Research Progresses of the Pharmacological Functions and New Formulations of Artemisinin and Its Derivatives

Artemisinin is a sesquiterpene lactone compound with a peroxide group structure extracted from the leaves of artemisia annua, family Asteraceae. The derivatives of artemisinin mainly include artemether, arteether, artesunate, and dihydro artemisinin. Artemisinin-based drugs are mainly used in the treatment of malaria. As research continues, it has been discovered that artemisinin compounds also have anti-tumor, antibacterial and insecticidal, antipyretic, anti-inflammatory, immunomodulatory and other functions. 

Even though artemisinin-based drugs have extraordinary antimalarial effects and other pharmacological functions, in clinical practice, a majority of them indeed have such problems of poor solubility, low bioavailability, high first-pass effect, high Plasmodium relapse rate and frequent dosing. Thus, the research on the formulation of artemisinin-based drugs has become a heated topic currently. With the advancement of pharmaceutical technology, many new technologies have been applied to the preparation of artemisinin and its derivatives, offering possible solutions for the therapeutical effect of artemisinin, such as nano preparations, solid dispersions, inclusion compounds, microemulsions, and transdermal drug delivery formulations. 

1. Nano preparations 

Nanometer drug delivery systems are generally known as a series of new tiny drug delivery systems with a nanometer-particle size. According to the decentralized motion states and properties of nanoparticles, nano delivery systems mainly include nanoparticles, liposomes, nano emulsions, polymeric micelles and nano suspensions. Such systems are characterized by good tumor targeting, comparatively long body circulation time, vulnerability to cell absorption, controlled drug release, as well as enhanced drug solubility and stronger drug stability. ① Nano emulsion is a stable and transparent colloidal dispersion consisting of surfactant, co-surfactant, oil and water phases, with a particle size between 10 and 100nm. In the research of some scholars on the use of artesunate for the treatment of Theileriosis and double buds piroplasmosis in cattle and sheep, polysorbate 80 is chosen as the emulsifier, n-butanol as the co-surfactant, and ethyl oleate as the oil phase for the preparation of artesunate nano emulsion injections. The problems of poor solubility of artesunate in water, inability to avoid the first-pass effect in the liver when administered orally, instability of commercially available artesunate sodium salt and inconvenience of clinical use have all been solved. ② Nanoparticles (NP), made from natural or synthetic polymers, are solid colloidal particles with a particle size between 1 and 100nm, including nanospheres and nanocapsules. The active components (drugs, bioactive materials, etc.) are dissolved or encapsulated inside particles, or adsorbed or attached to the surface. A modified self-emulsification/solvent diffusion method is used to make artesunate into biodegradable nanoparticles suitable for human bodies, and the specific recognizable ligand Tf on the surface of tumor cells is integrated to the drug-carrying nanocarrier to realize a targeted treatment of tumor tissues (cells). In the vivo experiments of animals, it shows that this new nano preparation has the properties of blood and bone marrow targeting. Nanocapsules containing artemether are prepared by the nascent state microcrystallization method, which can solve the drawbacks of artemether of insolubility, rapid metabolism and low utilization rate, and significantly improve the drug efficacy. ③ Nanoliposomes. Nanostructured lipid carrier (NLC) is a solid colloidal drug delivery system in which a certain proportion of liquid oil or other different lipids (e.g. lecithin, triglycerides, etc.) are used as carriers to encapsulate drugs in lipid-like nuclei, as well as a new type of nano drug delivery system with a particle size of 50 to 1,000nm. Some scholars have studied the inhibitory effect of dihydroartemisinin nanostructure lipid carrier and dihydroartemisinin suspension on liver cancer strains by animal tumor models, and confirmed that dihydroartemisinin nanostructure lipid carrier has stronger proliferation inhibitory effect on leukaemia cells K562 and glioma cells U87 than common suspensions, which provides a basis for the development of efficient and low toxicity anti-cancer drugs of dihydroartemisinin. Artesunate nanoliposomes can interfere the expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) in HepG2. It proves that artesunate nanoliposomes can inhibit the formation of tumor blood vessels to achieve the anti-tumor effect, and such effect is stronger than that of artesunate API, which has potential value in the treatment of liver cancer. 

2. Solid dispersion 

Solid dispersions refer to that drugs are highly dispersed in suitable carrier materials, which are similar to solid matters formed in liquid systems. The solid dispersions make drugs exist in amorphous, microcrystalline, molecular or colloidal dispersion state, and the dispersity is very large. When they contact with the liquid in the gastrointestinal tract, the dissolution rate and the absorption of drugs are accelerated, and the bioavailability is improved. In terms of the different properties of carriers and the characteristics of drug release, solid dispersions are divided into fast-release, slow-release and enteric solid dispersions. ① Fast-release solid dispersions are prepared by hydrophilic carrier materials. Drugs are highly dispersed in carrier materials. Due to the hydrophilicity of materials, drugs will have good wettability, which can achieve rapid release, and improve the solubility, bioavailability and dissolution rate. For insoluble drugs, it is a very good solution to solve the dissolution problem. For example, some scholars have prepared solid dispersions of the low-water-soluble drug, dihydroartemisinin, with polyvinylpyrrolidone as a carrier. The X-ray diffraction (XRD) and differential scanning calorimetry (DSC) were applied for comparison and detection. It is found that dihydroartemisinin is in an amorphous complex, and the solubility is 50 times higher than that of the API, which significantly improves the bioactivity. ② Slow-release solid dispersions are prepared with water-insoluble or fat-soluble carriers. This system can be considered as a solubility-diffusion system. ③ Enteric solid dispersions are prepared with enteric carriers, which can facilitate intestinal release. Due to the special pH conditions for the dissolution of carrier materials, colon-targeting drug-release solid dispersions will not be released or released less in stomachs and small intestines, and can be released quickly only after reaching colons.

3. Cyclodextrin inclusion compound

Cyclodextrin inclusion compound is an assembly with a complex structure and special functions created by introducing drug molecules into cyclodextrin supramolecular system as blocks, so that insoluble drugs can be included by cyclodextrin to enhance their solubility and stability in water, thus improving the bioavailability of drugs. Artemisinin nanoparticles and artemisinin β-cyclodextrin inclusion compound are prepared by the evaporation-precipitation method. Both of them can improve the solubility and dissolution rate of artemisinin significantly. Some scholars synthesized artesunate-cyclodextrin bonding prodrugs, and the cell activity was determined by MTT method. It was proved that this series of new compounds had good anti-colorectal cancer activity and certain targeting. 

4. Transdermal drug delivery preparation

Transdermal drug delivery preparation refers to the preparation of drugs for transdermal administration, including ointment and pressure sensitive adhesive patch. This preparation allows drugs to quickly penetrate the skin, and get into the blood circulation for the systemic treatment, which can avoid the "first-pass effect" of liver and gastrointestinal damage. Some scholars prepared artemether soluble microneedle transdermal patches. Compared with intramuscular injection, when the bioavailability is similar, the plasma-drug concentration is more stable, and a new antimalarial formulation with slow-release effect can be developed. 

References

[1] Li Haibo, Qin Dapeng, Ge Wen, Wang Zhenzhong, Cao Liang, Xiao Wei, Yu Yang and Yao Xinsheng. Research Progresses of the Chemical Constituents and Pharmacological Functions of Artemisia annua [J]. Chinese Traditional and Herbal Drugs, 2019, 50(14): 3461-3470. 

[2] Zhang Wenfei, Guan Wutai, Chen Fang, Zhang Shihai, Deng Yuelin, Shi Hequn, Xu Guohuan. Research Progresses of Artemisinin and Its Derivatives in Livestock Production [J]. Feed Industry, 2019, 40(15): 22-27. DOI: 10.13302/j.cnki.fi.2019.15.004. 

[3] Li Wenting, Zhang Guoli, Zhang Ruiwu, Duan Guolei, Yang Zhaoxiang. Research Progresses of New Formulations of Artemisinin-based Drug [J]. Rural Economy and Science Technology, 2019, 30(12): 299-300. 

About the Author

Xiaomichong, a researcher in pharmaceutical quality, has been dedicated to pharmaceutical quality research and verification of drug analysis methods for a long time. Currently, she works in a large domestic pharmaceutical research and development company, engaged in drug inspection analysis and verification of analytical methods.