When Size Matters or What Is Small Is Effective
The systemic effect of an orally administered drug can be expected, among other things, if it has suitable physicochemical properties. How can insufficient absorption or poor solubility be solved? We provide the answer below.
Bioavailability and its assessment
Bioavailability of a drug represents one of the important factors influencing the resulting therapeutic effect. It is determined by many properties of the substance, such as solubility in water and fats, polarity, or molecular weight. Given that good solubility of the substance in an aqueous environment does not automatically mean a good ability to pass through the intestinal wall into the bloodstream, solubility alone cannot be considered a measure by which the bioavailability of drugs can be assessed.
Therefore, the so-called biopharmaceutical classification system (BCS) is used to assess it. It is an experimental model that ranks the drug substance into one of 4 categories (classes), depending on its solubility and permeability when administered orally. A drug with low solubility and low intestinal permeability is classified as Class IV BCS, hence its ideal bioavailability cannot be assumed. This is exactly where various technological modifications of drug substances can be applied, leading to increased solubility and thus bioavailability.
Fixed ratio mixture of components
Diosmin (diosmetin-7-O-rutinoside) is a natural flavonoid that is abundantly found in the pericarp of citrus fruits. It can also be obtained by dehydrogenating another flavonoid – hesperidin. During this reaction, several other substances (isorhoifolin, linarin, etc.) are also formed, but the major portion is diosmin. In the European Pharmacopoeia, diosmin is defined as a flavonoid mixture containing 90% of diosmin itself. For other components of the mixture (impurities), the maximum allowable content is specified, with a maximum of 4% of the original hesperidin.
Solution to poor solubility? Crushing and milling particles
The problem with diosmin, which otherwise has several significant therapeutic effects, is that it is practically insoluble in water. To improve the bioavailability of poorly soluble substances, including diosmin, many procedures have been developed. In the case of flavonoids, micronization has proven to be the most effective, which is one of the most common physical methods. It is based on the reduction of drug particle size, which leads to an increase in the specific surface area of the particles, thus increasing the dissolution rate and absorption rate.
The process of reduction is a highly sophisticated procedure where particles are crushed using various types of mills. A jet mill utilizes supersonic speeds of a compressed air stream, resulting in ultra-fine milling (micronization in the true sense of the word). Particles can have a final size of up to 1–0.1 µm, with the average diameter of micronized flavonoid fraction particles being around 1.7 µm.
Micronization improves clinical effect
Reducing the particle size of a drug substance represents a safe way to increase solubility without negatively affecting the chemical properties of the substance. At the same time, micronized particles are more available for active transport systems of enterocytes and passive diffusion. For diosmin, this means better intestinal absorption, bioavailability, and clinical effect.
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Sources:
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2. Hörter D, Dressman JB: Influence of physicochemical properties on the dissolution of drugs in the gastrointestinal tract. Adv Drug Deliv Rev 2001; 46 (1–3): 75–87, doi: 10.1016/S0169-409X(00)00130-7.
3. Slíva J. Diosmin – still an important modality in the treatment of venous insufficiency. Vnitřní lékařství 2019; 65 (7–8): 524–526.
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