Inhalable Sustained Release Preparations Of Octreotide Loaded On Nanocarriers

Octreotide（OCT）is a synthetic cyclic polypeptide drug that selectively inhibits the secretion of growth hormone.OCT is the drug of choice for the treatment of acromegaly which usually requires long-term administration.It is susceptible to enzymatic degradation,short half-life,low bioavailability,and poor patient compliance for OCT administered orally or by injection.And there is an urgent need for new non-invasive delivery methods and preparations.In this dissertation,to meet the needs of OCT non-invasive long-acting preparations,inorganic and polymeric nanocarriers with good biocompatibility and sustained release function were designed and prepared.Inhalable sustained release micropowder preparations were constructed by loading OCT with different composite processes.The physical,chemical,and delivery properties of the carriers and the micropowder preparations were compared and studied,and the biological effects of the preferred carriers and the micropowder preparations were studied.The main research results and conclusions were as follows:（1）Four mesoporous silica（mSiO₂）carriers with different physicochemical properties were designed and prepared by the sol-gel method.The m SiO₂-OCT micropowder preparations were constructed by immersion,adsorption,and freeze-drying process.The m SiO₂ carrier materials were able to achieve effective loading of OCT,among which the micropowder preparations made by nanoscale microspherical silica carriers had the best overall performance with a drug loading of 13%,a sustained in vitro drug release time of 24 h,and good in vitro inhalation deposition performance（the emitted dose reached 100%and the fine particle fraction was greater than 80%）.Furthermore,the regular and homogeneous spherical shape of the micropowder preparations made by nanoscale microspherical silica carriers were maintained,which were conducive to the accuracy and reproducibility of the drug dose in delivery.（2）The nano calcium carbonate（nCaCO₃）carrier was prepared by the complex decomposition method decomposition method.And three types of nCaCO₃ carriers with different physicochemical properties were successfully obtained by using the modulation effect of polyacrylic acid（PAA）and sodium polyaspartate（PASP）.The nCaCO₃-OCT micropowder preparations were constructed by immersion,adsorption and freeze-drying process.All nCaCO₃ carrier materials could realize the effective loading of OCT,among which the micropowder preparations constructed from spherical rod hybrid calcium carbonate had the best overall performance with a drug loading capacity of 31.3%,in vitro sustained release time of 48 h,the emitted dose of 100%,and the fine particle fraction of 42%.（3）The nano poly lactic-co-glycolic acid（PLGA）-OCT micropowder preparations were constructed by super-gravity reverse-solvent precipitation-impregnation-adsorption-freeze-drying and multiemulsion solvent volatilization and encapsulation,respectively.Among which,the micropowder preparations with embedded drug loading had the best comprehensive performance with the drug loading of 2.0%,the continuous release within 108 h,the dissolution rate of 74%,the emitted dose of 100%,and the fine particle fraction of 53.4%.（4）The biological effects of the selected carrier and its micropowder preparations were evaluated in terms of cytotoxicity,inflammatory effects,in vivo distribution after inhalation,transmembrane transport properties,and drug metabolism studies.The results showed that nCaCO₃ and PLGA and their micropowder preparations were biocompatible and did not cause inflammatory effects and cytotoxicity.High concentration of m SiO₂and micropowder preparations caused inflammation and cytotoxicity to some extent.After pulmonary administration,nCaCO₃-OCT and PLGA-OCT micropowder preparations had better drug metabolism performance than the original drug,which half-life was extended from 56.7 min to 162.9 min and 187.1 min,respectively and the relative bioavailability was increased to 148.0%and 170.2%,respectively.Among them,the PLGA-OCT micropowder preparation with embedded drug had the best comprehensive performance,which extended the peak time to 120 min after administration and the peak concentration was 56.3 ng/m L.It proves the feasibility of the technical path of preparing inhalable sustained-release preparations by loading polypeptide drugs with nano-carriers.