Dry Powder Inhalers Of Natural Lipidic Drugs For Treatment Of Acute Lung Injury

Lung is an important organ for gas exchange.Particles,chemicals,pathogens,etc.in the air can cause lung diseases and systemic diseases when they enter the lungs.Pulmonary diseases include various pneumonias?bacterial,fungal,viral or aspiration pneumonia?,pulmonary fibrosis,asthma,lung cancer,and so on.These diseases often cause acute lung injury?ALI?,which manifests as diffuse alveolar and capillary membrane damage.If untreated timely,it can develop into acute respiratory distress syndrome?ARDS?,leading to refractory hypoxemia results in up to 35-40%mortality.At present,there are no specific drugs for treating ALI in the clinic.Nebulized inhaled hormone drugs are commonly used to relieve ALI,but long-term use has side effects and tolerance.Zedoary turmeric oil is a mixture extracted from curcumae rhizoma.The main ingredients include curcumol,curcumindione,elemene,geimadone and curcumone.In recent years,the antitumor,antiviral,antibacterial,anti-inflammatory,antithrombotic and other activities of zedoary turmeric oil and its active ingredient curcumol have been studied a lot.There are also studies on atomization of zedoary turmeric oil injection to treat viral upper respiratory tract infections,but there are no reports on zedoary turmeric oil and curcumol lung inhalation preparations and a comparative study of them.Jojoba oil?JJBO?is a light-yellow liquid oil,which include polyphenols,flavonoids,and alkaloids.It has anti-oxidant,anti-inflammatory and anti-fungal effects.It is widely used in folk and cosmetics to treat sunburn,skin trauma and other diseases.JJBO has been proven to have anti-inflammatory effects in vitro,but it has poor solubility and low bioavailability in vivo,which limits its clinical application.This article was divided into two parts:1.Based on the properties of zedoary turmeric oil and curcumol and the characteristics of pulmonary inhalation,zedoary turmeric oil and curcumol were prepared into dry powders,which suitable for pulmonary inhalation,and administered by intratracheal.These drugs directly applied to the lung tissue to treat LPS-induced ALI,and compared the pharmacodynamic differences between them;2.Based on the properties of JJBO and the characteristics of pulmonary inhalation,JJBO was prepared into nanoemulsion and then frozen.The powder was prepared into a dry form suitable for inhalation in the lungs,and the drug was directly applied to the lung tissue through intratracheal to treat LPS or H₂O₂-induced ALI,and its anti-inflammatory and anti-oxidative mechanisms in vivo were explored.1. Preparation and properties of zedoary turmeric oil dry powders?ZDPIs?and curcumol dry powders?CDPIs?Zedoary turmeric oil emulsion and curcumol emulsion were prepared and the optimal prescription was obtained by single factor study.And 0.39 g of egg yolk lecithin was added,dissolved in 5.5 m L of absolute ethanol?1:14,w/v?,and zedoary turmeric oil?0.55 g?or curcumol?0.55 g?was stirred.Used a high-speed disperser?30000 rpm?,add ultrapure water?73.5 m L?while stirred to obtain zedoary turmeric oil emulsion and curcumol emulsion.Zedoary turmeric oil dry powders?ZDPIs?and curcumol dry powders?CDPIs?were obtained by adding 5%mannitol to lyophilization.ZDPIs and CDPIs powder were loose white powders,and their aerodynamic particle size?D_a?were3.02?m and 2.67?m,respectively,and they were suitable for pulmonary inhalation.Scanning electron microscopy observations showed that the morphology of zedoary turmeric oil and curcumol powder particles were aggregated from cylindrical mannitol crystals.Both zedoary turmeric oil and curcumol were adsorbed or embedded in mannitol.2. Pharmacodynamics of ZDPIs and CDPIsAfter the acute lung injury?ALI?model was established by inhalation of LPS solution,the animals were divided into five groups:the healthy group,the model group,the dexamethasone group,the CDPIs group and the ZDPIs group.Lung tissues appearance and histopathology showed reduced lung tissues injury in the ZDPIs and CDPIs groups.Compared with the model group,the expression of TNF-?,IL-6 and protein in the lung tissues were significantly reduced in the ZDPIs and CDPIs groups.Zedoary turmeric oil and curcumol could alleviate ALI in rats by inhibiting the production of inflammatory factors,and proved that the non-curcumol components in zedoary turmeric oil have anti-inflammatory effects.3. Preparation and properties of jojoba oil nanoemulsion dry powdersJojoba oil nanoemulsion?JNE?was prepared and the optimal prescription was obtained by single factor investigation.And 0.39 g of egg yolk lecithin was added,dissolved in 5.5 m L of absolute ethanol?1:14,w/v?,and JJBO?0.55 g?was stirred,and ultrapure water?73.5 m L?was added with a high-speed disperser?30000 rpm?while stirred to obtain JNE.After adding 5%lactose and lyophilizing,jojoba oil nanoemulsion dry powders?JNDs?were obtained.JNDs were white loose powders.The D_aof JNDs was 5.86±0.13?m,the lung deposition rate of JNDs was 39.11%,and the MMAD of JNDs was 4.17?m,which proved that JNDs were suitable for pulmonary inhalation.The powder under the scanning electron microscope was a fan-shaped powder,and JJBO was distributed on the surface of lactose.Both the JJBO and JNDs were determined by electron spin resonance method to eliminate free radicals,and the elimination rate of JJBO was 29.89%,and the elimination rate of JNDs was 31.57%.4. Pharmacodynamics of JNDsAfter the ALI model was established by inhalation of LPS or H₂O₂ solution,the animals were divided into four groups:the healthy group,the model group,the dexamethasone group and the JNDs group.Lung tissues appearance and histopathology showed reduced lung tissues injury in the JNDs group.Compared with the model group,the NF-?B inflammatory pathway and Caspase-3 oxidative apoptosis pathway in the lung tissue of the JNDs group can be inhibited.TNF-?,IL-1?,IL-6 and protein content in the lung tissues were significantly reduced;ROS,MDA levels in the lung tissues were significantly reduced,SOD and GSH levels in the lung tissues were significantly increased.It proved that JJBO can exert anti-inflammatory and anti-oxidant effects by inhibiting the NF-?B and Caspase-3 pathways,reducing the levels of inflammatory factors?TNF-?,IL-1?,IL-6?and oxidizing factors?ROS,MDA?,and increasing the levels of reducing factors?SOD,GSH?to reduce ALI in rats.