulation.Chapter IV Characterization of linalool loaded nanostructured lipidcarriersThis chapter adopted various methods to reach the purpose of verification and properties characterization on linalool loaded nanostructured lipid carriers. The final particle size was 52.72 nm with polydispersity index of 0.172, and the zeta potential of-16.0 mV. Additionally, the encapsulation efficiency and drug loading of linalool loaded nanostructured lipid carriers was 79.563% and 7.555%, respectively. Furthermore, this preparation could store at room temperature(25°C) for 1 month at least. All of these results implied that the linalool loaded nanostructured lipid carriers prepared by high pressure homogenization method possesses a serious of advantages, such as small particle size, homogeneous distribution, good stability and high drug content. The transmission electron microscope imaging of linalool loaded nanostructured lipid carriers revealed spherical shape with uniform particle size distribution. There were also no obvious particle aggregations in the imaging. Furthermore, the results of differential scanning calorimetry and X-ray diffraction demonstrated that linalool loaded nanostructured lipid carriers were successfully prepared in the present study. In addition, the in vitro release results showed that nanostructured lipid carriers could be used as sustained release carrier for drug, it can not only delay the release time of drug, but also no obvious burst release was observed through the release phase.Chapter V Pharmacokinetics and pharmacodynamics study of linaloolloaded nanostructured lipid carriersThis chaper built the HPLC analysis method of linalool in vivo. Furthermore, the pharmacokinetics study was carried out to verify whether nanostructured lipid carriers could improve the absorption and bioavailability of linalool. In addition, an ear swelling model in KM mice was established for the anti-inflammary effect evaluation of linalool loaded nanostructured lipid carriers. Protein precipitation was adopted as the pretreatment method of plasma samples, which was characterized by easy operation, strong specificity and good linear relation in the range of 45.45-1818.18 ng?mL-1. In the pharmacokinetics study, all the pharmacokinetic parameters of rats in preparation group(t1/2, MRT, tmax and Cmax was 110.50 min, 146.66 min, 60 min and 2182.45 ng·m L-1, respectively) were better than those of free linalool administration group(t1/2, MRT, tmax and Cmax was 44.72 min, 45.66 min, 40 min and 1915.45 ng·mL-1, respectively) after administration, and the relative bioavailability reached to 393.34%. These results not only declared that linalool loaded nanostructured lipid carriers possesses sustained release effect, but also gave more support on the hypothesis that nanostructured lipid carriers could improve the absorption and bioavailability of linalool. Moreover, the results of pharmacodynamics study showed that there was no significant difference of anti-inflammatory effect between middle dosage linalool loaded nanostructured lipid carriers group(200 mg·kg-1) and LL-suspension group(400 mg·kg-1), which implied that the dosage was smaller of linalool loaded nanostructured lipid carriers than that of free linalool with the same anti-inflammatory effect. In addition, it also showed that the bioavailability of linalool was improved by nanostructured lipid carriers. Furthermore, all the evaluation indexes of high dosage preparation group were better than those of commercial preparation administration group, an excellent anti-inflammatory effect of linalool loaded nanostructured lipid carriers was observed and also its great potential values in clinical application was exhibited. |
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