Optimization of artemisinin rapid release solid dispersion preparation process using dual carrier system
Malaria is a highly lethal malignant infectious disease caused by malaria parasites, transmitted by mosquitoes, and widely spread worldwide. The cyclic transmission and complex life cycle of malaria parasites have made it difficult to completely eradicate malaria. Most traditional antimalarial drugs, such as chloroquine, quinine, imiquine, and piperaquine, have developed resistance and become ineffective. Artemisinin (ART) class antimalarial drugs have a rapid effect and are currently recognized to have low toxicity, and have not yet shown obvious resistance and become first-line antimalarial drugs. ART is a sesquiterpene lactone extracted from Artemisia annua L. leaves. It is not only the only first-line antimalarial drug for treating malaria, but also has various biological activities such as antiviral, immune regulation, anti-inflammatory, antiparasitic, antifungal, and anti-tumor. However, due to its poor water and lipid solubility, it is a poorly soluble drug with incomplete absorption in vivo and low bioavailability. In order to effectively solve these problems that restrict the clinical application of artemisinin, many new methods have been applied to artemisinin based drug formulations in recent years, among which solid dispersion technology has received attention.

Solid dispersion (SD) is a dispersion system formed by dispersing solid hydrophobic active pharmaceutical ingredients in a molecular or microcrystalline state in a solid hydrophilic inert carrier. It can significantly increase drug solubility and dissolution, promote oral absorption of drugs, improve bioavailability, and can also achieve stable and highly dispersed drugs or even achieve sustained and controlled release effects by selecting appropriate carriers and excipients. Ansari et al. prepared a solid dispersion of dihydroartemisinin using PVP K30 as a single carrier, and found that dihydroartemisinin existed as an amorphous complex with the carrier, with a solubility 50 times higher than that of the active pharmaceutical ingredient; Yang et al. prepared a solid dispersion of evodiamine using poloxamer 188 as the optimal carrier, which greatly improved the dissolution of the drug without affecting its content and morphology; Li et al. prepared ART solid dispersion (ART-SD) and sustained-release ART-SD using PEG 6000 lecithin as a dual carrier and III acrylic resin as a single carrier. Compared with a single carrier, the preparation of solid dispersions using a mixed carrier composed of two or more carriers may have more advantages in regulating drug release rate and improving drug dissolution. However, it is currently unclear whether the type of carrier has an impact on the dissolution of ART, and the process conditions for preparing rapid release ART-SD using dual carriers have not been optimized. This article uses lecithin, a commonly used carrier for solid dispersions, and PEG 6000 or PVP K30 as dual carriers to compare the effects of different carrier types and ratios on drug dissolution. The preparation process of dual carrier rapid release ART-SD is optimized, and the existence status of drug carriers in the solid dispersion prepared with the optimal prescription is clarified through IR and DSC methods, laying an important foundation for improving the clinical efficacy of poorly soluble drugs.

Solid dispersion technology disperses drugs highly in suitable carrier materials and exists in amorphous, microcrystalline, molecular dispersed, or colloidal dispersed states. After contact with gastrointestinal fluids, the drug dissolution rate is accelerated, promoting drug absorption and improving bioavailability, thus improving the problem of poor oral absorption of poorly soluble drugs. According to the properties of the carrier and the characteristics of drug release, solid dispersions are divided into rapid release, controlled release, and enteric coated solid dispersions. This article selects hydrophilic carrier materials and utilizes their good wetting properties to enable rapid release of ART in the rapid release ART-SD. The dissolution rate within 50 minutes is much higher than that of physical mixtures and ART raw materials, which is beneficial for solving the problem of incomplete absorption of ART oral administration.

Secondly, dual carriers can increase drug dissolution to a greater extent than single carriers. Soy lecithin has solubilization properties, while PVP K30 has the characteristics of increasing wetting, reducing surface tension of dissolution media, and inhibiting drug crystallization. PVP K30 is widely used to improve the dissolution of poorly soluble drugs. PEG 6000 has also been mixed with lecithin as a dual carrier for the preparation of ART-SD, but the effect of different composite carriers on the dissolution of ART from ART-SD is currently unclear, and the process conditions for preparing ART-SD using dual carriers have not been optimized. This article investigates the effect of phosphatidylcholine combined with PVP K30 and PEG 6000 as dual carriers on the dissolution of ART. It is found that phosphatidylcholine PVP K30 is superior, and the ratio of the two is determined. Based on this, the process conditions for preparing rapid release ART-SD by dual carrier solvent method are optimized, laying an important foundation for the development of new ART formulations.

In this experiment, the dissolution rate of ART was used as the evaluation index. Through single factor screening of dual carrier types, composite carrier ratios, reaction time, solvent dosage, etc., the optimal formulation for preparing rapid release ART-SD using dual carrier system was determined as: 50 mg ART, 50 mg soy lecithin, 350 mg PVP K30 (soy lecithin and PVP K30 ratio 1:7). The drug content in the solid dispersion prepared by the optimal process was 10.55% ± 0.04%, reaching dissolution equilibrium at 30 minutes. The dissolution rate within 50 minutes was 87.21% ± 2.28%, significantly higher than PM 3.45% ± 1.68% and ART raw material 0.05% ± 0.15%. DSC and IR analysis indicate that hydrogen bonds are formed between ART and the carrier and exist in a new amorphous state. Further research will be conducted to determine whether ART-SD can improve the low oral bioavailability of ART as a poorly soluble drug, enhance its anti malarial activity, and provide more effective anti malarial drugs for clinical use.