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The Pharmacological Effects of Imperatorin and its Preformulation Study

2021-09-06
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The pharmacological studies of imperatorin extracted from the dried root of the Umbelliferae plant Angelica dahurica have various effects such as antibacterial, anti-asthmatic, anti-allergic, dilation of blood vessels, and inhibition of tumor cell proliferation. Lipid microspheres and liposomes are drug carriers prepared from natural lipid materials such as phospholipids and cholesterol. With this carrier, drugs can be delivered to the diseased site to take effect, and drug molecules can be protected from degradation by biological enzymes. The preformulation research and drug stability test of imperatorin can provide a theoretical basis for designing the formulation optimization of imperatorin lipid microspheres for injection. The application of lipomicrosphere technology to imperatorin drug research can reduce the kidney toxicity and side effects of the drug while maintaining the curative effect of the precursor.

Medicilon has been offering high quality analytical testing services to the pharmaceutical industry for decades. We offer a wide range of quality control testing services to support drug research, registration and production. Biopharmaceutical companies also use many of the same services and Medicilon has also added new services to accommodate their unique needs (detailed in the following section).

preformulation research

The drug preparation process based on lipomicrospheres and liposomes can develop longer-acting drugs, and is especially suitable for the secondary development of drugs that have been on the market but have limited clinical applications, to develop safer and more efficient high-end drug formulations. However, the preparation process is extremely complicated and the industrialization technology is difficult. Therefore, domestic marketed products are scarce and cannot meet the needs of clinical and patient needs in my country. The preformulation research of imperatorin lipid microspheres for injection provides a research direction for the application of lipid microspheres. Medicilon is a pre-clinical CRO company. For a very small amount of active pharmaceutical ingredients or candidate compounds with druggability, it can provide professional preformulation services and excavate valuable information, leading the compound to enter the later stage of development. Medicilon’s preformulation research team has extensive experience in the research and development of various compounds, helping customers to successfully promote the early screening of compounds.

The pharmacological research of imperatorin

(1) Suppress epileptic seizures

The maximum electroshock seizure threshold model in mice was used to study the effect of imperatorin in inhibiting seizures. His research found that intraperitoneal injection of 50 and 100 mg·kg-1 imperatorin 30 minutes in advance can increase the voltage threshold of epileptic seizures by 38% and 68% in mice, respectively, and proved that imperatorin can increase seizures in mice under electrical stimulation. The effect of the threshold is dose- and time-dependent.

(2) Dilate blood vessels and inhibit myocardial hypertrophy

Various in vivo and in vitro experiments have shown that imperatorin has a significant vasodilator effect, and the latest research also shows that imperatorin has a significant effect on inhibiting myocardial hypertrophy. Use different solvents (cyclohexane, ethyl acetate, acetone, methanol, 95% ethanol, water) to extract the effective ingredients in Angelica dahurica to make an extract, which acts on the thoracic artery of mice pretreated with norepinephrine and used High performance liquid chromatography was used to determine the content of active ingredients in the extract. The results showed that the vasodilator effect of imperatorin was dose-dependent, and the cyclohexane extract had the strongest vasodilator effect. At the same time, the concentration of imperatorin was the highest (4.09%, w/w), and the blood vessel of imperatorin The expansion effect is 4 times that of isoimperatorin.

The heart weight ratio of spontaneously hypertensive rats treated with imperatorin was significantly reduced, indicating that imperatorin showed anti-cardiac hypertrophy effects both in vivo and in vitro. Imperatorin can reduce the protein content of cardiomyocytes pre-stimulated by angiotensin Ⅱ, reduce the cell volume, and its effect is dose-dependent.

(3) Anti-tumor activity

The human pancreatic cancer cell line PANC-1 was used to screen out the components that inhibit the proliferation of cancer cells from the fruit extract of Angelica sinensis. They are imperatorin and xanthotoxin. The half effective amount of imperatorin is 2.7 mg·ml-1. The study also found that imperatorin can inhibit the expression of cell adhesion molecule-1. Inhibiting cell adhesion may be one of the mechanisms by which imperatorin inhibits tumor cell proliferation.

(4) Antibacterial and antiviral activity

Studies have found that imperatorin has strong inhibitory activity against both gram-positive and gram-negative bacteria (the minimum inhibitory concentration is 32-128mg·ml-1). Studies have shown that imperatorin can inhibit the infection of T cells and HeLe cells by human immunodeficiency virus type I (HIV-1) of vesicular stomatitis virus pseudotype or glycoprotein gp160 enveloped human immunodeficiency virus type I (HIV-1).

(5) Improve the activity of drug metabolizing enzymes

Imperatorin has a certain effect on the activity of drug metabolizing enzymes-cytochrome P450 and glutathione S-transferase. Researchers studied the effects of simple coumarin, linear furanocoumarin, and keratofuranocoumarin on the activity of liver drug metabolizing enzymes (cytochrome P450 and glutathione S-transferase, GST) in mice, and found These coumarins can all increase the activity of glutathione S-transferase, and imperatorin, a representative compound of linear furanocoumarin, can also significantly increase the activity of P450, especially P450 2B and 3A subtypes.

Preformulation study of imperatorin lipid microspheres

The apparent oil-water partition coefficient of imperatorin in n-octanol-water/buffer was determined by the combination of shake flask method and high performance liquid chromatography, and the apparent oil-water partition coefficient of imperatorin in n-octanol-water/buffer was determined by high performance liquid chromatography. , Soybean oil for injection (LCT)/medium-chain fatty acid glyceride (MCT) for injection in different ratios of oil phase equilibrium solubility, and according to the 2015 edition of the “Chinese Pharmacopoeia” raw materials and preparation stability test guidelines for imperatorin The factors influencing factors are tested and investigated. It was found that the equilibrium solubility of imperatorin at pH 2.0, 4.0, 6.0, 7.4, 8.0, 9.0 buffers at 25℃ were 0.36, 2.45, 1.14, 2.45, 2.66, 2.52μg/mL, and the apparent oil-water distribution The coefficient is 16.76 (log P=1.22), and the solubility in MCT is the largest, 26.3mg/g.

The degradation rate of imperatorin solution under strong light (4500±500Lx) for 10 consecutive days does not exceed 10%, which is relatively stable. The degradation rate for 10 consecutive days under high temperature (60℃) is 19.9%, which is unstable. Therefore, imperatorin is a poorly water-soluble, fat-soluble drug, stable under light, and unstable under high temperature. Lipid microspheres serve as a good carrier for fat-soluble drugs, suggesting the feasibility of imperatorin as lipid microspheres.

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