| Respiratory diseases have always been a major problem in the field of public health with high morbidity and high mortality seriously endangering human health.The pulmonary delivery system can deliver drugs directly to the respiratory tract and lungs to take effect.Compared with systemic drug delivery,it has advantages such as fast effect,less required dose and fewer systemic side effects,which has shown obvious advantages in the treatment of respiratory diseases.Based on this,traditional Chinese medicine(TCM)injection is often used in clinical off-label nebulization for the treatment of respiratory diseases.A number of clinical studies have shown that nebulized inhalation of traditional Chinese medicine has the same or better efficacy and safety than intravenous injection,and has the potential to replace intravenous injection.However,previous studies have found that most TCM components can be rapidly absorbed and cleared in the lung,restricting their pulmonary bioavailability and action time,and it is necessary to prolong the lung retention time of drugs by means of preparation.However,due to the unique physiological barrier of the lung and the limited use of excipients approved for lung administration,the commonly used sustained-release formulation strategies are limited,and there are major difficulties in developing TCM inhalation sustained-release formulations based on lung compatible excipients to improve the residence of lung drugs and prolong the duration of pulmonary drug effect.Based on this.this paper intends to construct a drug-phospholipid complex loaded porous macroparticle by using the monomer Chinese medicine ChuanHu-Ning(dehydroandrographolide succinate,DAS)and the compound Chinese medicine Shuang-Huang-Lian as model drugs,and select the lung compatible phospholipid as excipients,so as to explore if the carriers are capable of spatially and temporally controlled pulmonary delivery to improve the lung delivery efficiency and prolong the local action time of Chinese medicine.Firstly,spray-dried porous particles loaded with DAS-phospholipid complex were prepared(DAS-PC@SDPP).The physicochemical properties of the particles and the aerodynamic properties of the dry powder inhaler were characterized.The results showed that the phospholipid complex was formed by charge interaction between the drug and phospholipid.After hydration,the phospholipid complex could self-assembly into 200-300 nm stable structure,which was then mixed with a water-in-oil emulsion containing perflubron to produce porous particles by spray drying.The aerodynamics particle size of the aerosolized dry powder inhalant based on porous particles is 2～3 μm,and the fine particles fraction is～60%.which has a good lung deposition efficiency.The phospholipid complex maintained stable physicochemical properties and nanostructures during preparation.The in vitro release of porous particles showed that compared with the rapid release of free DAS within 5 min,the phospholipid carrier had a sustained release effect,showing a two-phase release behavior of sudden release and sustained release,and the sustained release lasted for 12 h after bursting release.Then,the release behavior and mechanism of phospholipid complex in vitro,cell and lung tissue were investigated.The phospholipid complex of Rhodamine B was synthesized by labeling phospholipids with fluorescein isothiocyanate(FITC).The release mechanism of phospholipid complex was elucidated in vitro and at Calu-3 lung epithelioid cell level by fluorescence resonance energy transfer(FRET)effect.The in vitro release results showed that the slow release behavior of phospholipid complex was due to the drug dissociation from the complex and its slow release from the nanostructure.The compound has a good affinity with lung epithelial cells.After being uptaken by Calu-3 cells in the form of phospholipid complex,the drug can prolong intracellular residence and delay intracellular release by reducing the complex dissociation rate.The lung affinity of phospholipid complex was evaluated on in vitro lung tissue model.The results showed that there was no significant difference in uptake process between complex and free drug,but the formation of complex significantly reduced the desorption rate from lung tissue and improved the lung tissue affinity of the free drug.Subsequently,the pulmonary distribution characteristics of different preparations were compared by intratracheal administration of DAS solution,physical mixture of DAS and blank particles(DAS+SDPP),DAS loaded porous particles(DAS@SDPP),and DASPC@SDPP to mice.Upon deposition into the lung,inhaled preparations firstly release in the lung epithelial lining fluid(ELF).Consistent with in vitro release,the DAS solution was rapidly cleared from the ELF within 1 hour,whereas phospholipid-based particles could continuously release drugs or phospholipid complexes in the ELF.Phospholipid complex can achieve delayed clearance from the lung epithelial cell and lead to prolonged lung tissue retention.Compared with other free drug preparation groups,inhalation of DAS-PC@SDPP resulted in significantly higher lung tissue drug concentrations,improved local lung bioavailability by 3-14 fold,and reduced plasma bioavailability of drugs.Overall,the phospholipid complex loaded porous microparticles increased the lung to plasma drug concentration ratio by a factor of about 100 through a double slow-release mechanism,achieving prolonged lung retention.In a lipopolysaccharide-induced pneumonia mouse model,DAS solution group maintained significant anti-inflammatory effect for only 3 h at the dose of 20 mg/kg DAS,and the effect was extended to 12 h by drug-loaded porous particles DAS@SDPP.The action duration was extended to 12 h at a dose of 2.2 mg/kg DAS-PC@SDPP,and there was a good correlation between pulmonary bioavailability and local efficacy.Finally,the pulmonary biopharmaceutics of the three main components of ShuangHuang-Lian(SHL)after intratracheal administration and their pharmacokineticpharmacokinetic correlation were evaluated.On this basis,SHL-phospholipid complex loaded porous particles(SHL-PC@SDPP)were prepared,and their pulmonary processes and pharmacokinetic effects were evaluated.Comparative study on plasma and lung bioavailability of main active components of Shuang-Huang-Lian after intratracheal or intravenous administration showed that,compared with intravenous injection of ShuangHuang-Lian,intratracheal administration prolonged lung retention time,increased local lung bioavailability by more than 500 times,and enhanced local anti-inflammatory effect.However,after intatracheal administration,components except baicalin were rapidly cleared from lung tissue and the action time was not sufficient.The SHL-PC@SDPP can simultaneously extend the concentration and retention time of the three main components in the lung,and the duration of action can be extended from 12 h to 24 h compared with the SHL loaded porous particles(SHL@SDPP).In addition,the addition of hyaluronic acid,a bioadhesive material with good lung compatibility,into porous particles can further delay the drug release rate of the inhaled dry powder formula,significantly prolong the retention time of the active ingredient in the ELF,and reduce the effective dose for 24 hours by 2 times.In conclusion,this paper prepared an inhalable dry powder of drug-phospholipid complex loaded spray-dried porous particles.The formula consists only of lung biocompatible excipients phospholipid,which has good lung safety.At the same time,the delivery system can achieve good lung deposition efficiency and prolong cell retention,and has shown good effects in the pulmonary delivery of Chuan-Hu-Ning monomer and Shuang-Huang-Lian compound,which has high clinical conversion potential,providing the possibility to improve the treatment of respiratory diseases(such as pneumonia and acute respiratory distress syndrome). |
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