Hyaluronic Acid: New Delivery System Provides Enhanced Absorption of Joint and Skin Nutrient

By Karen Brown, PhD and Carol Cooper, PhD

Hyaluronic acid (HA or hyaluronan) is a naturally occurring biopolymer found in the extracellular matrix of all vertebrates, in the tissues and body fluids. It is a long unbranched chain comprised of two repeating disaccharide units, N-acetlyglucosamine and glucuronic acid, which can twist and fold back onto itself in a variety of three dimensional structures. Glucosamine is a raw material for the biosynthesis of hyaluronic acid. Glucosamine is also produced as a metabolite of HA. In fact, taking oral HA is like taking a time-release glucosamine.

HA belongs to a family of endogenous polysaccharide polymers known as glycosaminoglycans, a class which also contains such molecules as heparin and chondroitin sulfate. While different repeating units distinguish these molecules, their overall physical structures are very similar. Although these molecules attach to the same cell-surface receptor, they do so at a much reduced efficiency (see below).

Recently, HA has gained attention because it has been shown to impact numerous functions within the body. In its high molecular weight form, it is injected intra-articularly under the knee cap as a joint fluid replacement.¹ It is also used in horses as an intravenous injection, where it works systemically to relieve inflammation of the joint.² The scientific literature shows that high molecular weight (HMW) HA functions physiologically as an anti-inflammatory. The work of Ialenti and DiRosa examined both acute and chronic inflammation and showed that HA was able to resolve both.³

Capsules containing hyaluronic acid are now commonly available as nutritional supplements used for joint and skin health. However, high molecular weight oral liquids, as well as the new oral lozenge, are especially promising as delivery systems for hyaluronic acid because they are designed to be absorbed within the oral cavity.

Oral Cavity Absorption

The administration of active ingredients by way of the oral mucosa is becoming therapeutically more important. Delivery through the oral cavity is easy to administer and has the potential to provide efficient absorption because the oral mucosa is highly vascularized. Additionally, the “active” ingredient can bypass the acidic environment of the stomach, enzymatic activity of the intestine, and move directly into the bloodstream. Thus, the active ingredient can be effective in smaller, more controlled doses.

Scientists have grappled with the problems of oral delivery mechanisms for decades. Designing biologically effective dosing forms that can be absorbed in the mouth is not easy due to the integrity of the lining of the oral cavity. Compatibility with the oral mucosa is key.

Much can be learned from this research which is directly applicable to hyaluronic acid and reinforces the observation that oral absorption of liquid hyaluronic acid is the preferred delivery route.

When designing medicines that will be absorbed via the oral cavity, scientists first look for high compatibility between the lining of the mouth and the active ingredient itself. Often a carrier molecule must be used to enhance compatibility.

In this case, hyaluronic acid has a great advantage. The tissues that comprise the mucous membrane of the oral cavity are rich in high molecular weight (HMW) hyaluronic acid. When HMW liquid HA is put into the mouth, the lining can recognize the added HA and readily accept it into the membrane. HA is highly compatible with the oral mucosa.

Hyaluronic acid has already been shown to be a good candidate for oral drug delivery systems because it is highly compatible with the tissues of the oral mucosa, which already contains large amounts of HA.⁴ Therefore, no carrier molecule needs to be added to HA to enhance its oral absorption.

Pulling HA into the Membrane

Scientists designing active ingredients to be absorbed via the oral mucosa also look for additional factors, like receptor sites, which can promote absorption. Such factors help to “pull” the actives into the mucosa so that the active can be delivered into the blood stream.

In the case of hyaluronic acid, the receptor CD44 provides such an added advantage. The buccal cavity is highly vascularized and contains large quantities of CD44, a receptor molecule specific for hyaluronic acid.⁵ CD44 can attract and attach to the hyaluronic acid and move it into the blood stream where it can do its work.

CD44 is a powerful cell-surface receptor, with a high affinity for HA. In fact, CD44 is specific for HA. It is a key player in the health of the immune system, and the primary driver for the anti-inflammatory properties of HA. The oral mucosa is rich in CD44. It can promote absorption of HA by pulling the molecule through the mucosa and into the blood stream.

Advantage of a Lozenge

It is well-known that only hyaluronic acid of high molecular weight (HMW) is active as an anti-inflammatory. For that reason, it is important to preserve the molecular weight, and thus the activity, of the HA molecule. When HA of high molecular weight of at least 2.4 million Daltons reaches the stomach, it is broken down into smaller, less effective fragments by the acidic environment. Chemically, it would be expected that the glycosidic bond present in hyaluronic acid would be broken down by stomach acid, rendering it less effective.⁶ Indeed acid hydrolysis (the breaking of the chemical bond) is often used to analyze biopolymers in analytical experiments.^7-8

Capsules containing solid HA powder are designed to work in the stomach. The lining of the stomach, under normal conditions contains little CD44.⁹ Therefore, absorption of high molecular weight HA via the stomach is limited and HA administered via this route would be expected to be less effective.

As indicated above, the most effective delivery of HA is via the mucous membranes, including the lining of the mouth, the tongue and the gums.

Formulation of HA into a lozenge provides the necessary stabilization for the high molecular weight HA molecule. Additionally, the mild stickiness produced upon dissolution in the mouth and mixing with the saliva allows the HA to attach to the extensive surfaces that are available (lining of the mouth, tongue, gums). This produces a time-release effect.

The mucous membranes of the mouth offer extensive numbers of CD44 receptors to attract and bind the HA, as well as the necessary vascularization to receive the HA molecule once it is pulled through the membranes via the receptors. Extending the time that the HA molecule remains in the mouth via formulation into a lozenge extends the time allowed for absorption and increases the effectiveness of the HA.

Conclusion

Hyaluronic Acid is commonly used to promote joint and skin health and to reduce inflammation. Now, a new high molecular weight HA lozenge provides a highly bioavailable form of this nutrient that is well absorbed through the oral mucosa.

Karen Brown, PhD, received her BS from Washburn University, Topeka, KS in Chemistry and Biology, and her PhD from Oklahoma State University in Biochemistry and Microbiology. She has worked for 28 years in the area of hyaluronic acid.

Carol Cooper, PhD, received her BS from Wayne State University, Detroit, MI, in Chemistry, and her PhD from Wayne State in Biochemistry. She has worked in the area of hyaluronic acid for more than 15 years.

References

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2. Kawcak, CE, DD Frisbie, GW Trotter, CW McIlwraith, SM Gillette, BE Powerw, RM Walton  Effects of intravenous administration of sodium hyaluronate on carpal joints in exercising horses after arthroscopic surgery and osteochondral fragmentation Am J Vet Res 58(10) 1132-40 (1997).

3. Ialenti, A. and M. Di Rosa Hyaluronic Acid Modulates Acute and Chronic Inflammation Agents Actions, 43, 44-47 (1994).

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6. Xiang, Qian, Y.Y.Lee, Par O. Petterson and Robert W. Torget Heterogeneous aspects of acid hydrolysis of a-cellulose in Applied Biochemistry and Biotechnology Humana Press, Inc. 107(1-3) pp 505-521 Spring, 2003.

7. Bosworth, TR and JE Scott A specific fluorometric assay for hexosamines in glycosaminoglycans, based on deaminative cleavage with nitrous acid Anal Biochem 223(2):266-73 (1994).

8. Sobocinski PZ, WJ Canterbury, KH Jurgens Improved continuous-flow method for determination of total serum hexosamines Clin Chem 22(8):1394-6 (1976).

9. Washington, K., MR Gottfried and MJ Telen Expression of the cell adhesion molecule CD44 in gastric adenocarcinomas Hum Pathol 25(10):1043-9 (1994).