WO2010121700A1

WO2010121700A1 - Compositions containing hyaluronic acid, sulphated hyaluronic acid, calcium and vitamin d3 for the treatment of osteoarticular and musculoskeletal disorders

Info

Publication number: WO2010121700A1
Application number: PCT/EP2010/002042
Authority: WO
Inventors: Antonella Schiavinato; Piera Parenzan; Giovanni Gennari; Lanfranco Callegaro
Original assignee: Fidia Farmaceutici S.P.A.
Priority date: 2009-04-21
Filing date: 2010-03-31
Publication date: 2010-10-28
Also published as: IT1393945B1; ITMI20090664A1

Abstract

The present invention relates to compositions containing hyaluronic acid (HA) mixed with sulphated hyaluronic acid with degree of sulphation (1) (HAS1), calcium and vitamin D3, for use to prepare oral supplements for the prevention and treatment of osteoarticular and musculoskeletal disorders and osteoporosis.

Description

COMPOSITIONS CONTAINING HYALURONIC ACID, SULPHATED HYALURONIC ACID, CALCIUM AND VITAMIN D3 FOR THE TREATMENT OF OSTEOARTICULAR AND MUSCULOSKELETAL DISORDERS

The present invention relates to compositions containing hyaluronic acid (HA) mixed with sulphated hyaluronic acid with degree of sulphation 1

(HASl), calcium and vitamin D3, for use to prepare oral supplements for the prevention and treatment of osteoarticular and musculoskeletal disorders and osteoporosis.

PRIOR ART

Osteoarthritis (OA) is a very common disorder, characterised by progressive degeneration of the joint cartilage which thins and deteriorates following loss of the cellular and extracellular component, and can even disappear entirely. The causes of the disease are only partly clear. They basically seem to involve a series of processes triggered by a mechanical imbalance that affects the entire joint after a trauma or mechanical stress, for example. Inside the cartilage there is a delicate balance between destruction of the exhausted extracellular matrix and formation of intact matrix. All this depends largely on enzymes produced by the chondrocytes, a cellular component of joint matrix. In the event of an excessive or unbalanced load on the joint, an inflammatory situation arises. This triggers the release of inflammatory cytokines which, in turn, stimulate the chondrocytes to produce metalloproteases (MMP), enzymes responsible for cartilage destruction, thus altering the balance between synthesis and degradation of the extracellular matrix. The scientific literature also describes in detail the cell death processes which affect the chondrocytes when they come into contact with substances produced by the breakdown of the matrix (Cao et al., Exp Cell Res, 1999, 246:527-37).

The integrity of the extracellular matrix is therefore crucial for the survival of the chondrocytes, and consequently for healthy cartilage.

The cartilage matrix is a three-dimensional structure consisting of collagen molecules and aggregated complexes of proteoglycans, which in turn are formed by: a skeleton of hyaluronic acid (HA), glycosaminoglycans (GAG) containing repetitive disaccharide units of glucosamine or galactosamine, which in turn carry negatively- charged carboxyls or sulphate groups, as a result of which the

GAGs form long negatively-charged chains, polypeptides.

HA is a polysaccharide molecule with considerable viscoelastic properties. It is present in the joint cavities as a fundamental constituent of synovial fluid, where it acts as a lubricant and shock-absorbing agent, and protects the chondrocytes against the action of inflammatory cytokines (Asari et al., Arch Histol Cytol, 1995, 58:65-76; Brun et al., Osteoarthr Cartil, 2003,

11 :208-16; Stove et al., J Orthop Res, 2002, 20:551-5). HA, as such or in derivatised form, has long been used to treat degenerative osteoarthritis, either as a "viscosupplement" or a lubricant.

The oral treatments according to the prior art involve the administration of sulphated GAGs such as glucosamine sulphate and chondroitin sulphate in association with HA and hydrolysed collagen, in order to promote HA synthesis in the joint cavity and protect the chondrocytes in an osteoarthritic joint (US 6,645,948; US 6,476,005).

Scientific evidence clearly demonstrates the efficacy of sulphated GAGs in increasing the HA content in the synovial fluid of patients suffering from inflammatory osteoarthritis (McCarty et al., Med Hypoth, 2000, 54:798- 802; McCarty MF, Med Hypoth, 1998, 50:507-510).

Further patents and patent applications are also known which disclose and claim new treatments for inflammatory osteoarthritis involving intraarticular administration of HA in association with chondroitin sulphate (US 6,906,044), or claim oral treatment with HA at given doses (patent US 6,607,745), possibly also in association with glucosamine, chondroitin sulphate or glucosamine sulphate (US 6,924,273); finally, the use of HA with high molecular weight for the prevention and treatment of osteoporosis is known (patent application WO2005/032276). Another sulphated GAG used for chondroprotection, apart from glucosamine sulphate and chondroitin sulphate, is HA, suitably sulphated as described in the prior art; in particular, US20040053885 describes the use of sulphated hyaluronic acid (subsequently referred to as HA-S) in the intraarticular treatment of inflammatory arthritis, and specifically rheumatoid arthritis (autoimmune disease), while EP 754460 B l claims the use of HA-S in the parenteral injectable treatment of disorders such as joint rheumatism.

Finally, patent application WO2007/137674 describes formulations based on chemically sulphated HA, in particular HA chemically modified by sulphation as described in EP 702699 Bl, for oral administration or intra- articular injection, which effectively slow joint degeneration and promote reconstruction of the extracellular matrix in joints affected by chronic degenerative osteoarthritis.

Osteoarthritis is very often associated with other musculoskeletal disorders, such as reduction of muscle tone, muscle fatigue and loss of elasticity of the tendon structures, which adversely affect the patient's quality of life. Moreover, due to physiological aging of the population, specific disorders or the use of particular medicaments, osteoporosis may cause symptoms associated with neuromuscular functionality. There is consequently an evident need to act specifically and globally in terms of both prevention and treatment of osteoarticular, cartilage and neuromuscular disorders, by means of an approach that involves every aspect of those disorders. DESCRIPTION OF THE INVENTION

(which therefore contains one -SO3 group per repetitive unit of HA), calcium and vitamin D3, for use as oral supplements for the prevention and treatment of osteoarticular disorders substantially due to aging, wear caused by sport, traumas, postural disorders and the like. The compositions described herein are also indicated for the prevention and treatment of musculoskeletal disorders characterised by loss of muscle tone and musculotendinous tone and elasticity, and in the prevention and treatment of osteoporosis. Sulphated hyaluronic acid with degree of sulphation 1 is hereafter abbreviated to HAS l .

Said compositions can be administered one or more times a day, according to the patient's physiopathological state and the protocol established by the doctor.

More particularly, the present invention relates to compositions wherein:

• the HA/HAS 1 mixture is present in a variable proportion, between 90%- 10% and 50-50% respectively;

• the total amount of HA + HAS l used is preferably between 80 g and 150 mg; • calcium is present in the form of calcium carbonate in amounts ranging between 300 mg and 1600 mg per unit dose, corresponding to 120-640 mg of calcium ion (and therefore equal to 15%-80% of the RDA); • vitamin D3 is present in amounts ranging between 1.3 mg and 10.4 mg per unit dose, corresponding to 100-800 IU (and therefore equal to 50-400% of the RDA);

According to a preferred aspect, the present invention relates to compositions wherein:

• the HA/HAS 1 mixture is present in the proportion of 70%-30% respectively;

• the total amount of HA + HASl used is 80 mg; and

• calcium is present in the form of calcium carbonate in the amount of 600 mg, equivalent to 240 mg of calcium ion per unit dose, corresponding to 30% of the RDA;

• vitamin D3 is present in the amount of 2.6 mg per unit dose, equivalent to 200 IU (corresponding to 100% of the RDA);

The HA used in the present invention may be obtained from various sources, such as extraction from rooster combs (EP 138572 B l), fermentation

(EP 716688 Bl), or technological means, and have a molecular weight of between 50 Kda and 1000 Kda. According to a particularly preferred aspect,

HA with a molecular weight of between 150 Kda and 300 Kda is used.

If desired, the compositions according to the invention can also contain other molecules with complementary or otherwise useful activity for the purposes of the invention, such as substances and extracts of plant origin like equisetum, fenugreek, flavonoids and Boswellia serrata; other vitamins, such as vitamin C; mineral salts, such as phosphorus, magnesium or zinc salts; components of the cartilage matrix or their degradation products, such as collagen, chondroitin sulphate, glucosamine, or other pharmacologically or biologically active substances.

An example of the preparation of a composition according to the invention is set out below. In any event, the compositions in question can be prepared by one skilled in the art in accordance with conventional techniques.

Preparation example

Micronised hyaluronic acid sodium salt, micronised sulphated hyaluronic acid (degree 1) and calcium carbonate (previously sieved through an 0.8 mm mesh screen) are mixed. The mixture thus obtained undergoes fluid-bed wet granulation with a binder solution consisting of water and approx. 70% of the total amount of carboxymethylcellulose sodium salt. The granulate obtained is sieved through an 0.8 mm mesh screen.

The remaining ingredients (vitamin D3, calcium phosphate, microcrystalline cellulose, carboxymethylcellulose sodium salt and silica) are mixed, and sieved through an 0.8 mm mesh screen.

The granulate previously obtained is mixed with the pre-constituted mixture of the remaining ingredients (extragranules), and finally mixed with magnesium stearate (previously sieved through an 0.8 mm mesh screen) and compressed.

The film-forming solution is prepared by solubilising the film-coating agents (hydroxypropyl methylcellulose, microcrystalline cellulose, stearic acid and flavouring) in water.

The film-forming solution is sprayed onto the tablets (cores) in a coating pan, followed by final drying.

The compositions according to the invention can be formulated according to conventional methods well known in pharmaceutical technology, such as those described in "Remington's Pharmaceutical Handbook", Mack Publishing Co., N.Y., USA. Some examples of preparation of the formulations to which the present invention relates, for oral administration, are described below by way of example and not of limitation.

HA-S can be formulated in all known ways according to the state of the art in association with stabilisers, excipients, preservatives and/or other substances considered useful to obtain the best possible formulation, for the preparation of granulates, suspensions, solutions, capsules and tablets.

FORMULATION 1

Film-coated tablets based on HA/HAS 1 + Ca + Vit. D3

FORMULATION 1 (COMPOSITION OF CORE)

Dose (HA + HASiytablet: 80 mg. HA/HASl ratio: 70:30

Weight of core: 850 mg + 3% film coating= 875.5 mg

Film-coating agents: hydroxypropyl methylcellulose, microcrystalline cellulose, stearic acid, flavouring.

** overage added to ensure the stability of the product

FORMULATION 2 (COMPOSITION OF CORE)

Dose (HA + HASl)/tablet: 80 mg. HA/HAS1 ratio: 70:30

Weight of core: 850 mg + 3% film coating= 875.5 mg

** overage added to ensure the stability of the product

FORMULA TION 3 (COMPOSITION OF CORE)

Dose (HA + HASl)/tablet: 80 mg. HA/HAS1 ratio: 70:30

Weight of core: 1 g + 3% film coating= 1.03 g

** overage added to ensure the stability of the product FORMULA TION 4 (COMPOSITION OF CORE)

Dose (HA + HASl)/tab: 80 mg. HA/HAS1 ratio: 70:30

Weight of core: 1.4 g + 3% film coating= 1.44 g

Film-coating agents: hydroxy propyl methylcellulose, microcrystalline cellulose, stearic acid, flavouring.

** overage added to ensure the stability of the product

Claims

1. Compositions comprising hyaluronic acid (HAS) in a mixture with sulphated hyaluronic acid with degree of sulphation 1 (HAS l), calcium and vitamin D3, for the prevention and treatment of osteoarticular disorders, musculoskeletal disorders and osteoporosis.

2. Compositions according to claim 1, wherein:

• the HA/HAS 1 mixture is present in amounts ranging between 90%- 10% and 50-50% respectively; • the total amount of HAS + HAS l used ranges between 80 g and

150 mg;

• calcium is present in the form of calcium carbonate in amounts ranging between 300 mg and 1600 mg per unit dose, corresponding to 120-640 mg of calcium ion, equivalent to 15%- 80% RDA; and

• vitamin D3 is present in amounts ranging between 0.3 and 10.4 mg per unit dose, corresponding to 100-800 IU, corresponding to 50- 400% RDA.

3. Compositions according to claim 2, wherein: • the HA/HAS 1 mixture is present in the proportion of 70%-30% respectively;

• the total amount of HAS + HAS l used is 80 mg;

• calcium is present in the form of calcium carbonate in the amount of 600 mg, corresponding to 240 mg of calcium ion per unit dose, corresponding to 30% RDA; and • vitamin D3 is present in the amount of 2.6 mg per unit dose, corresponding to 200 IU, corresponding to 100% RDA.

4. Compositions according to the above claims, wherein hyaluronic acid with molecular weight ranging between 50 KDa and lOOOKda is used.

5. Compositions according to claim 4, wherein hyaluronic acid with molecular weight ranging between 150 KDa and 300Kda is used.

6. Compositions according to the above claims, further containing pharmacologically or biologically active substances.

7. Compositions according to claim 6, wherein the pharmacologically or biologically active substances are selected from substances and extracts of vegetable origin, vitamins, mineral salts, cartilage matrix components or the degradation products thereof.

8. Compositions according to claim 7, wherein the substances and extracts of vegetable origin, vitamins, mineral salts, cartilage matrix components or the degradation products thereof are selected from equisetum, fenugreek, flavonoids, Boswellia serrata; vitamin C, mineral salts, collagen, chondroitin sulphate and glucosamine.

9. The use of hyaluronic acid (HAS) in a mixture with sulphated hyaluronic acid with degree of sulphation 1 (HASl), calcium and vitamin D3, to prepare oral supplements for the prevention and treatment of osteoarticular disorders, musculoskeletal disorders and osteoporosis.

10. Use as claimed in claim 9, wherein:

• the HA/HAS 1 mixture is present in amounts ranging between 90%- 10% and 50-50% respectively; • the total amount of HAS + HASl used ranges between 80 g and 150 mg;

• calcium is present in the form of calcium carbonate in amounts ranging between 300 mg and 1600 mg per unit dose, corresponding to 120-640 mg of calcium ion, equivalent to 15%-

80% RDA; and

• vitamin D3 is present in amounts ranging between 0.3 and 10.4 mg per unit dose, corresponding to 100-800 UI, equivalent to 50- 400% RDA.

11. Use according to claim 10, wherein:

• the HA/HAS 1 mixture is present in the ratio of 70%-30% respectively;

• the total amount of HAS + HASl used is equivalent to 80 mg;

• calcium is present in the form of calcium carbonate in amounts of 600 mg, corresponding to 240 mg of calcium ion per unit dose, equivalent to 30% RDA; and

• vitamin D3 is present in the amount of 2.6 mg per unit dose, corresponding to 200 IU, equivalent to 100% RDA.

12. Use according to claim 9, wherein the osteoarticular disorders are due to aging, workout stress, traumas and postural disorders.

13. The use of hyaluronic acid (HAS) in a mixture with sulphated hyaluronic acid with degree of sulphation 1 (HAS l), calcium and vitamin D3, to prepare oral supplements for the prevention and treatment of loss of muscle elasticity and tone.

14. The use of hyaluronic acid (HAS) in a mixture with sulphated hyaluronic acid with degree of sulphation 1 (HASl), calcium and vitamin D3, to prepare oral supplements for the prevention and treatment of the loss of tendon elasticity and tone.