Overview of the application of prodrug technology in pulmonary inhalation preparations

By Sharo

Compared with systemic administration such as oral or injection, lung inhaled drugs directly enter the respiratory tract through a special drug delivery device to exert a therapeutic effect, and has shown obvious advantages in the treatment of asthma and chronic obstructive pulmonary disease
.

Inhalation administration can maintain a high local drug concentration at the respiratory tract infection site, thereby reducing the risk of drug resistance, but it is usually quickly absorbed from the lungs into the systemic circulation after administration, requiring high-dose administration; and the drug is difficult to accumulate in the lesion , Effective treatment cannot be achieved, and effective inhalation drugs need to be further developed.
Therefore, tailoring the structure of candidate drugs to meet the requirements of inhalation therapy is the development path of inhalation drugs that can be selected at present
.

1.
The concept and classification of prodrugs

Prodrugs, also called prodrugs, were first proposed by Albert in 1958.
Prodrugs are compounds that show pharmacological effects after biotransformation
.

1.
1 Improve physical and chemical properties

The self-dissolving properties of some drugs are not suitable for pulmonary inhalation delivery.
The use of prodrugs can change the original physical and chemical properties of the drugs, thereby facilitating pulmonary administration and improving patient compliance
.

Low drug loading is a major problem in inhaled drug carriers
.

1.
2 Attenuation

Due to the high toxicity of some drugs, severe toxic and side effects can occur during multiple or high-dose administrations.
Relieving the toxic and side effects of drugs is the key to drug delivery
.

Polymyxin E is used to treat gram-negative bacterial infections.
Due to the toxicity caused by inhalation, it is usually made into an inactive prodrug-polymyxin E sodium methanesulfonate (CMS)
.

1.
3 Long-term effect

For drugs that act locally in the lungs, the residence time and local drug concentration in the lungs directly determine their efficacy in the lungs
.

Esterification is a common method for prolonging the pulmonary retention of drugs, which can improve the lipophilicity of drugs, increase the pulmonary affinity of drugs, delay absorption and clearance, and prolong pulmonary retention
.

Coupling of drugs with macromolecular compounds is also a common strategy for prolonging the retention of inhaled small molecules in the lungs
.
PEGylation is the most common means of pulmonary delivery of macromolecular prodrugs
.
The absorption half-life of mono- and di-substituted prednisolone-polyethylene glycol hydrolyzed ester (2kDa) conjugates through the isolated rat lung epithelium was prolonged by about 4 and 8 times, respectively, compared with the free drug solution
.
Paclitaxel and PEG (20kDa and 6kDa) conjugates showed better anti-tumor effects when administered to the lungs than the commercial preparation Paclitaxel (Taxol)
.
And because the 20kDa conjugate stays longer in the lungs, the anti-tumor efficacy of a single dose of tracheal instillation in a mouse lung cancer model is significantly stronger than that of 6kDa
.

1.
4 Targeting

Pulmonary drug delivery itself is a drug delivery route that targets lung organs, and prodrug technology can further achieve targeted effects through active targeting or targeted biological activation
.

Epidermal growth factor receptor (EGFR) is overexpressed in human tumors, especially non-small cell lung cancer
.
Cisplatin was loaded onto gelatin nanoparticles through a ligand exchange reaction, and the surface of the gelatin-cisplatin (GP-Pt) nanocomposite was modified with biotinylated epidermal growth factor (bEGF)
.
Inhaled GP-Pt-bEGF can target cells with high expression of epidermal growth factor receptor, thereby obtaining high cisplatin doses in lung tumors
.

Aiming at the special physiological conditions in the target area that are different from other tissues, it can achieve targeted biological activation and release of drugs
.
Metastatic tumors have high levels of reactive oxygen species (such as hydrogen peroxide).
Prodrugs can be activated by hydrogen peroxide in tumor cells and trigger potential anti-metastatic treatments
.
ProDrug7, a therapeutic drug activated by hydrogen peroxide, uses borate as the trigger unit, and coumarin is used as a fluorophore to monitor the release of the active ingredient hydroxycamptothecin.
It is a mouse model of metastatic lung cancer after intratracheal administration.
It shows effective anti-tumor activity
.

Prodrug design can meet the different requirements of the development of new inhaled drugs.
Through esterification modification or coupling with macromolecular compounds, it can delay the absorption of drugs from the lungs and prolong the residence time of the lungs; take advantage of the special structure or physiological conditions of the target site, Modification of the target head or specific chemical bonds can achieve active targeted drug delivery or targeted bio-responsive drug release in the lung; through personalized modification, physical and chemical properties suitable for pulmonary drug delivery can be obtained and the systemic and pulmonary toxicity of the drug can be reduced
.
In general, the application of prodrug technology can meet the different needs of inhaled drug development and provide ideas for the development of new inhaled drugs
.

references:

[1] Chen Weiya, Yang Feifei, Liao Yonghong.
Application of prodrug technology in the research and development of pulmonary inhalation drugs[J/OL].
Acta Pharmaceutical Sciences.
https://doi.
org/10.
16438/j.
0513-4870.
2021-0588.

[2] Wan Ni, Chen Bin, Li He, Ye Weilun, Wang Hui.
Research progress of lung inhalation drug delivery system[J].
Chinese Journal of New Drugs, 2021, 30(15): 1386-1395.