Lung Inhalation Nano Drug Delivery System
Lung diseases, such as asthma, emphysema, chronic obstructive pulmonary disease, and cystic fibrosis, are increasing with the increase in air pollution. In lung therapy, the use of systemic drug delivery is prone to cause adverse reactions, and the distribution of drugs in the lungs may be less, so the development of lung inhalation drug delivery systems has become a research hotspot. People have recognized that lung inhalation is the simplest and most effective route of administration for the treatment of the above diseases. At the same time, the lungs are also a good absorption site for systemic administration. The advantages of pulmonary drug delivery include: 1, The lungs have a large absorption area. Adults have 300 to 400 million alveoli, with a total area of 70-100m2, which can deliver drugs efficiently; 2, The drugs can be quickly absorbed into the blood through the alveoli. The alveoli are composed of a single layer of epithelial cells with abundant capillaries. Drugs are easily absorbed through the surface of the alveoli; 3, The blood flow in the lungs is large, up to 5000mL/min. Almost all blood discharged from the right heart passes through the lungs, and the substances absorbed by the lungs can be absorbed. Rapidly distributed throughout the body, easy to form a concentration gradient between the alveoli and blood stream, which is conducive to drug absorption; 4, The lungs have low chemical degradation and enzymatic degradation, and the drug is less degraded. It is suitable for the delivery of protein and peptide drugs; 5, The drug passes through the lungs Absorption into the blood avoids the first pass effect of the liver and improves the bioavailability of the drug; 6, For lung diseases, the drug can directly reach the target site with fast onset, reducing the dosage, toxicity and adverse reactions.
The diameter of particles inhaled by the lungs affects their deposition in the respiratory system. Particles with a particle size greater than 5.0um are deposited in the pharynx, larynx and upper respiratory tract due to inertial collisions between particles; particles with a particle size of 1.0 to 5.0um are mainly deposited into the deep part of the respiratory tract by gravity, including the trachea, bronchi and alveolar surface; Particles with a particle size of 0.5～1.0um are deposited on the respiratory bronchioles and alveolar walls; particles with a particle size of ≤0.5pm are exhaled with the airflow due to Brownian motion, usually 80% are discharged, and basically cannot be deposited in the respiratory tract. Particles with a particle size of 1.0～3.0um have the highest sedimentation rate in the bronchioles and alveoli, and are often used as the range of choice for lung inhalation preparations.
The particle size of the nano drug delivery system is nanometer, and its specific surface area is extremely large. After entering the human body, the contact area with the action site is extremely large, which can greatly increase the dissolution and absorption of the drug. Nano drug delivery system can also solve the problems of poor water solubility, poor absorption, and instability of many drugs. Nano drug delivery system has outstanding advantages for lung inhalation drug delivery. After inhalation, it can enter the deep lung tissue and directly contact the alveoli with a large contact area. Therefore, the concentration of the drug in the alveolar tissue is greatly increased and the drug effect can be quickly exerted .
Pulmonary Inhalation Drug Delivery Device
At present, there are mainly three kinds of devices for inhalation and drug delivery in the lungs: ①Nebulizer (NEB); ②Pressurized metered-dose inhaler (pMDI); ③Dry powder inhaler (Dry powder inhaler) , DPI). Each drug delivery device has its own advantages and disadvantages. A good inhalation drug delivery device needs to have the following characteristics: it can produce suitable size droplets (0.5~5um), the dosage is reproducible, and the preparation can be guaranteed stable. In addition, it should be simple, inexpensive, and portable.
Nebulizer is the first device to be marketed as a product, but the disadvantages of nebulization are low efficiency, poor reproducibility, large variability, heavy equipment, and difficulty in self-administration. Atomized inhalation administration takes a long time, and it takes about 30 minutes from device assembly, administration to cleaning. Research on pMDI began in the 1950s and quickly became the mainstream drug delivery method for the treatment of asthma. However, pMIDL is not good for the environment. The propellant evaporates quickly to produce a cooling effect during startup. The propellant Freon affects the environment and restricts its application. In addition, it cannot be used for active protein and peptide drugs because they have poor solubility in propellants, and their stability and dosage are difficult to meet the requirements. Because the particle escape rate is inconsistent with the inhalation rate, only a small part of the drug can enter the patient’s lungs. The drug loss rate of this pressure dosing device is as high as 70%, and sometimes even exceeds 90%, which limits its scope of application.
In response to the shortcomings of NEB and pMDI, a small inhalation device DPI that does not use propellants came into being. The DPI device adopts a “breath-driven” mode, which combines the characteristics of powder technology and particle distribution in the respiratory tract. It does not require excitation and inhalation coordination, and is actively inhaled by the patient. Compared with PMDI, the delivery efficiency of the lung is significantly improved. The “breath-driven” inhaler can sense the patient’s breathing and initiate inhalation simultaneously.
There are currently two main types of DPI: single-dose and multi-dose packaging. A single-dose inhalation device requires a capsule to store the medicine, also known as a capsule-type inhalation device. Connect the capsule containing the dry powder to a rotator and a metal needle. During the inhalation process, the rotor begins to rotate, the pointed needle pierces the capsule, and the drug powder is sent into the respiratory tract along with the inhalation airflow. Although the dosage of single-dose dry powder inhalation is accurate and reliable, the capsule needs to be replaced frequently, which is inconvenient to use. The multi-dose inhalation device can be divided into vesicle type and reservoir type according to different storage methods. The internal structure of the vesicle type inhalation device is complicated. Each dose of medicine is stored in a vesicle made of double-layer aluminum foil. When in use, press down the handle on the outside of the device to drive the lead wheel, shrink wheel and bottom wheel to rotate. The guide wheel releases a section of aluminum foil tape, and a capsule moves below the interface. At this time, the shrink wheel pulls one side of the aluminum foil tape to expose the powder, and the bottom wheel rolls up the vacant aluminum foil. On the other side, and at the same time drives the dose indicator to rotate to display the remaining The number of doses. Each dosage unit is individually packaged and sealed, which greatly improves the moisture-proof performance of the medicine and ensures the consistency of the released dosage. However, the structure of the device is complicated and the production cost is high. The multi-dose storage device can store nearly 200 doses. When using the rotating base, the medicine is released from the storage to the turntable and is scraped to the medicine passage by the scraper. Therefore, it must be operated vertically when charging. There is a double spiral channel at the suction nozzle, and the suction power generates turbulent airflow. The particles collide with each other in the channel, and the drug is easily separated from the carrier to form finer particles, which is beneficial to increase the amount of drug deposited in the lungs. Reservoir-type inhalation devices are relatively simple in structure and low in cost, but such devices are not very accurate in dividing the dose, the patient is in danger of overdose, and the moisture-proof performance is not good.