The membrane permeability of protein and peptide macromolecular drugs is poor, so the clinical administration of these drugs is mainly by injection. Long-term medication and high costs increase the mental burden of patients.Scientists are now looking for new non-injection routes of proteins and peptides that are more acceptable to patients, including oral, nasal, intraocular, transdermal, rectal, and pulmonary .

Compared with other methods, pulmonary drug delivery has the following advantages: a larger absorption area with a total area of 80-140m2;The alveolar epithelial cell layer is very thin with abundant capillaries, so the drug can be quickly absorbed through the alveoli and directly enter the blood circulation. This avoids the liver's first pass effect and improves the availability of drugs; The chemical degradation and enzymatic reaction of Lung is low, so the degree of damage to the drug is small and the dosage , side effects can be reduced.

In addition to the traditional solution, emulsion and suspension aerosol, dry powder inhalation is currently the most researched dosage form. The products currently on the market are mainly used to treat asthma as antihistamines and steroid hormones. Studies have shown that dry powder inhalation can effectively increase the stability of protein peptide drugs and improve bioavailability.

The launch of insulin pulmonary inhalation powder in 2006 illustrates the good prospects of protein and peptide pulmonary .

The problem is that the therapeutic effect of pulmonary drug delivery is easily affected by the physical and chemical properties of the drug, dosage form factors, and drug delivery device. How to increase the effective amount of lung deposition and increase the absorption of drugs in the lungs is a problem that needs to be solved at present

What is dry powder inhalation (DPI)?

Dry powder inhalation is also called aerosol of micropowders for inhalation,It is a new dosage form developed on the basis of pressurzied inhalation aerosol.Specifically, it refers to the production in which the patient inhales the atomized medicine into the lungs by using a special dry powder inhalation device after mixing the solid micronized medicine and the carrier. Since no propellant is used, it has achieved greater development after the ban on Freon. Compared with aerosols with quantitative absorption, they have the advantages of high stability, high efficiency and no contamination by microorganisms.

Dry powder inhalation mainly include carrier type and carrier-free type. The carrier type is mainly formed by mixing a carrier with a particle size of 50-100 microns and a drug powder. The small dose of drug powder is adsorbed on the surface of the carrier to improve the fluidity and reduce the sedimentation in the mouth, throat and upper respiratory tract.This make the medicine reach the lungs more effectively.The carrier-free type is composed of a certain dose of drug powder alone, the particle size is generally 0.5-5 microns. Its affected by electrostatic attraction, liquidity is relatively poor.Next are 5 important aspects

1. Drug Micronization Technology

2. Commonly used carriers for dry powder inhalation 

3. Drug prescription factors

4. Powder properties

5. Strategies to increase lung deposition rate

1. Drug Micronization Technology

To make dry powder inhalants, you first need a suitable micropowder of the drug. The ideal particle size of the drug for lung inhalation is 0.5-5 microns, but a large number of particles in this range are easily deposited in the upper respiratory tract and cannot enter the bronchus. The smaller particles are distributed into the alveoli through Brown diffusion, but they are easily exhaled with the airflow.

The currently applied technologies include spray drying technology, grinding method, supercritical fluid technology,crystallization etc.

Spray freeze drying,SFD

The aqueous drug solution is atomized into a spray chamber filled with cryogenic liquid through an ultrasonic nozzle. The atomized droplets solidify quickly when they come into contact with the low-temperature medium. This process quickly takes only a few milliseconds, and the low-temperature liquid needs to be stirred. Most unstable drugs (such as peptides, proteins, DNA) and other particles obtained by spray freeze-drying have good stability and dispersibility.

Supercritical fluid fluid, SCF

This technique is widely used in the production of particles. At the critical point of the fluid, the rapid decompression of the supercritical liquid containing the solute will form a large number of fine crystals. Carbon dioxide is a commonly used solvent in the SCF method. Its production process is gentle, suitable for the micronization of proteins and peptides, so that it can maintain biological activity.

2.Commonly used carriers for dry powder inhalation 

Most protein and peptide drugs require relatively small doses to function. At the same time, after the drugs are micronized, they have higher surface free energy, and the powder particles are easy to aggregate into agglomerates. It is necessary to add carrier materials as fillers to improve their fluidity.

When the dry powder inhalation device is used, the medicine and the carrier enter the upper respiratory tract by the inhalation air flow. As the air flow speeds up, the medicine and the carrier separate, and the medicine enters the human lungs under the action of the high-speed air flow. The ideal carrier should be non-toxic, crystalline, suitable size, good fluidity, abundant and stable sources. The currently used carriers are lactose, mannitol, erythritol, xylitol, etc.

Lactose

Lactose has been approved by the US FDA as a carrier for dry powder inhalation. The currently marketed dry powder inhalants all use lactose monohydrate as a carrier, such as Pulmicort Flexhaler, Pulmicort Turbuhaler, Spiriva, etc. The raw material of lactose monohydrate is easily available and inexpensive to produce, has no pharmacological toxicity, and is easy to modify. Crude lactose (30-100 microns in particle size) has been successfully marketed as a carrier for dry powder inhalation. Coarse lactose can improve the fluidity and dispersion of dry powder

Mannitol

Mannitol is a non-reducing sugar and has the effect of stabilizing protein. It is widely used in protein drugs such as insulin (Exubera) for the treatment of type I and type II diabetes. It is composed of 60% recombinant human insulin and mannitol, glycine, sodium citrate and sodium hydroxide. In recent years, it has been increasingly used to replace lactose as a DPI carrier.

3.Drug prescription factors

There are many factors that affect the lung deposition of dry powder inhalation. In addition to the nature of the fine powder of the drug itself, the nature of the carrier, the ratio of drug/carrier , the mixing sequence and time all have an important impact on the DPI content and the lung deposition rate.

Carrier properties

The type, shape, surface roughness and particle size of the carrier will affect the deposition of inhaled powder in the lungs. Compare the fluidity, surface morphology and aerodynamics of mannitol, sorbitol, and xylitol after mixing with budesonide. Mannitol is the most suitable carrier for budesonide. According to reports, the most suitable fine powder particle size for DPI is 5-8 microns.

Drugs and carriers

The ratio of drug to carrier affects the lung deposition rate of inhaled powder. There are a certain number of active sites on the surface of the carrier, exceeding the number of sites will affect the amount of inhaled drug. The mixing method and time will also affect its lung deposition rate. There are also interactions between the drug and the carrier: there are three basic forces in dry powder inhalants, Vander Waals force, electrostatic and capillary force. Direct measurement of the interaction force between the drug and the carrier can be used as a reference for the design of dry powder inhalation .

Using atomic force microscopy (AFM) technology can directly measure the energy required to separate the drug and the carrier, and quantitatively study the interaction between the drug and the carrier. Another method is the tensile strength method, which can be used to measure the binding force between particles of the same substance.

4.Powder properties

The type, size, surface properties, density, aerodynamics and other properties of the carrier will affect the lung deposition rate of the drug

The aerodynamics of the powder and the airflow inhaled by the human body determine the mechanism of particle deposition. The diameter of the particles suitable for pulmonary administration is 0.5 to 5 microns. There are many types of particles: needle, polygon, fibrous, flake, etc. Generally speaking, spherical aerosol particles are better.

The characteristics of low-density porous large particles have good lung deposition performance, and their several particle sizes are usually 5-20 microns. During the production process, the powder will aggregate and adhere due to static electricity which will affect its use. Properly increase the environmental humidity, and add surfactants to eliminate the effect of static charge.

Fluidity is one of the important properties of powder. The fluidity depends on the characteristics of the substance itself, and other factors are also affected: the friction of the relative movement of particles, surface tension, capillary gravitation, etc.

5.Strategies to increase lung deposition rate

There is a common problem after the drug and the carrier are mixed: the drug and the carrier are too strong, and the separation efficiency from the carrier is low, reaching only 20% of the lungs. Changing the particle size, shape, structure and density of the carrier can change the binding force between the drug and the carrier.

We can consider changing the fluidity and dispersion of the powder to improve the lung deposition rate. The surface of the particles is chemically modified to reduce the adhesion between the powders. Consider adding magnesium stearate and L-leucine to promote powder dispersion and greatly improve the fluidity of the powder.

Another strategy is to reprocess the powder. It exists as a certain volume of aggregates before inhalation, to forming loose pellets. As the airflow accelerates when inhaled through the respiratory tract, the drug pellets disintegrate into particles, achieving the purpose of enhancing lung deposition.

In addition, the use of hydrophilic particles to modify hydrophobic drugs can effectively increase lung deposition. If silicic acid is highly hydrophilic, mixing it with sodium cromoglycate and a carrier can effectively increase the deposition rate.

Reference:

1. Kaialy W,Larhrib,H,Martin GP,et al.The effect of engineered mannitol-lactose mixture of dry powder inhaler performance [J].Pharm Res,2012.29:2139-2156

2. Du P,Du J.Smyth HDC,Evaluation of granulated lactose as a carrier for DPI formulations I:effect of granule size [J],AAPS pharm Scitech.2014.15:1414-1428

3. Tee SK,Zeng SM,Martin GP,et al,The use of different sugars as fine and coarse carriers for aserosolised salbutamol suiphate [J] ,Int J Pharm.2000.208:111-123