Approached solvent: glucose rings improved blood pressure medications

Chemists have increased the solubility of the blood pressure-lowering drug telmisartan by 20 times by combining it with a substance in the form of a ring of linked glucose molecules. The original medical drug is poorly soluble in the blood, and therefore must be taken in large doses to achieve an effect. As part of the complex, the drug is better and faster absorbed, and therefore the concentrations used for treatment will be smaller, and therefore the risk of side effects will be reduced.

How the blood pressure medicine was improved

Scientists from the G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences (Ivanovo) synthesized complexes of telmisartan and cyclodextrins. Cyclodextrin is a substance in the form of a ring of glucose molecules, which is obtained by processing starch. On its surface there is a large number of hydroxyl groups of hydrogen and oxygen, thanks to which the compound interacts well with water and is absorbed into the blood. The inside of the ring contains carbon atoms, hydrogen atoms and ether bonds that create a kind of cavity that "repels" water.

The chemists placed the telmisartan molecule into the cavity of cyclodextrin, doing so in two different ways: in the first case, cyclodextrin and telmisartan were ground together, and in the second case, they dissolved it in ethanol and then dried it.

-The obtained complex can be recommended for testing on mice and later on humans. The results will be useful in creating innovative dosage forms of telmisartan, which will increase the effectiveness of treatment of cardiovascular diseases and reduce the risk of undesirable side effects. The methods used in this work can also be used to improve the properties of other poorly soluble drugs, - said the project leader, candidate of chemical sciences, senior researcher of the laboratory of physical chemistry of medicinal compounds of the Institute of Solution Chemistry Angelika Sharapova.

Side effects of blood pressure medications

Scientists tested the solubility of the resulting complex compounds at temperatures between 20°C and 40°C in a solution with a chemical composition similar to blood plasma. The experiments showed that the complex dissolved 20 times better than pure telmisartan at human body temperature. The researchers also found that grinding as a method of obtaining complexes leads to a more effective interaction of the drug with cyclodextrin. The scientists observed that the obtained solid forms of the drug compound with cyclodextrin dissolve in aqueous medium not only better, but also faster, and therefore, accelerate the onset of drug action.

Despite the wide range of antihypertensive drugs, only a small number of patients with arterial hypertension (AH) are treated effectively, SM-Clinica cardiologist Anastasia Malay told Izvestia. Telmisartan blocks receptors in the body that normally bind to a hormone called angiotensin II. When angiotensin II binds to these receptors, it causes blood vessels to constrict. Blocking them helps the blood vessels relax so that blood can flow through them more easily. This can help lower blood pressure and reduce the risk of heart attack and stroke.

- Telmisartan provides better blood pressure control over 24 hours, especially in the last six hours of the dosing interval, compared to other antihypertensive drugs. It also has pleiotrophic effects on lipid and glucose metabolism, but has no evidence of efficacy in reducing vascular events. Other properties of the drug that are desirable in an antihypertensive agent include minimal renal clearance and lack of interaction with the P-450 cytochrome pathway," the expert said.

There are numerous studies that show the ability of modified cyclodextrin to form an inclusion complex with telmisartan, a poorly soluble drug, and the associated effects on dissolution rate and relative bioavailability, she said.

- The inclusion complexes showed improved dissolution rate compared to the pure drug. Thus, cyclodextrin can be successfully used as a carrier for oral administration of telmisartan with improved bioavailability and industrial application in terms of scale-up," said Anastasia Malay.

The bioavailability of telmisartan is about 50% - that is, only about 50% of the drug is absorbed from the dose taken, enters the blood and reaches the site of action in the body, said cardiologist, candidate of medical sciences, leading specialist of the network of clinics "Semeynaya" Elena Golikova.

- Therefore, the development of means of drug delivery that can increase its absorption and, consequently, the necessary dose, will certainly be useful. Although it should be noted that even unimproved telmisartan has a fairly high rate of absorption and in existing doses very rarely causes serious side effects," she said.

The results of the study, supported by a grant from the Russian Science Foundation (RNF), were published in the journal Colloids and Surfaces A: Physicochemical and Engineering Aspects.