Influencing Factors of Particulate Pulmonary Deposition
The deposition of particles in the lungs is affected by particle characteristics (particle size distribution, morphology, roughness, porosity), carriers, drugs, and breathing methods.
Particle Size and Shape
Particle size, particle morphology, and particle density are important factors that determine lung deposition. Particles of different aerodynamic diameters (Dae) collide, settle and diffuse inertially when entering the lungs. Dae is an imaginary particle size that describes the movement of particles. It is defined as: to make the unit density sphere moving at low Reynolds number in still air, and the actual diameter reached the same final particle sedimentation rate, which is the actual particle size in terms of equivalent aerodynamic characteristics of the same diameter, that is, the actual particle size The diameter is converted into an equivalent diameter with the same aerodynamic characteristics.
There are three main mechanisms for the deposition of drugs with different aerodynamic diameters in the lungs: 1. Inertial embedding. Particles with Dae greater than 5μm have a higher weight and velocity. They are deposited in the oropharynx and upper respiratory tract due to inertial collisions, and there is not much deposition in the lungs; 2. Sedimentation, due to inertial collision and sedimentation, smaller particles with a Dae of 0.5-5μm easily reach the deep part of the respiratory tract and deposit on the surface of the trachea, bronchi and alveoli; 3. Brownian diffusion, most of the particles smaller than 0.5μm are due to Brownian motion Suspended in the air and diffused, it is exhaled out of the body, usually 80% is expelled, basically can not be deposited in the respiratory tract, so the best Dae for depositing particles in the alveolar area is 0.5-5μm.
Particles with smaller aerodynamic particle size will also be deposited in the lower respiratory tract, such as large porous particles (LPP) with a particle size of 5μm or more and a density of less than 0.4g/cm3. LPP overcomes the traditional atomization of micropowder (ball) drug delivery system Shortcomings such as low efficiency, easy adhesion and easy aggregation, LPP is not easy to be cleared by the alveoli, easy to deposit in the lower respiratory tract, and can make the drug slow release in the lungs. Using para-acetamidosalicylic acid as the model drug, DPPC as the carrier material, spray drying method to prepare the macroporous microsphere lung inhalation drug delivery system, Dae is 7.0~7.5μm, the proportion of inhalable particles (FPF) is 31%~39 %, the drug load is 95%. Animal experiments have shown that the blood drug concentration reaches its peak after 15 minutes of administration, and the effective lung drug concentration is maintained for more than 3 hours.
Single photon emission computed tomography was used to study the pulmonary deposition of mannitol powders with three different particle sizes (Dae: 2.7μm, 3.6μm and .5.4μm) labeled with radiolabel Tc-DTPA. The lung deposition of 2.7μm and 3.6 μm particles is twice that of 5.4 μm particles. The deposition of smaller particles is negligible. 75.9% of 5.4μm particles are deposited in the upper respiratory tract and have no therapeutic effect. The smaller the particle size, the less the upper respiratory tract deposition (42.4% for 3.6μm and 36% for 2.7μm). This result confirms that lung deposition depends on Particle size, especially aerodynamic particle size.
Carriers and Drugs
The drug in dry powder inhalation needs to be micronized to reach the appropriate particle size. Micronization methods mainly include grinding and spray drying. The grinding method cannot well control the particle size and particle morphology. Spray drying is the use of an atomizer to disperse the drug solution into fine droplets, and quickly evaporate the solvent in a thermal drying medium (such as hot air) to form dry powder or particles, with high cleanliness, narrow particle size distribution, and easy industrial production.
After the drug is micronized, the surface energy is large, it is very easy to agglomerate and is difficult to disperse, which brings great difficulties to the packaging and delivery of the drug. Therefore, dry powder inhalants often use larger particle size carriers to assist in the dispersion of small drug particles, and the commonly used carriers are 60~80pm Of lactose. Lactose is the only dry powder inhaler carrier approved by the US FDA. The small drug particles are loosely adsorbed on the surface, and the fluidity is improved. When the patient inhales, the shearing force generated by the air turbulence separates the drug from the carrier. Small particles of the drug fall off the surface of the carrier and enter the trachea with the airflow, while the large particle carrier is deposited in the oropharynx due to too much momentum. The commonly used lactose is in the form of a hydrate. However, lactose may have an effect on peptide and protein drugs and is not suitable for diabetic patients. Some sugar alcohols such as mannitol are not degradable and have less hygroscopicity than lactose, so they can be used as carriers.