Tetrahydropalmatine-based Dry Powder Inhalation Using Cyclodextrin Metal-organic Framework Particles

Background:It is of greater potential and higher significance to offer an attractive platform for enhancing therapeutic efficacy delivery of the drug.Direct drug delivery to the lungs for local and systematic effects can be achieved via pulmonary administration.Tetrahydropalmatine(THP)loaded in cyclodextrin metal-organic frameworks(CD-MOF)was made into inhalable dry powders inhalers used coarse carrier lactose as an excipient.Due to the low oral availability,hence development of new formulation is an important era to achieve the maximum drug absorption.There are two main reasons behind selection of the drug,one is its low oral availability and another is its activeness inside the lungs.There is an urge to develop better and new modalities,due to the large surface area in the lungs,drug can be easily absorbed.In order to improve its oral availability extensive researches have been done including use of nanosuspensions and self-emulsifying drug delivery system and several studies have been undertaken to improve its oral bioavailability.Dry powder inhaler is a new form of passive respiratory pulmonary administration developed on the basis of powder engineering and had the advantages of good stability at room temperature and high suction efficacy.Tetrahydropalmatine-dry powder inhalation(THP-DPI)was prepared by mixing THP-CD-MOF powders with inhalable lactose as carriers.The modified formulation of THP-DPI was evaluated,including its physicochemical properties,flowability and in vitro pulmonary deposition.At the level of single particle,the mechanism of interaction between particles and lactose was investigated which provided guidance for the pulmonary delivery of THP-DPI.Methods:For the preparation of?-CD-MOF previously reported method in our lab was used to synthesize the carrier particles using solvent impregnation method.For the critical process of drug loading neutral CD-MOF was used as carrier particles for the loading of THP in the CD-MOF cavities.The drug loading was optimized on the basis of some parameters such as CD-MOFs,molar ratio of drug and CD-MOF,temperature,stirring speed and time.The THP-CD-MOF powder was modified using lactose as a carrier particle for the dry powder inhalation.Different types of lactose were optimized based on several parameters of aerosol deposition measurements.The inhalation based physicochemical properties were investigated.The homogeneity mixing ratio,composition of lactose,of THP-DPI were determined to achieve the ideal powder formulation.Results:For the purpose both high performance liquid chromatography(HPLC)and UV-VIS spectroscopy methods were developed for determination of THP.The standard curve equation and correlation coefficient obtained were as follows:y=7.7486 x-0.7431,R~2=0.9999.For the UV-VIS spectroscopy,the peak was detected at 282 nm wavelength.The standard curve equation and correlation coefficient obtained were as follows:y=0.014 x+0.074 c,R~2=0.9999.Based on the solubility of THP,acetone was selected and used as solvent to dissolve the drug.After successfully synthesis of CD-MOF,the drug loading was determined at 282 nm wavelength.For the purpose of drug loading,the process was optimized and the conditions were as follows:the molar ratio of THP to CD-MOF was 10:1,the temperature was 25?,the stirring speed was400 rpm and the time was 2 h.The obtained powder after drug-loading was quite stable with high drug loading of 19%.The characterization was done after synthesis of THP-CD-MOF.The results showed that the prepared formulation was crystalline in nature even after drug loading and the obtained thermograms demonstrated the powders were thermally stable.The morphology was identified using SEM micrographs,which depicted the cubic shape of the particles with size less than 5?m.On the basis of flowability test,the fluidity of the powders was found to be very poor.Based on the in vitro drug release test,the bioavailability of the THP-CD-MOF was improved.The fine particle fraction(FPF)for the THP-CD-MOF was 25%but powders possessed very poor flowability which was not conductive for the inhalation.From the results of in-vitro drug release profile,it can be observed that the drug profile of the raw material and the drug loaded CD-MOF differs.Fast drug release observed in the THP-MOF loaded formulation and in contrast to the slow release rate of the raw THP.More than 50%of the drug released within two hours in case of THP-MOF and in contrast only 30%drug released when raw THP was used.The empty rate of the powders was less than 100%with 3 um size of mean median aerodynamic diameter(MMAD)quite suitable for the inhalation.THP powder was prepared into an inhalable size loaded in CD-MOF with adequate particle size less then 5?m to meet the requirements of inhalation administration according to the US Pharmacopeia.The best mixing condition was 40 rpm for 15 min.For the formulation,various grades of lactose such as ML001,ML003,SV003,SV010 were optimized based on their particle size.The physicochemical characterizations were performed.For all formulation,the content uniformity test was measured and all powder exhibited RSD%less than 5%.The Powder diffractometry results confirmed the highly crystalline nature of all of the powders.The results of thermal gravimetric analysis(TGA)showed that THP was thermal protected by CD-MOF.The prepared formulations exhibited the desirable MMAD values for alveoli deposition 3.0?m for THP-MOF,2.8?m for ML001-THP-MOF,3.1?m for ML003-THP-MOF,3.3±0.18?m for SV003-THP-MOF,3.5±0.12?m for SV010-THP-MOF.GSD was also less than 2 indicated the formulation deposition better for inhalation.Based on the flowability,homogeneity,morphology,thermal stability and crystalline nature it was concluded that SV010-THP-MOF significantly improved the in vitro pulmonary deposition of THP powder.In conclusion,the formulation using CD-MOF carrier particles proved to be promising respirable powder for inhalation using ideal SV010 lactose particles with passable flowability.This formulation proposed a fast onset action of such active drug in the lungs and can be aid to the drug delivery system in the near future.This research emphasizes the recent progress on the synthesis of THP based on CD-MOF for the direct delivery of drug inside the lungs.