Preparation And Characterization Of Octreotide Inhalable Micropowders

Polypeptide drugs have a good application prospect in the treatment of diseases,but they have short half-life and low bioavailability,and they are easy to be decomposed and eliminated by enzymes when administered by oral or intravenous administration.At present,the main preparation form is intravenous or subcutaneous injection requiring repeated administration.The patient’s compliance is low,it is inconvenient to use,and it is easy to cause damage to cell tissues and cause infection.Therefore,there is an urgent need for new non-invasive drug administration mode and its preparations.The dry powder inhalation for pulmonary administration is easy to carry and operate,patient compliance is good,and there is no need of propellants,preservatives and solvents,the delivery dose is easy to control.The dry powder inhalation is suitable for the inhalation of polypeptide drugs.Inhalable micropowders are the key elements in preparation of dry powder inhalation.In this paper,octreotide was used as a model drug,supercritical fluid anti-solvent,freeze drying,and spray freeze drying technology were used to prepare high drug-loading octreotide inhalable micropowders which are suitable for heat-sensitive peptide drugs The evaluation methods and systems of properties has been established,and the systematic properties research has been carried out.The law of the effect of the preparation technology,process conditions and formulation system on the properties of the micropowder has been analyzed and clarified.And then,the main research results and conclusions are as follows:1.An evaluation system of octreotide inhalable micropowders has been established,including physical and chemical properties,aerodynamic properties and release and absorption properties.The evaluation system with strong points and take the individual particles,the micro and macro and micro powder collection etc and multiple layers,which can satisfy the octreotide can be observed powder preparation technology and absorption performance study of demand.2.Octreotide inhalable micropowder has been prepared by supercritical anti-solvent(SAS)technique.The preparation process and formulation system were optimized by single factor experiment and orthogonal experiment,and the effect of SAS process conditions(temperature,pressure,concentration and rate)and auxiliaries were analyzed.The optimal condition was performed at a temperature of 40 ℃,at a pressure of 8 MPa,at a concentration of 10 mg/mL and at a rate of 0.3 mL/min,and 5% poloxamer 188 was added as optimized formulation system.The micromorphology of the prepared powders was spherical particles with uniform particle size,and the median particle size(MMAD)of aerodynamic mass was 0.863μm.The emptying rate(ED),effective site deposition rate(FPF,interception diameter < 5.0 μm)and FPF(interception diameter < 10 μm)measured by the Anderson cascade impactor are 90.65%,47.09% and 65.58% respectively.The reproducibility of the yield and aerodynamic particle size of the micropowders was good,and the preparation process was stable.3.Octreotide inhalable micropowders were prepared by freeze drying(FD)technology.The preparation process conditions and prescription system were optimized through single-factor experiments,and the influence laws such as the concentration,the type and content of auxiliaries were analyzed.The optimal condition was performed at a concentration of 30 mg/mL,and 15% L-leucine was added as optimized formulation system.And the micromorphology of the prepared powder was mainly flake particles,MMAD 1.52 μm,ED 89.04%,FPF(interception diameter < 5.0 μm)and FPF(interception diameter < 10 μm)were 45.38% and 66.09%.The reproducibility of the yield and aerodynamic particle size of the micropowders was good,and the preparation process was stable.4.Octreotide inhalable micropowders were prepared by spray freeze drying(SFD)technology.The preparation process and formulation system were optimized by single factor experiment and orthogonal experiment,and the conditions(atomization pressure,concentration and rate)were analyzed.The optimal condition was performed at a atomization pressure of 0.2 MPa,at a concentration of 20 mg/mL and at a rate of 500 mL/h.And the micromorphology of the prepared powders was low density,porous and large particles with regular spherical shape(MMAD 0.997 μm,ED 92.09%).FPF(interception diameter < 5.0 μm)and FPF(interception diameter < 10 μm)were 51.85%and 75.62%,respectively.5.The properties of the octreotide inhalable micropowder prepared by the three technical optimization processes was systematically evaluated,it was confirmed that the octreotide absorbable powder prepared by the three technologies had good physical and chemical properties,aerodynamics properties and in vitro release properties,and the spray freeze drying technology was determined as the optimal preparation technology.Compared with subcutaneous injection,the peak time of octreotide was delayed from 15 min to 30 min,and the half-life was slightly increased.The relative bioavailability of octreotide was 94%,which can realize the pulmonary administration of octreotide inhalable micropowder.Octreotide micropowder prepared by three kinds of technology methods has good physical and chemical properties,aerodynamics,compared with subcutaneous injection.And octreotide powder can be observed absorption after pulmonary drug delivery to achieve higher relative bioavailability.The results of this paper can provide a research basis for the development of new preparations of octreotide and other polypeptide drugs.