Lung Inhalation Nano Drug Delivery System Dosage Form
The existing pulmonary inhalation nano drug delivery system dosage forms are mainly divided into two types: liposomes and nanoparticles.
Liposomes
Among the various dosage forms for pulmonary administration, liposomes have obvious advantages, such as being suitable for encapsulating lipophilic drugs, avoiding local irritation, enhancing curative effects, reducing toxic and side effects, and evenly distributing active drugs in the lungs. Lung-administered liposomes can also be used for gene therapy. Compared with viral vectors, liposomes are simple to prepare, have no damage to normal tissues, and have high safety.
Liposome pulmonary drug delivery has the following characteristics: 1. The main component of alveoli is lipids, among which phospholipids account for 80% of the lipid components, and liposomes are also composed of phospholipids, which have good compatibility; 2. Drugs The absorption process in the lungs is mainly passive diffusion. The fat solubility of the drug affects the absorption, and the poorly fat-soluble drug encapsulated in liposomes can increase its bioavailability; 3. Reduce the systemic toxicity of anti-tumor drugs; 4. Long-acting slow Interpretation effect.
The influencing factors of the efficacy and pharmacokinetic characteristics of liposome pulmonary administration include: 1. The smaller the liposome particle size, the faster the absorption; 2. The higher the cholesterol content, the stronger the liposome rigidity and the slower the drug release. The longer the residence time in the lung; 3. Saturated phospholipids such as hydrogenated phospholipids are more stable than unsaturated phospholipid liposomes, and have lower membrane permeability; 4. Negatively charged lipids accelerate the release of drugs in liposomes, which may be related to opsonins The result of the interaction; 5. Disease affects the inner diameter and reactivity of the respiratory tract, which in turn affects drug absorption and distribution. As a carrier for pulmonary drug delivery, liposomes still have some problems, such as low drug loading.
Stability of Liposomes for Pulmonary Delivery
There is a mucociliary clearance mechanism in the respiratory tract. During tracheal instillation, a considerable part of the drug is cleared, and the drug cannot completely reach the alveoli and enter the systemic circulation. Therefore, liposomal pulmonary administration is mostly used for aerosol inhalation, but aerosol inhalation may affect the stability of drug liposomes. If the liposome leaks rapidly during the aerosolization process, its pulmonary administration is meaningless. The addition of cholesterol helps to improve the stability of liposomes and reduces the leakage rate of hydrophilic drugs from 15%-20% to 8%. The liposomes modified by phytohemagglutinin have good stability and adhesion, significantly increase the affinity of liposomes and cells, and are stable during the process of atomization.
Liposome Pulmonary Pharmacokinetics
The tissue distribution after liposome pulmonary administration is related to liposome materials, particle size, surface modification, drug properties and other factors, but almost all reports suggest that liposome pulmonary administration can reach the ideal concentration in the lungs . After atomizing and inhaling the liposome of camptothecin dilauroylphosphatidylcholine to mice, the absorption was rapid. After 30 minutes, the drug concentration in the lung was 310ng/g, and it was quickly distributed in the liver (192ng/g) and brain (61ng/g), the concentration of the drug in other tissues is very low; however, after intramuscular injection of camptothecin dimethyl sulfoxide solution, the absorption of the drug is very slow. The drug is mainly distributed in the liver (136ng/g), and only dstribution of trace (24ng/g) in the lung, so the pulmonary administration of camptothecin liposomes has a good application prospect in the treatment of lung, liver, and brain tumors in the future. Nebulized gas also has an impact on the pharmacokinetics of liposomes after pulmonary administration. Using air containing 5% CO2 to inhale camptothecin liposomes and paclitaxel liposomes in mice is the highest in the lungs. The drug concentration is 24 times that of normal air, and the drug concentration in the liver, spleen, kidney, brain and blood is also higher than the latter.
Pharmacodynamics
Lung administration of liposomes has obvious advantages in the treatment of local lung diseases (such as fungal infections and tumors). Compare the curative effect of amphotericin B liposome and its deoxycholate atomized inhalation on severely immunosuppressed rats with pulmonary aspergillosis. The liposome preparations can significantly prolong the survival time of rats at different concentrations and have an effect on alveolar surface activity. The substance has no inhibitory effect, and the latter has a significant dose-effect relationship and inhibits alveolar surface active substances. Lipopolysaccharide is a component of the cell wall of gram-negative bacteria, which can stimulate phagocytes to produce metabolites and play an important role in acute lung injury. Dexamethasone liposomes can prevent acute lung injury caused by lipopolysaccharide. Dexamethasone liposome and its free drug (800mg/kg) were administered to the lungs of rats, and it was found that the efficacy of dexamethasone liposome in preventing lung inflammation and other injuries was significantly better than its free drug.
Safety Evaluation
The safety evaluation of liposome pulmonary administration has achieved satisfactory results in animal and human trials. Cationic liposomes can induce dose-dependent toxicity and pulmonary inflammation, and multivalent cationic liposomes are more toxic than monovalent cationic liposomes, but neutral and negative ion liposomes have no pulmonary toxicity; The release of reactive oxygen intermediates (ROI) caused by multivalent cationic liposomes is the main cause of its pulmonary toxicity.
Nanoparticles
Nanoparticles have a large specific surface area, an increased dissolution rate, and an increased saturation solubility of the particles. They are often used to increase the bioavailability of poorly soluble hydrophobic drugs. There are usually two methods for preparing drug-loaded nanoparticles for lung inhalation: 1. Depositing particles from solution (bottom-up), including spray drying, freeze drying, supercritical fluid extraction, microemulsion, electrospray, and solvent replacement Recrystallization; 2. Obtained from the crushing of large particles (from top to bottom), including wet grinding and high pressure homogenization.
Compared with traditional powder aerosol and liquid pulmonary drug delivery preparations, the advantages of the lung inhalation nano drug delivery system include: 1. The surface area of nanoparticles is large, and the bioavailability of insoluble drugs is greatly improved; 2. The particles are easier to control than dry powder inhalants. Appearance, low-density particles can be obtained, which is more conducive to reaching the deep lungs. However, problems such as residual solvents, cytotoxicity, low drug loading and difficulty in large-scale production restrict the commercialization of nano-pulmonary drug delivery systems.