SPECIAL MOLECULES WITH UNIQUE CAPABILITIES

Enhanced Curcumin Bioavailability Through Molecular Encapsulation with Cyclodextrin

Cyclodextrins are molecules with special capabilities: they can host, protect or stabilize selected hydrophobic molecules and release them through an equilibrium-controlled process. This principle paves the way for an innovative technology platform that creates applications of interest in the food industry - particularly enhancing the bioavailability of health-beneficial compounds with hydrophobic structure such as curcumin. Functional foods are experiencing strong growth in popularity because consumers worldwide prefer nutritional supplements or foods with added benefits to maintain and improve their health. As a result, scientists and food researchers are continuously discovering new health-beneficial compounds needed to make the body resistant to environmental stress, prevent certain diseases and even slow down the aging process. However, functional foods may also require consideration when formulating the products in question. Health-enhancing substances such as vitamins, antioxidants, sweeteners and numerous different plant extracts are often affected by light, low pH values or high temperatures and therefore must be stabilized. Furthermore, many compounds are also not water-soluble. For this reason, it is very difficult to formulate stable functional foods or dietary supplements with hydrophobic active compounds and at the same time ensure sufficient bioavailability of these products for the consumer. An appropriate solution to achieve this is cyclodextrin technology.

Cyclodextrin Technology

Cyclodextrins are ring-shaped sugar molecules (chiral cyclic oligosaccharides) with technical properties known to science and research for over 100 years. They are classified as α-, β- and γ-cyclodextrin according to the number of glucose units: α-, β- and γ-cyclodextrin consist of six, seven and eight glucose units respectively. Natural cyclodextrins are colorless, non-hygroscopic crystalline solids that can also withstand temperatures up to 220°C. The molecules are stable in an alkaline environment, but are hydrolyzed in acidic solutions (pH < 2.5). Cyclodextrins produced from renewable raw materials are natural starch-derived products. For industrial use, they are produced biotechnologically from raw materials containing plant starch such as corn or potatoes through enzymatic degradation. Specific enzymes separate each piece from the starch's helical carbohydrate and combine it into a ring-shaped oligosaccharide: the resulting product is cyclodextrin. What distinguishes cyclodextrins is their hollow, cavity-shaped, ring-shaped three-dimensional structure. All hydroxyl groups of a cyclodextrin are located on the outside of the molecule and explain why the outer surface is hydrophilic in nature. The interior of the cyclodextrin contains only glycosidic oxygen atoms and hydrogen atoms directly bonded to carbon atoms. The cavity portion is therefore hydrophobic and significantly less polar than the outer part. This inner cavity, provided that size and shape are compatible, can host a lipophilic "guest" molecule. On the other hand, the hydrophilic outer part provides compatibility in aqueous systems. In the presence of water, functional compounds encapsulated with cyclodextrin form "molecular dispersions," which results in much better bioavailability of hydrophobic substances.

Enhanced Bioavailability of Curcumin

Due to the nature of their inner cavities, cyclodextrins can bind and stabilize contents, release them again or - through the hydrophilic outer surface - mediate a specific increase in solubility. In the food industry, cyclodextrins currently target three main effects: masking unpleasant taste, protecting sensitive compounds such as antioxidants or vitamins, and improving bioavailability of active compounds. A good example regarding increased bioavailability is the complexation of curcumin with cyclodextrin: Curcumin is the biologically active component of turmeric or Curcuma longa and is its main coloring agent. For centuries, it has been part of traditional medicines, particularly in Indian and Chinese medicine. Today, modern science has proven its positive effects and current clinical studies make curcumin one of the best-studied natural compounds to date. Since curcumin is a powerful antioxidant, its main mechanism of action is free radical scavenging: it has been shown to have anti-inflammatory, anti-arthritic and hypoallergenic, antibacterial and even anticarcinogenic effects. The most fundamental problem in formulating curcumin for food products is that it exhibits a high degree of hydrophobic properties - which is why curcumin is absorbed very little by the blood. Only a few curcumin molecules can be absorbed from the small surface area of the agglomerated structure, and most of it is excreted without being taken up by the body. Conversely, hydrophilic ("water-friendly") compounds have much greater absorption. This is where γ-cyclodextrin comes into play. The interior of cyclodextrins is hydrophobic, while the exterior is hydrophilic. Fat-soluble curcumin enters the γ-cyclodextrin nucleus. The hydrophilic surface of the resulting structure increases bioavailability and thus the solubility of curcumin in the human body (see Figure 1).

Figure 1: γ-cyclodextrin acts as a hydrophilic carrier for hydrophobic curcumin binding in its own inner cavity (Figure: Wacker Chemie AG).

When taken as a dietary supplement, mostly in capsule form, the curcumin-cyclodextrin complex is transferred unchanged from the stomach to the upper intestinal system (step 1, Fig. 2). There, only curcumin molecules are absorbed through epithelial cell membranes into the body (step 2). The oligosaccharide γ-cyclodextrin is hydrolyzed by human pancreatic amylase, producing mainly maltose, some maltotriose and smaller amounts of glucose (step 3). Maltose and maltotriose are then reduced to glucose and absorbed from the small intestine into the blood (step 4). As a result, approximately 40 times more curcumin is absorbed directly into the bloodstream compared to pure curcumin powder and some leading commercial curcumin supplement products (step 5).

Figure 2: Mechanism of curcumin-cyclodextrin complex in the human intestinal tract (figure: Wacker Chemie AG).

Proven Effects

The positive effects of complexation of curcumin with γ-cyclodextrin have been tested in various scientific studies. For example, in a human clinical trial, researchers compared the curcumin-cyclodextrin complex with pure curcumin extract (95%) and two commercially available curcumin preparations designed to enhance bioavailability in terms of relative absorption. In the trial design, four different curcumin preparations were orally administered to 12 different subjects (fasted overnight) - with a one-week washout period between the four formulations. After product intake, blood samples were taken and analyzed every hour for 12 hours (plasma samples shown as dots in the graph). Blood concentration and relative absorption of curcumin and its metabolites were determined (see Figures 3 and 4).

Figure 3: Blood concentration comparison of curcumin encapsulated with γ-cyclodextrin (CAVACURMIN®), commercially available curcumin products (CP) and pure standard extract.

Calculation of AUC (area under the curve), plasma concentration and relative absorption clearly demonstrated that the complexed formulation was absorbed 40 times more effectively than the standard extract and at least 4.5 times better absorbed than the next best comparable commercial product.

Figure 4: Comparison of relative absorption: Relative absorption of total curcuminoid content after oral intake compared to standard curcumin, two commercial bioavailability formulations (CP-1 and CP-2) and CAVACURMIN®.

These results underscore the significant increase in curcumin bioavailability in a cyclodextrin-based formulation. Moreover, this data demonstrates that curcumin-cyclodextrin complex can provide the benefits of curcumin, a powerful antioxidant, to a much greater extent than currently available commercial products.

Conclusion

Through complexation with cyclodextrin of compounds that are challenging to formulate, such as curcumin, the dispersibility and thus bioavailability of this oleophilic substance can be significantly improved. Cyclodextrins, which are biotechnological products derived from renewable plant raw materials, are completely suited to the trend toward avoiding animal raw materials, particularly as consumers increasingly demand products containing naturally produced or renewable resource-based products. Cyclodextrin-based formulations are presented as dry, free-flowing powders that easily disperse in aqueous systems. They are therefore particularly suitable for use in dry or powder-form dietary supplement products such as tablets, capsules and nutrition bars, and in beverages. As a result of all this, cyclodextrin formulations are an ideal solution for food and beverage applications aimed at increasing the bioavailability of poorly absorbed substances.     Author Rachela Mohr Business Development Manager Wacker Biosolutions         Author Benjamin Bath Sales Manager Wacker Biosolutions         Translation Gürkan Altunok Technical Manager, Pharmaceutical Division IMCD Turkey