DE102018129398A1 - Hyaluronan-containing oral composition - Google Patents

Abstract

The invention provides an oral composition as a dietary supplement or dietary supplement comprising two distinct fractions of hyaluronan, wherein the first hyaluronan fraction has an average molecular weight of ≤100,000 daltons and the second hyaluronan fraction has an average molecular weight of ≥800,000 daltons.

Description

The invention relates to a hyaluronan-containing oral composition for use as a dietary supplement or dietetic food.

The aging of people is mainly visible on the skin, for example in the form of wrinkles. Biologically, the rate of cell renewal slows down, and the ability to store moisture decreases as the skin's ability to replenish its hyaluronic acid stores decreases with age. The endogenous synthesis of hyaluronic acid (HA) decreases with age. However, if hyaluronic acid deficiencies are due to e.g. With increasing age, the skin structure and function can be significantly improved and regenerated in the deeper skin layers.

Hyaluronic acid is not only an important component of the connective tissue of the skin but also of bones, cartilage and fascia. It not only binds moisture in the skin, but also in the connective tissue and fascia, and functionally also acts as a lubricant and shock absorber in joints.

There are many cosmetic products available that contain hyaluronic acid. Topical applications of cosmetics such as creams, lotions or serums, however, can only compensate for a shortage of hyaluronic acid deficiency or do not reach the deeper skin layers, especially the dermis. In addition, it is known to inject hyaluronic acid into the skin and joints. Hyaluronic acid injections, however, only act locally. There is also the risk of a bacterial infection. Also for an oral intake of hyaluronic acid, a positive effect has been shown with regard to skin aging and dry skin ( Kawada, C .; Yoshida, T .; Yoshida, H. et al .: Ingested hyaluronan moisturizes dry skin. Nutrition Journal Jul 2014, 13:70; Kawada, C .; Yoshida, T .; Yoshida, H. et al .: Ingestion of hyaluronan (molecular weights 800k and 300k) improved dry skin conditions: a randomized, double blind, controlled study. Journal for Clin. Biochem. Nutrition. Jan 2015, Vol. 56, No.1, 66-73; Sato, T., Sakamoto, W., Odanaka, W., Yoshida, K., Urishibata, O .: Clinical effects of dietary hyaluronic acid on dry, rough skin. Aesthetic Dermatology (2002), 12, 109-120 ).

However, oral administration has hitherto been considered largely unsuitable because it has been generally accepted that only small amounts of hyaluronic acid in suitable (higher molecular weight) form pass from the stomach into the blood system when administered orally (see introduction of the description) DE 69731610 T2 ). It has been thought that some of the oral form of hyaluronic acid in the stomach is digested by gastric acid, degraded, or broken down into smaller sugar components before a substantial amount of higher molecular weight (greater than 1000 daltons) of hyaluronic acid can enter the blood system.

In the DE 69731610 T2 For example, oral dosage forms of hyaluronic acid in a biologically active form (30,000 daltons to 2,000,000 daltons according to the dextran standard) are described for disease-preventive or therapeutic purposes, eg for the prevention of restenosis or for the treatment of myocardial infarction or stroke. It also states that the oral hyaluronic acid had a lower molar mass (about 30,000 to 80,000 daltons) than before administration. Oral hyaluronic acid is also used in the treatment of inflammatory and degenerative diseases of the joints and articular cartilage and connective connective tissue (see, eg US 6607745 B2 ; US 20020173484 A1 ; DE 202007011252 U1 ; DE 1020080.36954 A1 ; Balogh, A. et. al., 2008, Absorbance, Uptake and Tissue Affinity of High Molecular Weight Hyaluronan after Oral Administration in Rats and Dogs, Journal of Agricultural and Food Chemistry 56 (22), 10582-10593; Oe, M. et al. 2016, Oral hyaluronan relieves knee pain: a review, Nutrition Journal (2016) 15:11, 3 ).

Studies have shown uptake in the blood and in biologically active form in the skin (see Kawada, C. et al., 2014, Ingested hyaluronan moisturized dry skin, Nutrition Journal 13:70; Kawada, C. et al., 2015, Ingestion of hyaluronan (molecular weights 800k and 300k), improved dry skin conditions: a randomized, double blind, controlled study, Journal of Clinical Biochem., Nutrition 56, 66-73). In a placebo-controlled double-blind study, the increase in moisture in the skin was detected with the use of nutritive hyaluronic acid.

Orally ingested hyaluronic acid, like other glycosaminoglycans, is degraded by intestinal bacteria to mono- or oligosaccharides for uptake of the metabolites in the small intestine (Balogh, A. et al., 2008, Absorption, Uptake and Tissue Affinity of High Molecular Weight Hyaluronan after Oral Administration in Rats and Dogs, Journal of Agricultural and Food Chemistry 56 (22), 10582-10593; Oe, M. et al. 2016, oral hyaluronan relieves knee pain: a review, Nutrition Journal (2016) 15:11, 3) , These can be from the Small intestinal mucosa are absorbed, causing them to enter the bloodstream. Hyaluronic acid is distributed through the blood in the human body and reaches the dermis of the skin and fascia of, for example, joints.

It has also been found that radioactively labeled hyaluronic acid has already reached tissue before blood radioactivity could be measured (Balogh, A. et al., 2008, Absorption, Uptake and Tissue Affinity of High Molecular Weight Hyaluronan after Oral Administration in Rats and Dogs, Journal of Agricultural and Food Chemistry 56 (22), 10582-10593). It could be concluded that in addition to the blood circulation and the lymphatic system ensures that hyaluronic acid is transported from and to cells.

There is still a need for non-invasive agents which, in particular, have a skin-improving effect and reduce the visible signs of aging.

The object of the present invention is therefore to provide such a means.

To achieve the object, the invention provides an oral composition as dietary supplement or dietary food comprising two distinct fractions of hyaluronan, wherein the first hyaluronan fraction has an average molecular weight of ≤100,000 daltons and the second hyaluronan fraction has an average molecular weight of ≥800,000 daltons.

The composition of the invention provides hyaluronan in a well bioavailable and effective form. The composition has a skin-improving effect and, when taken regularly, can reduce the visible signs of aging. The composition according to the invention is particularly well suited as a nutritional supplement or as a dietetic food, for example in the context of a balanced diet. The composition according to the invention is particularly advantageously usable as a nutricosmetic for improving the moisture content of the skin and for reducing or preventing wrinkles. By combining long-chain and short-chain hyaluronic acid in the oral composition according to the invention, on the one hand the bioavailability in the tissue as the sum of blood transport and lymph transport can advantageously be increased and on the other hand the characteristic of the hyaluronic acid fragments arriving in the tissue can be optimized for increased water binding and viscosity increase.

Without wishing to be bound by theory, it is believed that this may be due to the composition being more amenable to absorption by the lymphatic system of intact hyaluronic acid molecules as well as to physiological decomposition (depolymerization) of high molecular weight hyaluronic acids to optimal levels and the largest possible metabolite size for absorption in the gastrointestinal system, in particular the small intestine. Different rates of resorption of the various hyaluronic acid weights also suggest an increased stimulation effect for the mechanism CD44 which produces the natural hyaluronic acid in the fibroblasts (Kawada, C., Yoshida, T., Yoshida, H. et al .: Ingested hyaluronan moisturized dry skin Nutrition Journal, July 2014, 13:70).

By the term "hyaluronan" (HA) is meant a glycosaminoglycan, i. a polysaccharide consisting of a linear chain of repeating disaccharide units, the disaccharide unit consisting of D-glucuronic acid and N-acetyl-D-glucosamine. The glucuronic acid is β-1 → 3-glycosidically linked to the N-acetyl-D-glucosamine, which in turn is linked to the following in the polymeric chain glucuronic acid β-1 → 4-glycosidic. For example, a chain may consist of 250 to 50,000 disaccharide units. Molecular weights may be, for example, 5000 Da to 20,000,000 Da. The term "hyaluronan" as used herein includes both hyaluronic acid and physiologically acceptable salts thereof, for example, sodium or potassium salts. Unless expressly stated otherwise, the terms hyaluronan, hyaluronic acid and hyaluronic acid salt are used synonymously herein.

The term "two distinct fractions of hyaluronan" means that there are two distinct and distinct individual fractions of hyaluronan. According to the invention, the hyaluronan fractions differ by their average molecular weight (molecular mass) or by their molecular weight distribution. The composition according to the invention thus has at least two hyaluronan fractions with different molecular weight distribution, which have clearly distinguishable weight-average molecular weights (Mw = weight average molar mass). Partial overlaps in the molecular weight distribution are not excluded. However, the distributions preferably overlap to less than 40%, more preferably less than 30, 20, 15, 10, 5, 3, 2 or 1%.

As used herein with respect to hyaluronan, an average molecular weight is meant the weight average molecular weight as determined by size exclusion chromatography (SEC), eg, gel filtration / permeation chromatography (GPC), with respect to a dextran standard.

The term "bioavailable" in the context of hyaluronan refers in particular to the proportion of hyaluronan, which reaches the target site in the body, ie the connective tissue.

The term "effective" refers to a (nutritional) physiological effect in the organism, in the context of hyaluronan, in particular on the water-binding and viscosity-influencing properties of hyaluronan.

By the term "oral composition" herein is meant a composition, i. a mixture or mixture of at least two components, understood, which is suitable and intended for oral use.

By "trace element" is meant an inorganic nutrient (mineral substance), which is needed by humans only in very small quantities (traces). Trace elements, with the exception of iron, are present in human tissues with a mass fraction of less than 50 mg / kg. Examples of trace elements are iron, iodine, copper, cobalt, selenium, chromium, fluoride, manganese, molybdenum, silicon, vanadium and zinc.

A "nutritional supplement" is understood to mean a concentrated source of nutritional or other substances having a nutritional or physiological action intended to complement the normal diet (see § 1 of the German Dietary Supplements Ordinance of 24 May 2004 (BGBl 1011), as last amended by Article 11 of the Regulation of 5 July 2017 (Federal Law Gazette I p. 2272) Dietary supplements are marketed in dosed form, for example in the form of pills, tablets, troches, capsules, powder sachets, liquid ampoules , measured amounts of liquids, etc.

The term "nutricosmetic" is composed of the English term "Nutrition" and the term "cosmetic", and is understood as an oral, to be taken care of cosmetics.

A "dietary food" is understood to mean a food intended for a particular diet (see § 1 of the German Dietary Diet (Diet Ordinance) in the version published on 28 April 2005 (BGBl. I p. , as last amended by Article 22 of the Ordinance of 5 July 2017 (Federal Law Gazette I p. 2272).

The term "dosage unit" refers to a certain amount of the composition. A dosage unit may be distributed in one or more portions, for example several tablets or bottles. For example, it may be an amount of the composition that corresponds to a suitable daily portion of the composition for a human having a particular body weight. A daily serving is an amount of the composition that is to be delivered or delivered per day.

The oral composition according to the invention may be in solid form, for example as a powder, granules or, what is preferred, in liquid form. Liquid nutrients are generally absorbed faster and better, both from the gastrointestinal system and the lymphatic system. In liquid form, which is administered orally, the composition or its constituents can be absorbed more easily, so that the ingredients are available to the body quickly and effectively. The oral composition according to the invention may for example be in the form of a tablet, capsule, troche, sachet, dragee, gel or in liquid form.

In a preferred embodiment, the first hyaluronan fraction in the oral composition of the invention has an average molecular weight of ≤90,000 daltons, ≤80,000 daltons, ≤70,000 daltons, ≤60,000 daltons, ≤50,000 daltons, ≤40,000 daltons, ≤30,000 daltons, ≤25,000 daltons, ≤ 20,000 daltons, ≤ 15,000 daltons or ≤10,000 daltons.

In the oral composition according to the invention, the second hyaluronan fraction preferably has an average molecular weight of ≥ 900,000 daltons, ≥ 1,000,000 daltons, ≥ 1,100,000 daltons, ≥ 1,200,000 daltons, ≥ 1,300,000 daltons, ≥ 1,400,000 daltons, ≥ 1,500 .000 daltons or ≥ 1.600.000 daltons. In a preferred embodiment, the first hyaluronan fraction in the oral composition according to the invention has, for example, an average molecular weight of ≤80,000 daltons and the second hyaluronan fraction in the oral composition according to the invention has an average molecular weight of ≥1,500,000 daltons on. Of course, however, any other combinations are possible, so that, for example, the first Hyaluronanfraktion an average molecular weight of 40,000 daltons and the second Hyaluronanfraktion an average molecular weight of 1,000,000 daltons, or the first Hyaluronanfraktion an average molecular weight of 75,000 daltons and the second Hyaluronanfraktion a middle Molecular weight of 1,800,000 daltons may have.

The content of hyaluronan in the oral composition is preferably 0.3 to 10% by weight based on the total weight of the oral composition.

The mass ratio between the first and second hyaluronan fractions may, for example, be from 10:90% to 90:10% by weight, based on the mass fraction of hyaluronan in the oral composition. Preferably, the ratio is 0:80 wt .-% to 80:20 wt .-%. In a preferred embodiment of the oral composition, the mass fraction of the first hyaluronan fraction is less than the mass fraction of the second hyaluronan fraction, i. <50% by weight. For example, the proportion of the first hyaluronan fraction may be 15-25% by weight, e.g. 20% by weight while the proportion of the second hyaluronan fraction is 75-85% by weight, e.g. 80 wt .-%, is.

The oral composition preferably further contains physiologically acceptable, i. physiologically compatible additives. These may be nutritive substances such as vitamins, trace elements and the like, or agents which facilitate, for example, the formulation, dosage or formulation of the composition, for example release agents, lubricants, binders, buffer substances, etc.

1. a. Vitamin C, und/oder
2. b. mindestens ein Carotinoid, vorzugsweise ausgewählt aus der Gruppe bestehend aus Alpha-Carotin, Beta-Carotin, Lutein, Lycopin, Zeaxanthin und Astaxanthin, und/oder
3. c. N-Acetyl-Glukosamin, und/oder
4. d. mindestens ein B-Vitamin, vorzugsweise ausgewählt aus der Gruppe bestehend aus Biotin, Niacin und Riboflavin, und/oder
5. e. mindestens ein Spurenelement, vorzugsweise Zink.

In a preferred embodiment, therefore, the oral composition further comprises

1. a. Vitamin C, and / or
2. b. at least one carotenoid, preferably selected from the group consisting of alpha-carotene, beta-carotene, lutein, lycopene, zeaxanthin and astaxanthin, and / or
3. c. N-acetyl-glucosamine, and / or
4. d. at least one B vitamin, preferably selected from the group consisting of biotin, niacin and riboflavin, and / or
5. e. at least one trace element, preferably zinc.

The hyaluronan used in the oral composition can be prepared or obtained in any manner, for example by extraction from animal tissue of e.g. Rooster combs. However, hyaluronan biotechnologically produced by bacterial fermentation is preferred.

In another aspect, the present invention also relates to a dosage unit comprising an oral composition of the invention.

The dosing unit preferably comprises 0.25 mg to 8 mg hyaluronan per kg body weight, preferably 0.5 mg to 6 mg hyaluronan per kg body weight or 0.5 mg to 3 mg hyaluronan per kg body weight, more preferably 1 mg to 2 mg hyaluronan per kg body weight.

The formulation according to which the dosing unit comprises a certain amount of hyaluronan per kg of body weight is to be understood as meaning that the dosing unit contains such an absolute amount of hyaluronan that when a dosing unit is taken by a human person or an animal, in particular a mammal (eg dog , Cat or horse) with a certain body weight the absolute amount of hyaluronan divided by the body weight of the person or animal results in the specified amount of hyaluronan. The absolute amount of hyaluronan in the dosing unit can be chosen so that on average the amount of hyaluronan per kg of body weight is achieved. The dosing unit can be adapted, for example, to the age and / or sex of the person or animal taking the oral composition. A dosage unit may correspond to a portion of a physical dosage form, for example be contained in a tablet, capsule or the contents of a liquid ampoule. However, it can also be distributed over several portions of one or more dosage forms, for example on several tablets, capsules and / or liquid ampoules. The dosing unit preferably contains an amount of hyaluronan such that its ingestion corresponds to the daily portion of a human person or an animal.

The dosing unit according to the invention preferably also comprises amounts of, for example, vitamin C, a carotenoid, N-acetyl-glucosamine, a B-vitamin and / or of a trace element, wherein the Preferably, orient the quantities of vitamins and trace elements to nutrient reference values (NRVs), for example the reference levels according to Annex XIII of Regulation (EC) No 1169/2011. For example, the amounts may be 15-100% of the respective reference quantity.

• a. ≥ 0,13 mg bis ≤ 1,45 mg Vitamin C pro kg Körpergewicht, und/oder
• b. ≥ 0,5 mg bis ≤ 20 mg mindestens eines Carotinoids pro kg Körpergewicht, wobei das mindestens eine Carotinoid vorzugsweise ausgewählt ist aus der Gruppe bestehend aus Alpha-Carotin, Beta-Carotin, Lutein, Lycopin, Zeaxanthin und Astaxanthin, und/oder
• c. 0,55 mg bis 12 mg N-Acetyl-Glukosamin pro kg Körpergewicht, und/oder
• d. 0,0003 mg bis 0,3 mg mindestens eines B-Vitamins pro kg Körpergewicht, wobei das B-Vitamin vorzugsweise ausgewählt ist aus der Gruppe bestehend aus Biotin, Niacin und Riboflavin, und/oder
• f. 0,02 mg bis 0,18 mg mindestens eines Spurenelements, vorzugsweise Zink, pro kg Körpergewicht.

In a particularly preferred embodiment of the oral composition, the dosage unit according to the invention comprises

• a. ≥ 0.13 mg to ≤ 1.45 mg vitamin C per kg body weight, and / or
• b. ≥ 0.5 mg to ≤ 20 mg of at least one carotenoid per kg of body weight, wherein the at least one carotenoid is preferably selected from the group consisting of alpha-carotene, beta-carotene, lutein, lycopene, zeaxanthin and astaxanthin, and / or
• c. 0.55 mg to 12 mg N-acetyl-glucosamine per kg body weight, and / or
• d. 0.0003 mg to 0.3 mg of at least one B vitamin per kg body weight, wherein the B vitamin is preferably selected from the group consisting of biotin, niacin and riboflavin, and / or
• f. 0.02 mg to 0.18 mg of at least one trace element, preferably zinc, per kg of body weight.

The amount of hyaluronan in the dosing unit preferably corresponds to a daily portion of hyaluronan. The dosing unit preferably comprises 10 to 200 mg of hyaluronan, preferably 30 to 160 mg of hyaluronan, 60 to 150 mg of hyaluronan, 80 to 150 mg of hyaluronan, particularly preferably 100 to 150 mg of hyaluronan.

The dosing unit can be present, for example, in tablet, capsule, lozenges, sachet, dragee, gel or liquid form. Preferably, the metering unit is in liquid form.

embodiment

An exemplary composition according to the invention contains the following ingredients:

Water, pomegranate juice concentrate (5.0%), coconut blossom syrup, sodium hyaluronate, L-ascorbic acid, sodium hyaluronate (20% by weight HA 31,000 Da, 80% by weight HA 1.66 million Da), coloring food (concentrates of carrot and safflower ), Preservative (potassium sorbate), acidulant (citric acid), nicotinamide, zinc citrate, riboflavin, D-biotin. The nutritional values are as given in Table 1: Table 1: Nutritional information for an exemplary composition according to the invention Per serving (10 ml) % NRV energy 15.0 kJ 3.5 kcal fat <0.1 G - hereof: saturated fatty acids <0.1 G carbohydrates 0.8 G - of which sugars 0.7 G protein <0.1 G salt 12:02 G vitamin C 20.0 mg 25 Vitamin B2 12:45 mg 32 Niacin (NE) 6.4 mg 40 biotin 18.0 ug 36 zinc 3.0 mg 30 hyaluronic acid 100 mg

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• DE 69731610 T2 [0005, 0006]
• US 6607745 B2 [0006]
• US 20020173484 A1 [0006]
• DE 202007011252 U1 [0006]
• DE 102008036954 A1 [0006]

Cited non-patent literature

• Kawada, C .; Yoshida, T .; Yoshida, H. et al .: Ingested hyaluronan moisturizes dry skin. Nutrition Journal Jul 2014, 13:70; Kawada, C .; Yoshida, T .; Yoshida, H. et al .: Ingestion of hyaluronan (molecular weights 800k and 300k) improved dry skin conditions: a randomized, double blind, controlled study. Journal for Clin. Biochem. Nutrition. Jan 2015, Vol. 56, No.1, 66-73; Sato, T., Sakamoto, W., Odanaka, W., Yoshida, K., Urishibata, O .: Clinical effects of dietary hyaluronic acid on dry, rough skin. Aesthetic Dermatology (2002), 12, 109-120 [0004]
• Balogh, A. et. al., 2008, Absorbance, Uptake and Tissue Affinity of High Molecular Weight Hyaluronan after Oral Administration in Rats and Dogs, Journal of Agricultural and Food Chemistry 56 (22), 10582-10593; Oe, M. et al. 2016, Oral hyaluronan relieves knee pain: a review, Nutrition Journal (2016) 15:11, 3 [0006]
• Oe, M. et al. 2016, Oral hyaluronan relieves knee pain: a review, Nutrition Journal (2016) 15:11, 3) [0008]

Claims (12)

An oral composition as a dietary supplement or dietary supplement comprising two distinct fractions of hyaluronan, wherein the first hyaluronan fraction has an average molecular weight of ≤100,000 daltons and the second hyaluronan fraction has an average molecular weight of ≥800,000 daltons. Oral composition after Claim 1 wherein the first hyaluronan fraction has an average molecular weight of ≤ 90,000 daltons, ≤ 80,000 daltons, ≤ 70,000 daltons, ≤ 60,000 daltons, ≤ 50,000 daltons, ≤ 40,000 daltons, ≤ 30,000 daltons, 25,000 daltons, ≤ 20,000 daltons, ≤ 15,000 daltons or ≤ 10,000 Dalton has. Oral composition after Claim 1 or 2 wherein the second hyaluronan fraction has an average molecular weight of ≥ 900,000 daltons, ≥ 1,000,000 daltons, ≥ 1,100,000 daltons, ≥ 1,200,000 daltons, ≥ 1,300,000 daltons, ≥ 1,400,000 daltons, ≥ 1,500,000 daltons or ≥ 1,600,000. An oral composition according to any one of the preceding claims, wherein the hyaluronan content is 0.3 to 10% by weight, based on the total weight of the oral composition. Oral composition according to one of the preceding claims, wherein the mass ratio between the first Hyaluronanfraktion and the second Hyaluronanfraktion based on the mass fraction of hyaluronan in the oral composition 10: 90 wt .-% to 90:10 wt .-%, preferably 20:80 wt. -% to 80:20 wt .-% is. An oral composition according to any one of the preceding claims, further comprising a. Vitamin C, and / or b. at least one carotenoid, preferably selected from the group consisting of alpha-carotene, beta-carotene, lutein, lycopene, zeaxanthin and astaxanthin, and / or c. N-acetyl-glucosamine, and / or d. at least one B vitamin, preferably selected from the group consisting of biotin, niacin and riboflavin, and / or e. at least one trace element, preferably zinc. An oral composition according to any one of the preceding claims, wherein the hyaluronan is biotechnologically produced by bacterial fermentation. Dosing unit comprising an oral composition according to one of Claims 1 to 7 , Dosing unit after Claim 8 comprising 0.25 mg to 8 mg hyaluronan per kg body weight, preferably 0.5 mg to 6 mg hyaluronan per kg body weight or 0.5 mg to 3 mg hyaluronan per kg body weight, more preferably 1 mg to 2 mg hyaluronan per kg body weight , Dosing unit according to one of Claims 8 or 9 comprising a. ≥ 0.13 mg to ≤ 1.45 mg vitamin C per kg body weight, and / or b. ≥ 0.5 mg to ≤ 20 mg of at least one carotenoid per kg of body weight, wherein the at least one carotenoid is preferably selected from the group consisting of alpha-carotene, beta-carotene, lutein, lycopene, zeaxanthin and astaxanthin, and / or c. 0.55 mg to 12 mg N-acetyl-glucosamine per kg body weight, and / or d. 0.0003 mg to 0.3 mg of at least one B vitamin per kg body weight, wherein the B vitamin is preferably selected from the group consisting of biotin, niacin and riboflavin, and / or e. 0.02 mg to 0.18 mg of at least one trace element, preferably zinc, per kg of body weight. Dosing unit according to one of Claims 8 to 10 comprising 10 to 200 mg hyaluronan, preferably 30 to 160 mg hyaluronan, more preferably 60 to 150 mg hyaluronan, 80 to 150 mg hyaluronan or 100 to 150 mg hyaluronan. Dosing unit according to one of Claims 8 to 11 , wherein the dosage unit is in tablet, capsule, lozenges, sachet, dragee, gel or liquid form.