Study On The Preparation Of Lungs Containing Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLN) consist of natural solid lipids, which have the properties of good physiological compatibility and in-vivo degradation. From the viewpoint of biocompatibility, SLN are regarded as an ideal carrier for pulmonary drug delivery (PDD). Nonetheless, the suitability of such a carrier to PDD, particularly dry powder inhaler (DPI) and metered dose inhaler (MDI), has yet been established so far. Therefore, the main aims of the present study are to investigate the applicability of SLN as PDD carriers to DPI, MDI and nebulizer (Neb).Firstly, fluorescent and gas chromatographic (GC) methods were developed and validated to determine coumarin-6and fresh essential oil from heartleaf houttuynia, respectively. The result showed that the methods were ’fit for purpose’ to quantify formulations as well as bio-samples in terms of the linearity, accuracy, precision and extracted coefficient of recovery. In the essential oil, the contents of α-pinene and bornyl acetate were both less than1%whereas the content of2-undecanone was approximately10%, as a result,2-undecanone was used as the chemical maker of fresh essential oil.Secondly, this thesis has investigated the preparation and characterization of SLN. The result showed that high shear homogenization was most suitable for the preparation of SLN. In addition, SLN with different lipids and particle diameters were prepared and the sustained release characteristics of Compritol888ATO appeared to be the best among all the lipids. All SLN with different particle diameters from～200to～800run had the good sustained release characteristics, independent of particle size.Thirdly, the present thesis has investigated the droplet sizes, particle diameters, Zeta potentials, in-vitro sustained release of SLN aqueous suspensions as Neb, and in vivo pulmonary sustained release of SLN with different lipids and particle size in rats. Nebulized SLN aqueous suspensions had the droplet sizes of3.4-3.8μm, and no apparent changes of particle size, Zeta potentials and in-vitro sustained release properties were observed after nebulization. Pharmacokinetic study revealed that compared to intravenous administration of essential oil, aerosolized SLN formulations resulted in prolonged lung retention of essential oil and increases the lung bioavailability by26-44fold.Fourthly, this thesis has studied the the stabilization of spray-dried SLN in terms of reconstituted particle size and zeta potential, spray-drying yield and aerodynamic inhaled characteristics. The results showed that spray-drying drastically changed reconstituted particle size of SLN with or without optimization of spray-drying parameters, whereas the presence of different excipients led to different extent of stabilization. L-Leucine appeared to be more effective in the stabilization of SLN than trehalose, sucrose, lactose or mannitol, leading to that the reconstituted particle size of SLN was almost the same as that before spray drying. When the content of leucine was added to40%w/w or higher, the fine particle fractions of spray-dried powder dispersed through a Cyclohaler were more than48%. The overall results demonstrated that the presence of leucine conferred to effective stabilization of SLN during spray-drying and improved the inhalability of the spray-dried SLN. The mechanism underlying the enhanced respirability was attributed to the enrichment of leucine on the surface of spray-dried particles, leading to reduced interparticle adhension.Lastly, the thesis has investigated the presence of SLN in MDI on the aerosol performance of MDI. The results showed that MDI containing salbutamol sulphate particles with a mean diameter of2.4μm produced by wet milling conferred to a fine particle fraction (FPF) of8.7%. Following the presence of SLN, the FPF was increased to18.5%, suggesting that the incorporation of SLN into MDI improved the aerosol performance.In conclusion, SLN can be utilized as a carrier for pulmonary delivery, including Neb, DPI and MDI. The SLN aqueous suspension could be readily used for nebulization, resulting in pulmonary sustained release of drugs, e.g. essential oil from heartleaf houttuynia. In addition, upon spray-drying, the SLN can be delivered to the lung via DPI. More importantly, SLN can not only be used as a drug carrier, but also act as dispersing agent, when incorporating into MDI, and therefore it is potential suitable for the compound preparation of MDI.